2025 JSH指南：血压升高和高血压的管理

AUTHORS

Yusuke OHYA (Okinawa Hokubu Medical Foundation, Okinawa, Japan)

Kimika ARAKAWA (Kyushu Medical Center, NHO, Fukuoka, Japan)

Naoko ARATA (National Center for Child Health and Development, Tokyo, Japan)

Shuji ARIMA (Kindai University, Osaka, Japan)

Hisatomi ARIMA (Fukuoka University, Fukuoka, Japan)

Kei ASAYAMA (Teikyo University, Tokyo, Japan)

Yasuaki DOHI (Nagoya Gakuin University, Aichi, Japan)

Ako FUKAMI (Kurume University, Fukuoka, Japan)

Masato FURUHASHI (Sapporo Medical University, Hokkaido, Japan)

Kenichi GOTO (Kyushu University, Fukuoka, Japan)

Rei GOTO (Keio University, Kanagawa, Japan)

Tsuguru HATTA (Hatta Medical Clinic, Kyoto, Japan)

Nobuhito HIRAWA (Yokohama City University Medical Center, Kanagawa, Japan)

Yoshitaka HIROOKA (Fukuoka Sanno Hospital, Fukuoka, Japan)

Takashi HISAMATSU (Okayama University, Okayama, Japan)

Satoshi HOSHIDE (Jichi Medical University, Tochigi, Japan)

Yohei IKEZUMI (Fujita Health University, Aichi, Japan)

Shigeru INOUE (Tokyo Medical University, Tokyo, Japan)

Mari ISHIDA (Hiroshima Shudo University, Hiroshima, Japan)

Toshihiko ISHIMITSU (Utsunomiya Chuo Hospital, Tochigi, Japan)

Yoshio IWASHIMA (The University of Osaka, Osaka, Japan)

☑ Yusuke Ohya ohya@cs.u-ryukyu.ac.jp

Mai KABAYAMA (The University of Osaka, Osaka, Japan)

Tomoyuki KABUTOYA (Jichi Medical University,

Tochigi, Japan)

Hisashi KAI (Yokokura Hospital, Fukuoka, Japan)

Hidehiro KANEKO (The University of Tokyo Hospital, Tokyo, Japan)

Yoshihiko KANNO (Tokyo Medical University, Tokyo, Japan)

Tomohiro KATSUYA (Katsuya Clinic, Hyogo, Japan)

Toru KIKUCHI (Saitama Medical University, Saitama, Japan)

Masatoshi KOGA (National Cerebral and Cardiovascular Centre, Osaka, Japan)

Masataka KUDO (Osaki Citizen Hospital, Miyagi, Japan)

Masanari KUWABARA (Jichi Medical University, Tochigi, Japan)

Kiyoshi MATSUMURA (Kitakyushu Wakasugi Hospital, Fukuoka, Japan)

Hirohito METOKI (Tohoku Medical and Pharmaceutical University, Miyagi, Japan)

Asako MITO (National Center for Child Health and Development, Tokyo, Japan)

Shin-ichiro MIURA (Fukuoka University, Fukuoka, Japan)

Katsuyuki MIURA (Shiga University of Medical Science, Shiga, Japan)

Kazutoshi MIYASHITA (International University of Health and Welfare, Tochigi, Japan)

Masaki MOGI (Ehime University, Ehime, Japan)

Fumiko KAWAKAMI-MORI (Mitsui Memorial Hospital, Tokyo, Japan)

Satoshi MORIMOTO (Tokyo Women's Medical University Adachi Medical Center, Tokyo, Japan)

Mikio MUKAI (Osaka Center for Cancer and Cardiovascular Disease Prevention, Osaka, Japan)

Masashi MUKOYAMA (Omuta Tenryo Hospital, Fukuoka, Japan)

Masanori MUNAKATA (Tohoku Rosai Hospital, Miyagi, Japan)

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Naoki NAKAGAWA (Asahikawa Medical University, Hokkaido, Japan) Takayoshi OHKUBO (Teikyo University, Tokyo, Japan) Takafumi OKURA (Saijo Central Hospital, Ehime, Japan) Hiromi RAKUGI (Osaka Rosai Hospital, Osaka, Japan) Shigeru SHIBATA (Teikyo University, Tokyo, Japan) Keisuke SHINOHARA (Kyushu University Hospital, Fukuoka, Japan) Takeshi TAKAMI (Clinic Jingumae, Nara, Japan) Hiroyuki TAKASE (Enshu Hospital, Shizuoka, Japan) Yukari TAKEMI (Kagawa Nutrition University, Saitama, Japan) Atsushi TANAKA (Saga University, Saga, Japan) Hirofumi TOMIYAMA (Tokyo Medical University, Tokyo, Japan) Kazunori TOYODA (National Cerebral and Cardiovascular Toyoda: Center would be better, Osaka, Japan) Takuya TSUCHIHASHI (Steel Memorial Yawata Hospital, Fukuoka, Japan) Shinichiro UEDA (University of the Ryukyus, Okinawa, Japan) Eiichiro YAMAMOTO (Kumamoto University Hospital, Kumamoto, Japan) Koichi YAMAMOTO (The University of Osaka, Osaka, Japan) Atsushi SAKIMA (University of the Ryukyus, Okinawa, Japan) FAIRPERSON

CHAIRPERSON

Yusuke OHYA (Okinawa Hokubu Medical Foundation)

EXECUTIVE COMMITTEE

Yusuke OHYA (Okinawa Hokubu Medical Foundation) Nobuhito HIRAWA (Yokohama City University Medical Center) Hisatomi ARIMA (Fukuoka University) Takeshi TAKAMI (Clinic Jingumae) Ako FUKAMI (Kurume University) Katsuyuki MIURA (Shiga University of Medical Science) Hiromi RAKUGI (Osaka Rosai Hospital) Atsushi SAKIMA (University of the Ryukyus)

DEVELOPMENT COMMITTEE

Yusuke OHYA (Okinawa Hokubu Medical Foundation) Nobuhito HIRAWA (Yokohama City University Medical Center) Atsushi SAKIMA (University of the Ryukyus)

Hisatomi ARIMA (Fukuoka University)Yasuaki DOHI (Nagoya Gakuin University)Ako FUKAMI (Kurume University)Shigeru FURUHASHI (Sapporo Medical University)Satoshi HOSHIDE (Jichi Medical University)Toshihiko ISHIMITSU Utsunomiya Chuo HospitalMai KABAYAMA (The University of Osaka)Hisashi KAI (Yokokura Hospital)Masatoshi KOGA (National Cerebral and CardiovascularCentre)Katsuyuki MIURA (Shiga University of Medical Science)Masashi MUKOYAMA (Omuta Tenryo Hospital)Masanori MUNAKATA (Tohoku Rosai Hospital)Takayoshi OHKUBO (Teikyo University)Hiromi RAKUGI (Osaka Rosai Hospital)Shigeru SHIBATA (Teikyo University)Takeshi TAKAMI (Clinic Jingumae)Yukuri TAKIBI (Kagawa Nutrition University)Koichi YAMAMOTO (The University of Osaka)

Japan Pharmaceutical Association Ryohkan FUNAKOSHI (Japan Pharmaceutical Association) Japan Medical Association Hidehito IMAMURA (Jiaikai) Patient and Public Representative Hiroshi KAWAKATSU (The Japan Stroke Association) The Japan Stroke Society Masatoshi KOGA (National Cerebral and Cardiovascular Centre)

Masatoshi KOGA (National Cerebral and Cardiovascular Centre)

The Japanese Circulation Society Chisa MATSUMOTO (Tokyo Medical University) Japan Medical Association Mauni JIMAYANGU (Miyakawa International Medicine & Pediatrics)

Japan Pharmaceutical Association

Japan Pharmaceutical Association

Japan Pharmaceutical Association

Ryohkan FUNAKOSHI (Japan Pharmaceutical Association)

Japan Medical Association

Hidehito IMAMURA (Jiaikai)

Patient and Public Representative

Hiroshi KAWAKATSU (The Japan Stroke Association)

The Japan Stroke Society

The Japanese Circulation Society

Chisa MATSUMOTO (Tokyo Medical University)

Japan Medical Association

Masaaki MIYAKAWA (Miyakawa Internal Medicine & Pediatrics)

Japanese Nursing Association

Naomi MIYAMATSU (Shiga University of Medical Science)

The Japan Dietetic Association

Junichi MIYAZAKI (Saiseikai Maebashi Hospital)

The Japan Diabetes Society

Yoshihiko NISHIO (National Hospital Organization Kagoshima Medical Center)

The Japanese Society of Cardiovascular Disease Prevention

Nagako OKUDA (Kyoto Prefectural University)

Japanese Society of Nephrology

Shigeru SHIBATA (Teikyo University)

The Japan Endocrine Society

Masakatsu SONE (St. Marianna University School of Medicine)

The Japan Dietetic Association

Jun WATANABE (Hamamatsu University Hospital)

Patient and Public Representative

Ikuko YAMAGUCHI (Consumer Organization for Medicine & Law)

The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and...

The Japan Geriatrics Society Koichi YAMAMOTO (The University of Osaka) Japan Atherosclerosis Society Hiroshi YOSHIDA (The Jikei University Kashiwa Hospital)

WRITING COMMITTEE

Kimika ARAKAWA (Kyushu Medical Center) Naoko ARATA (National Center for Child Health and Development) Shuji ARIMA (Kindai University) Hisatomi ARIMA (Fukuoka University) Kei ASAYAMA (Teikyo University) Yasuaki DOHI (Nagoya Gakuin University) Ako FUKAMI (Kurume University) Masato FURUHASHI (Sapporo Medical University) Kenichi GOTO (Kyushu University) Rei GOTO (Keio University) Tsuguru HATTA (Hatta Medical Clinic) Nobuhito HIRAWA (Yokohama City University Medical Center) Yoshitaka HIROOKA (Fukuoka Sanno Hospital) Takashi HISAMATSU (Okayama University) Satoshi HOSHIDE (Jichi Medical University)

Takashi HISAMATSU (Okayama University) Satoshi HOSHIDE (Jichi Medical University) Yohei IKEZUMI (Fujita Health University) Shigeru INOUE (Tokyo Medical University)

Mari ISHIDA* (Hiroshima Shudo University) Utsunomiya Chuo Hospital Yoshio IWASHIMA (The University of Osaka) Mai KABAYAMA (The University of Osaka) Tomoyuki KABUTOYA (Jichi Medical University) Hisashi KAI* (Yokokura Hospital) Hidehiro KANEKO (The University of Tokyo Hospital) Yoshihiko KANNO (Tokyo Medical University) Tomohiro KATSUYA (Katsuya Clinic) Toru KIKUCHI (Saitama Medical University) Masatoshi KOGA (National Cerebral and Cardiovascular Centre) Masataka KUDO (Osaki Citizen Hospital) Masanari KUWABARA (Jichi Medical University) Kiyoshi MATSUMURA* (Kitakyushu Wakasugi Hospital) Hirohito METOKI (Tohoku Medical and Pharmaceutical University) Asako MITO (National Center for Child Health and Development) Shin-ichiro MIURA (Fukuoka University) Katsuyuki MIURA* (Shiga University of Medical Science) Kazutoshi MIYASHITA (International University of Health and Welfare) Masaki MOGI (Ehime University) Fumiko KAWAKAMI-MORI (Mitsui Memorial Hospital)

Satoshi MORIMOTO (Tokyo Women's Medical University Adachi Medical Center) Mikio MUKAI (Osaka Center for Cancer and Cardiovascular Disease Prevention) Masashi MUKOYAMA (Omuta Tenryo Hospital) Masanori MUNAKATA (Tohoku Rosai Hospital) Naoki NAKAGAWA (Asahikawa Medical University) Takayoshi OHKUBO (Teikyo University) Yusuke OHYA (Okinawa Hokubu Medical Foundation) Takafumi OKURA (Saijo Central Hospital) Shigeru SHIBATA (Teikyo University) Keisuke SHINOHARA (Kyushu University Hospital) Hiroyuki TAKASE (Enshu Hospital) Yukari TAKEMI (Kagawa Nutrition University) Atsushi TANAKA (Saga University) Hirofumi TOMIYAMA (Tokyo Medical University) Kazunori TOYODA (National Cerebral and Cardiovascular Centre) Takuya TSUCHIHASHI (Steel Memorial Yawata Hospital) Shinichiro UEDA (University of the Ryukyus) Eiichiro YAMAMOTO (Kumamoto University Hospital) Koichi YAMAMOTO (The University of Osaka) * Lead author

SYSTEMATIC REVIEW (SR) COMMITTEE

Makiko ABE (Fukuoka University)**Hiroshi AKASAKA (Iwate Medical University)Yuichi AKASAKI** (Kagoshima University)Tatsuhiko AZEGAMI (Keio University)Kengo AZUSHIMA (Yokohama City University)Takako FUJII (Fukuoka University)Akira FUJIWARA (National Hospital Organization Yokohama Medical Center)Takeshi FUJIWARA** (Jichi Medical University)Kaori HAYASHI** (Keio University)Tatsuya HAZE (Shin-Yokohama Daiichi Clinic)Daisuke ICHIKAWA** (St. Marianna University School of Medicine)Yori INOUE (Fukuoka University)Shintaro ISHIDA (Fukuoka University)Tomohiko KANANOKA (Yokohama City University Hospital)Kenichi KATSURADA** (Jichi Medical University)Wakako KAWARAZAKI (International University of Health and Welfare)Sho KINGUCHI (Yokohama City University Medical Center) Kenichiro KINOUCHI** (Keio University)Kento KITADA (Kagawa University)Yusuke KOBAYASHI (Yokohama City University)

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Takuro KUBOZONO (Kagoshima University) Masanari KUWABARA (Jichi Medical University) Toshiki MAEDA** (Fukuoka University) Tatsuya MARUHASHI** (Research Institute for Radiation Biology and Medicine, Hiroshima University) Chisa MATSUMOTO** (Tokyo Medical University) Asako MITO (National Center for Child Health and Development) Kenichi MIYOSHI** (Saiseikai Matsuyama Hospital) Einosuke MIZUTA** (Sanin Rosai Hospital) Nagisa MORIKAWA (Kurume University) Michiaki NIGAI (Hiroshima City North Medical Center Asa Citizens Hospital) Hajime NAGASU (Kawasaki Medical School Hospital) Sayaka NAGATA (Minami Kyusyu University) Keisuke NARITA (Jichi Medical University) Tetsutaro NIIJIMA (Okinawa University) Norifumi NISHIDA (Tateishi Clinic) Yume NOHARA (Kurume University) Yoichi NOZATO** (Toyonaka Municipal Hospital) Yukako OGOYAMA (Jichi Medical University Hospital) Sayoko OGURA (Nihon University) Yuichiro OHYA (NHO Okinawa Hospital) Norihito OKINA (Omina City Hospital) Sanae SAKA (Shinsekai Yokohamashi Nanbu Hospital) Yuki SAKAMOTO (Nippon Medical School) Satoko SAKATA (Kyushu University) Atsushi SATOH (Kobe Pharmaceutical University) Hiroyoshi SEGAWA (Hirose Mirai Clinic) Yuhei SHIGA (Fukuoka University) Keisuke SHINOHARA (Kyushu University) Yukiko SHINOHARA (Fukuoka University) Yasunori SUEMATSU (Fukuoka University) Naoki SUGANO (The Jikei University School of Medicine) Jun SUZUKI (Ehime University Hospital) Kazuhiro TADA (Fukuoka University Hospital) Yukako TATSUMI** (Teikyo University) Kazushi UNEDA (Aizu Medical Center, Fukushima Medical University) Daisuke YAMAZAKI (Osaka City General Hospital) Yuichi YOSHIDA (Oita University) Ryo ZAMAMI (University of the Ryukyus Hospital)**Team Leader

SECRETARY GENERAL

Atushi SAKIMA (University of the Ryukyus)

Introduction

The Japanese Society of Hypertension (JSH) Guidelines for the Management of Hypertension 2019 (JSH2019) have been revised, and the JSH Guidelines for the Management of Elevated Blood Pressure and Hypertension 2025 (JSH2025) have now been published. In accordance with the "Minds Manual for Guideline Development 2020. ver. 3.0" by the Medical Information Network Distribution Service (Minds) in Japan, clinical questions (CQs) concerning the management of elevated blood pressure and hypertension were formulated, with systematic reviews (SRs) and meta-analyses performed on the evidence regarding these CQs. Based on this methodology, CQ recommendations were developed after clarifying and reviewing the latest available evidence. Furthermore, following the approach of JSH2019, and based on the guide-line development policy, textbook-style descriptions were added to the CQs. This introduction outlines the fundamental policy and methodology applied in developing JSH2025.

1. Purpose and scope of JSH2025

Hypertension is a major cause of cerebro- and cardiovascular disease (CVD) and kidney diseases. Furthermore, it affects a large proportion of the adult population. Therefore, the primary objectives of JSH2025 as a whole are: "To prevent the onset/progression of hypertension-related complications involving the brain, heart, and kidney, through the management of blood pressure in hypertensive patients with hypertension and individuals with elevated blood pressure, who are encountered frequently in daily clinical practice. It also aims to provide standardized, evidence-based guidelines with a rationale for treatment and appropriate blood pressure management for all healthcare professionals, patients, the public, and healthcare stakeholders." The blood pressure management for the general Japanese population and for patients remains sub-optimal. JSH2025 aims to be more than simply an explanation of existing evidence; it seeks to be practical guidelines that lead users to take action to lower their patients' blood pressure or to prevent its elevation. The target population for blood pressure management in JSH2025 includes not only hypertensive patients with blood pressure ≥140/90 mmHg, but also those with elevated blood pressure (130-139/80-90 mmHg) and all individuals with blood pressure ≥120/80 mmHg, in which there is a rise in

The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and...

CVD risk with an increased BP. The intended users of JSH2025 are "all healthcare professionals who prevent, diagnose, manage, and treat hypertension, patients, clinical practitioners, and public health administrators." In consideration of this wide range of users, JSH2025 is structured in three parts, each with a different scope.

Scope 1 (Part 1) "Population-wide blood pressure management," primarily targets public health and administrative officials, healthcare professionals, and members of the general public engaged in hypertension prevention and awareness activities. Hypertension countermeasures are a crucial component of healthcare policy. Therefore, providing systematically organized evidence through objective methods and disseminating it to society is essential in ensuring consistency between these guidelines and public policy. Specifically, blood pressure management is incorporated into measures designed to improve public literacy regarding lifestyle-related diseases and health promotion, specific health checkups and guidance, occupational health, corporate health management initiatives, and health promotion programs by local governments and corporate organizations. Furthermore, to facilitate consensus-building among stakeholders, the guidelines demonstrate the rationale for hypertension countermeasures in the context of the prevention of cerebrovascular disease, chronic kidney disease (CKD), and dementia.

Scope 2 (Part 2) "Management and Treatment for Hypertensive Patients," is primarily intended for healthcare providers engaged in the practical management of hypertension, as well as for patients and their families. Hypertension is the most prevalent lifestyle-related disease, making it difficult to manage solely by specialists; in daily practice, it is largely managed and treated by primary care physicians. Recognizing this reality, Scope 2 is principally designed for primary care physicians. Focusing predominantly on patients with essential hypertension, it outlines methods for determining treatment plans and assessing treatment efficacy, along with corresponding strategies. It is intended to facilitate shared decision-making and consensus-building between patients and healthcare providers. The certification, "Certified Cardiovascular Disease Prevention Educator" was developed collaboratively by JSH, the Japan Society for Prevention of Cardiovascular Diseases, and the Japanese Society for Atherosclerosis. This certification is a qualification granted to professionals such as public health nurses, registered nurses, pharmacists, registered dietitians, physical therapists, clinical psychologists, medical psychologists, clinical laboratory technologists, and certified health exercise instructors. These professionals possess the ability to provide appropriate guidance for improving and preventing lifestyle-related diseases like hypertension, as well as managing other risk factors, in the prevention of cardiovascular diseases. JSH2025 is designed for use by these

professionals. Additionally, JSH2025 is eligible for use by companies developing antihypertensive drugs, hypertension treatment devices, and hypertension treatment methods utilizing digital technology.

The principal users for Scope 3 (Part 3), "Management and Treatment of Secondary Hypertension and Special Conditions," are those engaged in specialized medical care of hypertension, cardiovascular disease, nephrology, endocrinology, and geriatrics, as well as the patients and their families. It is intended to be used for investigating suspected causes of special hypertension, determining treatment plans at specialized medical institutions, and facilitating treatment agreements between patients and healthcare providers.

JSH2025 serves as the central reference manual for patients and healthcare providers to consult while jointly discussing and determining plans for management and treatment. It does not constrain the prescribing discretion of the attending physician nor constitute a standard for judgment in medical disputes or litigation. Management and treatment plans are determined individually based on the patient's background and comorbidities.

At the same time, when the attending physician adopts a management or treatment plan differing from JSH2025, it is important to ensure that the patient receives sufficient information and gives consent, with the reasons for this deviation documented in the medical record.

2. Guidelines Development Committee Structure

The Main Committee was composed of 1) Executive Committee members, 2) Development Committee members, 3) Writing Committee members, 4) Systematic Review (SR) Committee members, and 5) SR Support Committee members.

The Development Committee members and Writing Committee members were selected by the chairperson, based on the policy that "the JSH develops the guidelines for hypertension management under the responsibility of the entire society" and in accordance with both the individual's expertise and the COI criteria outlined in "the Guidance on Eligibility Criteria for Participation in Clinical Practice Guideline Formulation 2023" of the Japanese Association of Medical Sciences. The proposal was drafted by the chairperson after consultation with the Executive Committee members, and it was then finalized. The 30 Development Committee members included JSH members and representatives from citizens and patient organizations, with nominees from the Japan Dietetic Association, the Japan Pharmaceutical Association, the Japan Nursing Association, and related academic societies. The Development Committee played a key role in the guideline development process, including establishing the basic policy for guide-line development (such as drafting the SCOPE), selecting

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clinical questions (CQs), determining CQ recommendations, and conducting peer review.

The Writing Committee was made up of 56 professionals, primarily composed of council members of the Society. The SR Committee members were selected based on their past achievements and expertise, with 58 individuals chosen upon recommendation by the chairperson and Coordinating Committee members. Five members were appointed as SR Support Committee members.

Society council members, honorary members, directors, and drafting committee members were widely solicited online for the writing of individual CQs, commentaries, and textbook-style descriptions, internal review and evaluation. Furthermore, JSH Guidelines Development Committee requested online external reviews and evaluation feedbacks from the Japanese Society of Public Health, Japanese Association for Home Care Medicine, Japan Society of Obstetrics and Gynecology, the Japanese Circulation Society, the Japanese Society of Cardiovascular Disease Prevention, Japan Pediatric Society, Japanese Society of Nephrology, Japanese Heart Failure Society, the Japanese Association of Cardiac Rehabilitation, the Japanese Society of Renal Rehabilitation, Japanese Society of Gout and Uric & Nucleic Acids, the Japanese Society for Dialysis Therapy, the Japan Diabetes Society, Japan Atherosclerosis Society, the Japan Endocrine Society, Japan Society for the Study of Hypertension in Pregnancy, the Japan Stroke Society, Japan Society for the Study of Obesity, Japan Primary Care Association, the Japanese Society of Clinical Nutrition, Japan Physicians Association, the Japanese Society of Clinical Pharmacology and Therapeutics, the Japan Geriatrics Society, the Japan Dietetic Association, Japan Pharmaceutical Association, Japanese Nursing Association, Japan Medical Association, and patient organizations such as the Japan Stroke Association, and Sasaeai Medical Human Rights Center COML, a Japanese nonprofit organization advocating for patient rights and healthcare communication.

3. Guidelines development strategies and procedure

JSH2025 adheres to the "Minds Manual for Guideline Development 2020 ver. 3.0" and is an evidence-based consensus guideline. The basic principle of JSH2025 is to develop a highly transparent guideline which considers conflicts of interest (COI). To promote dissemination, awareness, and improve the quality of hypertension management in Japan, JSH2025 will be published on the JSH website (https://www.jpnsh.jp/index_e.html).

JSH 2025 is structured using two descriptive formats: the CQ format and the textbook-style format. In the CQ format, SRs and meta-analyses were conducted for the 19 CQs, and recommendation statements were formulated. The SRs were

primarily undertaken by SR teams composed of two mid-career council members for each CQ. Relevant studies were identified, and all selected literature was evaluated according to outcome and study design. The results were synthesized into a body of evidence, assessed, and integrated. Outcomes of interventions included expected benefits and adverse events or harms. Based on the balance of benefits and harms, “recommendations” were formulated using the Delphi method (summarizing opinions through three rounds of online voting). The consensus rate for each CQ was also documented in the guideline. In the textbook-style format, although there was insufficient evidence to conduct SRs, 11 items deemed necessary to address the clinical questions of practitioners were presented as Questions (Qs), and consensus-based answers were provided.

The committee conducted internal reviews, followed by external reviews involving relevant academic societies and taking into consideration public comments. Appropriate revisions were made to create the final draft of the guidelines. The final draft was evaluated according to AGREE II (Appraisal of Guidelines for Research & Evaluation II).

4. Levels of evidence and grades of recommendation

Based on the "Minds Clinical Guideline Development Manual 2020 ver. 3.0," the levels of evidence and strengths of recommendations for each CQ statement were evaluated as follows:

Strength of Recommendation

1. (Strong): Recommendation "implementing" or "not implementing" 2. (Weak): Suggests "implementing" or "not implementing"

Recommendation withheld: No clear recommendation can be made

Strength of Evidence

A (Strong)

B (Moderate)

C (Weak)

D (Very weak)

5. COI management and disclosure

The Development Committee members were organized by the JSH Committee for Developing the "the JSH Guidelines for the Management of Elevated Blood Pressure and Hypertension 2025 (JSH2025)" based on the Japanese Medical Association's "Guidance on Eligibility Criteria for Participation in Developing Clinical Practice Guidelines 2023" and in accordance with the "the JSH Guidelines for the Management of Elevated Blood Pressure and

The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and...

Hypertension 2025 (JSH2025): Conflict of Interest (COI) Management Policy." Furthermore, the COI status of the Development committee members for the past three years (FY2022-FY2024) is disclosed on the JSH website (https://www.jpnsh.jp/data/jsh2025/jsh2025_coi.pdf).

Part 1. Population-wide blood pressure management

Chapter 1. Epidemiology of hypertension

[POINT 1]

1. The higher the blood pressure (BP) level exceeds 120/80 mmHg, the higher the morbidity/mortality risks from stroke, coronary artery disease, chronic kidney disease (CKD), heart failure, atrial fibrillation, and dementia become. 2. Cerebro- and cardiovascular disease (CVD) deaths due to high BP in Japan are estimated to be 170,000 per year. Hypertension is the most prominent risk factor for CVD deaths; approximately 40% of CVD deaths are estimated to be due to high BP (>120/80 mmHg). 3. Systolic blood pressure (SBP) is the strongest predictor of CVD among the BP indices, with the risk increasing further when combined with other factors.

4. There are estimated to be 43 million hypertensive individuals in Japan, including 31 million with poorly controlled hypertension. Of these 31 million hypertensive individuals, 14 million are unaware of their hypertension, 4.5 million are untreated despite disease awareness, and 12.5 million are poorly controlled even with treatment.

5. The salt intake in Japan is high, and reducing salt intake is the challenge for lowering BP levels. Also, the prevalence of obesity-related hypertension has increased.

1. Hypertension and associated diseases

1) Stroke/Coronary artery disease

Hypertension is the most significant risk factor for stroke/coronary artery disease, and the risk of CVD increases as BP levels rise [1–14]. EPOCH-JAPAN was an integrated project of a meta-analysis of 10 cohorts in Japan (which included about 58,000 drug-naive individuals). The results showed a nearly log-linear association between BP level and hazard ratio (HR) for CVD mortality in middle-aged (40–64 years) and older adults (65–89 years), with a steeper slope in the younger age group (Fig. 1-1) [7]. CVD mortality risk was the lowest in those with BP <120/80 mmHg across all age groups. A consistent association between BP and mortality risk was observed across

Fig. 1-1 HR and PAF of CVD mortality risk by BP categories. *1: HRs were adjusted for age, sex, total cholesterol, smoking, drinking, BMI, and diabetes. *2: PAF indicates the proportion of deaths that may have been prevented if all individuals had shown BP of<120/80 mmHg. (Adapted from ref. [7] with modifications)

EPOCH-JAPAN: a meta-analysis of 10 cohorts in Japan (which included about 58,000 antihypertensive drug-naive individuals). Stratified by age group.

 Total PAF: 56%

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 subtypes, including all strokes, cerebral infarction, cerebral hemorrhage, and coronary artery disease. The associated mortality risk was particularly strong with cerebral hemorrhage [6, 7, 9]. In hypertensive individuals, the lifetime risk of stroke is estimated to be 17–33%, coronary artery disease 15–27%, death from stroke 8–15%, and death from coronary artery disease 3–7% [3, 15, 16].

Similar associations were observed in the results of Japanese cohort studies investigating morbidities as an outcome [1, 2, 4, 8, 10–12]. Studies using the BP categories which were updated in JSH2019, demonstrated that the associations between BP and CVD risks were incremental and continuous. CVD risk was lowest in BP of <120–129/80 mmHg [1, 2, 4]. In an overseas epidemiological study, the risk of CVD in a man, whose BP was high-normal BP when he was 18 years old, significantly increased after 36 years (at age 54) [17], indicating the importance of maintaining a normal BP level (<120/80 mmHg) from a younger age for the prevention of CVD.

Recent cohort studies have shown the percentage of excess deaths/morbidity in individuals with BP >120/80 mmHg using an indicator of PAF [1, 7–12]. Estimating from EPOCH-JAPAN, 39% of total CVD deaths (56% middle-aged adults, 23% older adults) (Fig. 1-1), 38% of stroke deaths, and 26% of coronary artery disease deaths were attributed to high BP (>120/80 mmHg), and excess deaths in the grade I hypertension group were the highest

[7]. In NIPPON DATA80, follow-up data for 24 years estimated that 43% of CVD deaths (81% middle-aged men) were attributed to BP > 120/80 mmHg [9]. In addition, the J-ECHO study, which included recent middle-aged workers, revealed that there was a small percentage of patients with grade II–III hypertension, and the highest excess CVD patients were those with elevated BP (PAF 18%) [1]. The improvement of lifestyle and prevention of hypertension have become more crucial goals. According to estimates based on the results of past epidemiological studies, hypertension is the most significant cause of CVD deaths in Japan, with an estimated 170,000 people dying from high BP in 2019 (increased from approximately 100,000 people in 2007, due to the aging population) (Fig. 1-2) [18].

Among the BP indices including SBP, diastolic blood pressure (DBP), and pulse pressure, SBP shows the strongest association with the risk of future CVD [19–21]. Most studies have used office BP or BP measured during physical examinations when examining the association between BP and CVD risk. Notably, however, home BP and 24-h ambulatory BP monitoring (ABPM) have been considered better predictors of CVD risk than office BP [22–25]. (See Chapters 2 and 5). It has also been reported that the visit-to-visit variability in office BP and the day-to-day variability in home BP are associated with an increased risk of CVD [26].

2) Kidney disease

Hypertension increases the risk for reduced estimated glomerular filtration rate (eGFR), developing chronic kidney disease (CKD) and end-stage kidney disease (ESKD) [27–35]. In a study that followed specific health checkup recipients (approximately 140,000 individuals) for 2 years, the higher the BP, the greater the eGFR decline, and this association was particularly pronounced among those with positive urinary protein [28]. In the Ohasama study [29], ISSA-CKD study [32], and JMDC database study [33], the CKD risk increased with the increase of BP; some showed a significant difference starting at BP ≥120/80 mmHg. In a cohort study in Okinawa (approximately 100,000 individuals) [27] and the CKD-JAC study [34], the risk of ESKD incidence increased by 10–35% per 10 mmHg increase in SBP. In another cohort study in Okinawa (approximately 70,000 individuals), the risk of ESKD was approximately three times higher in those with a continuous SBP >140 mmHg during the first 3 years, than those with an SBP of <120 mmHg [35].

3) Heart failure/Atrial fibrillation

An international meta-analysis has shown that hypertension is a risk factor for the incidence of heart failure and atrial fibrillation [36, 37]. A domestic study (EPOCH-JAPAN) demonstrated that BP level is significantly associated with the risk of the risk of heart failure mortality [6, 7]. A study using domestic claims data (JMDC) reported that the hazard ratio (HR) for developing heart failure was 1.30 in the

The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and...

untreated BP 130–139/80–89 mmHg group and 2.05 in the untreated BP ≥140/90 mmHg group, with PAFs of 6.1% and 11.9%, respectively [38]. In the Suita study, the HR for heart failure was significantly increased in patients with ≥130/80 mmHg or isolated systolic hypertension. Furthermore, the increased HR for heart failure associated with elevated BP was attenuated after hypertension treatment, suggesting the need for management in individuals with BP ≥130/80 mmHg [39].

Regarding the incidence of hypertension and atrial fibrillation, in addition to reports showing an association with systolic and diastolic hypertension [40, 41], the JDMC study also demonstrated that the HR for developing atrial fibrillation was 1.21 in the untreated 130–139/80–89 mmHg group and 1.52 in the untreated ≥140/90 mmHg group, with PAFs of 5.1% and 7.5%, respectively, compared with the <120/80 mmHg group [38].

4) Dementia, total mortality and other risks

Epidemiological studies have not concluded an association between hypertension and dementia in old age [42–48]. On the other hand, hypertension in middle age is a risk factor for dementia [42]. In the Honolulu-Asia Aging Study, including Japanese-American men, cognitive impairment after 26 years (mean age 78) was 2.1 times greater in the group with SBP ≥160 mmHg than in the group with SBP <110 mmHg at middle age [49]. In the Adult Health Study (AHS) of the Radiation Effects Research Foundation and the Hisayama Study, hypertension in middle age was associated with an increased risk of developing vascular dementia in old age [44, 50]. This indicates that counter-measures against hypertension in middle age are essential in preventing cognitive impairment.

In the Ohasama study [51] and the Hisayama study [52], day-to-day variability in home BP was associated with future cognitive decline and the development of dementia. In an epidemiological study in Sagae City, variability in 24-h ABPM was related to cognitive decline 4 years later [45].

Hypertension also increases the risk of total mortality. In a meta-analysis of 13 domestic cohorts (n = 180,000) the EPOCH-JAPAN study, the risk of total mortality increased with the rise in BP levels across all age groups [53]. In NIPPON DATA80, hypertension was associated with a 2–3 year reduction in life expectancy [54]. In NIPPON DATA90, healthy life expectancy was reduced by 3–4 years in patients with grade II/III hypertension compared with normal BP [55]. Regarding these results, considering that the effect of antihypertensive treatment during the follow-up period was not adjusted for, the actual reduction in the average life expectancy is presumed to be even more remarkable. It has also been reported that hypertension in middle age increases the risk of future decline in activities of daily living (ADL) [56].

5) Metabolic syndrome and CVD

Metabolic syndrome defines a condition that includes high BP as one of the diagnostic criteria. When the abdominal circumference is ≥85 cm in men and ≥90 cm in women, and two or more of the following three conditions are met, it is diagnosed as metabolic syndrome: high BP (≥130/85 mmHg), fasting hyperglycemia (≥110 mg/dL), and abnormal lipids (triglycerides ≥150 mg/dL and/or HDL cholesterol ≤40 mg/dL) [57]. An increased risk of CVD due to metabolic syndrome has been reported in many domestic cohort studies, with a 1.5 to 2.4-fold increased risk of CVD morbidity/mortality [58–60]. In contrast, reports have been published on the accumulation of risk factors, both with and without obesity, from cohort studies with CVD morbidity as an endpoint [61–63], CVD mortality as an endpoint [64–66], and also in pooled analyses of cohort studies [67, 68]. Taken together, when multiple risk factors are considered, it is crucial to treat lifestyle-related disease not only in obese individuals but also in non-obese individuals.

2. Japanese population's BP status and trends

Due to an update in the method of BP measurement for the National Health and Nutrition Survey in 2019, direct comparisons with BP values from before 2019 are no longer possible. This section is based on BP measurements from before 2016.

The prevalence of hypertension (SBP ≥ 140 mmHg, DBP ≥ 90 mmHg, or taking antihypertensive medications) has shown a downward trend in every age group in women over the past 36 years, however, the trend is not clear in men aged ≥50s years (Fig. 1-3A) [69]. Up to 2016, the prevalence of hypertension exceeded 50% in men aged ≥50 years and in women aged ≥60 years. With the aging of the population, the prevalence of hypertension in Japan is expected to increase further in the future.

The hypertension treatment rate (the percentage of those taking antihypertensive medication per all hypertensive individuals) has been on the rise for both men and women during the past 36 years; in 2016 it reached ≥50% for men and women in their 60s and ≥60% for men and women in their 70s (Fig. 1-3B) [69].

The hypertension control rate (the percentage of those taking antihypertensive medication with SBP<140 mmHg and DBP<90 mmHg) has increased for both men and women over the past 36 years, but as of 2016, it remains at about 40% for men and 45% for women (Fig. 1-3C) [69]. Some reports suggest that the control rate of hypertension is 55-60%, however, even this level may be inadequate [70].

According to the Basic Survey of Adult Diseases, the Basic Survey of Cardiovascular Diseases, and the National Health and Nutrition Examination Survey initiated by the

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government in 1961, the Japanese population's mean SBP has decreased significantly over the past approximately 60 years in both sexes and all age groups (Fig. 1-4A) [69]. The mean SBP has decreased by about 10-20 mmHg in each age group in both sexes, and a similar trend has been shown in other studies in Japan. The large decrease of >20 mmHg, especially for those aged ≥60 years in both sexes, is undoubtedly the most significant factor of the

remarkable reduction in stroke mortality/incidence in Japan during that period. It is said that the population's BP decrease has been brought about by the widespread screening for hypertension in health checkups, the progress and spread of hypertension treatment with anti-hypertensive drugs, and the changes in the lifestyle and living environment in Japan, such as by the decrease in sodium intake. However, while the average DBP has shown

  The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and...

[1st National Survey on Adult Diseases, 2nd National Survey on Adult Diseases, 3rd National Survey of Circulatory Disorders (NIPPON DATA80), 4th National Survey of Circulatory Disorders (NIPPON DATA90), 5th National Survey of Circulatory Disorders, National Health and Nutrition Survey (2010), and National Health and Nutrition Survey (2016); each adopting the first recorded blood pressure level]

     a similar downward trend in women, it has not been indicated for men of <60 years of age (Fig. 1-4B) [69].

The number of hypertensive individuals in Japan in 2017 was estimated to be 43 million in total; 31 million were poorly controlled (SBP>140 mmHg or DBP>90 mmHg), and of these, 14 million were unaware of their hypertension, 4.5 million were aware but untreated, and 12.5 million were treated but poorly controlled (Fig. 1-5) [69]. An analysis using the National Database of Health Insurance Claims and Specific Health Checkups of Japan (NDB) in 2014 showed that the number of people taking antihypertensive drugs was about 24 million, which was relatively consistent with the above-mentioned estimate [71]. Also, from an international perspective, BP control in Japan is poor and needs improvement [72]. The Japanese Society of Hypertension (JSH) has

prepared a “Future Plan” statement, outlining national strategies and measures against hypertension. The goal is to reduce the number of poorly controlled hypertensive people in the population by 7 million over the 10-years period to 2028, from an estimated 31 million in 2018 [69, 73].

3. Characteristics of Japanese hypertension

1) Excessive salt intake

Many observational and interventional studies have demonstrated that higher sodium intake increases BP levels, and conversely, reducing sodium intake decreases BP levels [74–77].

A study conducted in the Tohoku region of Japan in the 1950s, estimated salt intake based on 24-h urine samples to

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Individuals with hypertension 43 million Individuals with BP ≥140/90 mmHg 31 million

 be as high as of 25 g/day on average [78]. In the INTER-MAP study (1996–1999), the mean salt intake based on 24-h urine samples was estimated to be 12.3 g/day for men and 10.9 g/day for women, in four Japanese regions (Hokkaido, Toyama, Shiga, and Wakayama prefectures) [79]. Salt intake as evaluated by the weighting method in the National Health and Nutrition Survey tended to decrease year by year. Still, in the 2023 survey, the mean salt intake was 10.7 g/day for men (aged ≥ 20 years) and 9.1 g/day for women (aged ≥ 20 years) [80]. According to the Dietary Reference Intakes for Japanese 2020, the recommended salt intake was <7.5 g/day for adult men and 6.5 g/day for adult women [81]. Health Japan 21 (3rd term) in 2023 set the goal of reduced mean salt intake to 7 g/day by 2032 [82]. The World Health Organization (WHO) guidelines on sodium intake published in 2012 state that the goal should be set at 5 g/day for general adults [83]. The current status in Japan is still far from this goal. In order to prevent hypertension, further promotion of sodium reduction throughout the entire population is necessary.

2) Increase in obesity

There are relatively few obese people in Japan compared to other developed countries. However, the mean body mass index (BMI), which is an index of obesity, has been

increasing year by year in men. The percentage of obese men (BMI ≥ 25 kg/m$^{2}$) was 31.5% in the 2023 National Health and Nutrition Survey, which is approximately double the number of obese men (aged ≥ 20) over the past 30 years [80, 84, 85]. In contrast, based on the National Health and Nutrition Survey, there has been no distinct increase in the percentage of obese women (aged ≥ 20) over the past 30 years, and the proportion was 21.1% in the 2023 survey [80].

In the past, many Japanese hypertensive individuals were thin, with a high salt intake. However, in recent years, obese hypertension has been on the increase, particularly among men. An analysis of changes in NIPPON DATA during the 3 decades from 1980 to 2010, showed the proportion of hypertensive men, for whom obesity contributed to hypertension, increased gradually over this time [84].

The number of obese people in the United States has increased markedly since the 1990s. According to a 2023 report, the percentage of obese people with a BMI of ≥30 kg/m$^{2}$ was 42.8% [86]. In Japan, the figure was 4.6% [86]. In the future, the number of obese people is likely to increase due to the westernization of lifestyles; therefore, measures to prevent obesity need to be strengthened.

Chapter 2. Blood pressure screening

[POINT 2]

1. Hypertension is a major risk factor for CVD, and young adults with hypertension have a high lifetime risk. Early detection through BP screening at routine health checkups and at other opportunities, combined with timely and appropriate intervention, is crucial.

2. Following a proper measurement method is essential when using automatic rolling-type sphygmomanometers in settings such as occupational health checkups. While kiosk BP measurements are convenient, they should not be used for diagnosis or treatment decisions due to potential inaccuracies related to the device and measurement environment.

3. Home BP monitoring (HBPM) is valuable for assessing long-term BP levels and identifying white-coat and masked hypertension. For HBPM, a validated upper-arm oscillometric cuff device should be used appropriately under the correct measurement procedures. Currently, cuffless BP measurement devices are not recommended for clinical use in diagnosis or treatment.

4. Medical consultation is recommended for individuals with a screening BP of ≥140/90 mmHg or a home BP of ≥135/85 mmHg. Consultation is also recommended when home BP readings are highly variable or if the

The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and...

 device indicates a warning, such as an irregular pulse (arrhythmia).

1. BP screening at medical checkups, etc

Although hypertension is typically asymptomatic, it is the leading risk factor for CVD. It is well-established that younger adults with long-standing hypertension face a higher lifetime risk of developing CVD and chronic kidney disease [3, 87]. Since BP can be controlled through lifestyle modifications and antihypertensive treatment, early detection of hypertension and timely, appropriate intervention are crucial for extending healthy life expectancy in individuals. To this end, BP screening through measurements in various settings is an effective strategy. An emphasis on the prevention of hypertension in daily life is desirable to avoid its initial development.

In Japan, alongside health checkups that employers are required to conduct for their employees and various screenings undertaken by municipalities, the Specific Health Checkup (Tokutei Kenko Shinsa) program was introduced in 2008. BP measurement is a required component of all these occasions, and is also considered a mandatory item in voluntary health checkups such as

comprehensive health examinations (Ningen Dock). The standard measurement procedure is outlined in the "Standard Health Checkup and Health Guidance Program" by the Ministry of Health, Labour and Welfare (MHLW) [88]. As a general rule, BP should be measured twice in accordance with the standard procedure of office BP measurement. However, a single measurement may be acceptable depending on the situation.

An automated sphygmomanometer with its cuff automatic rolling-type sphygmomanometer, requires different handling precautions than conventional devices where the upper-arm cuff is wrapped manually. Fig. 2-1 shows the recommended measurement procedure using an automatic rolling-type sphygmomanometer. It is challenging to follow the standard conditions for measuring BP when many individuals receive health examinations at facilities that screen them within a short period [89]. Nevertheless, it is essential to adhere to the recommended procedures for measurement as closely as possible, because BP measurement is fundamental to the diagnosis and treatment of hypertension.

The term kiosk BP measurement refers to the self-measurement of BP using an automatic BP monitor at a public facility (e.g., gyms, municipal facilities, or

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workplaces), without the assistance of a healthcare professional [90, 91]. The high accessibility and the fact that no appointment is required for measurement make kiosk BP measurement a useful tool for BP screening. However, due to a lack of professional oversight, there is little guarantee of reliability in several aspects of BP measurements: whether the device's characteristics and cuff size are appropriate for the user, whether the measurement is performed correctly in a suitable environment, and whether the machine is regularly maintained and calibrated. Furthermore, there are no established thresholds of the kiosk BP measurement values. Therefore, while kiosk BP measurements can be used for screening, they must not be used to make diagnostic or therapeutic decisions. Providers of kiosk BP measurement devices should ensure they are placed in a quiet and comfortable environment, and should clearly display instructions on proper posture and measurement method for users [91]. BP measured at pharmacies, as with kiosk BP, should not be used as the basis for diagnosis or treatment of hypertension [91]. However, with pharmacist oversight, kiosk BP measurement can discover hypertension in patients with other diseases or confirm hypertension as a side effect of a prescribed drug.

2. Home BP measurement

Home BP has become widespread in Japan [92, 93]. HBPM allows for relatively easy standardization, enables multiple readings over long-term periods as a fixed-point observation, and helps increase an individual's health awareness. HBPM is also useful for identifying white-coat, morning, and masked hypertension. Even when the office BP in clinical practice is not high, there will be a high risk of CVD in individuals if the home BP level is high [94]. HBPM devices also capture pulse rate, and some models can simultaneously display warnings for conditions that may indicate diseases, such as an irregular heartbeat.

Routine HBPM also facilitates early detection of hypertension, and its clinical value is further enhanced by performing standardized measurements. When measuring home BP, an upper-arm cuff-oscillometric device should be used in accordance with the measurement conditions shown in Table 2-1. Regarding the devices for HBPM that are commercially available in Japan, objective information, such as validation test results for accuracy, is summarized on the JSH website [95]. Whereas, sphygmomanometers based on cuffless technologies (cuffless BP devices) are not currently recommended for the diagnosis and treatment of hypertension due to concerns about the reliability of their readings [96].

Table 2-1 Methods and conditions for home BP measurement

Measurement device

An upper-arm cuff-oscillometric sphygmomanometer, commercially available in Japan.

Measurement environments

1) A quiet, appropriate environment at room temperature$^{a}$ 2) In principle, sit on a chair with a backrest with legs uncrossed 3) No conversation before or during the measurement 4) Avoid smoking, alcohol, and caffeine before the measurement 5) Placement of the cuff should be maintained at the heart level Measurement conditions 1) Essential requirements 1) Morning Within 1 hour after waking up After urination Before morning medication Before breakfast 1) After 1-2 min resting in a sitting position 6) Evening At bedtime After 1-2 min resting in a sitting position After 1-2 min resting in a sitting position 2) Additional opportunities for measurement 6) Before dinner, before evening medication, before bathing, before consuming alcohol, during sleep at night, etc., as instructed 6) In the presence of symptoms, during the daytime on holidays, etc., as needed. Measurement frequency and treatment of results$^{b}$ Measurement frequency and treatment of results$^{c}$ In principle, two measurements are taken per occasion, and the mean value of the two measurements should be adopted. When the BP is measured only once, that BP value is used. Measurement period 6) As long as possible Recording 1) All results should be recorded.

2) Additional opportunities for measurement a) Before dinner, before evening medication, before bathing, before consuming alcohol, during sleep at night, etc., as instructed b) In the presence of symptoms, during the daytime on holidays, etc., as needed.

Measurement frequency and treatment of results$^{e}$

In principle, two measurements are taken per occasion, and the mean value of the two measurements should be adopted.

When the BP is measured only once, that BP value is used.

Measurement period

As long as possible

Recording

All results should be recorded.

ªAlthough no specific rule is defined, BP is higher when measured in a cold room, especially in winter

$^{b}$Except in exceptional cases, it is not recommended to measure four or more times per occasion

Note 1: If the act of measuring your home BP causes you anxiety, you are not forced to measure home BP

Note 2: Do not become overly pleased or concerned by individual readings. Focus on tracking your home BP over a long period for a proper medical evaluation

Note 3: You must not arbitrarily discontinue, increase, or decrease your medication on your own based on your readings

Note 4: Home BP should be measured on your non-dominant arm, as a general rule. If there is a consistent left-right arm difference in BP readings, consult a healthcare professional or your attending physician

Note 5: Note that BP readings taken after drinking alcohol or bathing tend to be lower

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3. Recommendation for medical consultation

In principle, if BP at a health checkup is ≥140/90 mmHg, or if the average home BP measured over five or more days is ≥135/85 mmHg, a medical consultation is recommended. A consultation is also warranted when daily home BP readings are highly variable despite adherence to the recommended measurement conditions, or the device displays a warning, such as for an irregular pulse. It is recommended that patients bring their home BP records to the consultation.

0.1 Can BP screening at health checkups improve the BP control rate in the population?

$\bullet$ BP measurement during health checkups is expected to contribute to the improvement of BP control rates of the population, because it provides an opportunity for the early detection and treatment of hypertension as well as high-normal BP and elevated BP, while also serving as a platform for individual education and awareness. $\bullet$ To improve the population's BP control rate, it is essential to provide appropriate guidance and management by expert healthcare professionals, to outreach to individuals who do not undergo regular screening, and to promote the widespread use of HBPM among the general population.

Explanation

Hypertension is estimated to affect 43 million people in Japan, approximately half of the adult population, and intervention for these individuals is essential. Furthermore, even if they do not have hypertension, those with higher BP (high-normal BP and elevated BP) have a higher risk of CVD compared with those with normal BP (office BP <120/80 mmHg, home BP <115/75 mmHg) [97, 98]. Since this group is large, it leads to a high burden of morbidity and mortality in the population. Therefore, it is crucial to improve the BP control rate overall by also targeting individuals with high-normal and elevated BP.

Although no randomized controlled trials (RCTs) have reported that BP screening at health checkups improves prognosis [99], there is no doubt that BP screening has a substantial benefit for the early detection of hypertension [99]. This is because antihypertensive drug treatment improves the prognosis of CVD, regardless of initial BP levels or the presence of comorbidities [100]. It has also been reported that community-level health promotion initiatives can reduce the incidence of CVD [101]. In managing BP across a population, regular screening for a wide variety of individuals is desirable. According to the U.S. guidelines, for example, BP measurement at 3- to 5-year intervals is recommended for those aged 18-39 years who are not at risk for hypertension and whose

BP has been within the normal range [99], while those aged 40 years or older, or with high risk factors for hypertension such as obesity, should be screened annually [99]. In Japan, as described in "Chapter 2, Section 1: BP screening at medical checkups, etc.", adults aged 18–39 also undergo regular BP measurement through various systems, such as workplace health checkups provided by employers, various screenings conducted by municipalities, the Specific Health Checkup program, and voluntary examinations like "Ningen Dock". Identification of individuals with hypertension or higher BP within these screened populations paves the way for individualized guidance and management strategies. Moreover, health checkups serve as an essential venue for awareness and education. By making individuals aware of the usefulness of BP measurement and of the high CVD risks of hypertension, such health checkups are expected to improve the BP control in the population.

Meanwhile, many people do not undergo health check-ups for various reasons. Home BP is an excellent tool that enables the entire population to self-measure their own BP and, if continued, contributes to raising health awareness. Moreover, some conditions like white-coat and masked hypertension are identified by the combination of office BP readings and out-of-office BP readings, including home BP. It is desirable for BP screening to be conducted at home and in non-clinical settings, not just at health checkups. The results should then be interpreted by expert healthcare professionals, leading to appropriate diagnosis and treatment. As BP specialists, the JSH —in addition to the Certified Hypertension Specialist system— collaborates with the Japanese Society of Cardiovascular Disease Prevention and the Japan Atherosclerosis Society to operate the Certified Therapeutic Instructor for Cardiovascular Disease Prevention (Jyunkan-ki-byo Yobo Ryoyo Shido-shi) program aimed at medical staff and public health nurses. These certified instructors have the expert knowledge and skills to provide lifestyle guidance on all risk factors for CVD, not limited to hypertension. They can also provide appropriate advice and guidance for both the prevention and therapeutic management of patients with hypertension.

Chapter 3. Strategies for lifestyle modifications in Japan

POINT 3

1. Raising awareness and providing information are essential for all individuals who have undergone screenings, such as specific health examinations. It is necessary to give health guidance to high-risk individuals, with encouragement to receive health checkups and support to modify their lifestyle.

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2. Raising awareness for lifestyle modification throughout the course of their life should be conducted by using all available venues and methods, such as school health, occupational health, community organizations, mass media, and social media.

1. Health advice after health checkup and specific health guidance

In recent years, health guidance after a health checkup has become an increasingly crucial strategy against hypertension. It is the role of insurers to educate and provide information to all screened populations in specific health checkups. Also, to encourage medical consultations and support high-risk individuals with modifications to their lifestyle [88, 102]. For those whose specific test results indicate a need for a medical examination, the health guidance provider ensures medical consultation at a healthcare institution. In addition, health guidance providers should explain the importance of modifying their lifestyle habits to those with a high BP. These modifications include reducing salt intake, increasing potassium intake, reducing excessive alcohol consumption, increasing physical activity, maintaining or losing an appropriate amount of weight, and quitting smoking. These recommendations are based on the principle that the subjects should make their own decisions [88]. It has been reported that those who receive specific health guidance are more likely to have a lower BP than those who did not receive such guidance [103]. However, in Japan in 2019, the uptake remained insufficient, with 55.6% receiving specific health checkups and only 23.2% receiving specific health guidance [88]. Good examples of initiatives include collaborating with medical associations, developing human resources in the community and encouraging participation in specific health checkups and health guidance by taking into account each individual's reasons for non-attendance. In specific health checkups, standardized questions are asked about factors related to BP, such as exercise, weight gain, alcohol consumption, and sleep. This makes it possible to provide health guidance and recommendations on the same day as the checkup. The effectiveness of this method has been recognized [104–106]. Health guidance should accurately grasp the needs of the target population and respond in accordance with the stages of behavior change. Also to consider and devise effective guidance content and methods, including the use of ICT, such as applications and software [88].

2. Awareness raising and promotion of lifestyle modification

It is vital, as a means to achieve lifelong modifications in lifestyles, to aim high in promoting nutritional education

and health literacy awareness, in cooperation with school health education [107]. Additionally, it has been reported that family health awareness and health habits are improved by health education in elementary schools [108].

In industrial healthcare, it has been reported that the introduction of salt check sheets (dietary salt intake questionnaires) and urine sodium/potassium (Na/K) ratio measurements for all employees at a workplace helped individuals evaluate their own dietary habits relating to their BP levels and motivated them to reduce salt intake [109]. In local communities, it is effective to support residents in promoting health activities on their own initiative, by using community organizations in health awareness raising activities. This support can include the training of volunteers required to promote these activities [110, 111]. In addition, by preparing channels for disseminating health-related information such as local circulars and publicity from chambers of commerce and industry, it is possible to provide information to a wide range of people [112]. The use of “nudges” is also effective, a method to guide people towards favorable changes in behavior whilst respecting their decision-making [113, 114].

Mass media campaigns through TV/movie ads, radio, billboards, magazines, newspapers, and transportation ads can contribute to long-term BP reduction [115–117]. Such campaigns can effectively deliver information to high-risk populations and have a far-reaching impact [118, 119]. When tailored to a target group, social media-based dissemination of information to raise health awareness is effective, through group encouragement and the maintenance of motivation [120–122].

Health professionals, knowing the impact over a lifetime, must follow strategic initiatives and collaborate with a wide variety of related organizations to spread awareness of the importance of lifestyle change, including for those less interested in their health [123].

CQ1 For a group within a population, are efforts to reduce salt intake helpful in controlling BP and preventing the occurrence of CVD?

$\blacktriangleright$ In BP management, efforts to reduce dietary salt intake are strongly recommended for groups such as communities, workplaces, schools, and households.

[Strength of recommendation – 1, Strength of evidence – B, Rate of Agreement – 100%]

$\blacktriangleright$ In order to prevent CVD, more evidence is necessary. [Strength of Recommendation – Withheld, Strength of Evidence – C, Rate of Agreement – 100%]

Summary of evidence

A systematic review (SR) of cluster and quasi-cluster RCTs was conducted to assess salt intake, urinary sodium (Na)

The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and...

excretion, and BP [124]. A total of 36 articles (n = 66,803 subjects) were extracted from cluster RCTs (34 studies, 35 articles) and quasi-cluster RCTs (1 study, 1 article) comparing salt reduction intervention and control groups in terms of BP change from baseline. The primary endpoint was the difference in SBP (mmHg), and secondary endpoints were DBP (mmHg), salt intake (g/day), urinary sodium excretion (mmol/day), urinary potassium (K) excretion (mmol/day), urinary sodium/potassium (Na/K) ratio (molar ratio), poor BP control, and a composite of cardiovascular events, cardiovascular event, stroke, all-cause mortality, and adverse events.

Explanation

The results are described by outcome type (BP level, salt intake, cardiovascular events, etc.), target population (adults, children, community, workplace, etc.), intervention method (salt reduction guidance, alternative salt use, etc.), and intervention period.

1) Decrease in BP

SBP in the intervention group was significantly lowered by 2.64 mmHg (95% CI 1.80 to 3.48) compared to the control group. Heterogeneity between studies was high ($I^2 = 94\%$) (Fig. CQ1-1). Effectiveness was greater for

![|Study or Subgroup|Mean Difference|SE|Weight|IV, Random, 95% CI|\n|:---:|:---:|:---:|:---:|:---:|\n|Arrol 1995|2.9|4.8|0.7%|-2.91 [-12.31, 6.51]|\n|Bembe 2012|3.1|0.03|4.2%|-1.29 [-1.17]|\n|Beune 2014|3.69|2.37|1.8%|-3.69 [-8.34, 0.96]|\n|Borah 2018|5.3|1.58|2.7%|-5.30 [-8.40, -2.20]|\n|Brown 2015|0.3|1.79|2.4%|-3.30 [-3.81, 3.21]|\n|Cappuccio 2006|0.3|1.2|1.7%|-0.30 [-8.20, 2.00]|\n|Cotter 2013|4.4|4.21|0.8%|4.40 [3.85, 12.65]|\n|Gamme 2020|5.7|1.56|2.7%|-5.70 [-8.76, -2.64]|\n|He 2015|2.3|1.14|3.3%|-2.30 [-4.53, -0.07]|\n|He 2020|2.53|0.7|3.8%|-2.53 [-3.90, -1.16]|\n|He, children 2015|0.8|1.15|3.2%|-0.80 [-3.05, 1.45]|\n|He, children 2020|1.19|0.8|3.7%|-1.19 [-2.76, 0.38]|\n|Jafar 2010|1.4|0.29|4.1%|-1.40 [-1.97, -0.83]|\n|Kaur 2020|0.07|1.15|3.2%|0.07 [-2.18, 2.32]|\n|Kondal 2022|2.76|1.3|3.0%|2.76 [0.21, 5.31]|\n|Li 2016|1.1|1.12|3.3%|-1.10 [-3.30, 1.10]|\n|Liu 2022|2.95|0.26|4.2%|-2.95 [-3.46, -2.44]|\n|Mu 2009|7.1|0.34|4.1%|-7.95 [-7.77, -6.43]|\n|Mukhopadhyay 2023|4.7|0.83|3.6%|-4.70 [-6.33, -3.07]|\n|Neal 2021|3.4|0.82|3.7%|-3.40 [-5.01, -1.79]|\n|Niranjan 2014|3|2.29|1.9%|0.3 [1.49, 7.49]|\n|Rubenstein 2016|0.37|0.91|3.6%|-0.37 [-2.15, 1.41]|\n|Takada 2016|3.57|4.17|0.8%|-3.57 [-11.74, 4.60]|\n|Takada 2018|4.4|0.82|3.7%|-4.40 [-6.01, -2.79]|\n|Thapa 2023|2.8|0.97|3.5%|-2.80 [-4.70, -0.90]|\n|Toft a 2020|0.96|5.13|0.6%|-0.96 [-9.09, 11.01]|\n|Toft_a, children 2020|1|3.5|1.1%|1.00 [-5.86, 7.86]|\n|Toft_b 2020|2.64|5.1|0.6%|-2.64 [-12.64, 7.36]|\n|Toft_b, children 2020|1|2.84|1.5%|1.00 [-4.57, 6.57]|\n|Wang 2020|5.8|0.48|4.0%|-5.80 [-6.74, -4.86]|\n|Wong 2021|4.97|2.12|2.1%|-4.97 [-9.13, -0.81]|\n|Yokokawa 2021|1.83|1.11|3.3%|-1.83 [-4.01, 0.35]|\n|Yu 2021|4.58|0.51|4.0%|-4.58 [-5.58, -3.58]|\n|Yuan 2023|7.1|1.71|2.5%|-7.10 [-10.45, -3.75]|\n|Zhang 2023|1.98|0.8|3.7%|-1.98 [-3.55, -0.41]|\n|Zhou 2016|5.72|1.49|2.8%|-5.72 [-8.64, -2.80]|\n](1/parseimages/figure45b0098e212c4647be547f3c86591dce_0_6.png) Y. Ohya

adults (30 papers) than children (5 papers). The target populations in the adult studies were classified as community (13 papers), family (9 papers), health care institution (4 papers), school (2 papers), and workplace (2 papers), with greater intervention effects in the workplace. Intervention methods used were salt reduction education (7 papers), reduced dietary salt intake (3 papers), salt substitution (6 papers), health monitoring (3 papers), and a composite of lifestyle modifications (11 papers). Among them, the effectiveness on SBP was significant regardless of the method. The duration of intervention was categorized as 6 months or less (12 papers), 12 months or less (10 papers), or more than 12 months (8 papers), and among them, the effectiveness on SBP was significant regardless of the intervention duration.

2) Changes in dietary intake of Na (salt) and K, and urinary excretion

In the studies that evaluated salt intake (22 articles), salt intake was significantly lowered in the intervention group by 0.82 (95% CI 0.53 to 1.12) compared to the control group, but heterogeneity across studies was high ($I^2=85\%$). Studies that evaluated urinary Na excretion (17 papers) also showed significantly lower urinary Na excretion in the intervention group. For urinary K excretion, the effectiveness was significantly higher in intervention studies using salt substitutes (4 articles). For the urinary Na/K ratio, the effectiveness was significantly lower in the intervention studies using salt substitutes (2 papers).

3) Decrease in CVD events, etc.

In studies that evaluated a composite of CVD events (3 papers), the relative risk (RR) was significantly lower in the intervention group by 0.82 g/day (95% CI 0.70 to 0.97). RRs were also significantly lower for stroke events (2 articles) and all-cause mortality (6 articles).

Summary

A population-based sodium reduction intervention was shown to significantly reduce SBP, DBP, salt intake, and urinary sodium excretion in adults. Stratified analysis showed that the antihypertensive effect was independent of intervention method and duration, though the effect tended to be higher in the occupational setting in terms of population characteristics. However, only two studies were conducted in the occupational setting. In contrast, the intervention method for children did not show a significant effect. The urinary K excretion and urinary Na/K ratio showed an effect for alternative salt intervention, but the number of studies was limited. The strength of evidence ranged from "weak" to "very weak", due to the limited number of studies, for the relationship between sodium reduction interventions and a composite of cardiovascular events, a single cardiovascular event, stroke, all-cause

mortality, and adverse events in the population. The strength of evidence was only "weak" to "very weak.

Literature search

Six SR committee members conducted a literature search to identify articles applicable to this CQ through the primary screening of 1533 articles in PubMed, 3382 articles in the Cochrane Library, and 37 articles on the Ichushi-Web, for a total of 4141 articles.

Chapter 4. Society-wide strategies

[POINT 4]

1. As established in "Health Japan 21", it is crucial to reduce the average BP for the whole population through lifestyle modifications.

2. To improve the food environment for salt reduction, it is essential to: 1) reduce salt in processed foods, 2) implement front-of-pack labeling, 3) reduce salt in workplace canteens and ordered boxed lunches, and 3) conduct mass media campaigns.

3. To promote physical activity, it is essential to develop both physical and social environments for lifestyle activities and exercise in each community.

4. "The Japanese National Plan for Promotion of Measures Against Stroke/Cerebrovascular and Cardiovascular Disease" was published on the basis of "the Stroke/Cerebrovascular and Cardiovascular Disease Control Act" (a Japanese national law). The main aims of this plan are to prevent the onset/progression/recurrence of CVD, including hypertension (the leading risk factor for CVD), to disseminate knowledge and understanding of CVD from childhood, and the comprehensive risk management of CVD.

1. Health Japan 21

As many epidemiological studies have shown, more than half of CVD deaths/morbidities occur due to higher BP of a rather low degree (grade I hypertension or below) [8–12, 14, 125]. To reduce excess mortality and morbidity in this population, it is not sufficient to undertake the high risk strategies which target hypertensive individuals only. Therefore it is essential to have a population strategy that shifts the BP distribution of the entire population to the lower BP level (Fig. 4–1) [126, 127].

The "Third National Health Promotion Campaign in the 21st Century" (Health Japan 21 (the third term)]" announced by the Ministry of Health, Labour and Welfare in 2023, set

The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and...

a goal of reducing the average SBP of the population by 5 mmHg by 2032 (compared to the values of the 2024 National Health and Nutrition Survey) [82]. This is in the direction of a lower distribution of BP levels for the whole nation. This can be considered as a population strategy aimed at shifting the distribution of BP levels throughout

 Fig. 4-1 Strategy to shift the distribution of SBP of Japanese population to a lower level

the entire population in the direction of lower levels (Fig. 4-1).

Figure 4-2 shows a logic model for setting targets for CVD prevention in Health Japan 21 [82]. We estimate that a reduction of 5 mmHg in average SBP in the entire population can be achieved by implementing nutritional and dietary measures to decrease salt intake (to 7 g/day), to increase vegetable intake (to 350 g/day), to increase fruit intake (to 200 g/day), and to reduce obesity, and implementing measures to increase physical activity and exercise, and implementing measures to reduce heavy alcohol drinkers. We also aim to reduce the rates of age-adjusted CVD mortality by decreasing rates of smoking, limiting the increase in the prevalence of diabetes mellitus, and decreasing the prevalence of high LDL cholesterol levels.

Healthy Japan 21 (the third term) sets four basic aims. (1) The extension of healthy life expectancy and the reduction of health disparities. (2) Improvement of individual habits and levels of health. (3) Improvements in the quality of the social environment. (4) The raising of health promotion throughout a lifetime. Regarding (3), the promotion is required of a more natural and healthy environment, one that encourages physical activity, exercise and a healthy

<CVD prevention>

![graph TD\n A1[Decrease in age adjusted cerebrovascular mortality rate] --> A2[Decrease in age adjusted cerebrovascular mortality rate]\n A2 --> A3[Decrease in age adjusted heart disease mortality rate]\n A3 --> A4[Decrease in age adjusted heart disease mortality rate]\n A4 --> A5[When the goals of 4 risk factors are achieved]\n A5 --> A6[<Reduction of risk factors(underlying conditions) >]\n A5 --> A7[<Lifestyle modification >]\n A5 --> A8[Diabetes mellitus Lifestyle modification for improvement/prevention of diabetes mellitus(Refer to Chapter 10, “Diabetes mellitus”)]\n A5 --> A9[Lower prevalence of high LDL cholesterol]\n A6 --> A10[Lower prevalence of hypertension]\n A6 --> A11[Lower smoking rate]\n A6 --> A12[Stop increase in diabetes mellitus prevalence]\n A7 --> A13[Nutrition/Diet - Decrease in salt intake - Increase in vegetable consumption - Increase in fruit consumption - Decrease in obesity]\n A7 --> A14[Physical Activity/Exercise - Increase in steps - Increase in regular exercise]\n A7 --> A15[Alcohol Consumption - Decrease in people drinking high amounts of alcohol which increases the risk of lifestyle related diseases]\n A7 --> A16[Increase in antihypertensive drug use among people with hypertension]\n A7 --> A17[Decrease in the intake of saturated fats]\n A7 --> A18[Increase in medication treatment rates among those with hypercholesterolemia]\n](1/parseimages/figure068ee2cbdf9343d69ab73579ebe51375_0_8.png) Fig. 4-2 Logic model for CVD prevention in Health Japan 21 (3rd Edition). (Adapted from ref. 82)

Y. Ohya

diet. These are important measures for lowering the average BP of the entire population.

2. Improvement of food environment

The improvement of food environment consists of access to both healthier food and appropriate information and promoting them in an integrated manner. To improve food environment for population salt reduction, the WHO recommends: 1) reformulation of policies for sodium reduction of processed foods, 2) front-of-pack labeling of foods, 3) reducing salt content in public food procurements, such as school lunches, and 4) public communication strategies and mass media campaigns to encourage changes in behavior [128]. In the United Kingdom, these measures have reduced the national salt intake and achieved a reduction in CVD deaths [129].

In 2021, the Ministry of Education, Culture, Sports, Science and Technology-Japan partially amended the school lunch standards [130]. The amount of salt in school lunches in Japan was reduced to 1.5 g/serving for children ages from 6 to 7 years, 2.0 g/serving for ages from 8 to 11 years, and 2.5 g/serving for ages from 12 to 14 years. Japan has a high coverage rate for school lunches, more than 90% of students are now provided with school lunches with reduced salt. Japan urgently requires the development of its own nutrient profiling model for the comprehensive labeling of the front of food packages.

The highest priority for the future is to improve the food environment by reducing the amount of salt in foods and meals. It is necessary to strongly promote the reduction of salt in foods, such as processed seafood, bread, and noodles, with a focus on seasonings, which account for approximately 60% of the salt intake of the Japanese population [131]. Since 2013, the Japan Society of Hypertension has been screening low-sodium foods and publishing the "JSH Low-Sodium Food List." The cumulative relative salt reduction of the products on the list reached 9678 tons in 2013–2023, with sales of 54.7 billion Japanese yen in fiscal 2023 [132]. Encouragement of such industry and academic collaboration efforts is necessary. In addition, for the working generation, it is necessary to reduce the amount of salt in the meals provided at workplaces, i.e., company cafeterias and ordered lunch boxes [133, 134].

In 2022, the Ministry of Health, Labour and Welfare launched the "Strategic Initiative for a Healthy and Sustainable Food Environment: HSFE", which is a collaborative organization of industry, government, and academia. HSFE is placed salt reduction as top priority [135]. One of the goals of "improving the quality of the social environment" in Health Japan 21 (the third term) is to expand this initiative to all 47 prefectures.

3. Environmental improvements to promote physical activity

Physical activity is related to the local environment including the following factors: urban structure where people live, convenience of public transportation, access to green spaces/parks/gymnasiums/other places for exercise, traffic safety, public security, and environmental aesthetics [136, 137]. Health Japan 21 (the third term), which started in 2023, has adopted the goal of "increasing the number of municipalities that aim to create comfortable and inviting urban centers to walk" and exploring measures to improve the environment [82]. In addition, the Ministry of Health, Labour and Welfare's "Physical Activity Guide for Health Promotion 2023" introduced the concept of a physical activity environment. This framework identifies four domains: 1) the physical environments that promote life-style activities, 2) the social environments that promote lifestyle activities, 3) the physical environments that promote exercise, and 4) the social environments that promote exercise [138]. In the future, it is desirable to promote environmental improvement in each of the above domains 1) to 4). The aim should be to provide more specific exercise guidance in healthcare, focusing on the characteristics of the specific community in which the patient lives, and appropriate physical activity resources (exercise places, opportunities, instructors, etc.).

4. Japanese national law's "the Stroke/Cerebrovascular and Cardiovascular Disease Control Act" and related healthcare

"The Stroke/Cerebrovascular and Cardiovascular Disease Control Act" was enacted on December 1, 2019 [139]. The main aims of this law are to prevent the onset/progression/recurrence of CVD, extend healthy life expectancy, and reduce the burden on health and nursing care.

CVD is not only a major cause of death, but it also accounts for many patients requiring nursing care and a significant portion of medical expenses. Therefore, it is necessary to promote comprehensive and systematic measures to prevent CVD. "The Japanese National Plan for Promotion of Measures Against Stroke/Cerebrovascular and Cardiovascular Disease" was published on the basis of "the Stroke/Cerebrovascular and Cardiovascular Disease Control Act", which sets the two main goals of extending healthy life expectancy by three years or more by 2040 compared with 2016 and decreasing age-adjusted mortality of CVD. Following this national plan, each prefecture in Japan has formulated a plan and is promoting locally appropriate CVD control measures. In addition, as prefectural medical care plans and prefectural long-term care insurance plans

The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and...

have been updated from 2024, the second phase of the prefectural plan for promoting CVD countermeasures was developed concurrently. The "Health Japan 21" (the third term)" was launched in 2024, and its contents are linked to the national plan.

"The Japanese National Plan for Promotion of Measures Against Stroke/Cerebrovascular and Cardiovascular Disease" was approved by the Cabinet in October 2020 [140, 141]. This indicates the need for not only primary prevention but also the prevention of its recurrence, complications, and aggravation, as CVD is characterized by a tendency to relapse, even after passing through the acute, convalescent, and chronic phases. Based on the development of a system for collecting and providing medical information on CVD, the national plan includes three major measures: 1) spreading awareness of prevention measures and accurate information on CVD; 2) enhancing service provision systems related to health, medical care, and welfare services; 3) promoting research on CVD. This content has also been carried forward into the second phase of the national plan, which was approved by the Cabinet in March 2023 [142].

Hypertension is mentioned in the national plan as a major risk factor for CVD, along with dyslipidemia, diabetes, hyperuricemia, chronic kidney disease, and others, as lifestyle-related diseases. The plan also states that "through the activities of the Healthy and Sustainable Food Environment Strategy Initiative, the development of foods that allow everyone to naturally reduce salt intake, including those who are less concerned about their health, will be promoted as well as public relations activities".

The "Five-year Plan for Overcoming Stroke/Cerebrovascular and Cardiovascular Disease" developed by the Japan Stroke Society, the Japanese Circulation Society, and several academic societies, is also utilized for controlling CVD, including hypertension. The JSH shares the same goals and promotes measures against CVD through regional medical cooperation.

Part 2. Management and treatment for hypertensive patients

Chapter 5. Measurement and clinical evaluation of blood pressure

[POINT 5a] [BP measurement/assessment]

1. Office BP should be measured by placing the forearm on a support table and maintaining the arm-cuff position at the heart level during rest in a seated

position. The measurement must be performed two or more times at intervals of 1-2 min, and the mean value of two measurements that provides stable values (difference in the values: <5 mmHg) should be used. Diagnosis of hypertension should be based on office BPs measured on at least two different occasions.

2. Office BP is measured by the auscultation method or by an automatic sphygmomanometer of the upper arm type.

3. Home BP measurement and 24-h ABPM are useful for the diagnosis of hypertension, white coat hypertension and masked hypertension, as well as for evaluating the drug effect and its duration.

4. Home BP should be measured with upper-arm devices. As a rule, it must be determined twice per occasion, and the mean value should be used as a BP value on the occasion. When the measurement is performed only once per occasion, its value should be used as a level on the occasion. For the diagnosis of hypertension and the evaluation of responses to antihypertensive drugs, the mean of morning and evening BP readings for 7 days (at least 5 days) should be used.

5. Cutoff values for hypertension differ among office BP, 24-h ABP and home BP. An office BP of ≥140/90 mmHg, a home BP of ≥135/85 mmHg and a mean 24-h ABP of ≥130/80mmHg are regarded as indicators of hypertension.

6. When there is a discrepancy of diagnosis between office BP and home BP, a home BP-based diagnosis should have priority.

7. In the treatment of hypertension, attention should be paid to diurnal variation patterns of BP (non-dipper, riser, dipper, etc.), nocturnal BP, early morning BP, and BP in the workplace.

8. Every BP measurement should use a sphygmomanometer having undergone periodical inspection, taking into consideration its durability and past frequency of use. In addition, aneroid sphygmomanometers require immediate disposition and exchange when deterioration is suspected because errors are theoretically more likely to result in this type of sphygmomanometer following exposure to shock or changes over time.

1. BP measurement

1) Office BP

Correct measurement of BP is necessary for the diagnosis of hypertension. In a clinical setting (for example, an outpatient office), it is recommended to use an electronically generated pressure column (quasi-mercury)

Y. Ohya

Table 5-1 Measurement of the office blood pressure

|Device|a. The auscultation method using a mercury or aneroid sphygmomanometer, of which the accuracy has been established, is employed. The use of an electronic sphygmomanometer of which the accuracy has been established is also possible (*1). b. A cuff with a bladder 13 cm wide and 22-24 cm long is used for the auscultation method. (A cuff for children is used for a brachial girth of <27 cm. When the arms are thick (arm girth ≥34 cm), a large cuff for adults is used.) Measurement conditions a. A quiet, appropriate environment at room temperature. b. After resting for a few minutes in a seated position on a chair with a support for a back with the legs not crossed. c. No conversation d. Smoking and alcohol/caffeine consumption should be avoided before measurement. Measurement methods a. With the forearm placed on a table, and the cuff center is maintained at the heart level (*2). b. Sit up straight. c. Take measurements on bare skin or wearing light clothing. Do not wrap the cuff over a heavy shirt or jacket as the upper arm will be compressed. d. With the auscultation method, the cuff is rapidly inflated while palpating the radial or brachial artery, and the stethoscope is used after BP has risen to 30 mmHg or more above the pulse rate disappearing level. e. The rate of cuff deflation is 2-3 mmHg per beat or second f. In the auscultation method, the BP at the start of the first Korotkoff sound is regarded as the SBP, and that at the fifth Korotkoff sound*3 as the DBP. Measurement is performed two or more times at 1- to 2-min intervals in one office visit. When two measurements differ markedly*4, additional measurement is performed. e. The mean value of two measurements that provide stable values*4 is adopted as the office BP value. b. Hypertension should be diagnosed on the basis of BP measured on at least two different occasions. Other cautions a. On the initial office visit, bilateral brachial BP should be confirmed. On subsequent visits, the measured side (right or left) is described. b. In persons with diabetes or older persons*5, the BP should be measured after 1- and 3-min standing to confirm the presence or absence of orthostatic hypotension. c. Examiners with sufficient audibility who have completed training for measurement should perform auscultation. d. The pulse rate must also be measured and recorded.| |---|---|

*1 An electronic pressure pillar (pseudo mercury) sphygmomanometer is a sphygmomanometer that uses an electronic analog column instead of a mercury meter (see Figure 5-1). An anoid sphygmomanometer is a sphygmomanometer with a spring-loaded needle that moves in an arc (see Figure 5-1). This type is prone to errors due to shocks and aging, and should not be used beyond its useful life span. If deterioration is suspected, it should be discarded and replaced. Automatic sphygmomanometers should be periodically inspected, with the service life and number of measurements described in the accompanying documentation for each device. When automatic sphygmomanometers are used in waiting rooms, etc, large errors can occur if measurements are not taken under adequate guidance and control (see Chapter 2 for details). *2 Wrap the cuff so that it is not too loose but not tight. If it is wound loosely, BP will be measured higher. If the device has instructions in the attached document, wrap the cuff as described. *3 Start of phase V is defined as the disappearance of Korotkoff sounds. This definition is common to European and American guidelines (ESC2024, ESH2023, ACC/AHA2017). *4 A stable value is, as a rule of thumb, a difference between measured values of less than 5 mmHg. *5 See "Chapter 10, 11 Older Adults" for further information on measurements in older adults.

sphygmomanometer (using an electronic analog column instead of a mercury column) or a spring-loaded aneroid sphygmomanometer for the auscultation method, or to use an automatic upper-arm sphygmomanometer with an accuracy equivalent to auscultation [Fig. 5-1].

Office BP measurement by the auscultation method should be carried out by a well-trained examiner by the method shown in Table 5-1 adequately. If this is difficult, the use of an automatic sphygmomanometer is recommended. The brachial cuff sphygmomanometer is based on the cuff oscillometric method. In terms of the accuracy of automatic sphygmomanometers, there is no significant problem when a device made by a Japanese manufacturer is

used. The results of accuracy test of automatic sphygmomanometers are given in the website of the JSH (http://www.jpnsh.jp/ac_wg1.html). For precautions when using an automatic rolling type sphygmomanometer for office BP measurement, please refer to Chapter 2.

For BP measurement in adults using the auscultation method, cuffs with rubber bags 13 cm wide and 22-24 cm long are usually used. Internationally, however, cuffs with a width of ≥40% of the brachial girth and a length sufficient to cover at least 80% of the brachial girth are recommended.

Office BP measurement requires periodical inspection of the sphygmomanometer and use of the sphygmomanometer taking into account its durability and frequency of use. In

The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and...

 addition, aneroid sphygmomanometers require immediate disposition and exchange when deterioration is suspected because errors are theoretically more likely to result in this type of sphygmomanometer following exposure to shock or changes over time.

A problem encountered in BP measurement is the presence of false hypertension related to incomplete compression of the brachial artery by an increase in arterial stiffness. The presence of incomplete compression of the brachial artery by an increase in arterial stiffness can be predicted, based on Osler's sign (case in which the brachial or radial artery is still palpable at the periphery of the cuff even when pulsation has been stopped by sufficient inflation) [143].

If pulses of the lower-limb arteries (femoral, poplital and dorsalis pedis arteries) are weak or not palpable, BP is measured in the leg to exclude peripheral artery disease. For the measurement of BP in the leg, an arm cuff is applied to the lower leg, and auscultation is performed using the

||Office BP|Home BP|ABP| |---|---|---|---| |Frequency of measurement|Low|High|High| |Measurement standardization|possible $^{(a)}$|possible|unnecessary| |Reproducibility|Unfavorable|Most favorable|Favorable| |White coat phenomenon|Presente|Absent|Absent| |Drug efficacy assessment|possible|Optimal|Appropriate| |Evaluation of the duration of drug efficacy|impossible|Most favorable|Possible| |Evaluation of short-term variability (variations at 15- to 30- min intervals)|Impossible|Impossible|possible| |Evaluation of diurnal changes (evaluation of nocturnal BP)|Impossible|possible $^{(b)}$|possible| |Evaluation of day-to-day variability|Impossible|possible|Impossible| |Evaluation of long-term variability|possible|Most favorable|possible|

ªStandardized measurement increases the clinical value of office BP. In clinical practice, standardized measurement is often not performed. Standardized office BP measurement is strongly recommended

$^{b}$Home BP-measuring devices that can monitor BP during sleep at night are available

dorsalis pedis or posterior tibial artery, or the cuff is applied dorsalis pedis or posterior tibial artery, or the cuff is applied auscultation is performed using the popliteal artery. Currently, lower-limb BP measurement at the lower leg by the cuff-oscillometric method and ankle-brachial index (ABI) measurement during brachial-ankle pulse wave velocity (baPWV) measurement are commonly used.

In patients with arrhythmia (premature beats), SBP is overestimated and DBP is underestimated by the auscultation method [144]. Therefore, the effects of arrhythmia must be excluded by repeating the measurement three or more times and adopting their average. In patients with atrial fibrillation, accurate sphygmomanometry is often difficult, but proportionate values of SBP and DBP can be obtained by the cuff-oscillometric method unless the patients have bradycardia [145]. In this case, the measurement must also be repeated three or more times and adopting their average [146].

In pregnant women, Korotkoff sounds (vascular murmurs) are occasionally heard at 0 mmHg. In this case, the BP at the starting point of the fourth Korotkoff sound (muffling of the sound) is regarded as the diastolic pressure.

As BP can be extremely variable, it occasionally shows marked increases even under routine measuring conditions. Therefore, a diagnosis of hypertension should be made on the basis of BP measurements taken on two or more different occasions.

Y. Ohya

Table 5-3 Methods for evaluating Home BP

1. Measure twice on each occasion, and use the average value. If only one measurement is taken, this BP value is used.

2. For the diagnosis of hypertension and the determination of the effect of antihypertensive drugs, the average of 7-days (minimum 5-days) readings in the early morning and evening are used.

3. When either or both of the early morning or evening home BP averages meet the diagnostic criteria, it is diagnosed as home BP hypertension.

4. The goal of BP reduction is determined as being achieved when the target BP level is achieved in both early morning and evening BP averages.

2) Out-of-office BP

Self-measurement of BP at home (home BP measurement) and ABPM are methods for BP measurement in an out-of-office setting. These BP measurements also have value as BP information differing in nature (Table 5-2).

(1) Home BP

Home BP measurement is useful for improving the treatment adherence of patients and for preventing an excessive or insufficient antihypertensive effect of drugs. Home BP measurement is also useful for the diagnosis of white coat hypertension, morning hypertension or masked hypertension and for making a diagnosis of resistant hypertension and deciding the therapeutic strategy [147]. As home BP can be frequently measured over a long period, it is also useful for the evaluation of BP variability over an extended period such as seasonal variations of BP [148]. Many studies, including the Ohasama study [24, 149], have reported that home BP is a more reliable predictor of prognosis than office BP [150–156].

Using standardized methods of measurement enhances the clinical value of home BP. Therefore, healthcare providers are strongly advised to provide instruction in the methods of measuring home BP, based on the measurement conditions in Chapter 2, Table 2-1.

It is recommended that home BP be evaluated by the method shown in Table 5-3. BP should, in principle, be measured twice per occasion, and the value obtained should be used as a BP level on the occasion. If subjects spontaneously measure BP three times, the mean of three measured values may be used as a BP level on the occasion. Adherence to measurement decreases if too many measurements are requested on each occasion [157]. Therefore, four or more measurements per occasion should not be recommended. Concerning records, all values measured on one occasion should be recorded in a recording sheet, as previously described.

To evaluate hypertension, normal BP and the effects of antihypertensive drugs based on home BP, the mean of the morning values and that of the evening values measured 7 days (at least 5 days) should be used.

Table 5-4 Indications for ABPM

1. When a home BP fluctuates around 135/85 mmHg or an office BP of fluctuates around 140/90 mmHg, making diagnosis of hypertension difficult. 2. When an elevated value (125-134/75-84 mmHg) is obtained on home BP measurement.

3. When there is marked variability in the home BP.

a. When a definitive diagnosis of white coat hypertension is not made based on the home BP level.

b. When a definitive diagnosis of masked hypertension is not made based on the home BP level.

c. When self-measurement of BP is impossible at the workplace and workplace hypertension is suspected.

d. When a definitive diagnosis of resistant hypertension is not made based on the home BP level.

e. When the nighttime BP is not measured on home BP and nocturnal hypertension (non-dipper, riser) is suspected.

4. When the information on short-term variability of BP is warranted.

a. When incidental, transient hypertension or hypotension is observed.

b. When the home and office BP levels markedly change.

The wrist-cuff device for BP measurement is easy to use, but often provides inaccurate measurements because of the difficulty in correcting the difference in hydrostatic pressure between the heart level and wrist level, and because of the difficulty in completely compressing arteries due to anatomical issues with the wrist [158]. At present, therefore, a blood-pressure-measuring device with an upper-arm cuff is used for home BP measurement [159]. However, for obese individuals with quite thick and short brachium, the use of a wrist-cuff device should also be considered because compression of the brachium is sometimes difficult. The accuracy of upper-arm-cuff devices for home BP measurement using the cuff-oscillometric method is generally acceptable if they are the products of Japanese companies. The results of tests of the accuracy of various home BP-measuring devices are provided in the website of the JSH (http://www.jpnsh.jp/com_ac_wg1.html).

(2) 24-h ABPM

If an automatic device based on the cuff-oscillometric method is used for noninvasive measurement of BP at intervals of 15–30 min over 24 h ABPM, BP information can be collected in a nonclinical setting such as a 24-h BP profile or BP information during specific periods (24 h, in the daytime, nighttime and early morning). In Japan, guidelines on ABPM has been published by the Japanese Circulation Society (“Guidelines for the clinical use of 24-h ABPM (JCS 2010)”) [160].

It has also been shown that the 24-h average of ABP is correlated more closely with the severity of hypertensive target organ damage than office BP, and that it is closely associated

The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and...

|Classification|Office BP (mmHg)|Office BP (mmHg)|Office BP (mmHg)|Home BP (mmHg)$^{a}$|Home BP (mmHg)$^{a}$|Home BP (mmHg)$^{a}$| |---|---|---|---|---|---|---| |Classification|SBP|SBP|DBP|SBP||DBP| |Normal BP|<120|and|<80|<115|and|<75| |High normal BP|120-129|and|<80|115-124|and|<75| |Elevated BP|130-139|and/or|80-89|125-134|and/or|75-84| |Grade I Hypertension|140-159|and/or|90-99|135-144|and/or|85-89| |Grade II hypertension|160-179|and/or|100-109|145-159|and/or|90-99| |(Isolated) Systolic hypertension|≥180|and/or|≥110|≥160|and/or|≥100| |(Isolated) Systolic hypertension|≥140|and|<90|≥135|and|<85|

ªIn this table, home BP values show that it has the same risk of CVD as office BP, but the values are classified in increments of 5 or more, so the actual point estimate may differ by several mmHg

with the regression of target organ damage mediated by anti-hypertensive medication [23, 25, 144, 161–167].

ABPM is particularly useful for the diagnosis of white coat hypertension. It is indicated for the diagnosis of white coat hypertension, poorly controlled hypertension and resistant hypertension. The indications for ABPM are presented in Table 5-4. However, the reproducibility of the mean values of 24-h, daytime (waking hour) and nighttime (sleep) BPs on ABPM, as well as that of diurnal variations in BP, is not always favorable, depending on activity and sleep conditions during the day. A single session of ABPM does not accurately reflect personal BP information [168].

2. Diagnosis of hypertension

1) Classification of office BP levels

Among most international guidelines, including those in Japan, it is common to regard patients with office BP levels of 140/90 mmHg or more as having hypertension.

In the Hisayama Study in Japan, the cumulative mortality rate due to cardiovascular diseases was lowest when the SBP and DBP were <120 and <80 mmHg, respectively, and the risks of cardiovascular diseases increased significantly when the SBP was ≥140 mmHg compared with <120 mmHg, and when the DBP was ≥90 mmHg compared with <80 mmHg, including in older individuals [169, 170]. Moreover, according to the Tanno/Sobetsu Study, an 18-year prospective epidemiological study in Hokkaido, Japan, an SBP of ≥140 mmHg and a DBP of ≥90 mmHg were considered significant risk factors for cardiovascular and total mortality [171]. Similarly, in NIPPON DATA80, a significant increase in the mortality rate due to cardiovascular diseases was observed at a BP of ≥140/90 mmHg [13]. Therefore, in these guidelines, a BP of ≥140/90 mmHg is adopted as the criterion for grade I or higher hypertension (Table 5-5).

The results of observational studies in Europe and the United States [172, 173] and studies in Japan [174, 175] have shown that the incidences of cardiovascular diseases in individuals with a BP of 120-129/80-84 mmHg and those with a

BP of 130-139/85-89 mmHg are higher (in the ascending order) than in those with a BP of <120/80 mmHg. Furthermore, it has been shown that in the former two groups (120-139/80-89 mmHg), the chances of developing hypertension are higher than in the third group [176]. Therefore, it does not seem appropriate to regard an office BP of ≥120/80 mmHg as a normal BP. An office BP of <120/80 mmHg is therefore defined as normal in JSH2019. In addition, other non-hypertensive levels below Grade I hypertension were classified as high-normal BP and elevated BP. The DBP category of elevated BP was defined as 80-89 mmHg, the level in JSH2019 for initiating antihypertensive drug treatment. The usefulness of the BP classification as stated by JSH2019 has been recently demonstrated [1, 7] The subclasses “normal BP” and “high-normal BP” employed in JSH2019 are classified and expressed as “high-normal BP” and “elevated BP,” respectively, in these guidelines. For consistency with the goal of antihypertensive measures in these guidelines (see Chapter 6), the DBP range or these two classes is set at <80 mmHg and 80-89 mmHg, respectively (Table 5-5). It should be noted that the health guidance cutoff values in specific physical examinations (SBP of ≥130 mmHg, DBP of ≥85 mmHg) and cutoff values for elevated BP in the guidelines (SBP 130-139 mmHg, DBP 80-89 mmHg) differ [88].

BP diagnosis using the office BP data should be based on at least two BP measurements, taken on separate occasions in the absence of antihypertensive treatment. On each occasion, BP should be measured many times at intervals of 1–2 min and the mean of two stable values (difference less than 5 mmHg) should be adopted as the BP value at a given occasion.

2) Classification based on out-of-office BP measurement

(1) Classification based on home BP

In many international guidelines, including Japanese guidelines, 135/85 mmHg (Tables 5-5, 5-6) has been adopted as a cut off value for hypertension on the basis of the results of meta-analysis of the data from 5018 individuals (International Database of Home BP in relation to

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Cardiovascular Outcome: IDHOCO) involving cross-sectional/follow-up studies in USA/Europe and Japan as well as Ohasama Study and Tsurugatani Study in Japan [98, 177–181]. Also in these guidelines, a home BP of ≥135/85 mmHg was adopted as a criterion for hypertension. Furthermore, these guidelines classify home BP into normal, high normal and elevated BP, similar to the classification of office BP, on the basis of the data on untreated inhabitants collected in IDHOCO [98] and Ohasama Study [182] (Table 5-5). As described in the preceding section, classification of home BP uses the mean of morning BP and that of evening BP each measured for 7 days (at least 5 days) (see Q2). Each of these categories of BP is adopted in case in which the mean of home BP in the morning or the mean of home BP in the evening or both satisfy the criteria.

(2) Classification based on ABPM

Many international guidelines, including those in Japan, propose to make a diagnosis of hypertension if the 24-h BP measured by ABPM is ≥130/80 mmHg, the daytime BP is ≥135/85 mmHg and the nighttime BP is ≥120/70 mmHg on the basis of the results from cross-sectional/follow-up surveys in USA/Europe and Japan as well as their meta-

||SBP (mmHg)|SBP (mmHg)|DBP (mmHg)| |---|---|---|---| |Office BP|≥140|and/or|≥90| |Home BP|≥135|and/or|≥85| |ABP|||| |24-h|≥130|and/or|≥80| |Daytime|≥135|and/or|≥85| |Nighttime|≥120|and/or|≥70|

analysis [160, 168, 180, 181, 183]. Also in these guidelines, a diagnosis of hypertension is made if the mean of 24-h BP is ≥130/80 mmHg, the mean of daytime BP is 135/85 mmHg and the mean of nighttime BP is ≥120/70 mmHg, regardless of where BP is measured (Table 5-6).

3) Classification by systolic and diagnostic BPs

For both the classification based on office BP and the classification based on out-of-office BP, SBP and DBP are mutually independent risk factors, and if they belong to different BP categories the individual is classified by the higher category.

The frequency of isolated systolic hypertension increases in older people because SBP increases, whereas DBP often decreases due to a reduced compliance of the large elastic arteries caused by atherosclerosis. Several studies, including the cohort studies in USA/Europe [184–186]. Hisayama Study and Ohasama Study [170, 187] showed that isolated systolic hypertension was an important risk factor for cerebral or myocardial infarction in older people. Isolated systolic hypertension in older persons is classified into the burned-out type, caused by an aging-related decrease in DBP in cases of essential hypertension, and the de novo type, caused by a novel increase of SBP in old age.

4) BP measurement and procedures for hypertension diagnosis

Currently, in Japan, 72% of hypertensive patients have a sphygmomanometer for taking home BP measurement. Reportedly, 33% of non-hypertensive individuals possess a home sphygmomanometer [188]. In Japan, approximately 40,000,000 home sphygmomanometers have been sold every year [189]. On the other hand, in Japan, 74% of adult men and 66% of adult women undergo a health checkup in some form or other [190]. Therefore, individuals without a

 The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and...

Fig. 5-3 Masked hypertension pathophysiology and risk factors

 history of hypertension consult a medical facility if hypertension is shown by a health checkup or self-measurement of BP/home BP.

In medical facilities, office BP is measured. Simultaneously, the home BP measured by patients is reported to the facility, or patients begin to measure home BP before the start of treatment as per physicians' recommendations (Fig. 5-2). As criteria for the diagnosis of hypertension based on home BP have been established, a diagnosis of hypertension is made based on patients' office and home BP levels. In this case, when there is a discrepancy of decision between the two methods, a home BP-based diagnosis of hypertension has priority, because the prognostic value of home BP, that is, its clinical value, is higher than that of office BP. Furthermore, BP measurement in an out-of-office setting has already had priority over office BP for the diagnosis and treatment of white coat or masked hypertension.

In Japan, 40,000,000 home sphygmomanometers have been sold every year, whereas only six hundreds of ABPM devices have been sold every year [191]. Actually, the clinical application of ABPM is not easy. ABPM devices are expensive, and the mental/physical stress of individuals wearing them is great. In addition, there are manpower- and cost-related problems relating to the medical staff. These factors support the importance of home BP measurement

emphasized in the guidelines. However, ABPM has certain merits, and, if necessary, it is clinically important to perform ABPM. In these guidelines, it is recommended that ABPM should be performed, if possible, as a complementary measure for hypertension diagnosis by home/office BP measurement.

3. Classification and diagnosis based on BP variability

1) White coat hypertension

White coat hypertension is defined as elevated office BP with normal out-of-office BP measurements. (Fig. 5-3). With white coat hypertension, it is often reported that organ damage is milder and CVD prognosis is better, compared to those with sustained hypertension, where BP is elevated both in and out of office. In an SR conducted for JSH2019, white coat hypertension was associated with a increased risk of future CVD events compared to non-hypertensive patients, and therefore, requires careful follow-up [192]. In hypertensive patients receiving antihypertensive medication, white coat hypertension is referred to as hypertension with a white coat phenomenon or effect. Management based mainly on out-of-office BP is recommended, even during antihypertensive treatment, because poorly

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controlled office BP alone is not considered to increase the risk for CVD events.

2) Masked hypertension

Masked hypertension is defined as non-elevated office BP with elevated out-of-office BP measurements, irrespective of antihypertensive treatment. The risk of organ damage and CVD events in patients with masked hypertension is significantly higher than those with non-hypertension or white coat hypertension, and is comparable to that in patients with sustained hypertension [94, 193, 194]. The time of day (early morning, daytime, or nighttime) when hypertension occurs may vary according to the patient's background. Patients are considered to have masked hypertension if they are hypertensive at any of these times, yet their office BP remains non-hypertensive. These subtypes are classified as early morning hypertension, daytime hypertension, and nocturnal hypertension, each characterized by distinct risk factors (Fig. 5-3). Continuous evaluation of out-of-office BP is essential, because the diagnosis depends on it. Considering the need for repeated measurements of out-of-office BP, proactive assessment with home BP is recommended, with confirmation by ABPM if necessary. No clinical trials have yet examined whether intervention for masked hypertension reduces CVD events. There is one retrospective study reported reduced organ damage [195]. However, given the superior prognostic value of out-of-office BP over office BP, intervention for masked hypertension may reduce the incidence of CVD events.

3) Abnormal diurnal variation of BP When BP circadian rhythm is normal, the nocturnal BP is lower than the daytime BP by 10–20%, during waking hours. This normal type of BP is called dipper, with the other types being recognized as abnormal diurnal variations of BP. The nocturnal BP which drops, relative to daytime BP, by more than 20% is called extreme-dipper, by <0–10% is non-dipper, and by <0% is riser. The non-dipper and riser types show a progression of organ damage and a higher risk of CVD events compared to dippers [22, 196–198]. In addition, a rise in BP during night and early morning that exceeds the physiological range is considered a BP morning surge and is associated with an increased risk of CVD events [199]. Whether the risk of extreme-dipper is due to an excessive drop in BP at night, or to a BP morning surge or an increase in daytime BP, is debatable. Even with dipper-type normal diurnal variation in BP, BP morning surges are a stroke risk [200]. Regarding which is essential, BP level or abnormal BP diurnal variation, the above-mentioned risk of CVD events with abnormal BP diurnal variation is a risk factor, independent of 24-h BP. And even in those with normal 24-h BP, abnormal BP diurnal variation is associated with a progression of organ damage and an increased risk of CVD events. In addition, it has been

reported that risers have a higher risk of developing heart failure, even when adjusted for the value of nocturnal BP. This suggests that circadian rhythm disturbances may contribute to the risk of organ damage and CVD events, independent of BP or preceding BP levels. The standard method for evaluating diurnal BP variation, including nocturnal BP, is using ABPM. However, the number of home sphygmonameters that can measure BP at night is increasing. Although there is no established appropriate number of measurements per night or day, data has indicated that nighttime BP measured with a home BP monitoring, in addition to typical morning and evening BP at home, are associated with CVD events [201, 202]. There is insufficient evidence for the assessment of diurnal BP variation using a home BP monitoring for it to be called a "surrogate for ABPM" [202, 203].

4) Other BP variability

BP variability can be assessed through multiple BP measurements. BP variability includes beat-to-beat differences captured by continuous monitoring, relatively short-term fluctuations due to respiration and autonomic output, aforementioned short-term diurnal variations on ABPM, morning-evening differences and day-to-day variations in HBPM, and visit-to-visit office BP variation. Long-term HBPM can also capture seasonal and annual BP variations. White-coat and masked hypertension, nocturnal dipping, morning hypertension, and morning BP surge are other phenotypes of BP variability considered.

There are significant associations between visit-to-visit BP variability and CVD outcomes [204–206], as well as the significance of assessing diurnal and day-to-day BP variability using ABPM and HBPM [207–210]. However, when the prognostic ability of BP variability is evaluated after adjusting for the mean (averaged) BP level, visit-to-visit BP variability and day-to-day BP variability, each based on measurements with consistent internal conditions, generally do not surpass that of the mean BP level itself. [211–214]. On the other hand, epidemiological studies have shown that the day-to-day home BP variability is useful for predicting the onset and progression of dementia [52, 215]. Furthermore, the usefulness of capturing seasonal variability by long-term HBPM has been reported [216]. Seasonal variation is linked to changes in outdoor temperature, with BP rising in winter and falling in summer. However, many reports suggest that this change precedes the outdoor temperature at a population level [216, 217]. Seasonal BP change would be associated with hours of daylight, physical activity, and, in part, with the annual hormone cycle [218].

BP variability is strongly influenced by measurement conditions. Antihypertensive medication has no [214, 219] or little [220, 221] effect on changing visit-to-visit and day-to-day BP variability. Most types of BP variations cannot be

The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and...

Table 5-7 Medical history of hypertensive organ damage or CVD

1. Hypertension and treatment history Historical BP level, duration of hypertension and treatment course, efficacy and side effects of antihypertensive drugs 2. Predisposition to hypertension and history of pregnancy Family history: parents' histories of hypertension, diabetes mellitus, CVD (onset and age at onset) Birth weight/weight gain during childhood Pregnancy history: gestational hypertension, diabetes mellitus, kidney dysfunction/proteinuria 3. Lifestyle Exercise Sleep: length of sleeping time, quality of sleep Eating and drinking: diet-content/preferences, alcohol consumption, beverage consumption Smoking Personality/psychopathological state: tendency towards depression, degree of stress (workplace and home) 4. Information suggesting secondary hypertension Obesity: history of weight gain Sleep apnea syndrome: morning headache, daytime sleepiness, reduced concentration, nocturia, snoring and apnea (information from patient's families) Kidney disease: nocturia, hematuria, proteinuria, lower extremity edema, multiple cystic kidney disease (including family history) Drugs: Corticosteroids and nonsteroidal anti-inflammatory drugs, herbal medicines (e.g., licorice), oral contraceptives, etc. Pheochromocytoma: paroxysmal increase in BP, palpitations, sweating, headache Primary aldosteronism, renal vascular hypertension: weakness, periodic paralysis of the limbs, polyuria 5. Organ damage Cerebrovascular disease: transient ischemic attack, muscle weakness, dizziness, headache, visual impairment Heart disease: dyspnea (exertional/noctural attacks), weight gain, edema of lower extremities, palpitations, chest pain Kidney disease: dyspnea, weight gain, edema of lower extremities, polyuria, oliguria, nocturia, hematuria, proteinuria Lower extremity artery disease: intermittent claudication, coldness of lower extremities

considered modifiable risk factors and are currently not beyond the realm of risk markers. However, long-acting antihypertensive drugs are expected to create a more favorable 24-h BP profile [222]. In addition, early adjustment of antihypertensive medications has been shown to reduce seasonal variation in home BP among treated patients [223].

5. When secondary hypertension is suspected from the results of medical interviews, physical examinations, or general clinical examinations, specific screening tests should be performed.

4. Examination

1) Medical history

Ask the time and situation (physical examination, consultation, self-measurement, etc) when the hypertension was first noted, also duration, severity, and treatment history. In particular, if patients have a history of treatment, confirm the type of antihypertensive medication, its efficacy, and whether they have had any adverse reactions.

Check family member histories with regard to hypertension, diabetes mellitus or CVD, and the age of onset. Regarding the patient's medical history, record if the birth weight was low or any weight gain during childhood, which can lead to a risk of hypertension. For women with a history of pregnancy, record the presence or absence of hypertension, diabetes mellitus, kidney dysfunction, or proteinuria during pregnancy.

Regarding lifestyle behaviors, inquire about the following items: exercise habits (frequency and intensity), sleeping (time and quality), eating habits (diet and preferences for salty and sweet foods), alcohol beverage consumption and smoking (quantity and duration), personality and psychological state (anxiety and depression), and stress level (at work and at home) to obtain an overall picture of lifestyle behaviors.

[POINT 5b] [Examination and diagnosis]

1. A comprehensive examination of hypertension should be performed by evaluating an individual's BP, organ function, and risk of CVD, and then the tests that can lead to a diagnosis of secondary hypertension in a cost-effective manner should be undertaken. 2. For overall evaluation of CVD risk, in addition to BP levels, including Home BP, examinations should be made for factors related to metabolic syndrome and chronic kidney disease (CKD), as well as elements to evaluate target organ damage related to hypertension. 3. Assessment of organ damage in high risk patients, such as those with diabetes mellitus, CKD, or a history of CVD, is essential if their BP level is in or higher than High Normal. 4. Echocardiography (UCG), coronary artery CT, carotid ultrasonography, brain magnetic resonance imaging (MRI) and magnetic resonance angiography (MRA) are representative, special methods to assess target organ damage, and other additional recommended examinations should be conducted appropriately.

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Table 5-8 Physical findings suggestive of secondary hypertension, signs of heart failure, arteriosclerotic findings/organ damage, and CVD

1. BP/pulse rate Resting in the sitting position (at first visit, inter-arm BP difference, and orthostatic change in BP and pulse rate) 2. Generalized Height-weight (BMI: weight [kg)/height [m]$^{2}$), obesity (BMI≥ 25 kg/m$^{2}$) Wait circumference (umbilical circumference, in standing position) Buffalo hump Skin findings: thinning of the skin, reddish-purple skin striae, hypertrichosis (Cushing's syndrome) 3. Face/neck Anemia/jaundice Fundus oculi abnormality Goiter Carotid artery murmur Jugular vein distension Facial appearance (endocrine disorders: acromegaly face, moon face) 4. Chest Heart: abnormal apex beat and heart murmur: thrill vibration (strongest point and map the vibration), III sound, IV sound, arrhythmia Lung field: rales 5. Abdomen Vascular murmur and its direction of flow, palpation of pulsatile mass, hepatomegaly and tapping pain, renal enlargement (polycystic kidney) 6. Limbs Palpation (disappearance, attenuation, left-right difference) of arterial pulse (each superficial peripheral artery), coldness, ischemic ulcer, edema 7. Nerve Dyskinesia of limbs, sensory disturbance, hyperreflexia of tendons

Table 5-9 Assessment of hypertensive organ damage, comprehensive evaluation of CVD risk, and laboratory examinations screening of secondary hypertension

1. General examination (at initial visit, and several times per year during follow-up period) Initial visit: general examinations (blood, urine). During follow-up period (Risk-based examination) Biochemistry: creatinine (Cr), uric acid, electrolytes, lipid metabolism, glucose metabolism, liver function, etc. Urinalysis: urine protein, urine sediment

During follow-up period (Risk-based examination)

Biochemistry: creatinine (Cr), uric acid, electrolytes, lipid metabolism, glucose metabolism, liver function, etc.

Urinalysis: urine protein, urine sediment

eGFR is calculated from serum Cr. If there is a decrease in muscle mass such as sarcopenia, eGFR calculated from cystatin C is also used.

2. Screening examinations to exclude secondary hypertension (see Chapter 15)

Though hypertensive patients are usually asymptomatic, they need to be checked for the presence of specific symptoms that may suggest the presence of secondary hypertension, CVD complications, or hypertensive organ damage. Signs suggestive of secondary hypertension include a history of weight gain and other metabolic syndrome-related risk factors (diabetes mellitus and lipid metabolic abnormalities). Check if their family members have noticed snoring or apnea, and whether the patient has signs of sleep apnea such as morning headache, daytime sleepiness, depression, poor concentration, and nocturia. In addition, check for symptoms suggestive of kidney disease, such as nocturia, hematuria, and proteinuria, as well as the use of medications such as steroidal and nonsteroidal anti-inflammatory drugs, herbal medicines (e.g., licorice), and oral contraceptives.

The history of hypertensive organ damage or CVD is shown in Tables 5-7. For CVD, the following are notable: for cerebrovascular disease, transient ischemic attack, muscle weakness, dizziness, headache, and visual impairment; for heart disease, dyspnea (exertional and nocturnal

attacks), weight gain, lower extremity edema, palpitations, and chest pain; for kidney disease, dyspnea, weight gain, and lower extremity edema, as well as polyuria, oliguria, nocturia, hematuria, and proteinuria; for lower extremity arterial disease, intermittent claudication and coldness of lower extremities.

2) Clinical examination (physical findings)

At the initial visit in addition to BP and pulse rate, while sitting in a resting sitting position, the inter-arm difference in pulse (pulsation) and BP should be checked [224]. Furthermore, if lower extremity artery disease or orthostatic hypotension is suspected, the difference between the upper and lower limbs and the orthostatic changes in BP and pulse rate should be checked.

Measure the height and weight, and calculate BMI (weight [kg]/height [m]$^{2}$) to evaluate the degree of systemic obesity. In addition, measure the waist circumference (umbilical circumference, in the standing position) to evaluate the degree of abdominal obesity.

The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and...

The presence or absence of secondary hypertension, signs of heart failure, findings of arteriosclerosis: arteriosclerotic organ damage, or findings suggestive of CVD should also be checked (Table 5-8). Skin problems may include thinning of the skin, reddish-purple skin striae, and hypertrichosis (Cushing's syndrome); facial and neck problems include facial abnormalities (endocrine disorders: acromegaly face, moon face), buffalo hump, anemia/jaundice, abnormal fundus, goiter, carotid artery murmur (also listen for orbital vascular murmur if present), and jugular vein distension. Chest findings include apex beat abnormalities and arrhythmias, heart murmur: the thrill vibration (strongest point and map the vibration), III sound, IV sound, and the presence of rales in the lung field. For the abdomen, check for vascular murmurs and their direction of flow, palpation of pulsatile masses, hepatomegaly and tapping pain, renal swelling (polycystic kidney). For limbs, examine palpation (disappearance, attenuation, left-right difference) [224] of arterial pulse (radial artery, dorsal foot artery in the lower limbs, and if present, posterior tibial artery, popliteal artery, femoral artery, moving toward the center in that order), and coldness, ischemic ulceration, edema, dyskinesia of limbs, sensory disturbance, and hyperreflexia of tendons.

3) Laboratory examinations

Comprehensive evaluation of hypertensive organ damage and CVD risk in individuals, and specific examinations leading to a diagnosis of secondary hypertension should be performed in a cost-effective manner (Table 5-9).

(1) General examination

General examinations should be performed for hyper- tensive patients during their first visit and several times each year or annually during follow-up periods. These include general urinalysis, blood cell count, blood biochemistry, chest X-ray, and electrocardiography. These examinations may be substituted with data from general population health checkups or workplace health examinations.

At the initial visit, general laboratory examinations are performed, and during follow-up examinations for creatinine, uric acid, electrolytes, triglycerides, HDL cholesterol, total cholesterol (or LDL cholesterol), fasting blood glucose, liver function, depending on the patient's risk. Serum sodium (Na) and serum potassium (K) should be measured, especially in patients taking antihypertensive drugs (diuretics, renin-angiotensin system [RAS] inhibitors) and in older adults.

Although not covered by insurance for the management of hypertension alone, the usefulness of the following has also been reported:

(1) Calculation of eGFR by cystatin C in the presence of muscle mass loss such as sarcopenia [225].

(2) Dietary assessment by urine sodium/potassium (Na/K) ratio [226]

(3) Evaluation of early kidney dysfunction by micro-albuminuria [237]

(2) Other examinations

The patient is at high risk if hypertension is combined with a glucose metabolism disorder. If such complications are suspected, HbA1c measurement, fasting blood glucose measurement, or a 75 g oral glucose tolerance test (OGTT) should be considered, as appropriate (not covered by insurance for the management of hypertension alone) [228]. Orthostatic BP dysregulation (orthostatic hypotension and orthostatic hypertension) is an autonomic neuropathy which is more common in older adults and diabetic patients. It is associated with progressive organ damage and poor long-term survival outcomes [229, 230]. Although a "head-up tilting test" using a tilt table is necessary for a detailed examination of orthostatic hypotension, there is an orthostatic test which is a simple method for daily practice. Measure BP in the sitting (or supine) position 1–2 times after 5 min of rest, and 1–3 min after active standing, and evaluate the changes in BP [231]. If the increase in pulse rate is small compared to the fall in BP, a baroreflex failure is considered to be present. Symptoms of dizziness and unsteadiness are often seen immediately after standing up, and BP should also be measured immediately after standing up. Orthostatic hypertension caused by BP over-response during orthostasis is also associated with hypertensive organ damage, development of cerebrovascular disease, and a deterioration in long-term prognosis [230]. A consensus statement by the American Autonomic Society and the JSH defines an orthostatic hypertensive reaction as an increase in SBP by 20 mmHg or more with postural change from supine to upright position [232].

4) Assessment of hypertensive organ damage

To comprehensively assess organ damage caused by hypertension, it is necessary to understand the meaning of the various examinations that reflect the degree of damage for each organ and to measure and assess them continuously. In addition to these results, the severity of hypertension and the risk of other complications should be taken into consideration when deciding on a treatment plan. In high-risk hypertensive patients, such as with diabetes mellitus, or a history of CVD events, it is advisable to evaluate these organ damages from their BP in or higher than the high-normal BP (Table 5-10).

(1) Brain/fundus

Asymptomatic cerebrovascular diseases in the brain (asymptomatic cerebral infarction [including white matter lesions], asymptomatic intracerebral hemorrhage, asymptomatic cervical or intracerebral vascular stenosis or

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|Examination|Outcome predicting $ability^{a}$|Ease of use|Cost|Reproducibility|End point, cutoff value|Post treatment marker improvement and prognosis| |---|---|---|---|---|---|---| |■ Brain/fundus oculi|■ Brain/fundus oculi|■ Brain/fundus oculi|■ Brain/fundus oculi|■ Brain/fundus oculi|■ Brain/fundus oculi|■ Brain/fundus oculi| |MRI angiography|Good|-|High|Good|Asymptomatic cerebral infarction, cerebral white matter lesion, asymptomatic cerebral hemorrhage|Unknown| |Cognitive function test|Possible|Fair|Low|Good|Mini-Mental State Examination (MMSE)≤26 points Hasegawa's Dementia Scale-Revised score ≤ 25 points|Unknown| |Evaluation of depression|Possible|Fair|Low|Good|Geriatric Depression Scale (GDS) ≥ 10 points Beck Depression Inventory (BDI)> 10 points|Unknown| |Funduscopy (mild)|Possible|Fair (experience needed for reading)|Low|Fair|Arterial narrowing, blood pillar reflex, cross-reaction with vein|Unknown| |Funduscopy (severe)|Good|Fair (experience needed for reading)|Low|Good|Retinal hemorrhage, microaneurysm, cotton wool patch, papilledema|Unknown| |■ Heart|■ Heart|■ Heart|■ Heart|■ Heart|■ Heart|■ Heart| |ECG|Good|Good|Low|Good|Left ventricular hypertrophy Sokolow-Lyon: SV1+RV5≥35 mm, Cornell Voltage: SV3+RaVL > 28 mm (men) > 20 mm (women) Strain pattern|Prognosis improved| |UCG|Good|Fair|Moderate|Good|Left ventricular hypertrophy (No cutoff level set).|Prognosis improved| |Blood BNP/NT-proBNP|Good|Good|Low|Good|Pre-heart failure and heart failure BNP ≥35 pg/mL NT-proBNP ≥ 125 pg/mL|Prognosis improved| |■ Kidney eGFR|Good|Good|Low|Good|<60 mL/min/1.73 $m^{2}$|Prognosis improved| |Proteinuria (qualitative)|Good|Good|Low|Good|+ or higher|Prognosis improved| |Proteinuria (microalbuminuria) b|Good|Good|Low|Fair|0.15 g/gCr or more|Prognosis improved| |■ Blood vessel|■ Blood vessel|■ Blood vessel|■ Blood vessel|■ Blood vessel|■ Blood vessel|■ Blood vessel| |Carotid ultrasonography (IMT)|Good|Fair|Moderate|OMT ≥ 1.1 mm|Prognosis improved, but it takes time to improve markers Slight improvement|| |ABI|Good|oscillometric method is good, Doppler method is fair|Moderate|Good|≤0.90|| |cfPWV|Good|Fair|Moderate|Good|≥10 m/s|Unknown| |baPWV|Good|Good|Moderate|Good|Normal value: <14 m/s Border value: 1418 m/s Abnormal value: ≥18 m/s|Unknown| |CAVI|Good|Good|Moderate|Good|Normal value: <8.0 Border value: 8.09.0 Abnormal value: ≥9.0|Unknown| |FMD|Good|Fair|Moderate|Good|Normal value: ≥7.0 Border value: 4.07.0 Abnormal value: <4.0|Unknown| |RH-PAT, evaluated by fingertip plethysmogram|Good|Fair|Moderate|Good|Normal value: ≥2.10 Border value: 1.67 2.10 Abnormal value: <1.67|Unknown|

ªTests shown to be useful by meta-analysis

$^{e}$Covered by insurance in cases of diabetes nephropathy only

occlusion, unruptured cerebral aneurysm or unruptured cerebral arteriovenous malformation) are serious risk factors for stroke occurrence and dementia. They are also associated with depression and falls in older adults [233, 234]. MRI is superior to CT for their evaluation. However, in routine practice, CT and MRI are not commonly used in the screening for organ damage in hypertension.

Asymptomatic cerebrovascular diseases are increasingly being detected by brain check-ups and by other means. In particular, asymptomatic cerebral infarction is strongly

associated with hypertension; antihypertensive treatment is important to reduce the risk of progression to symptomatic brain lesions [235, 236].

Funduscopy is generally used as an examination. Minor fundus lesions such as arterial narrowing, blood column reflex, and venous crossing are considered risk factors for the development of CVD [237]. Artificial intelligence is expected to be used to improve the value of such examinations in the future [238]. In particular, funduscopy is essential for patients with diabetes mellitus. Retinal vein occlusion, which

The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and...

also causes fundus hemorrhage, is associated with a high percentage of poorly controlled cases of hypertension; thus careful identification and treatment of hypertension is necessary for cases of retinal vein occlusion [239]. Furthermore, papillary edema is seen in hypertensive encephalopathy, a hypertensive emergency. Malignant hypertension and fundus hemorrhage suggest severe hypertension and are associated with cardiovascular risk [240]. When such findings are observed, prompt action is required. If a hypertensive emergency is suspected, a funduscopy is strongly advised.

(2) Heart

Electrocardiogram (ECG) is one of general examination. In general, left ventricular hypertrophy can be inferred from an ECG showing high voltage (Sokolow-Lyon method, Cornell Voltage method, etc.); this is a simple examination method that can reflect the prognosis [241, 242]. Strain pattern is also a risk factor for CVD [243]. If atrial fibrillation is detected, consult a cardiologist.

Left ventricular mass and morphology (concentric hypertrophy) on echocardiography (UCG) are also prognostic factors, and they are sometimes used as a follow-up marker [244, 245]. In recent years, artificial intelligence has been used in an effort to promote and facilitate the use of UCG results [246]. In Japan, there are no diagnostic criteria for left ventricular hypertrophy/morphological abnormalities based on UCG findings. Improvement through antihypertensive treatment can be inferred from ECG or UCG. This will reflect an improved prognosis, and indicate the effectiveness of the antihypertensive treatment. However, the degree of improvement in hypertrophy varies depending on the type of antihypertensive drug [247]. In addition, left atrial diameter enlargement is also associated with the prognosis and development of atrial fibrillation [248].

Heart failure with preserved left ventricular ejection fraction (HFpEF) in the aging population has been much focused. UCG can evaluate potential left ventricular systolic and diastolic dysfunction in hypertension [249]; it should be performed when heart failure is suspected. However, the usefulness of left ventricular function assessment as a marker for the management of hypertension is not clear.

Brain (or B-type) natriuretic peptide (BNP) and/or N-terminal pro-BNP (NT-proBNP) in blood, isolated and identified in Japan, are markedly increased in patients with heart failure with reduced ejection fraction (HFrEF) and in symptomatic patients with heart failure with preserved left ventricular ejection fraction (HFpEF) (stage C heart failure) (note that the increase is smaller in obese patients). It has been widely applied clinically to diagnose and determine the effectiveness of treatment [250]. Clinically, BNP and NT-proBNP are useful as a screening test for heart failure in hypertensive patients with dyspnea and edema as well as for

pre-heart failure or heart failure in hypertensive patients. They may also be elevated in pre-heart failure (stage B heart failure), a condition in which there are no symptoms but rather, functional or structural abnormalities of heart. The risk of developing heart failure is high, making it useful for assessing the risk of heart failure in such hypertensive patients. In the case of high values (BNP≥35 pg/mL, NT-proBNP≥125 pg/mL), refer the patient for a thorough examination or refer to a cardiologist [251]. If hypertension is associated with pre-heart failure, a detailed examination including UCG should be performed, and antihypertensive drugs that have been shown to be effective in preventing heart failure should be used aggressively. The SPRINT sub-analysis study [252] examined the preventive effect of different antihypertensive drugs on heart failure and also RAS inhibitors on major composite CVD events. The authors reported the efficacy of thiazide diuretics in improving NT-proBNP levels, in reducing the risk of heart failure and major composite cardiovascular events in hypertensive patients with heart failure.

(3) Kidney

eGFR and proteinuria (qualitative) are used as general examinations to evaluate renal dysfunction [253]. Urinary protein quantification should be performed when necessary, because the risk of heart failure is increased. A urinary protein (+/-) trace reading by the paper method indicates that a small amount of protein is present. A urinary protein level of about 30 mg/gCr indicates that the albumin in the urine is within the normal range. [253].

CKD is defined as proteinuria ≥0.15 g/gCr (micro-albuminuria ≥30 mg/gCr) or eGFR<60 mL/min/1.73 m$^{2}$ or both, persisting for >3 months [253]. CKD severity classification by both indices is significantly associated with the progression of CKD, end-stage renal failure, CVD death, and all-cause mortality [254]. Furthermore, changes over time in eGFR and proteinuria are also useful in assessing changes in the severity and risk of developing CVD [255].

Recent studies have shown an association between microalbuminuria and prognosis also in hypertension [256] and that aggressive antihypertensive treatment reduces the incidence of CVD while improving microalbuminuria [257].

(4) Blood vessels

In clinical practice concerning hypertension, vascular disorders are evaluated morphologically (morphometric methods) and functionally (functional methods).

The most commonly used morphologic evaluation method in routine medical practice is carotid ultra-sonography. The most commonly used morphological evaluation indices are intima-media complex thickness (IMT), plaque number, and plaque height. These are

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independent prognostic indicators [258] and are also associated with cognitive dysfunction [259]. An abnormal IMT value is ≥1.1 mm (IMT at the distal wall [IMT-C10], measured centrally 10 mm from the transition between the common carotid artery and carotid sinus) [260, 261].

A meta-analysis, conducted in 2013, reported that adding IMT to conventional risk model assessments (e.g., Framingham risk score) did not significantly improve prognostic ability [262]. On the other hand, it was shown that improvement in IMT takes time, but that such improvement reflects a better prognosis [263].

An enlarged aorta on plain chest radiograph takes into consideration of a thoracic aortic aneurysm or aortic dissection, and a palpable abdominal pulsatile aneurysm suggests an abdominal aortic aneurysm or dissection. In the presence of such abnormalities, abdominal ultrasonography, CT, and MRI should be considered.

Endothelial function tests, pulse wave velocity (PWV), pulse wave analysis, and ankle/brachial BP ratio have been used as functional testing methods. These tests reflect the different pathophysiologies of functional vascular disorders and have been reported to be independent prognostic markers [224, 264].

① Endothelial function test

Endothelial function tests to evaluate endothelial dysfunction, an early pathology of arteriosclerosis, are covered by insurance [265]. Flow-mediated vasodilatation (FMD) and reactive hyperemia peripheral arterial tonometry (RH-PAT), using finger volume pulse wave, are used [266, 267], and reflect different pathologies [267].

② Pulse wave velocity (PWV)

PWV is a marker of arterial stiffness, and carotid-femoral PWV (cfPWV) and brachial-ankle PWV (baPWV) are used [266, 268, 269].

cfPWV and baPWV were reported to be independent prognostic markers in a direct data analysis (individual participant data [IPD] meta-analysis) that compiled data from previously published papers [266, 268, 269]; both were listed as useful markers of vascular damage in the 2023 European Society of Hypertension (ESH) Guidelines (ESH2023) [183]. PWV is decreased by the anti-hypertensive medication. However, in the SPARTE study, treatment strategies aiming at the normalization of cfPWV did not reduce the incidence of cerebrovascular disease compared to conventional antihypertensive treatment [270].

The cardio-ankle vascular index (CAVI) is an arterial elasticity index calculated from PWV and brachial BP, and is independent of BP at the time of measurement [265, 266].

The reference values for FMD, RH-PAT, baPWV, and CAVI have been reported by the Japanese Circulation Society and the Japan Society for Vascular Failure [266, 271].

③ ABI

The ratio of the higher value of either the left or right upper arm systolic pressure to the ankle systolic pressure is the ABI [265]. In Japan, the simple oscillometric method is mainly used to measure ABI [224, 265]. Since an ABI ≤ 0.90 reflects lower extremity arterial disease complications, referral to a specialist such as a vascular surgeon should be considered [224]. An ABI ≤ 0.90 or 0.91 to 1.00 increase the risk of developing CVD; also ABI ≥ 1.40 [Doppler] and ≥ 1.30 [oscillometric] show an increased risk, but in fewer patients [224, 272]. ABI measurement should be considered in high-risk patients [224, 265, 272].

5) Screening to exclude secondary hypertension

Secondary hypertension includes endocrine hypertension, renovascular hypertension, hypertension associated with renal parenchymal disease, sleep apnea syndrome, drug-induced hypertension, etc (see Chapter 15). Of these, primary aldosteronism (PA) is reported to account for 5-10% of all hypertensive patients and has the largest proportion of secondary hypertension [273–275]. The risk of complication is higher in patients with secondary hypertension than in those with essential hypertension. In the case of hypertension at a young age, and in those with sudden onset of hypertension, refractory hypertension, or strong organ damage relative to age or BP, secondary hypertension should be strongly suspected, and the medical history should be taken with reference to Table 5-7. The physical findings should be checked with reference to Table 5-8.

Regarding the laboratory tests that should be performed for an individual patient, the following tests should be considered: serum Na, K, creatinine, plasma renin activity (PRA) or active renin concentration (ARC), plasma aldosterone concentration (PAC), adrenocorticotropic hormone (ACTH), cortisol, blood free metanephrines (MN) 2 fraction, urinary MN fraction, thyroid hormones, parathyroid hormone (PTH), albumin, serum calcium, inorganic phosphorus (iP), urine qualitative and sediment analysis, polysomnography, abdominal ultrasonography, renal vascular ultrasonography, abdominal CT, etc.

A screening test should be performed before the start of medication since some antihypertensive drugs affect PRA, PAC, K, etc., or blood samples should be taken after discontinuation of medication (4 weeks for MR antagonists, 2 weeks for β-blockers, diuretics, angiotensin II receptor blockers [ARBs] and angiotensin converting enzyme [ACE] inhibitors). For more information on the difficulties of changing medications, see "Chapter 15, Section 1. Primary Aldosteronism."

The method of measuring PAC was changed from the RIA method to the CLEIA method in April 2021 [276]. The screening criteria for PA are the same as before: PAC ≥ 60 pg/mL and aldosterone-to-renin ratio (PAC/PRA [ARR])

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Table CQ2-1 RCTs included

|Author, Year of publication|Subject|Intervention outlined|Control outlined| |---|---|---|---| |Broege, 2001 [287]|40 hypertensive patients|Home BP data is collected by a nurse over telephone at intervals of 2 weeks and used for switching the medication. Physician provides treatment based on home BP, with a goal set at reducing maximum BP level to <150/90 mmHg.|Visiting the clinic at intervals of 2 weeks to receive adjustment of medication. Treatment provided to maintain maximum BP level <150/90 mmHg.| |Fuchs, 2012 [288]|121 patients receiving antihypertensive treatment and with poorly controlled BP|Pharmacist gives guidance on the basis of BP data (to half of the subjects). As a rule, switching of antihypertensive drug is avoided, and guidance on improvement of habits is provided. The goal of antihypertensive treatment not specified.|Conventional clinical care + pharmacist guidance (for half of all cases) provided. As a rule, switching of antihypertensive drug is avoided, and guidance on improvement of habits is provided. The goal of antihypertensive treatment not specified.| |Godwin, 2010 [289]|552 patients aged over 18 and diagnosed with hypertension or receiving antihypertensive treatment and with poorly controlled BP|Home BP is measured. As needed, physician checks the BP. Goal set at <135/85 mmHg.|Conventional clinical care; Canadian guidelines used as an indicator; Goal set at office BP <140/90 mmHg.| |Hanley, 2015 [290]|55 patients with a history of stroke/TIA (51 patients included in analysis)|Physician can access the home BP data transferred and provides treatment based on such data. Goal of antihypertensive treatment not specified. Telemonitoring performed.|Conventional clinical care; the goal of antihypertensive treatment is not specified.| |Ionov, 2021 [291]|240 patients with poorly controlled BP on antihypertensive treatment|Physician checks home BP entered in the mobile app every week and adjusts the antihypertensive medication based on the data. Goal set at home BP <135 mmHg. Telemonitoring is employed.|Conventional clinical care; goal is office BP <140 mmHg.| |Madsen, 2008 [292]|236 new patients with hypertension aged 20–80 or receiving antihypertensive treatment and poorly controlled as to BP|Physician and patient can access the home BP data at Web or via PDA cellphone. Medication switched on the basis of such data. Goal at home BP <135/85 mmHg. Telemonitoring performed.|Conventional clinical care; goal set at office BP <140/90 mmHg| |Martinez, 2018 [293]|136 white adult patients with type 2 diabetes and an office BP of 140–170 mmHg (116 patients included in analysis)|The nurse reports the home BP data brought by the patient to the physician, who adjusts the antihypertensive medication based on the data. The goal is home BP <135/85 mmHg.|Conventional clinical care; goal is office BP <140/90 mmHg.| |McKinstry, 2013 [294]|401 patients aged over 18 with office BP >145/85 mmHg (359 patients included in analysis)|Healthcare professionals and patient can access the home BP data. Goal set at <135/85 mmHg. Telemonitoring performed.|Conventional clinical care; goal set at <140/90 mmHg on the basis of British Hypertension Society's guidelines.| |Neumann, 2011 [295]|60 patients aged 18–80 with poorly controlled BP and receiving no ARB (57 patients included in analysis)|BP data is transmitted via cellphone. Physician is informed in case of failure to satisfy the antihypertensive criteria or excessive BP fall, to begin discussion with patient over therapeutic strategy. Physician always access the home BP data, and patient is given the home BP data once a month. Goal set at home BP <135/85 mmHg (<130/80 mmHg in cases complicated by diabetes or renal dysfunction). Telemonitoring performed.|Patients advised to call or visit physician upon poor reduction in BP or appearance of adverse reactions and to measure BP at home once daily. Goal of antihypertensive treatment not specified.| |Parati, 2009 [296]|298 patients with mild or moderate hypertension or poorly controlled BP|Physician can access the transferred home BP data and provides treatment on the basis of such data. Goal set at <135/85 mmHg. Telemonitoring performed.|Conventional clinical care (BP measured by physician; Goal set at office BP <140/90 mmHg)|

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Table CQ2-1 (continued)

|Author, Year of publication|Subject|Intervention outlined|Control outlined| |---|---|---|---| |Rinfret, 2009 [297]|223 hypertensive patients with high ABP levels|Self-measured BP data and self-assessed adherence data and prescription data are combined with prescription data and reported to physician/pharmacist/nurse. If BP is poorly controlled, nurse checks the patient and submits a report to doctor/pharmacist. Goal of antihypertensive treatment not specified. Telemonitoring performed.|Conventional clinical care; goal of antihypertensive treatment not specified.| |Rogers, 2001 [298]|121 patients poorly controlled BP and considering to switch the antihypertensive drug|Home BP data transferred and processed centrally, followed by weekly report to physician/pharmacist/nurse. Drug dose level adjusted on the basis of such a report. Goal of antihypertensive treatment not specified. Telemonitoring performed.|Conventional clinical care (in accordance with JNC6 guideline)| |Staessen, 2004 [299]|400 patients with office DBP ≥95 mmHg|Decision made by blinded physician at the coordination center on the basis of BP data. Medication adjusted on the basis of home DBP. Medication adjust to maintain diastolic pressure in the 80-89 mmHg range.|Treatment based on office DBP. Medication adjusted to maintain DBP in the 80-89 mmHg range.| |Verberk, 2007 [300]|430 patients aged over 18, with SBP 139-200 mmHg and DBP 90-120 mmHg|Steps of treatment are taken semi-automatically on the basis of home BP data. Home/office BP is controlled to 120-140/80-90 mmHg.|Physician takes the steps of treatment semi-automatically on the basis of home BP data. Randomly measured BP is controlled to 120-140/80-90 mmHg.|

≥200 is positive, and borderline of ARR is settled as 100–200 (when PAC/ARC is used to replace ARR, positive criteria for ARR is ≥ 40, borderline is 20–40). If the patient is borderline, the decision of whether to conduct a thorough examination is made after comprehensively considering hypokalemia, the presence of a tumor, and the patient's individual needs.

Cushing's syndrome, including mild autonomous cortisol secretion, cannot be ruled out based on temporal ACTH and cortisol values alone. In such cases, when an adrenal tumor is present, the patient should be referred to a specialist.

In order to exclude pheochromocytoma and paraganglioma, blood free and urinary MN fractionation is useful. However, given the extended time frame for test results, imaging tests are employed to swiftly diagnose tumors in the adrenal glands or ganglia, particularly in cases such as hypertensive emergencies or preoperative evaluations, where expeditious diagnosis is paramount.

CQ 2 Is antihypertensive treatment based on home BP recommended rather than that based on office BP in adults with essential hypertension?

$\blacktriangleright$ Antihypertensive treatment based on home BP is strongly recommended.

[Strength of recommendation – 1, Strength of evidence–B, Rate of Agreement– 100%]

Summary of evidence

We included 14 RCTs, comparing antihypertensive treatment based on home BP with antihypertensive treatment based on office BP. The degree of reduction in ambulatory SBP/DBP following antihypertensive treatment based on home BP was larger by 2.73 mmHg (95% CI 0.22 to 5.23) for SBP and by 1.61 mmHg (95% CI 0.01 to 3.21) for DBP than that following antihypertensive treatment based on office BP. No RCT evaluating the incidence of CVD or mortality was identified.

Explanation

A number of studies have shown that home BP is more reliable and reproducibly than office BP [159, 277] and is more closely associated with CVD and target organ damage [24, 98, 149, 278, 279]. On the basis of such evidence, the Guideline on Hypertension Treatment 2014 (JSH2014) states clearly: "If the office blood pressure differs from the home blood pressure, priority should be given to diagnosis based on the home blood pressure" [280, 281]. However, a part of clinicians have a view that office BP suffices [282]. To resolve such a difference in awareness/view, it is essential to compare antihypertensive treatment based on home BP with conventional antihypertensive treatment based on office BP and to demonstrate clearly whether the

The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and...

A

 B

 Fig. C2Q1 - Home blood pressure (BP)-based treatment versus office BP-based treatment for ambulatory systolic BP changes (A) and diastolic BP changes (B) in 14 studies. (Adapted from ref. 286)

prognosis and hypertension control will be improved by the use of home BP as an indicator.

With such a background, JSH2019 conducted SR by setting this CQ "Is thypihertensive treatment based on home blood pressure recommended rather than that based on office blood pressure in adults with essential hypertension?", with the conclusion "strongly recommend anti-hypertensive treatment using home BP as an index" [283–285].

In preparing JSH2025, we conducted an updated SR with similar CQ [286]. The following seven outcomes were set for this review: 1) incidence of CVD, 2) CVD mortality, 3) incidence of dementia, 4) incidence of chronic kidney disease, 5) 24-h ABPM, 6) serious adverse events (total mortality), and 7) non-serious adverse events (excessive BP reduction).

1) CVD incidence/mortality, incidence of dementia, incidence of chronic kidney, serious/non-serious adverse events

No RCT corresponding to outcome 1) was identified.

2) 24-h ABPM

Fourteen RCTs were included (Table CQ2-1) [287–300]. For the trials in which mean 24-h ABP levels had not been evaluated, mean daytime ABP was used as a surrogate outcome. The results of the meta-analysis showed that the difference in the degree of BP reduction between the home and office BP index groups was 2.73 mmHg (95%CI 0.22 to 5.23 mmHg) for SBP and 1.61 mmHg (95%CI 0.01 to 3.21) for DBP (Fig. CQ2-1) [286].

Summary

Antihypertensive treatment based on home BP has been shown to be more useful in reducing mean 24-h ABP levels than treatment based on office BP. On the other hand, no RCT adopting the reduction in the incidence or mortality of cardiovascular diseases was identified. Thus, there is no evidence directly confirming that antihypertensive treatment based on home BP can reduce the incidence or mortality of

cardiovascular diseases compared with antihypertensive treatment based on office BP. However, according to the metaanalysis of observational studies using mean 24-h ABP data among Asian subjects [301], the difference in anti-hypertensive efficacy by 3.64 mmHg (systolic pressure) and 2.16 mmHg (diastolic pressure) obtained from the above-mentioned meta-analysis of trials (having adopted reduction in mean ABP levels as the outcome) is suggested to be associated with a reduction of the risk for cardiovascular diseases by 10.9% and 10.6%, respectively. Furthermore, in the HOMED-BP Study conducted in Japan, involving patients with essential hypertension, the home BP during antihypertensive treatment was reported to be closely associated with the risk for onset of or death from cardiovascular diseases than office BP [278, 302]. This suggests that antihypertensive treatment.aimed at achieving the goal of home BP reduction proposed in these guidelines is useful also in reducing the incidence and mortality of cardiovascular diseases.

For the reasons given above, this CQ strongly recommends implementation of antihypertensive treatment based on home BP. However, it is essential to set the goal of treatment in line with the goal of BP reduction recommended in the present guideline. It is additional required that home BP measurement is conducted appropriately in accordance with the present guideline.

Literature search

Four SR committee members were divided into two pairs, and independently conducted a literature search in PubMed, Ichushi-Web, and Cochrane Library. Primary screening (title and abstract) identified 3989 papers, and 3936 were excluded according to the exclusion criteria. We then conducted a secondary screening (full text) of 62 papers, including three from review, four from the CQs of JSH 2019, and two additional papers identified by a manual search. Finally, a meta-analysis was performed using 14 papers that correspond to this CQ.

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CQ 3 Is intervention with self-measurement of BP at home (HBPM) using a cuff sphymomanometer effective in lowering BP in adults?

$\blacktriangleright$ In adults, intervention with self-measurement of BP at home (HBPM) using an upper arm cuff sphygmomanometer, is strongly recommended, especially when combined with telemonitoring or support from a healthcare provider.

[Strength of recommendation – 1, Strength of evidence – B, Rate of Agreement – 100%]

Summary of evidence

A literature search identified 65 RCTs (21,053 individuals in total; adults aged ≥18 years) that compared HBPM intervention using a cuff sphygmomanometer with a usual care group (group without HBPM intervention), using changes in BP as the outcome.

The reduction in BP values during the intervention by HBPM was 3.27 mmHg (95% CI 2.40 to 4.15) for SBP and 1.61 mmHg (95% CI 1.14 to 2.07) for DBP compared to the usual care group, indicating a significant reduction in BP.

The effect was more pronounced when additional interventions were involved, such as telemonitoring or support from a healthcare provider. No significant intervention effects on SBP were observed in studies that used wrist cuff sphygmomanometers rather than upper arm cuff sphygmomanometers.

Explanation

Many studies have reported that HBPM is more reliable and reproducible than office blood pressure [159, 277] and such measurements are strongly associated with identification of cardiovascular disease and target organ damage [24, 98, 149, 278, 279]. Based on this evidence, the Japan Society of Hypertension (JSH) Guidelines for the Treatment of Hypertension 2014 (JSH2014) clearly states that when there is a difference between office BP and home BP, "a home blood pressure-based diagnosis should have priority" [280, 281]. In addition, an SR review in CQ 1 of the Guidelines for the Management of Hypertension 2019 (JSH2019) showed that antihypertensive treatment using home BP as an outcome is more effective than treatment using office BP as an outcome in lowering mean ambulatory BP [283, 285]. However, there are limited SRs that have quantitatively evaluated the effect of HBPM on BP reduction compared to the control group without HBPM; there are no SRs that include recent studies. In addition, cuffless sphygmomanometers, which claim to be sufficiently

accurate to measure BP without the use of a cuff, have become more widespread in recent years. However, the validity of their measurements has been reported to be extremely low [96]. Therefore, we established this CQ in the Guideline and conducted an SR [303].

As a result, 65 RCTs were identified that compared the HBPM intervention using a cuff phygmomanometer with a control group; the outcome was a change in BP. Of the 65 trials, 63 trials included hypertensive patients. Twenty-six studies were from the United States, representing the largest number by country; no such study was conducted in Japan.

The intervention significantly reduced BP values by 3.27 mmHg (95% CI 2.40 to 4.15) for SBP and 1.61 mmHg (95% CI 1.14–2.07) for DBP compared to the usual care group. (Fig. CQ3-1, Fig. CQ 3-2).

A sensitivity analysis was conducted on 42 studies that added telemonitoring and healthcare provider support (such as regular follow-up, lifestyle guidance, and treatment adjustment suggestions) as intervention elements to HBPM. The results showed that the reduction in BP due to the intervention was more significant compared to the usual care group, with SBP reduced by 4.27 mmHg (95% CI 3.16–5.39) and DBP reduced by 1.89 mmHg (95% CI 1.24–2.55), indicating that additional intervention may enhance the BP lowering effect of HBPM [303].

A sensitivity analysis was conducted on the four studies that used HBPM with a wrist cuff sphygmanometer. The results showed that the reduction in the BP value due to HBPM compared to the usual care group was not statistically significant for SBP with 0.06 mmHg (95% CI -1.40 to 1.53), but the effect was significant for DBP with 1.20 mmHg (95% CI 0.17-2.22). Intervention by HBPM using a wrist cuff sphygmomanometer showed no significant effect when SBP was used as the outcome [303].

Summary

HBPM interventions with a cuff sphygmomanometer were shown to help lower BP in adults. The intervention effect was more pronounced when accompanied by telemonitoring/healthcare provider intervention, but the effect was attenuated when a wrist cuff sphygmomanometer was used.

Based on the above, this CQ strongly recommends intervention through HBPM using an upper arm cuff sphygmomanometer, especially with telemonitoring and healthcare provider intervention. In addition, verification of appropriate HBPM measurements and their interpretation during health and medication counselling should preferably be performed by a certified cardiovascular disease prevention educator.

In the studies selected for this SR, there were no reports of interventions lasting longer than 2 years, and the long-term antihypertensive effect of HBPM and its effect on the

The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and...

|First author, Year of publication|BP|Intervention period (months)|Difference in SBP change between groups [95%CI] (mmHg)| |---|---|---|---| |Vetter, 2000|OBP|2|-0.50 [-3.76, 2.76]| |Mehos, 2000|OBP|6|-10.10 [-24.43, 4.23]| |Rogers, 2001|24h-ABP|3|-4.80 [-9.43, -0.17]| |Broege, 2001|OBP|3|-2.00 [-27.52, 23.52]| |Rudd, 2004|OBP|6|-8.50 [-14.52, -2.48]| |Halme, 2005|OBP|6|-3.20 [-8.23, 1.83]| |Zillich, 2005|OBP|3|-4.50 [-11.70, 2.70]| |Marquez-Contreras, 2000|OBP|6|-4.50 [-8.91, -0.09]| |Verberk, 2007|OBP|12|0.50 [-4.75, 5.75]| |Kauric-Klein, 2007|OBP|3|-7.00 [-20.38, 6.38]| |Artinian, 2007|OBP|12|-4.00 [-10.22, 2.22]| |Tobe, 2008|OBP|1.5|-2.00 [-6.26, 2.26]| |Madsen, 2008|Day ABP|6|-2.30 [-6.10, 1.50]| |Green, 2008|OBP|12|-2.70 [-5.14, -0.26]| |Parati, 2009|OBP|6|-0.20 [-4.42, 4.02]| |da Silva, 2009|24h-ABP|6|-11.00 [-20.34, -1.66]| |DeJesus, 2009|OBP|6|-1.56 [-10.27, 7.15]| |Bosworth, 2009|OBP|24|-0.60 [-3.55, 2.35]| |Rinfret, 2009|24h-ABP|12|-4.80 [-7.57, -2.03]| |Godwin, 2010|24h-ABP|12|-0.30 [-4.24, 3.64]| |McManus, 2010|OBP|12|-5.50 [-8.79, -2.21]| |Varis, 2010|OBP|14|3.40 [-4.37, 11.17]| |Bosworth, 2011|OBP|18|-1.20 [-5.65, 3.25]| |Magid, 2011|OBP|6|-6.00 [-10.35, -1.65]| |Hebert, 2012|OBP|9|1.20 [-5.35, 7.75]| |Fuchs, 2012|OBP|3|-1.20 [-7.60, 5.20]| |Piette, 2012|OBP|1.5|-4.20 [-9.10, 0.70]| |Williams, 2012|OBP|9|-3.90 [-12.67, 4.87]| |Kerry, 2013|OBP|12|-2.40 [-6.89, 2.09]| |Magid, 2013|OBP|6|-12.40 [-16.25, -8.55]| |McKinstry, 2013|Day ABP|6|-4.08 [-6.39, -1.77]| |Margolis, 2013|OBP|12|-9.70 [-13.40, -6.00]| |Ogedegbe, 2014|OBP|12|-0.10 [-3.25, 3.05]| |Stewart, 2014|OBP|6|-5.30 [-10.60, -0.00]| |McManus, 2014|OBP|12|-8.80 [-12.70, -4.90]| |Hosseininasab, 2014|OBP|6|1.00 [-1.14, 3.14]| |Kim, 2014|OBP|12|-7.00 [-12.46, -1.54]| |Yi, 2015|OBP|9|-0.60 [-3.65, 2.45]| |Hanley, 2015|Day ABP|6|-6.40 [-17.14, 4.34]| |Aekplakorn, 2016|OBP|12|-2.50 [-7.25, 2.25]| |Kim, 2016|OBP|6|3.00 [-6.67, 12.67]| |Tzourio, 2017|OBP|24|-2.10 [-4.05, -0.15]| |Klarskov, 2018|OBP|10|-4.60 [-6.93, -2.27]| |Martinez, 2018|24h-ABP|24|-0.90 [-7.21, 5.41]| |McManus, 2018|OBP|12|-3.20 [-6.43, 0.03]| |Pan, 2018|OBP|6|-6.60 [-11.32, -1.88]| |Skolarus, 2018|OBP|6|3.10 [-8.42, 14.62]| |Cuffee, 2019|24h-ABP|3|-3.50 [-7.78, 0.78]| |Gu, 2020|OBP|12|0.10 [-4.90, 5.10]| |Oji, 2020|OBP|1|-6.00 [-13.07, 1.07]| |Zha, 2020|OBP|6|-3.60 [-8.83, 1.63]| |Ionov, 2021|OBP|3|-13.50 [-18.77, -8.23]| |McManus, 2021|OBP|12|-3.50 [-6.84, -0.16]| |Zhang, 2021|OBP|3|0.10 [-2.70, 2.90]| |Akl, 2021|OBP|1.5|1.90 [-4.78, 8.58]| |Margolis, 2022|OBP|12|-0.76 [-2.84, 1.32]| |Okoro, 2022|OBP|12|-2.73 [-12.47, 7.01]| |Muijsers, 2022|OBP|12|-5.60 [-10.54, -0.66]| |Calderon-Anyosa, 2023|OBP|12|-9.10 [-19.16, 0.96]| |Doogue, 2023|OBP|12|-17.20 [-32.44, -1.96]| |Hoppe, 2023|OBP|12|0.63 [-3.54, 4.80]| |Leupold, 2023|OBP|12|-5.60 [-9.09, -2.11]| |Martinez-Ibanez, 2023|OBP|12|-2.90 [-6.58, 0.78]| |Nejamis, 2023|OBP|3|2.45 [-0.98, 5.88]| |Ramos-Zavala, 2023|OBP|3|-5.80 [-10.22, -1.38]| |Pooled estimate ($1^2$ = 60.8%)|BP|3|-3.27 [-4.15, -2.40]| |BP was lowered in HBPM group|BP|20-15 -10 -5 0 5 10|BP was lowered in the usual care group $\rightarrow$| |BP was lowered in HBPM group|BP|20-15 -10 -5 0 5 10|20-15 -10 -5 0 5 10|

Y. Ohya

|First author, Year of publication|BP|Intervention period (months)|Difference in DBP change between groups [95%CI] (mmHg)| |---|---|---|---| |Vetter, 2000|OBP|2|-1.30 [-2.88, 0.28]| |Mehos, 2000|OBP|6|-6.70 [-19.22, 5.82]| |Rogers, 2001|24h-ABP|3|-4.10 [-7.20, -1.00]| |Broege, 2001|OBP|3|1.00 [-32.91, 34.91]| |Rudd, 2004|OBP|6|-3.10 [-6.12, -0.08]| |Halme, 2005|OBP|6|-1.50 [-3.95, 0.95]| |Zillich, 2005|OBP|3|-3.20 [-9.81, 3.41]| |Marquez-Contreras, 2000|OBP|6|-3.10 [-5.83, -0.37]| |Verberk, 2007|OBP|12|1.80 [-0.92, 4.52]| |Kauric-Klein, 2007|OBP|3|-1.00 [-8.87, 6.87]| |Artinian, 2007|OBP|12|-0.80 [-4.79, 3.19]| |Tobe, 2008|OBP|1.5|-1.00 [-4.52, 2.52]| |Madsen, 2008|Day ABP|6|-0.80 [-3.05, 1.45]| |Green, 2008|OBP|12|-0.80 [-2.14, 0.54]| |Parati, 2009|OBP|6|0.40 [-2.23, 3.03]| |da Silva, 2009|24h-ABP|6|-6.00 [-10.84, -1.16]| |DeJesus, 2009|OBP|6|1.58 [-3.68, 6.84]| |Bosworth, 2009|OBP|24|-1.20 [-2.85, 0.45]| |Rinfret, 2009|24h-ABP|12|-2.10 [-5.15, 0.95]| |Godwin, 2010|24h-ABP|12|-1.20 [-3.37, 0.97]| |McManus, 2010|OBP|12|-2.60 [-4.23, -0.97]| |Varis, 2010|OBP|14|2.40 [-1.54, 6.34]| |Bosworth, 2011|OBP|18|-0.50 [-3.15, 2.15]| |Magid, 2011|OBP|6|-2.30 [-4.65, 0.05]| |Hebert, 2012|OBP|9|-0.70 [-4.60, 3.20]| |Fuchs, 2012|OBP|3|-2.30 [-5.70, 1.10]| |Piette, 2012|OBP|1.5|-3.20 [-6.80, 0.40]| |Williams, 2012|OBP|9|0.85 [-3.22, 4.92]| |Kerry, 2013|OBP|12|-1.40 [-4.83, 2.03]| |Magid, 2013|OBP|6|-5.70 [-7.80, -3.60]| |McKinstry, 2013|Day ABP|6|-2.17 [-3.55, -0.79]| |Margolis, 2013|OBP|12|-5.10 [-7.40, -2.80]| |Ogedegbe, 2014|OBP|12|-0.70 [-2.09, 0.69]| |Stewart, 2014|OBP|6|-0.30 [-3.40, 2.80]| |McManus, 2014|OBP|12|-3.10 [-5.50, -0.70]| |Hosseininasab, 2014|OBP|6|-1.00 [-3.39, 1.39]| |Kim, 2014|OBP|12|-4.00 [-7.17, -0.83]| |Yi, 2015|OBP|9|-1.00 [-2.66, 0.66]| |Hanley, 2015|Day ABP|6|-3.20 [-10.44, 4.04]| |Aekplakorn, 2016|OBP|12|-1.20 [-4.45, 2.05]| |Kim, 2016|OBP|6|4.30 [-2.93, 11.53]| |Tzourio, 2017|OBP|24|-0.20 [-1.20, 0.80]| |Klarskov, 2018|OBP|10|-2.90 [-4.34, -1.46]| |Martinez, 2018|24h-ABP|24|-2.80 [-6.90, 1.30]| |McManus, 2018|OBP|12|-1.20 [-3.40, 1.00]| |Gu, 2018|OBP|6|-3.00 [-7.92, 1.92]| |Oji, 2020|OBP|1|0.90 [-5.71, 7.51]| |Zha, 2020|OBP|3|-2.00 [-8.42, 4.42]| |Ionov, 2021|OBP|3|-0.90 [-3.30, 1.50]| |McManus, 2021|OBP|12|-1.00 [-5.74, 3.74]| |Zhang, 2021|OBP|3|-0.56 [-9.20, 8.08]| |Akl, 2021|OBP|3|-5.90 [-8.89, -2.91]| |Margolis, 2022|OBP|12|-0.70 [-3.04, 1.64]| |Okoro, 2022|OBP|3|-0.20 [-1.95, 1.55]| |Muijsers, 2022|OBP|12|1.30 [-2.95, 5.55]| |Calderon-Anyosa, 2023|OBP|12|0.30 [-0.95, 1.55]| |Doogue, 2023|OBP|12|-0.54 [-6.11, 5.03]| |Hoppe, 2023|OBP|12|-5.00 [-8.39, -1.61]| |Leupold, 2023|OBP|12|-6.00 [-11.26, -0.74]| |Martinez-Ibanez, 2023|OBP|12|-4.40 [-25.34, 16.54]| |Nejamis, 2023|OBP|12|1.27 [-2.06, 4.60]| |Ramos-Zavala, 2023|OBP|12|-3.10 [-5.50, -0.70]| |Pooled estimate ($I^2$ = 46.7%)|||-1.10 [-3.19, 0.99]| |BP was lowered in HBPM group|||-0.38 [-2.02, 2.78]| |DP|DP|20-15 -10 -5 -0 5 10|0.38 [-7.50, -1.50]| |DP|DP|20-15 -10 -5 -0 5 10|0.38 [-2.02, 2.78]|

The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and...

long-term risk of death and events is not apparent. In addition, only two studies reported the effects of HBPM in non-hypertensive individuals, and those studies were conducted in patients with chronic kidney disease or previous pregnancy-induced hypertension. Therefore, further research is needed on HBPM in the long-term prevention of hypertension.

Literature search

Eleven SR committee members independently conducted literature searches in PubMed, Ichushi-Web, and the Cochrane Library, with 4378 studies selected for primary screening (title and abstract). This was followed by a secondary screening (full text) of 364 studies, excluding 4014 studies that met the exclusion criteria. A meta-analysis was conducted using the resulting 65 studies that met the CQ.

Chapter 6. Principles of management and treatment

[POINT 6a: Purpose and target population]

1. Antihypertensive treatment reduces mortality/risk to quality of life (QOL) caused by the incidence/ progression/recurrence of CVD. 2. All individuals presenting with a BP of ≥120/80 mmHg should be considered for BP management.

1. Purpose

The purpose of hypertension treatment is to reduce the incidence/progression/recurrence of CVD and the risk of death from CVD caused by persistent hypertension, and to help hypertensive individuals lead healthier daily lives with a high QOL. According to the meta-analysis of BP lowering drug treatment conducted by Blood Pressure Lowering Treatment Trials' Collaboration (BPLTTC), when SBP is reduced by 5 mmHg, the RRs of major cardiovascular events are reduced by 10%, stroke 13%, heart failure 13%, ischemic heart disease 8%, and cardiovascular death 5% [304]. These RR reductions are similar, regardless of age (at least up to 84 years old), gender, with/without a history of CVD, as well as the presence or absence of other comorbidities [100, 304–313]. These are similar for every level of BP, including not only hypertension but also high-normal BP/elevated BP.

Antihypertensive treatment is generally well tolerated, thus it can be used to reduce deaths and CVD with few side effects or adverse events [314]. However, some adverse events caused by antihypertensive treatment can occur, if the patients have sudden/excessive hypotension, orthostatic

hypotension, co-morbidities or complications including vascular stiffness/baroreflex abnormalities/stenosis of vital organ arteries/CKD, changes in living environment (temperature, humidity), and sick days, such as dehydration/ anorexia/vomiting/diarrhea. These individual conditions can induce adverse events including cerebral ischemic symptoms (dizziness, lightheadedness, dizziness, fainting, and syncope), decreased kidney function (especially acute kidney injury), and electrolyte abnormalities [183, 314, 315].

Therefore, we recommend individualized care to achieve the final target BP level by fine-tuning the rate and level of antihypertensive treatment with attention paid to subjective symptoms/out of office BP/laboratory findings, in order to avoid or minimize the risk of adverse events and side effects. Overall, regardless of age, gender, BP level, and background factors, it is important to maximize the benefits of antihypertensive treatment to reduce the incidence/progression/recurrence of CVD, and the risk of death from CVD.

2. Target population

The target population for BP treatment includes hypertensive individuals of all ages. HYVET, STEP, and meta-analysis have demonstrated reductions in CVD and all-cause mortality in very old adults with BP management [305, 316, 317]. In individuals with BP levels ≥120/80 mmHg, BP should be managed through non-pharmacologic therapy, such as lifestyle modifications, to prevent pro-gression to hypertension, maintain normotension, and reduce the risk of CVD in high-normal BP/elevated BP individuals. Pharmacologic therapy should also be con-sidered for high-risk elevated BP.

There is a large absolute risk reduction (risk difference) with antihypertensive treatment for high-risk patients based on substantial evidence from many clinical trials with high-risk patients. The absolute risk reduction for younger, middle-aged, and low risk patients is smaller, the effect of short-term treatment in reducing CVD is less apparent, and evidence from clinical studies is limited. However, the RR reductions are comparable [100, 304, 305, 308], suggesting a similar need for antihypertensive treatment. Due to the evidence of treatment efficacy in high-risk patients, treatment planning for elevated BP and low-to-moderate risk hypertensives should be carried out (with consideration to cost-effectiveness).

For white coat hypertension, drug treatment for BP should not be given. Explain the high likelihood of developing hypertension in the future, instruct patients on HBPM and lifestyle modifications, and conduct regular follow-up examinations.

[POINT 6b: Initial visit – Management plan, risk and disease assessment]

Y. Ohya

1. For the initial visit of a hypertensive patient, confirm that BP is persistently high, assess the level of BP, exclude secondary hypertension, and evaluate prognostic factors (risk factors, organ damage, CVD). 2. For a level of BP higher than elevated BP (≥130/80 mmHg), the risk of CVD is assessed as high, intermediate, or low, according to BP levels and other prognostic factors.

2. For a level of BP higher than elevated BP (≥130/80 mmHg), the risk of CVD is assessed as high, intermediate, or low, according to BP levels and other prognostic factors.

4. For Elevated BP (≥130/80 mmHg) with high risk and hypertensive individuals (≥140/90 mmHg), encourage planned lifestyle modifications and initiate antihyperative drug treatment if necessary.

5. For high risk hypertensive individuals (≥140/90 mmHg), initiate antihypertensive drug treatment (pharmacotherapy) without delay and start planned lifestyle interventions.

3. Risk and disease assessment

1) BP level

In daily medical practice, when office BP is high during the initial visit (except for a hypertensive emergency), check if BP is continuously high by measuring office BP again on another day, using the recent BP data at the medical checkup, and measuring home BP. Additionally, with HBPM, check for white coat hypertension, white coat phenomenon, and masked hypertension. If white coat hypertension or masked hypertension is suspected, or if large BP variability is expected, consider evaluation using 24-h ABPM. Office BP is used for risk assessment and management of hypertension. However, if there is a significant difference between office BP and home BP or ABPM readings, it is appropriate to judge with a strong emphasis on home BP and ABPM (see "Chapter 5, 2. Diagnosis of hypertension"). Using an HBPM that automatically records the measurements or an app that transmits data to a smartphone or other device, can be helpful for accurate evaluation.

2) CVD, organ damage, risk factors

Evidence from Japan indicates that risk factors for the development of CVD other than BP level include advanced age, gender (man), smoking, diabetes mellitus, dyslipidemia, chronic kidney disease (CKD), and obesity [4, 58–60, 174, 318–323]. Also the presence of atrial fibrillation as a comorbidity is a large contributing factor for the onset of stroke [4, 324]. For the assessment of organ damage associated with prognosis, left ventricular hypertrophy (electrocardiogram) [325–328], proteinuria (including albuminuria in diabetic patients) [329–331], and decreased eGFR [322, 323, 332] should be regarded, as they have a clear prognostic connection which is evident in a Japanese cohort, and they are simple to evaluate in daily medical

practice by general practitioners. Increased arterial stiffness (increased PWV), arteriosclerosis obliterans, and plaque or stenosis of the carotid artery are also indicators of organ damage and should be used as a reference for risk assessment when appropriate (see "Chapter 9. Diagnosis of Hypertension-Mediated Organ Damage and Treatment of Hypertension"). For the assessment of CVD, use diagnostically confirmed conditions, such as stroke (hemorrhagic stroke, ischemic stroke), coronary artery disease (myocardial infarction, angina pectoris, post coronary revascularization), and heart failure.

3) Risk classification

The assessment of risk of CVD in European and American guidelines is based on absolute risk obtained from cohort studies in Europe and the United States [333–336]. Therefore, the risk of developing coronary artery disease is more heavily weighted than the risk of stroke. In Japan, where strokes are more common, it is desirable to evaluate the overall risk of CVD, based on the Japanese population.

The basic policy of the risk assessment for CVD in the guidelines was to use the evidence from Japan. Absolute risk was calculated based on risk factors and used as a reference for risk stratification. Prognostic factors used for risk classification, in addition to BP level, were: age (≥65 years), gender (man), smoking, dyslipidemia, diabetes mellitus, hemorrhagic stroke, ischemic stroke, myocardial infarction, atrial fibrillation, and proteinuria (shown in bold in Table 6-1). Cohort studies have reported a BP-dependent increase in the risk of stroke, arterial embolism and all-cause mortality in patients with atrial fibrillation [337, 338]. That is why JSH2019 and JSH2025 address atrial fibrillation as an organ damage, which occurs due to aging and hypertension. Obesity and low eGFR were not used for risk classification, as they were not detected with any significance in the development of composite CVD events in the JALS [4] and Hisayama [339] studies.

Concrete examples of risk assessment policy for CVD are as follows:

a) Cases of CVD are high risk and secondary measures should be considered, b) If the patient has atrial fibrillation, they are also considered high risk, c) CKD with proteinuria and diabetes mellitus are considered high risk. End-stage kidney disease is high risk, but the hypertension treatment is different from other diseases, thus it is not discussed here (see "Chapter 9, Section 3. Kidney Disease"). d) For other patients, the absolute risk score is calculated for the occurrence of a composite CVD event. JALS [4] and Hisayama [339] studies are used for reference in risk assessment. The calculation of absolute risk in d) is not always easy in daily practice, the risk classification table (Table 6-2) classifies patients into low, intermediate, and high risk, reflecting the assessments of a) to d) above.

The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and...

Table 6-1 CVD prognostic factors

A. Non-BP level risk factors for CVD development

Advanced age (≥65 years)

Man

Smoking

Dyslipidemia^a

Hyper-LDL-cholesterolemia (≥140 mg/dL) Hypo-HDL-cholesterolemia (<40 mg/dL) Hypertriglyceridemia (≥150 mg/dL)

Obesity (BMI ≥25 kg/m$^{2}$) (especially visceral fat-type obesity)

Family history of juvenile CVD (<50 years)

Diabetes mellitus

Fasting blood glucose ≥126 mg/dL 75 g OGTT 2-hour value ≥200 mg/dL Casual blood glucose ≥200 mg/dL HbA₁C ≥6.5% (NGSP)

B. Organ damage/CVDs

Brain

Hemorrhagic stroke/ischemic stroke

Transient ischemic attack

Left ventricular hypertrophy (electrocardiogram and echocardiography) Angina pectoris, myocardial infarction, or after coronary revascularization Heart failure

Atrial fibrillation

Proteinuria

Low eGFR^b (<60 mL/min/1.73 m²)

Chronic kidney disease (CKD)

Macrovascular disease

Peripheral arterial disease (ABI ≤ 0.9)

Atherosclerotic plaque

Increased PWV (baPWV ≥18 m/s, cfPWV ≥10 m/s)

Increased cardiac ankle vascular index (CAVI ≥9.0)

Ocular fundus

Hypertensive retinopathy

Prognostic factors used for risk stratification are shown in bold

$^{a}$Non-HDL cholesterol (total cholesterol - HDL cholesterol) is used when blood is collected after meals, or the triglyceride is ≥400 mg/dL.ao

$^{b}$The eGFR is calculated using the following formula with serum creatinine (eGFRcreat). When the muscular volume is extremely small, the following formula with serum cystatin C (eGFRcys) is more appropriate

$$eGFRcreat (mL/min/1.73 m^2) = 194 \times Cr^{-1.094} \times \text{Age}^{-0.287} \times (0.739 \text{ for women})$$

$$ \text{eGFRcys (mL/min/1.73 m^2)} = (104 \times \text{Cys}^{-1.019} \times 0.996^{\text{age}} \times (0.929 \text{ for women}) - 8 $$

In Table 6-2, the first tier of risk is defined as the absence of prognostic factors other than the level of BP; the second tier of risk is age (>65 years), gender (man), dyslipidemia, or smoking, but no history of CVD, atrial fibrillation, diabetes, or CKD with proteinuria; the third tier of risk is defined as having a history of CVD, atrial fibrillation, diabetes mellitus, CKD with proteinuria, or those with three or more risk factors of the second risk stratum. In each risk stratum, patients were classified into three groups (taking into account the office BP level): low, intermediate, and high risk.

Each risk level was verified using actual data from JALS. The risk levels assigned to each column do not significantly deviate from CVD risk levels determined based on incidence rates calculated from the risk scores [4]. However, the final evaluation of each patient's risk is made by the primary doctor, including the presence or

absence of other prognostic factors such as BP level and organ damage.

The absolute risk is not necessarily higher in young and middle aged patients even if they have risk factors, since age makes a large contribution to absolute risk [4, 339]. Therefore, it is advisable to re-evaluate the risk for low and intermediate risk patients after about 3–5 years. In addition, in order to improve patient awareness of the benefit from lifestyle modifications, it may be useful to evaluate the lifetime risk of the disease [15, 16] and the RR in low and intermediate risk patients. However, the evidence for life-time risk calculation in Japan is limited.

4. Management plan: initial visit

Management plan for the initial visit of a hypertensive patient: 1) Confirm that BP is persistently high and assess

Y. Ohya

Table 6-2 Office BP-based classification of risk of CVD

|Classification of BP Risk Category|Elevated BP 130-139/80-89 mmHg|Grade I hypertension 140-159/90-99 mmHg|Grade II hypertension 160-179/100-109 mmHg|Grade III hypertension ≥180/10 mmHg| |---|---|---|---|---| |Category I No prognostic factor|Low risk|Low risk|Moderate risk|High risk| |Category II At least one of age (≥65), sex (man), dyslipidemia and smoking|Moderate risk|Moderate risk|High risk|High risk| |Category III At least one of CVD, atrial fibrillation, diabetes mellitus, and CKD with proteinuria, or 3 or more of Category II risk factors|High risk|High risk|High risk|High risk|

Risk of CVD was classified based on the combination of prognostic factors with reference to the absolute risk yielded from the JALS score and the Hisayama score

The prognostic factors used for classification are: BP, age (≥65), sex (man), dyslipidemia, smoking, history of CVD (hemorrhagic stroke, ischemic stroke, myocardial infarction), atrial fibrillation, diabetes mellitus and CKD with proteinuria

 Fig. 6-1 Hypertension management planning and initial visit BP. If a patient presents because of a recommendation from a health checkup, confirm whether their BP is still elevated and follow the flowchart. $^{*1}$ Planned lifestyle modification refers to the formulation of a specific treatment plan with the patient's consent, including future treatment goals (e.g., target BP) and lifestyle precautions, with treatment plan based comprehensive lifestyle-related management. $^{*2}$ If hypertension has been previously confirmed and lifestyle modification has been explained, starting of drug therapy may be considered, even if it is the first visit

the level of BP, 2) Rule out secondary hypertension, 3) Evaluate features that may affect the prognosis, such as risk factors, organ damage, and CVD, 4) Give instructions for lifestyle modification, and 5) Evaluate the need for pharmacologic therapy. These are performed sequentially or in parallel, as needed.

1) Confirmation of persistence of BP levels and evaluation of their level

Confirm the persistence of high BP levels and evaluate their levels as detailed in section 3. 1 of this chapter, BP Levels.

2) Ruling out secondary hypertension

Hypertension caused by one specific condition is called as secondary hypertension. The most common causes of secondary hypertension include renal parenchymal hypertension, PA, renal vascular hypertension, and sleep apnea syndrome. Based on patient history, examination findings,

and the general clinical examination, these diseases should be suspected and screened for. If necessary, the patient should be referred to a specialist or undergo the necessary specific diagnostic tests. For details, refer to "Chapter 15, Secondary hypertension".

3) Evaluation of prognostic factors

Search for the presence of risk factors of CVD other than hypertension and organ damage/CVD (see "Section 3, Risk and disease assessment" in this chapter). For elevated BP and hypertension, CVD risk is assessed based on risk factors and organ damage/CVD (Table 6-2). A management plan for hypertension (Fig. 6-1) should be developed according to office BP and CVD risk.

4) Lifestyle assessment

Lifestyle modification is recommended for all but normal BP. Planned lifestyle modification is instructed for those

The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and...

with BP levels of 130/80 mmHg or higher. This refers to the development of a specific treatment plan, formulated with the patient's consent, that includes future therapeutic goals (e.g., target BP) and lifestyle-related precautions, followed by comprehensive lifestyle management based on the treatment plan.

5) Evaluation of the need for drug therapy

In addition to the principles of target BP in anti-hypertensive treatment (see "Section 5. Target BP" in this chapter), the timing of initiation and dosage of anti-hypertensive drug, and the rate of BP reduction should be determined by considering the individual characteristics of the patient. The treatment plan should be made through shared decision-making with the patient.

Figure 6-1 shows the hypertension management plan at the initial visit for CVD free individuals. For those with normal BP (<120/80 mmHg), an appropriate lifestyle is recommended. For those with high-normal BP (120-129/<80 mmHg), instructions for lifestyle modification should be conducted and continued. BP levels should be reassessed after 1 year and 3-6 months for normal BP and high-normal BP, respectively. Elevated BP (130-139/80-89 mmHg) individuals with low and intermediate risk should try a planned lifestyle modification, and if sufficient BP reduction is not achieved within 3 months, planned lifestyle modification should be rigorously reinforced. Elevated BP (130-139/80-89 mmHg) individuals with a high risk should try a planned lifestyle modification. Individuals with hypertension (≥140/90 mmHg), with low and intermediate risk should introduce a planned and rigorous modification in lifestyle. Both should reassess BP within one month, and if sufficient BP reduction (<130/80 mmHg in principle) is not achieved, antihypertensive drug therapy should be initiated in addition to the reinforcement of planned lifestyle modification.

In high-risk patients with hypertension (≥140/90 mmHg), antihypertensive drug therapy (pharmacotherapy) should be started immediately, in addition to planned and rigorous lifestyle modification. In clinical practice, patients should be cautious of adverse events during the initial period of antihypertensive drug therapy, and pay attention to the rate of the reduction in BP whilst aiming towards the target BP.

Patients with a history of CVD are at high risk, and planned lifestyle interventions (lifestyle modifications) should be implemented for all BP levels. In addition, antihypertensive drug therapy should be started as early as possible with reference to the target of BP 130/80 mmHg. In addition, treatments for secondary prevention other than antihypertensive therapy (e.g., treatment of dyslipidemia, diabetes mellitus, smoking cessation, antithrombotic therapy, etc.) should also be reliably implemented.

[POINT 6c]

[BP targets]

1. As a rule, target BP should be SBP <130 mmHg. However, attention should be paid to the possibility of adverse events, such as acute kidney injury and symptomatic hypotension.

2. If SBP is lowered to <120 mmHg, be aware of possible adverse events due to excessive hypotension.

[Principles of treatment]

1. All hypertensive patients should be given the instructions for lifestyle modification, regardless of their BP level and whether or not they are taking antihypertensive drugs.

2. In principle, once daily antihypertensive drugs should be the mainstay of treatment, and combination therapy with appropriate antihypertensive drugs should be used to increase the effect while avoiding side effects. If aiming to reduce BP by 20/10 mmHg or more, consider combination therapy from the start.

3. In order to continue antihypertensive treatment, it is important to maintain adequate communication and to provide medical care based on shared decision making (SDM), and to improve QOL.

5. Target BP (Table 6-3)

In a follow-up study [340] examining the relationship between BP and cardiovascular death, the risk of stroke and ischemic heart disease mortality increased as BP elevated, in a wide age range from 40 to 89 years; this relationship continued not only with hypertension but also in the normal BP down to a level of about 115/75 mmHg. Therefore, we recommend lifestyle modification as described in Chapter 7, regardless of BP levels, to improve the health of the population.

In intervention trials of uncomplicated hypertensive patients, the prognostic benefit of lowering SBP to <130 mmHg was not clear [341], but there were significant reductions of CVD events with hypertensive patients,

Table 6-3 Target BP

Office BP <130/80 mmHg

Home BP <125/75 mmHg

* For individuals with elevated BP (130-139/80-89 mmHg) at low to moderate CVD risk (without organ damage or diabetes mellitus), lifestyle modification should be intensified

* During lowering BP, pay attention to possible adverse events such as symptomatic hypotension (dizziness, lightheadedness, postural hypotension, fatigue, syncope), orthostatic hypotension, acute kidney injury, or electrolyte abnormalities (hyperkalemia)

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including those aged 75 years or older, treated with anti-hypertensive therapy with a target of <120 or 130 mmHg in SPRINT [342] and STEP [317]. A meta-analysis including these studies, found that lowering BP to <130/80 mmHg significantly reduced CVD events [100, 343]. The results of an SR and meta-analysis, conducted to develop JSH2025, showed that in adults with hypertension (CQ4), patients with prior stroke (CQ8), hypertension associated with diabetes mellitus (CQ12), and hypertension in older adults aged ≥75 years (CQ14), lowering BP to a target SBP of less than 130 mmHg or 130/80 mmHg significantly reduced CVD events compared to lowering BP to a higher target. In heart failure with preserved left ventricular systolic contractility (CQ9), lowering BP to a target SBP of <130 mmHg significantly reduced heart failure hospitalizations compared with lowering BP to a higher target SBP. In CKD-associated hypertension (CQ10), lowering the target SBP to <130 mmHg tended to reduce all-cause mortality compared with lowering the target SBP to ≥130 mmHg (P=0.051). In contrast, regarding hypotension, an SBP aim of less than 130 mmHg resulted in an increase in symptomatic hypotension and acute kidney injury (CQ4).

There were no serious adverse events related to old age, pathological conditions and complications, which was a similar finding in all the studies (CQ8, 9, 10, 12, 14). Based on these findings, JSH2025 has set the target for lowering office BP to less than 130/80 mmHg, regardless of age, medical condition, or co-morbidities. However, it is important to proceed with BP reduction with caution, paying attention to the possible development of adverse events such as symptomatic hypotension (dizziness, light-headedness, presyncope, syncope, fatigue, etc.), orthostatic hypotension, acute kidney injury, and electrolyte abnormalities (hyperkalemia, etc.). In cases of elevated BP (130-139/80-89 mmHg) individuals at low to moderate risk with or without organ damage or diabetes mellitus, intervention should be through reinforcement of lifestyle modification, taking into consideration the cost/health benefits.

The target for home BP should be <125/75 mmHg based on the results of HOMED-BP [278, 302] and HONEST [344] in Japan (Table 6-3).

Both during and after achieving antihypertensive goals, be aware of the risk of excessive BP reduction. This is more likely to occur based on the level of target BP, but it can also occur from an increased speed and range of BP reduction, as well as a change in the patient's condition. Therefore, there is a need to decide on a case-by-case basis. Prospective clinical trials have not been conducted to investigate the BP levels at which a dose has resulted in excessive BP reduction. A retrospective study examined the relationship between BP levels achieved by intervention and the occurrence of events or adverse events and found an increase in death, stroke, and a decline in renal function for hypertensive patients with SBP lowered to below 120 mmHg [345]. The results of such retrospective analysis of lowered BP may be caused by a reversal of cause and effect. An RCT examining antihypertensive drugs with individual participant-level data, showed that the trend in the reduction of CVD events was the same between subjects with a BP reduction of 5 mmHg and subjects with a baseline SBP of <120 mmHg [304, 305]. In conclusion, when SBP is lowered to less than 120 mmHg, particular attention should be paid to adverse events. The decision of whether adverse events are due to an excessive BP reduction should be made on an individual basis.

6. Principle of treatment

Genetic predisposition and environmental factors are involved in the development and progression of essential hypertension. Therefore, treatment must include lifestyle modification (non-pharmacological therapy), which resolves many the environmental factors. However, few patients can achieve target BP levels with this alone, and most patients require drug therapy. Evaluate the individual patient's BP level, comorbidities, history, and risk factors for CVD (Table 6-1). Then comprehensively assess the risk (Table 6-2) and establish an appropriate treatment plan (Fig. 6-1).

1) Lifestyle modification

Hypertension is a lifestyle-related disease, and a modification in lifestyle can be expected to prevent hypertension

Table 6-4 Components of shared decision making (SDM) for the continuation of treatment

The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and...

and reduce BP [346–348]. Regardless of BP levels, promoting a healthy lifestyle is recommended. Lifestyle modification is a significant treatment method and a safe and cost-effective way for reducing risk factors, especially when combined with comorbidities such as dyslipidemia, diabetes mellitus, metabolic syndrome, and obesity. The doctor and patient will need to continue their efforts for a long time in order to maintain the antihypertensive effect of lifestyle modifications [349].

Many hypertensive patients are not able to achieve the target BP solely by lifestyle modification, but even after the start of BP-lowering drugs, lifestyle modification is still important. In fact, lifestyle modification does increase the efficacy of drugs and can reduce the frequency and dosage [350, 351]. The details of lifestyle modification are discussed in Chapter 7.

2) Drug therapy

Many hypertensive patients require drug therapy. Currently, the major antihypertensive drugs widely used are Ca channel blockers (CCBs), RAS inhibitors (ARB, ACE inhibitors), thiazide diuretics (including thiazide analogues), β-blockers, angiotensin receptor-neprilysin inhibitor (ARNI), MR blockers. In addition, depending on the patient's clinical condition, αβ-blockers, central sympatho-mimetics, hydralazine, and other agents may be added (see Chapter 8).

Points regarding the administration of antihypertensive drugs: (1) Priority should be given to once-daily drugs. (2) For patients at the initial visit with grade II or III hypertension (160/100 mmHg or higher) or high-risk grade I hypertension (140-159/90-99 mmHg), combination therapy should be considered from the beginning. (3) Appropriate combinations should be used to increase the antihypertensive effect without causing side effects. (4) If the effect of the administered antihypertensive drug is small or is not well tolerated (such as when side effects interfere with continued use), change to a drug with a different mechanism of action. (5) Take into account the comorbidities and disease status when selecting the appropriate antihypertensive drug. Also consider contraindications and clinical conditions requiring caution, while taking into account the interactions with concomitant drugs other than antihypertensive drugs.

3) Promotion of SDM

Since hypertension has few subjective symptoms, it is important to maintain good communication between the patient and the medical staff team. This includes doctors, nurses, pharmacists, registered dietitians, and nutritionists, in order to continue antihypertensive treatment for a long period of time. During this process, the patient should be made aware of the risks of developing CVD due to hypertension and the treatment options and benefits as well as possible disadvantages of treatment. Then after careful

discussion with the patient, the treatment should be selected, with respect to patient's wishes [352, 353]. The main points of the practice of using such information sharing and SDM are shown in Table 6-4.

QOL of hypertensive patients is objectively and comprehensively evaluated in terms of comfort, satisfaction with life, physical symptoms, sexual function, intellectual function, work efficiency, social activity status, and emotional state. Although treating hypertension improves the patient's QOL, antihypertensive medications can have side effects which can be a factor that worsens QOL. In addition, the raising of the patient's awareness of hypertension and eliminating their doubts and concerns improves QOL [354].

Thus, proceeding with treatment by SDM and maintaining the patient's QOL are effective in avoiding clinical inertia and discontinuation, non-compliance or dropout of treatment.

[POINT 6d]

[Digital health technologies for telemedicine and health guidance]

1. Suggest the use of digital technology for health guidance and telemedicine, such as smartphone applications and text messages for BP control in adults.

7. Digital health technologies for telemedicine and health guidance

Telemedicine and health guidance using digital technologies such as smartphone applications and text messages for BP management have several advantages and recent technological advancements are developing more effective methods [355–357]. An SR was conducted for the CQ on whether the use of such technology is useful for BP control in adults (see CQ5) [358]. The results showed that the use of digital technology in addition to standard healthcare (normal advice and treatment), significantly reduced BP in adults without increasing adverse events (see CQ5). Although this is not the only evidence in favor of online or telemedicine, this does not demonstrate it is a superior treatment for improving prognosis. Appropriate use of digital technology can reduce the frequency of hospital visits, making it convenient and cost effective. Digital health technologies are valuable not only for hypertensive patients and adults in general, but also for residents of remote areas, islands and other areas with limited access to healthcare or patients who have difficulty making hospital visits. However, there are issues to be addressed, such as privacy protection, data security, and instructing those unfamiliar with digital technology. It should be noted that patients who are at risk for acute pathological changes may require face-to-face consultations and periodic examinations

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by doctors. It is necessary to design an appropriate tele-medicine system to resolve these issues.

[POINT 6e]

[Cost-effectiveness]

1. Economic evaluations of healthcare are performed from a population perspective, such as public healthcare. If the effectiveness remains equivalent but costs are reduced, the decision will be the same whether from a population or an individual perspective. However, if the effectiveness is improved but the cost is increased, the decision will be difficult.

2. Treating hypertension with antihypertensive medication is considered cost-effective, and the results of overseas studies suggest that the cost-effectiveness of intensive antihypertensive treatment is also good.

3. The digital therapy for hypertension may also be cost-effective to encourage compliance and a healthy lifestyle.

3. The digital therapy for hypertension may also be cost-effective to encourage compliance and a healthy lifestyle.

8. Cost-effectiveness

Economic evaluation of healthcare, analyzing the cost-effectiveness of healthcare technologies, is attracting attention as a means of ensuring the efficient use of healthcare expenses, and also human and physical healthcare resources. From April 2019, the Central Social Insurance Medical Council (Chuikyo) began evaluating the cost-effectiveness of pharmaceuticals and medical devices. The evaluation of 41 items began at the end of FY2023 [359]. Antihypertensive drugs have never been listed for formal health economic evaluation. This is because selection priority is typically given to drugs with a large market share and new drugs commanding a premium price.

A chapter on the use of health economic evaluation, was established in the Minds Manual for Clinical Practice Guideline Development 2020 [360]. In that chapter the

importance of distinguishing between the perspective of individual patients and that of a population, such as the healthcare system or society, was pointed out. The objectives of maximizing treatment benefit relative to healthcare costs and resources differ substantially between individual patients and populations. In the economic evaluation of healthcare, analysis is often conducted from a population perspective. However, the two objectives may sometimes coincide in the case of an economic evaluation decision. This is when multiple medical technologies have similar "net outcomes" in terms of benefit and harm to patients. For example, if a generic drug and a new drug have similar "net outcomes", the least expensive one is recommended.

There has been no SR conducted on the cost-effectiveness of antihypertensive drugs since JSH 2019. The 2019 UK NICE guideline “Hypertension in adults: diagnosis and management” reported cost-effectiveness estimates consistent with those of the 2011 guideline, providing robust evidence of favorable cost-effectiveness [361]. The ESH 2023 Clinical Practice Guidelines noted that there is general agreement that the cost-effectiveness of antihypertensive drugs is favorable [183].

Regarding the cost-effectiveness of intensive anti-hypertensive treatment based on SPRINT results, there have been two reports published since JSH2019, from East Asian countries that, like Japan, have a universal health insurance system. A Korean study analyzed adherence to anti-hypertensive drugs under scenarios ranging from 50% to 62.5%. Even in the lowest-adherence scenario, the incremental cost-effectiveness ratio (ICER) was $4327/QALY, indicating favorable cost-effectiveness [362]. A Taiwanese study analyzed the data according to age, reporting ICERs of $12,487/QALY for those aged 70 and over (lowest) and $22,507/QALY for those in their 40s (highest), showing favorable cost-effectiveness [363].

There have been no new Japanese studies since JSH2019 on the cost-effectiveness of antihypertensive

Fig. CQ4-1 CVD Events (target SBP: <130 mmHg vs. ≥130 mmHg). (Adapted from ref. [375])

|Study|Intensive arm Events|Intensive arm Events|Standard Events|Standard Events|Armin|Armin|Right|RR [95% CI]| |---|---|---|---|---|---|---|---|---| |Study|Events|Total|Events|Total|Weight|88|Right|RR [95% CI]| |SPRINT|264|4678|354|4683|19.4%|0.75|0.64; 0.87|| |ACCORD|208|2362|237|2371|15.0%|0.88|0.74; 1.05|| |ESPRIT|547|5624|623|5631|35.7%|0.88|0.79; 0.98|| |Cardio-Sis|17|558|32|553|1.5%|0.53|0.30; 0.94|| |HOMED-BP|26|1759|25|1759|1.7%|1.04|0.60; 1.79|| |RESPECT|46|633|59|630|3.6%|0.78|0.54; 1.12|| |STEP|147|4243|196|4268|10.9%|0.75|0.61; 0.93|| |SPS3|160|1501|188|1519|12.1%|0.86|0.71; 1.05||

Total (95% CI) 1415 21358 1714 2141 100.0% 0.83 [0.76; 0.90] Heterogeneity: $Tau^{2}$<0.0|, $Chi^{2}$=7.43, $df$=7 (P=0.39); $I^{2}$=6%[0%; 69%]

0,25 0,5 1 2 Strict control better Standard control better

The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and...

|Study|Intensive arm Events|Intensive arm Events|Standard Events|Standard Events|Standard Events|Standard Events|Weight|RR [95% CI]|Risk for cardiovascular death| |---|---|---|---|---|---|---|---|---|---| |Study|Intensive arm Events|Intensive arm Events|||||||| |SPRINT|41|4678|71|4683|21.0%||0.58 [0.39; 0.85]||| |ACCORD|60|2362|58|2371|23.2%||1.4 [0, 73; 1.48]||| |ESPRIT|59|5624|97|5631|26.6%||0.61 [0.44; 0.84]||| |HOMED-BP|3|1759|5|1759|2.1%||0.60 [0.14; 2.51]||| |STEP|18|4243|25|4268|10.2%||0.72 [0.40; 1.33]||| |SPS3|36|1501|41|1519|17.0%||0.89 [0.57; 1.38]||| ||||||||||| |Total (95% CI)|217|20167|297|20231|100.0%||0.74 [0.56; 0.97]||| |Heterogeneity : Tau²=0,02, Chi²=7,23, df=5(P=0,20); Γ²=31%[0%; 72%]|||||||||| ||||||||||| ||||||||||| ||||||||||| ||||||||||| ||||||||||| ||||||||||| ||||||||||| ||||||||||| ||||||||||| ||||||||||| ||||||||||| ||||||||||| ||||||||||| ||||||||||| ||||||||||| |||||||<start>6<c||||

drugs. However, a study evaluating digital therapy was conducted based on the HERB-DH1 trial [364]. Using a Markov model, the study compared lifetime cost-effectiveness of standard lifestyle guidance (control group) with that of standard lifestyle guidance plus digital therapy. The base-case model assumed a 25% dropout rate every six months and a digital therapy cost of 10,000 yen per month, yielding an ICER of 1,199,880 yen/QALY, indicative of favorable cost-effectiveness. The parameters most influential on results were the dropout rate and the cost of digital therapy. However, dropout rates above 25% and attenuation of treatment effect were not examined.

Antihypertensive treatment in Japan focuses on home BP with ARBs, ACE inhibitors, CCBs, and thiazide diuretics, and previous studies have suggested that they are cost-effective. The cost-effectiveness of antihypertensive therapy is expected to improve further in the current context, where generic drugs dominate daily practice. When significant evidence on antihypertensive therapy emerges in the future, cost-effectiveness should continue to be examined, in line with the actual clinical practice in Japan.

CQ 4 In adult hypertensive patients, does anti-hypertensive treatment with a target SBP of <130 mm Hg reduce the incidence of, and death from, CVD?

$\blacktriangleright$ In adult hypertensive patients, antihypertensive treatment targeting an SBP of <130 mmHg is strongly recommended. However, it is necessary to be aware of possible adverse events such as acute kidney injury and symptomatic hypotension.

[Strength of Recommendation – 1, Strength of Evidence – A, Rate of agreement – 100%]

Summary of evidence

Eight RCTs compared antihypertensive treatment targeting SBP of <130 mmHg in adults aged ≥18 years. As primary outcomes, CVD events, cardiovascular death, all cause mortality, cognitive impairment, hypotension,

syncope, falls with trauma, acute kidney injury, composite kidney events, and serious adverse events were selected. There were four studies on high-risk hypertension [365–368], one study on elderly hypertension [317, 369–372], two studies on secondary prevention of CVD [373, 374], and one antihypertensive study using HBPM as an indicator [278, 375].

Regarding the value of antihypertensive treatment against these outcomes, the overall evidence was strong for CVD events, moderate for cardiovascular death, all-cause mortality, cognitive impairment, hypotension, syn-cope, falls with trauma, and acute kidney injury, and weak for combined renal events and serious adverse events.

Commentary

1) CVD events

Antihypertensive treatment targeting SBP <130 mmHg significantly reduced the incidence of CVD by 17% compared with antihypertensive treatment targeting SBP ≥130 mmHg (RR 0.83 [95% CI 0.76 to 0.90], eight trials) (Fig. CQ4-1) [278, 317, 365–368, 373, 374]. Heterogeneity was low ($I^2$ = 6%). In sub-analysis according to the target SBP of antihypertensive treatment, the incidence of CVD was reduced by 16% (RR 0.84 [95% CI 0.73 to 0.96]) for target SBP <120 mmHg [365–367, 373], 20% (RR 0.80 [95% CI 0.59 to 1.07]) for <130 mmHg [278, 317, 368, 374], and 33% (RR 0.67 [95%CI 0.28 to 1.62]) for <140 mmHg [369–372]. There was no interaction effect in the reduction of CVD events ($P$ = 0.67).

2) CVD deaths

Antihypertensive treatment targeting SBP <130 mmHg significantly reduced CVD mortality by 26% (RR 0.74 [95% CI 0.56 to 0.97], 6 trials) (Fig. CQ4-2) [278, 317, 365–367, 374]. Heterogeneity was low ($I^2$ = 31%).

3) All-cause mortality

Antihypertensive treatment targeting SBP <130 mmHg reduced all-cause mortality by 11% with no significant difference compared with antihypertensive treatment

Y. Ohya

|Study|Intensive arm Events|Standard arm Events|Standard arm Total|Weight|RR [95% CI]|Risk for serious adverse events| |---|---|---|---|---|---|---| |SPRINT|220|4678|118|4683|25.0%|1.87 (1.50; 2.33)| |ACCORD|77|2362|30|2371|15.7%|2.58 (1.70; 3.91)| |ESPRIT|72|5624|46|5631|17.8%|1.57 (1.08; 2.26)| |Cardio-Sis|72|558|61|553|20.0%|1.17 (0.85; 1.61)| |HOMED-BP|4|1759|3|1759|2.2%|1.33 (0.30; 5.95)| |STEP|21|4243|21|4268|10.1%|1.01 (0.55; 1.84)| |SPS3|23|1501|15|1519|9.2%|1.55 (0.81; 2.96)| |Heterogeneity : Tau$^{2}$ = 0.04, $Ch^{2}$ = 12.78, df = 6(P=0.05); $P^{2}$ = 53[0%; 80%]|||||||

targeting SBP ≥ 130 mmHg (RR 0.89 [95% CI 0.67 to 1.02], 8 trials] [278, 317, 365–368, 373, 374]. Heterogeneity was low ($I^2 = 20\%$).

4) Cognitive dysfunction

There were only three studies examining cognitive impairment [365, 373, 374]. There was no difference in the incidence of cognitive impairment between anti-hypertensive treatment targeting SBP <130 mmHg and SBP ≥130 mmHg (RR 0.93 [95%CI 0.68 to 1.26]). Heterogeneity was low ($I^2 = 38\%$).

5) Hypotension

Antihypertensive treatment targeting SBP <130 mmHg significantly increased hypotension by 96% (RR 1.96 [95% CI 1.04 to 3.70], 6 trials) [318,366–369,375. Heterogeneity was moderate

($I^2 = 57\%$). However, asymptomatic hypotension is included in hypotension.

6) Syncope

Antihypertensive treatment targeting SBP <130 mmHg significantly increased syncope by 136% (RR 2.36 [95% CI 1.95 to 2.85], 6 trials) [317, 365–367, 373, 374]. Heterogeneity was high ($I^2 = 61\%$).

7) Injurious fall

There was no difference in the incidence of injurious fall between antihypertensive treatment targeting SBP <130 mmHg and SBP ≥130 mmHg (RR 1.22 [95%CI 0.63 to 2.38], 6 trials) [317, 365–367, 373, 374]. Heterogeneity was high ($I^2 = 61\%$).

8) Acute kidney injury

Acute kidney injury was studied in 4 studies: anti-hypertensive treatment targeting SBP <130 mmHg significantly increased acute kidney injury by 165% (RR 2.65 [95%CI 1.78 to 3.95], 4 studies) [365–367, 373]. Heterogeneity was mild ($I^2 = 0\%$).

9) Composite of kidney events

Antihypertensive treatment targeting SBP <130 mmHg did not significantly affect composite kidney events (RR 1.38 [95% CI 0.67 to 2.31], 6 trials) [278, 317, 365–367, 374]. Heterogeneity was high ($I^2 = 86$%).

10) Serious adverse events

Antihypertensive treatment targeting SBP <130 mmHg significantly increased treatment-related serious adverse events by 59% (RR 1.59 [95% CI 1.19 to 2.12], 7 trials, Fig. CQ4-3] (278, 317, 365–368, 374). Heterogeneity was moderate ($I^2 = 53\%$). However, this result was significantly influenced by the results of RCTs which targeted SBP <120 mmHg. In the four trials which targeted SBP <130 mmHg, excluding the sub-group which targeted <120 mmHg, adverse events did not increase [375].

Summary

In JSH2019, an SR/meta-analysis (SR/MA) for similar CQs was conducted on antihypertensive treatment targeting <130/80 mmHg, which was considered to be strict anti-hypertensive treatment at the time [343]. In the present SR/MA, antihypertensive treatment targeting SBP <130 mmHg significantly reduced the risk of CVD incidence and cardiovascular death, and showed a decreasing trend in all-cause mortality. On the other hand, antihypertensive treatment targeting SBP <130 mmHg significantly increased the risk of hypotension, syncope, and serious adverse events. Treatment targeting SBP <130 mmHg significantly increased acute kidney injury, but there was no significant difference in the composite of kidney events. There was no apparent effect on cognitive dysfunction due to anti-hypertensive treatment. Outcomes of adverse events were highly heterogeneous due to the small number of events or differences in definitions. Furthermore, in trials targeting BP <130 mmHg (excluding the treatment targeting <120 mmHg), adverse events did not increase.

Note that the BPROAD trial [376] on type 2 diabetes was published after the completion of this SR/MA, with results consistent with those of this SR/MA.

Literature search

Six SR committee members independently conducted a literature search in PubMed, Cochrane Library, and ICHUSHI to identify articles applicable to this CQ.

The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and...

CQ 5 Do telemedicine and health guidance using digital technology have a beneficial effect on BP in adults?

$\blacktriangleright$ Telemedicine and health guidance using digital technology are weakly recommended for controlling BP in adults (both normotensive and hypertensive individuals).

[Strength of recommendation – 2, Strength of evidence – C, Agreement rate – 100%]

Summary of evidence

We conducted an SR of RCTs and observational studies of the usefulness of telemedicine and health guidance using digital technologies, such as smartphone applications and short message services (hereafter referred to as "digital technology"), on BP control in adults aged 18 years and older [357]. A total of 117 studies including 68,677 individuals were extracted (116 RCTs and one quasi-RCT). These compared the change in BP from baseline between the telemedicine/healthcare guidance group using digital technology and the control group (no intervention) with a follow-up of more than 3 months. The primary endpoint was the change in office BP; secondary endpoints were changes in 24-h BP and 24-h ABPM, and RR of adverse events.

Commentary

The result of the primary endpoint according to the intervention period, intervention modality, cohort, facility, and the results of secondary endpoints are described as follows:

1) Office BP

In the group of telemedicine and health guidance using digital technology after 3 months of intervention, compared to the control group, there was a significant decrease in office SBP of 3.21 mmHg (95% CI 1.90 to 4.51, 38 cases) and office DBP of 1.47 mmHg (95% CI 0.77 to 2.18, 38 cases), both were statistically significant. There was heterogeneity between trials ($I^2 = 75\%$), and patient backgrounds and various intervention modalities were suggested as contributing to this. Stratified analysis by intervention durations [3 months, 6 months (54 cases), 12 months (43 cases), and more than 12 months (9 cases)] showed a significant decrease in office SBP regardless of intervention duration, with no difference in the degree of change in SBP (Fig. CQ5-1) [358].

According to the intervention modality, the group using smartphone apps showed a significant decrease in office SBP by 3.01 mmHg (95% CI 1.61 to 4.40, 38 cases) and office DBP by 1.32 mmHg (95% CI 0.62 to 2.02) compared

![Difference in SBP change between groups (95%CI) (mmHg)\n13 months\n6 months\n>12 months\n>12 months\nDifference in SBP change between groups (mmHg)\nFig. CQ5-1 Intervention period differences in office SBP. (Adapted from ref. [357])\nDifference in SBP change between groups (95%CI) (mmHg)\nDifference in SBP change between groups (95%CI) (mmHg)\nDifference in SBP change between groups (mmHg)\nDifference in SBP change between groups (mmHg)\nDifference in SBP change between groups (mmHg)\nDifference in SBP change between groups (mmHg)\nDifference in SBP change between groups (mmHg)\nDifference in SBP change between groups (mmHg)\nDifference in SBP change between groups (mmHg)\nDifference in SBP change between groups (mmHg)\nDifference in SBP change between groups (mmHg)\nDifference in SBP change between groups (mmHg)\nDifference in SBP change between groups (mmHg)\nDifference in SBP change between groups (mmHg)\nDifference in SBP change between groups (mmHg)\nDifference in SBP change between groups (mmHg)\nDifference in SBP change between groups (mmHg)\nDifference in SBP change between groups (mmHg)\nDifference \n](1/parseimages/figure00374f71d38847028c26a00f2ce98a74_0_11.png)   to the control group. Similarly, the text message group (35 cases) and the group using a web screen such as a PC, showed a significant decrease in office SBP compared to the control group (34 cases). Both results had heterogeneity, suggesting a variety of subject characteristics across studies and a variety of combinations added to the intervention modality. There was no difference in the amount of change in SBP for each modality (Fig. CQ5-2) [358]. The results for office DBP were similar [357].

The stratified analysis of intervention results in the hypertensive and non-hypertensive cohorts showed the following (Fig. CQ5-3) [358]. In the hypertensive cohort, the intervention significantly reduced office SBP by 4.81 mmHg (95% CI 3.29 to 6.33, 41 cases). The intervention effect was also significant in the non-hypertensive cohort (66 cases), but the change was greater in the hypertensive cohort. The results for office DBP were similar.

Next, the results of the stratified analysis of intervention effects in medical and non-medical facilities (community centers and other localities, workplaces, universities, laboratories, and other facilities) are as follows (Fig. CQ5-4) [358]. In medical facilities, the intervention significantly reduced office SBP by 3.64 mmHg (95% CI 2.63 to 4.63,

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 74 cases). The intervention effect was also significant in non-medical facilities (33 cases), and the amount of change did not differ between facilities. The result for office DBP was similar [357].

2) Home BP

In studies that evaluated home BP, the change in home SBP was significantly lower in the intervention group compared to the control group, by 4.27 mmHg (95% CI 2.90 to 5.64, 12 studies). The heterogeneity across the studies was an acceptable level. The result for home DBP was similar (9 cases) [357].

3) 24-h BP

In the study of 24-h ABPM, 24-h SBP was significantly decreased after intervention by 3.64 mmHg (95% CI 0.29 to 6.99, 7 studies). But there was some heterogeneity among studies. Results for 24-h DBP were similar (9 studies) [357].

4) Safety

Compared to usual care, telemedicine and health guidance using digital technology did not increase adverse events (RR 1.00 [95% CI 0.91 to 1.09], 45 cases) [357].

Conclusion

Telemedicine and health guidance interventions using digital technology were shown to reduce BP significantly in adults without increasing adverse events. Note that the results do not indicate that telemedicine alone is beneficial for BP control compared to usual care, as most of the intervention groups were a hybrid of face-to-face healthcare and the introduction of digital technology. The results of the stratified analysis showed that the change in BP with intervention was significant, regardless of intervention duration (3, 6, 12, or >12 months), intervention mode (smartphone app, text message, PC or other web screen), and facility type (medical or non-medical facility). On the other hand, the change in BP was greater in the hypertension cohort than in the non-hypertension cohort. Based on the high heterogeneity among studies, the lack of evidence of long-term effects, the diversity in the functions of intervention modalities, certainty of the overall evidence, the balance of profit and loss, public values, cost-effectiveness, and the current status of telemedicine and health guidance in our country, we assigned

a strength of recommendation of 2 and a strength of evidence of C.

Literature search

A literature search was conducted using PubMed, Cochrane Library, and Ichushi-Web, and 80-90 articles were selected for primary screening. Excluding 7738 that met the exclusion criteria, a secondary screening of 352 articles was conducted, and a meta-analysis of 117 articles applicable to this CQ was performed [357].

02 Does intensive BP lowering treatment for diastolic hypertension (SBP below high normal) improve CVD events and death?

$\bullet$ Isolated diastolic hypertension is common in young and middle aged people. If the risk of CVD is low to moderate, intervention should focus on lifestyle modification. Intensive BP lowering drug treatment is not recommended. $\bullet$ Periodic assessment of BP should be conducted, as future SBP can often rise, making the patient eligible for BP lowering drug treatment.

Explanations

1) Diastolic hypertension and risk of CVD

Isolated diastolic hypertension (IDH) is defined as non-hypertensive SBP (<140 mmHg) with a high DBP (>90 mmHg). IDH is more commonly seen in young and middle-aged adults. This occurs when peripheral vascular resistance is increased and arterial wall elasticity is high, due to increased sympathetic nerve activity; the Windkessel effect buffers the increase in SBP due to cardiac output and diastolic blood flow is increased. This can easily lead to IDH [377].

In observational studies, SBP has a greater impact on the risk of CVD than DBP [378]. Intervention studies have shown a better reduction in CVD events from lowering SBP than DBP [379]. Few studies show a relationship between IDH and the risk of CVD, compared to isolated systolic hypertension, but a large meta-analysis did find an association between IDH and an increased risk of CVD events [380].

2) Interventions for diastolic hypertension

IDH is common in young and middle-aged adults; it rarely causes CVD events in the short term. There have been no RCTs of antihypertensive drug therapy for IDH. Therefore, there is no evidence to support intensive treatment for IDH. However, regular BP assessment should be performed for IDH, since the decrease in arterial wall

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elasticity with aging often results in an increase in SBP, rendering the patient to require antihypertensive drug therapy [381, 382]. In contrast, it has been reported that IDH is more commonly seen in young and middle-aged adults; yet it is often associated with lifestyle-related diseases such as obesity, smoking, hypercholesterolemia, high triglyceride levels, hyperglycemia, metabolic syndrome, and sleep apnea [383–385]. To improve these factors, it is recommended to implement measures such as losing weight, quitting smoking, reducing animal fat intake, and lowering calorie intake.

Antihypertensive drugs such as CCBs, ARBs, ACE inhibitors, and αβ-blockers, which exhibit vasodilating effects, are recommended to improve the lowering of DBP, because peripheral vascular resistance is often increased in IDH.

3) Evaluation of DBP in antihypertensive treatment

In antihypertensive treatment, even if SBP is reduced to <130 mmHg, DBP rarely exceeds 100 mmHg, except in special conditions, such as constrictive pericarditis or cardiac tamponade. It is necessary to first confirm that DBP is measured accurately for IDH, including in such cases. In auscultatory measurements, the following conditions can cause a high DBP value.

(1) The chest piece of the stethoscope is not placed over the brachial artery.

(2) The chest piece is pressed hard on the brachial artery and obstructs blood flow.

(3) The sound of phase IV of Korotkoff is of low volume, and the DBP is at Swan point 4 instead of Swan point 5.

(4) The membrane-type chest piece does not allow the low-pitched tapping sound of phase IV of Korotkoff sound to be heard.

(5) The rim of the bell-shaped chest piece is not fully in contact with the skin.

(6) Venous stasis in the upper extremities reduces the blood flow velocity in the brachial artery, resulting in a low Korotkoff sound.

These points should be noted and supplemented with measurements using an oscillometric automatic sphygmanometer that measures BP from cuff pressure fluctuations.

Conclusion

For IDH, intensive BP lowering drug therapy is not recommended and the main focus of intervention is on lifestyle modifications. However, periodic assessment of BP should be conducted, as future SBP can often rise, making the patient eligible for BP lowering drug treatment.

Chapter 7. Lifestyle modifications

[POINT 7]

1. Lifestyle modification is important not only for preventing hypertension, but also for hypertensive patients before and after the initiation of antihypertensive drugs.

2. Restriction of sodium (Na) (salt): Goal of salt intake is <6 g/day.

3. Dietary patterns and nutrients other than Na: Potas-sium (K)-rich fruits and vegetables, low-fat milk and dairy products should be actively consumed. The DASH and Mediterranean diets, which provide a complex intake of other nutrients effective in lowering BP, are also recommended. Endeavour to lower the Na/K ratio through salt reduction and increased K intake.

4. Maintain an appropriate body weight: BMI (weight [kg]/height [m]$^{2}$) <25.

5. Exercise: Perform light to moderate intensity aerobic endurance exercise for at least 30 min daily. Resistance exercise is also effective.

6. Reduction of alcohol intake: Limit ethanol consumption to less than 20–30 mL/day for men (roughly equivalent to one medium beer bottle, one glass of sake, one-half glass of shocku, one double shot of whiskey, two glasses of wine) and 10–20 mL/day for women.

7. Smoking cessation: Smoking should be avoided, including the use of new tabacco products, and care should be taken to prevent weight gain after quitting.

8. Other health points: Avoid exposure to cold, indoors and outdoors. Ensure adequate sleep (6–8 h), avoid constipation, and manage stress.

9. Telemedicine and health guidance using ICT, such as smartphone applications and digital technology, and devices that measure urinary Na/K ratio or diet/ urinary Na concentration may be useful in lowering BP.

1. Salt restriction

It has been proven that excessive salt intake is associated with a rise in BP [74, 386], and that Na restriction (a reduction in salt) lowers BP [387, 388] and reduces the incidence of CVD [389, 390]. This guideline sets the target value for salt restriction at <6 g/day based on the results of large-scale intervention studies in Europe and the United States [76, 391–393]. However, further reduction of BP can be expected by reducing salt intake further than 6 g/day, and guidelines in other countries have set lower targets for

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![Fig. CQ7-1 Differences in office SBP (after 6 months of intervention). (Adapted from ref.[516])\n| First author, Year of publication | Difference in SBP change between groups (95%CI) (mmHg)\n| Wang, 2023\n| Wong, 2023\n| Pletcher, 2022\n| Sakboonyarat, 2022\n| Xia, 2022\n| Zhang, 2022\n| Kario, 2021a\n| Kario, 2021b\n| Li, 2021\n| Lim, 2021a\n| Lim, 2021b\n| Cho, 2020\n| Lee, 2020\n| Lim, 2020\n| Takeyama, 2020\n| Wang, 2020\n| Yu, 2020\n| Apiñaniz, 2019\n| Choi, 2019\n| Contreras, 2019\n| Zha, 2019\n| Maddison, 2019\n| Pan, 2018\n| Rosario, 2018\n| Senecal, 2018\n| Kim, 2016\n| Rossi, 2010\n| Pooled estimate (P=79.2%)\n| Difference in SBP change between groups (mmHg)\n| T - 15 - 10 - 5 - 0 - 5 - 10 - 15 - 15 - 15 - 15 - 15 - 15 - 15 - 15 - 15 - 15 - 15 - 15 - 15 - 15 - 15 - 15 - 15 - 15 - 15 - 15 - 15 - 15 - 15 - 15 - \n](1/parseimages/figure12074d40be824fd6b2b88ce35f42c3df_0_2.png) Table 7-1 Combined lifestyle modifications

$\bullet$ Na restriction: Goal of salt intake is <6 g/day $\bullet$ Increased K (vegetables/fruit, low-fat milk and dairy products, etc), calcium, magnesium, dietary fiber, unsaturated fatty acids intake $\bullet$ Maintenance of proper body weight: keep a BMI ([body weight(kg)]÷[height(m)]$^{2}$) of <25 $\bullet$ Exercise: Mild to moderate intensity aerobic exercise daily for at least 30 min, low intensity resistance exercise may also be performed $\bullet$ Reduction of alcohol intake: Limit consumption to ≤20–30 mL ethanol per day in men and ≤10–20 mL ethanol per day in women $\bullet$ Smoking cessation; Smoking should be avoided, including the new tobacco products such as heated tobacco $\bullet$ Other health points: Avoidance of exposure to cold indoors and outdoors, ensuring adequate sleep, avoidance of constipation, management of stress

Combined lifestyle modification, smartphone apps, and digital technology can be more effective in managing BP Overconsumption of fruits/vegetables is not recommended in patients with renal impairment requiring K restriction Fruit intake may be recommended for patients with diabetes and obesity, but the amount should be adjusted individually

hypertensives and adults in general (see Q3) [183, 394, 395].

In the approach to reduce salt for an individual hypertensive patient, it is important to first assess the amount of salt intake. There are two methods of assessment. One method is based on dietary content such as a food frequency questionnaire, salt check sheets, and registered dietitians' 24-h recall. The other is based on measurement of urinary Na excretion [396]. Both methods

should be performed because they enable guidance on what foods and seasonings need to be reduced and by how much. Since an individual's salt intake fluctuates daily [397], repeated assessments of intake and guidance based on this assessment are necessary in order to maintain salt reduction over the long term. JSH's approved low-Na foods (seasonings and processed foods) are found on its website. The use of such foods can also help to reduce salt intake. It is also important to advise people to check the

The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and...

![84 RCTs of 5065 hypertensive patientsrandomized2700 to2365 toExerciseNon-exerciseOveral(mmHg)(95%CI)BPSBP-7.52(-8.77,-6.26DBP(-5.15,-3.57-4.36-5-1005Favors non-exercise→←Favors exerciseSub analysis: based on type of exercise intervenedSBPEffect size (mmHg)(95%CIAerobic-7.85 (-9.55,-6.15)-6.44 (-8.39,-4.49Dynamic resistance-6.27(-9.58,-2.96Isometric resistance-7.64(-11.70,-3.57Combined0-155-10-5←Favors exerciseP interaction: 0.815DBPEffect size (mmHg)(95%CIAerobic-4.70 (-5.69,-3.72Dynamic resistance-3.19(-5.83,-0.55Isometric resistance-3.51 (-5.70,-1.33-4.69 (-6.67,-2.70Combined-505-10←Favors exerciseP interaction: 0.417ig.CQ6-1 Effect of exercise therapy on BP. (Source: Prepared basen ref.[449]\n](1/parseimages/figurecc144f991fb940c0b3da2e8b2a50e540_0_1.png) nutritional information (salt equivalent content) when selecting foods. Although salt reduction is also effective for older adults [388], to avoid inadequate intake of the

necessary energy and nutrients, flexible guidance should be given to prevent low nutrition and frailty. When teaching salt reduction to frail older adults or chronic dialysis patients, the recommended salt intake should be appropriately adjusted based on body size, nutritional status, and physical activity level, rather than focusing solely on the target value of less than 6 g/day.

It is known that Na and K intake are significantly positively correlated [398]. In other words, a reduction in Na intake may also reduce K intake. That is why, the urinary Na/K ratio, which has been proposed as determining the balance between Na and K intake, is associated with BP and CVD [399–403]. Based on these reports, a consensus statement by a working group of JSH also considered the ratio to be a positive and significant factor associated with hypertension and CVD [404]. In Japan, studies using the spot urine Na/K ratio have reported reductions in Na intake and antihypertensive effects [405, 406]. Measuring this ratio, in addition to Na intake assessment at health check-ups, may be useful for the guidance of Na reduction which also considers K intake. However, at present, no target values have been set for patients with hypertension or other diseases (see Q5).

In addition, a report of a large RCT which used salt substitutes in which some of the Na in regular salt (Na chloride, NaCl) is replaced with K [407], the use of salt substitute was demonstrated to lower the BP, total and CVD mortalities [408], together with benefits in the cost of healthcare [409, 410]. Salt substitutes are also commercially available in Japan and for patients who do not require K restriction, it would be useful to recommend switching to these substitutes from the perspective of increasing K intake.

2. Dietary patterns and nutrients other than Na

Along with excessive Na intake, insufficient K intake is a risk factor for hypertension and CVD [400, 411]. It has also been shown that increased potassium intake has been shown to lower BP and reduce the risk of CVD events and death, especially in individuals with high Na intake and in hypertensive patients [407, 412–414]. For the prevention of lifestyle-related diseases, the Dietary Reference Intakes (DRI) for Japanese 2025 sets the target amount of K intake at ≥3000 mg/day for adult men and ≥2600 mg/day for adult women [415]. Based on the above evidence and the fact that K intake of Japanese adults is low at approximately 2200 mg/day [80], the guidelines recommends that hypertensive patients actively consume K to achieve at least the DRI target (≥3000 mg/day for adult men, ≥2600 mg/day for adult women). However, active K intake is not recommended for those with diseases or conditions such as chronic kidney disease stage 3b or higher. Those patients

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should be given individualized instructions on the appropriate K intake.

To achieve K intake goals while reducing Na intake, patients should be instructed to consume a combination of (1) 350 g of vegetables per day, (2) 200 g of fruits per day, and (3) low-fat milk and dairy products, green tea, coffee, etc. Fruit intake may also be recommended for patients with diabetes and obesity, but the intake recommendation should be individually tailored. In addition, there are reports from Japan showing that the use of seasonings and processed foods in which Na is replaced by K lowers the dietary Na/K ratio [416] and the urinary Na/K ratio and SBP [417], and switching to salt substitutes may have the additional effects of both reducing salt intake and increasing K intake.

DASH and Mediterranean diets provide calcium, magnesium, dietary fiber, and unsaturated fatty acids in addition to K, and are low in saturated fatty acids and dietary cholesterol [418, 419]. These diets have been shown to be effective in lowering BP and reducing the risk of CVD, and can be considered ideal diets [420–423]. In order to put this into practice, we should instruct our patients to eat mainly fish rather than meat, to include whole grains in the staple diet, to eat legumes, and to eat nuts (without salt) as snacks.

3. Maintain an appropriate body weight

In Japan, a BMI of 25 kg/m$^{2}$ or higher is defined as obesity [424]. According to the 2023 National Health and Nutrition Survey, there has been almost no change in the percentage of obese women over the past 10 years, but the percentage of obese men has increased from 28.6% in 2013 to 31.5% in 2023 [80]. In particular, more than 30% of men aged 30–69 years are obese. The contribution of obesity to the development of hypertension is high [425–430]; a high BMI [427–430] and an increase in body weight over time (especially from young adults to middle aged adults) [425, 429] are risk factors for developing hypertension. In addition, there is a high rate of progression from pediatric hypertension and obesity to adult hypertension and obesity, respectively [431]. They should be improved as early as possible.

The effect from losing weight to the lowering of BP is estimated to be a decrease in SBP of 1.1 mmHg and DBP of 0.9 mmHg per 1.0 kg body weight loss [432]. A decrease in BMI by 2.27 kg/m$^{2}$ results in a decrease in SBP by 5.79 mmHg and DBP by 3.36 mmHg [433]. Since obese Japanese patients show a significant reduction in BP with a weight loss of 3% or more [434], the first step is to lose weight through comprehensive lifestyle modifications. However, the weight loss and antihypertensive effects of diet are generally temporary [435]. Since the Cochrane SR reported a low level of evidence for antihypertensive effects

in patients on a weight loss diet [347], attention is necessary regarding the method, continuity, and other factors.

Obesity has two types of fat accumulation, visceral and subcutaneous. Visceral fat contributes to hypertension via increased expression of angiotensinogen in adipose tissue [436] and insulin resistance. In addition, hypoadiponectinemia [437] and increased plasminogen activator inhibitor 1 [438] lead to the development of atherosclerosis and thromboembolism. Furthermore, abnormal production of reactive oxygen species leads to mitochondrial dysfunction, which is associated with the development of various CVDs [439]. Although it is not clear whether weight loss reduces mortality [347], improvement of obesity and the reduction of visceral fat can improve each factor of lifestyle-related diseases, including antihypertensive effects, and they are useful in preventing CVDs. Visceral fat reduction is also necessary for patients with visceral fat accumulation, even if their BMI is less than 25 kg/m$^{2}$. Furthermore, since physical inactivity and weight loss are associated with frailty in patients with sarcopenia, maintenance of an appropriate body weight through low-intensity resistance exercise and nutritional therapy is recommended [440].

Obesity is also directly associated with abnormal meta-bolism of glucose, lipids, and uric acid, fatty liver and liver cancer, menstrual abnormalities, sleep apnea syndrome, orthopedic disorders, and hypertension. Obesity-related nephropathy [441] is also a complication [424], thus these conditions should be taken into consideration and strict weight control should be instructed during medical exam-inations. ARBs and ACE inhibitors that improve insulin resistance are recommended for antihypertensive treatment of obesity-associated hypertension. If antihypertensive treatment is inadequate, Ca channel blockers and low dose thiazide diuretics should be used. In addition to comprehensive lifestyle modification, obesity treatment includes pharmacotherapy and bariatric surgery. Stimulation of glucagon-like peptide 1 (GLP-1) receptors with incretin, a promising drug therapy, has the effect of decreasing appe-tite [442], gastrointestinal motility [443], and hypotension [444]. Bariatric surgical therapy is also performed in severely obese patients with comorbid hypertension and diabetes mellitus. It has been reported to be an effective method to control hypertension and to decrease the multi-drug therapy [445].

4. Exercise

Types of exercise include aerobic, resistance, and a combination of both. To date, aerobic exercise has been the main recommendation, with the effect of reducing BP by 2-5 mmHg/1-4 mmHg (SBP/DBP) [446]. Recently, resistance and combined exercises have been recommended

The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and...

along with aerobic exercise [447, 448]. In the latest meta-analysis, BP was reduced in the aerobic exercise group by 7.9/4.7 mmHg, in the resistance exercise group (dynamic [isometric/dynamic] by 6.4/3.2 mmHg, in isometric [isometric/static] by 6.3/3.5 mmHg) and in the combined exercise group by 7.6/4.7 mmHg, with no difference in the BP lowering effect between the exercise types [449]. Exercise therapy was associated with a reduction in body weight and body fat, an improvement in insulin sensitivity [450] and lipids, suppression of diabetes, maintenance of skeletal muscle mass, prevention and improvement of joint diseases [451], primary prevention of mental health problems [451], prevention of dementia [450], and reduction in the morbidity of chronic diseases [452] and mortality [453]. Subjects undergo a medical checkup in advance, and an appropriate exercise load should be set. In patients with BP levels below grade II hypertension and no cerebrovascular disease or with grade III hypertension, exercise therapy should be initiated after BP control. For patients with CVD, exercise should be restricted or prohibited as necessary. Furthermore, if the patient is older, do not restrict exercise due to age, but a prior medical checkup is mandatory and then appropriate exercise therapy can be planned [450].

Enter the exercise prescription (type, intensity, time/fre-quency, the increase in daily activity, and precautions to take during exercise) in the exercise section of the lifestyle-related disease treatment plan. In all patients with lifestyle-related diseases including hypertension, the results of a meta-analysis demonstrated a BP lowering effect of 5.48/3.07 mmHg through exercise [454]. Exercise prescriptions for hypertensive patients include two types: aerobic (isotonic and isometric) and resistance exercises. Aerobic exercise includes walking, jogging, using a treadmill, bicycle erg-meter, aerobic dancing, and swimming. Isotonic resistance exercise is muscle contraction with joint bending and stretching, with constant changes in muscle length and joint angle, and includes squats and push-ups with knee bending and stretching. Isometric resistance exercise is an exercise that exerts force at a fixed joint angle without joint bending and stretching, and contracts muscles without movement, such as pushing palms together in front of the chest (shoving exercise) and plank exercise, in which both arms support the upper body in a crawling position to strengthen the trunk. Therefore, the type of exercise should be selected and filled in according to an individual patient's background: aerobic exercise such as walking, resistance exercise such as squats and push-ups, or a combination of both.

The intensity of aerobic exercise should be light to moderate. Oxygen intake should be 40–60% of maximum at a subjective exercise intensity (rate of perceived exertion [RPE]) of easy to somewhat strenuous, with a Borg index of

11–13, at an intensity that allows for both breathlessness and conversation [446]. The target heart rate can also be calculated by the Karvonen method [target heart rate = (220–age–resting heart rate) × exercise intensity (%) + resting heart rate]. The intensity of resistance exercise should be measured as 1 maximal lifting weight (1 RM) and performed at 40–60% of 1 RM. During induction, it is also recommended that the intensity be set at 30% of 1 RM or an RPE of less than 12.

The duration and frequency for aerobic exercise is recommended to be at least 30 min daily [455]. Total exercise should be at least 40 min per day, each session at least 10 min long [456], totaling 150–300 min/week. For resistance exercise, 2–4 sets of 8–10 different exercises (8–12 times/set or 10–15 times/set) for 20 min per day is recommended. For a combination exercise 2–3 times per week is recommended. For example, 30 min of aerobic exercise plus 20 min of resistance exercise per day.

With regard to increasing activity, it has been reported that the longer the time of inactivity (sitting), the greater the decrease in survival rate [457]. A goal of 9000 steps/day is recommended to reduce the time of sitting and to increase healthy life expectancy [458].

During exercise take care to avoid dangers, such as over strain during isometric resistance exercises (Valsalva phe nomenon). High-intensity exercise is also dangerous because of a marked increase in BP during exercise and the activation of the endogenous hypertensive system following exercise [459]. Exercise should be limited to moderate intensity. Furthermore, when exercising at a target heart rate, caution should be used in administering drugs affecting heart rate, such as β-blockers.

Exercise therapy is recommended not only as a treatment for hypertensive patients, but also as a preventive medicine, including managing the risk of CVD.

5. Reduction of alcohol intake

A single use of alcohol leads to a decrease in BP that lasts for several hours [460], however, prolonged use leads to an increase in BP [461, 462]. Even in non-hypertensive adults, habitual alcohol consumption increases BP, and the association with SBP is direct and linear [463]. Hemorrhagic stroke increases linearly with alcohol consumption; in contrast, myocardial infarction and ischemic stroke are reported to be a lower risk in low and moderate drinkers, compared to non-drinkers [464–466]. On the other hand, in China and South Asia, both ischemic stroke and hemorrhagic stroke have been found to be monotonically increasingly associated with alcohol consumption [467]. Furthermore, heavy alcohol consumption increases

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mortality by causing alcoholic cardiomyopathy, atrial fibrillation, sleep apnea, and cancer, in addition to hypertension and stroke [468].

When alcohol consumption is restricted, a reduction in BP is observed within 1–2 weeks [469, 470]. Meta-analysis also shows a benefit from alcohol reduction, with a reduction in BP by about 3 mmHg in SBP and by 2 mmHg in DBP [471]. The elements of effective health guidance in the reduction of alcohol intake are feedback (explanation of the individual patient's test results and status, etc.), responsibility (clarification that the individual must take the initiative to reduce alcohol intake), advice (methods of alcohol reduction), menu (presentation of multiple methods), empathy, and self-efficacy (reinforcement of a sense of achievement). Self-monitoring is an effective method of managing drinking habits, through the use of an alcohol intake diary [472, 473].

In the management of hypertension, it is recommended that ethanol be limited to about 20–30 mL/day or less for men (roughly equivalent to one cup of sake, one medium beer bottle, half a bottle of shocku, one double shot of whiskey, or two glasses of wine) and about half of that for women (about 10–20 mL/day or less).

6. Smoking cessation

The association between active/passive smoking and hypertension [474, 475], CVDs [476, 477], and stroke [478, 479] is well known. However, smoking is a modifi-able risk factor, as cessation has been shown to reduce the incidence of CVD and death [480, 481]. In Japan, the number of users of heated tobacco products (HTPs) has been increasing, and the use of these types of cigarettes has been shown to cause health problems such as increased BP and pulse rate, decreased arterial stiffness, increased oxi-ative stress, and vascular endothelial dysfunction [482, 483]. There is concern about the health risks for the surrounding individuals as well [484]. Therefore, smoking cessation is recommended, including the new tobacco pro-ducts, such as HTPs.

Since the smoking cessation rate can be increased by brief instruction from medical practitioner [485], it is worthwhile to proactively provide such instruction, during medical examinations and health checkups, even if it is for a short time. The 5A approach (Ask, Advise, Assess, Assist, Arrange) [486] is recommended as a method for this. In addition, it is important to recommend nicotine replacement therapy and visiting a smoking cessation clinic. All healthcare providers should actively engage in smoking cessation counseling and treatment, utilizing resources such as the “Standard Procedures for Smoking Cessation Treatment”[487] and e-learning materials (J-STOP Next) [488].

It has been reported that the increase in BP associated with weight gain after smoking cessation [489] and the risk of developing hypertension in quitters who gained weight were not significantly different from those who continued to smoke [490]. For this reason, specific guidance should also be given on limiting calorie intake to prevent weight gain when quitting smoking, and on adopting exercise as an alternative to smoking. Particular attention should be paid to patients who smoke and are already obese.

7. Other lifestyle habits

1) Cold

It is known that BP increases during the winter months in association with cold temperatures. A decrease in both outdoor and indoor temperature is associated with an increase in BP [491, 492]. In addition, the variability of BP increases during the winter season [493]. It is known that the risk of death during bathing is high in Japan [494], and it has been shown that the rise in BP after bathing is particularly high in elderly people when the indoor temperature is low, thus care should be taken to adjust the temperature in the changing room. It has also been shown that an increase in BP after bathing is associated with an increase in heart rate, especially in elderly men, leading to an increase in double product (DP) or rate-pressure product (SBP × heart rate) [495].

2) Sleep

Both excessively short and excessively long sleep durations are considered bad for one's health. A higher incidence of hypertension has been observed in Japanese men who sleep less than 6 h or more than 8 h, compared with those who sleep about 7 h [496]. There are individual differences in adequate sleep duration, and sleep quality should also be evaluated. The Sleep Guide for Health Promotion 2023 [497] recommends that adults should sleep for at least 6 h, while it also recommends that the time in bed should not exceed 8 h for the elderly in terms of health risk (mortality risk).

3) Constipation

Constipation is also known to be associated with CVD events [498]. Constipation tends to increase with age and often coexists with cardiovascular risk factors. In addition, straining may trigger an increase in BP, which in turn may trigger CVD events [499].

4) Stress

Regarding the relationship between stress and BP, meta-analysis has shown that psychological and social stress more than doubles the risk of hypertension [500]. In a study using actigraphs, the effect of psychological stress on BP elevation was observed even when the influence of physical activity was taken into account [501]. There is also a report on the relationship between psychological stress and

The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and...

![Difference in SBP change between groups (95%CI) (mmHg)\n\nNormotensives*\np=0,058 for interaction\n3 months\n6 months\n12 months\nPooled estimate ($I^2$=78,7%) P=0,792 for interaction\nHypertensive participants\n3 months\n6 months\n12 months\nPooled estimate ($I^2$=99,2%) P=0.058 for interaction\nDifference in SBP change between groups (mmHg)\nFig. CQ7-2 Differences in office SBP (per intervention period, Nor-motensive/Hypertensive). (Adapted from ref. [516]). Subjects of studies with inclusion criteria that do not specify a particular disease\n](1/parseimages/figure42592a78886d4765b11a53c2f46855be_0_1.png) increased BP measured with a wearable wrist-based (cuff-type, oscillometric method) syphgmomanometer [502]. It is expected that various digital devices will enable the assessment of risk, including stress, in the future [503]. Some applications for hypertension treatment that incorporate stress and sleep management are already covered by insurance [504].

8. Using digital technologies

1) Smartphone applications

The HERB-DH1 trial [504] demonstrated the BP lowering effects of a hypertension treatment aid app, and it was covered by insurance. An SR showed that intervention using a smartphone app reduced SBP up to 3 months after the start of the intervention for healthy individuals and up to 6 months for hypertensive patients [358] (Fig. CQ7-2 in this chapter). However, there is insufficient evidence for long-term effects (see CQ7 in this chapter).

2) Telemedicine and health guidance

An SR showed that, in addition to face-to-face medical care, telemedicine and health guidance using digital technologies, such as smartphone apps and text messages, significantly reduced BP [358] (see Chapter 6, Section 7. Digital health technologies for telemedicine and health guidance, and CQ5).

3) Urinary Na/K ratio, dietary or urinary Na concentration measurement devices.

An SR demonstrated that utilizing devices that measure the urinary Na/K ratio, or dietary or urinary Na concentration in health management, dietary guidance, and clinical practice are useful in lowering SBP and salt intake [358].

4) Wearable devices

At present, there is insufficient evidence for the interventions using wearable devices [358].

5) Artificial Intelligence (AI)

To date, there is insufficient evidence on BP management using AI based medical/health guidance support [358].

CQ 6 Is resistance exercise as effective as aerobic exercise in lowering BP?

$\blacktriangleright$ Resistance exercise is strongly recommended as an exercise therapy for hypertension because it has a similar antihypertensive effect as aerobic exercise. However, the type of exercise should be individually selected according to the patient's background and status.

[Strength of recommendation – 1, Strength of evidence – A, Agreement rate – 100%]

Summary of evidence

Moderate aerobic exercise has been recommended as an exercise therapy for hypertensive patients. Resistance exercise (dynamic [isotonic/dynamic] and isometric [isometric/static]) has been recently reported to have a significant antihypertensive effect in addition to aerobic exercise; a combination of both exercises has a significant antihypertensive effect. No significant difference in effect was found between the different types of exercise in lowering BP.

Commentary

According to a report on the contribution of various risk factors to increasing the probability of deaths from CVD in Japan, the leading risk factor is hypertension, and the second is physical inactivity [505]. Therefore, it is expected that the number of deaths will be greatly reduced if exercise can lower BP.

The Hypertension Treatment Guidelines for the Management of Hypertension 2019 [283, 284] state that 30–60 min of aerobic exercise reduces SBP/DBP by 4.6/2.4 mmHg [506]. In Japan, Arakawa et al. have examined the effects of exercise therapy on hypertensive patients since the 1980s [459, 507–511]. Although the 1983 WHO guidelines stated that “the antihypertensive effect of exercise is not certain,” the 1991 WHO guidelines changed this statement to “exercise is recommended for hypertensive patients”. Subsequently, the 1993 guidelines of the International Society of Hypertension (ISH) and the American Joint Committee on Hypertension shared the same statement. It has been reported that the antihypertensive mechanism of exercise involves the inhibition of the sympathetic nervous system and renin system, which are pressor systems, as well as the inhibition of cardiac output and

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peripheral vascular resistance by activation of the diuretic peptide system, dopamine system, and kallikrein system, which are pressor systems [512].

To date, aerobic exercise of mild to moderate intensity (e.g. walking, jogging, treadmill, ergometer, aerobic dance, or swimming) has been recommended as the type and intensity of exercise that produces a lowering in BP. Recently, however, there have been numerous reports on the BP lowering effects of resistance exercises. Examples include stretching and strength training, low-intensity resistance exercises using rubber tubing or balls, squats and calf raises using body weight, weights and equipment. In a meta-analysis examining the BP lowering effects of aerobic and resistance exercise, Cornelissen et al. reported the effects of aerobic endurance training in lowering the BP of hypertensive patients. Their results showed that exercise decreased SBP by 8.3 mmHg and DBP by 5.2 mmHg [513]. In addition, a meta-analysis of the antihypertensive effects of isotonic and dynamic resistance exercise in hypertensive patients showed a 3.9 mmHg reduction in SBP [514]. Furthermore, a meta-analysis on the antihypertensive effect of endurance and resistance exercise combined, showed a 7.6 mmHg reduction in SBP [515]. Subsequently, in 2020 the ISH published the Global Hypertension Practice guidelines, which recommends aerobic endurance exercise and resistance exercise, as well as exercise combining both therapies [447]. Furthermore, in 2022, the Council of the European Society for Preventive Cardiology and the European Society of Cardiology (ESC) published a consensus document [448]. Endurance exercise is the initial therapy to be implemented in hypertensive patients, with a reduction in SBP/DBP of 7.4/4.5 mmHg, followed by isometric and resistance exercise, each with a reduction of 5.1 mmHg. Regarding BP, isometric and resistance exercises reduced BP by 5.1 mmHg/5.2 mmHg and 2.3/2.4 mmHg, respectively. A combination of both exercises reported a reduction of 5.3/5.6 mmHg.

These meta-analyses were not sufficient to draw a comparison between aerobic and resistance exercises. For the CQ "Is resistance exercise as effective as aerobic exercise in lowering BP?", meta-analysis was conducted (Fig. CQ6-1) [449]. The method was to extract RCTs with exercise intervention in adults aged 18 years or older using Ovid MEDLINE from 1946 to 2021 and the Cochrane Library from 1951 to 2021. Eighty-four studies (5065 subjects) were included, in which hypertensive patients were selected to examine changes in BP. The patients were divided into an aerobic exercise group, a resistance exercise group (isotonic/dynamic exercise group and isometric/static exercise group), and a combination of both groups, according to the type of exercise intervention The reduction in SBP/DBP in all subjects was 7.5/4.4 mmHg. The reduction in the aerobic exercise group was 7.9.47 mmHg, the isotonic/

dynamic exercise group 6.4/3.2 mmHg, the isometric/static exercise group 6.3/3.5 mmHg, and the combination group 6.3/3.5 mmHg. The interaction between SBP and DBP was not significant (P = 0.815/P = 0.417). There was no significant difference between the types of exercise in the antihypertensive effect (Fig. CQ6-1).

Conclusion

In exercise therapy for hypertensive patients, significant antihypertensive effects were observed for aerobic exercise, resistance exercise (isotonic/dynamic and isometric/static), and combination exercise. There was no difference in antihypertensive effect by type of exercise. It is recommended that the type of exercise be selected individually according to the BP level and the background of the hypertensive patient.

Literature search

The SR committee members independently conducted a literature search in Ovid MEDLINE from 1946 to 2021 and Cochrane Library from 1951 to 2021. In total, 13,284 articles were identified for primary screening, and 3142 articles were selected for secondary screening (full text) after excluding those that met exclusion criteria. As a result of further screening, a meta-analysis was conducted using the 84 articles that corresponded to this CQ.

CQ 7 Do interventions using smartphone BP management apps lower BP in the general adult population?

$\blacktriangleright$ We suggest interventions using smartphone BP apps for the management of BP in the general adult population (normotension and hypertension). However, the evidence for long-term effects (beyond 6 months) is insufficient.

[Strength of Recommendation - 2, Strength of Evidence - A, Agreement rate - 100%]

Summary of evidence

Sixty-nine RCTs and 30 observational studies (seven meta-analysis, 30 overall) examining the effectiveness of smartphone apps on BP in adults aged ≥18 years were identified (Overall: 57,937 in intervention in total, with 20,147 in the control group; meta-analysis: 26,312 in intervention in total, with 20,312 in the control group). The meta-analysis showed a significant reduction of 2.76 mmHg in office SBP at 6 months after the start of intervention compared to the group without the app. In healthy subjects, SBP at 3 months was lower than in the no app group, but no effect was demonstrated after 6 months of intervention. In hypertensive patients compared to the no-app group, SBP

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was lower at 3 and 6 months, but no effect was demonstrated after 12 months. When smartphone apps were examined according to their function, the antihypertensive effect tended to be greater in apps using a wireless connection with a sphygmomanometer to obtain accurate BP values.

Commentary

With the spread of smartphones, numerous applications have been developed for BP management. Using a smartphone, one can input BP data anytime and anywhere, analyze the data, and display the average value and changes in BP on a graph. In addition, apps have been developed that enable users to share BP, and so on, with medical institutions and to receive feedback from and communicate with healthcare providers (Certified Cardiovascular Disease Prevention Educators, hypertension specialists, etc.). Additionally, apps with functions have been developed that promote behavioral change through education and motivation.

Below are the results of an SR [516] on general smartphone apps for BP management. A stratified analysis by function is also presented since there is a large difference between the functions added to the smartphone apps.

When using smartphone apps in interventions for BP management, it is advisable to use them under the supervision of a healthcare provider with the correct knowledge of BP, for both healthy individuals and hypertensive patients.

1) BP

A total of 24 RCTs and three observational studies have reported office BP after 6 months of intervention. The results of the meta-analysis on the lowering effect of office BP are shown in Fig. CQ7-1. Although the group using the smartphone app had significantly lowered office SBP by 2.76 mmHg (95%CI 1.58 to 3.94) at 6 months of intervention, compared to the group not using the app, there was $I^2$ of 79.2% indicating high heterogeneity. DBP was also reduced by 1.23 mmHg (95%CI 0.67 to 1.80), with an $I^2$ of 61.3%. The reason for the high heterogeneity among the studies was thought to be due to the diversity of the subjects and the combination of functions added to the smartphone app.

2) Stratified analysis by intervention period in healthy individuals and hypertensive patients

The results of stratified analysis by intervention period, in healthy individuals and hypertensive patients, are shown in Fig. CQ7-2. In healthy individuals, compared to the group not using the smartphone app, office SBP was significantly reduced by 4.44 mmHg (95%CI 1.92 to 6.96) after 3 months of intervention using the smartphone app. However, no effect of BP reduction after 6 months was shown. In hypertensive patients, office SBP was reduced by 7.71 mmHg (95%CI 4.79 to 10.63) after 3 months and by 1.88 mmHg (95%CI 0.35 to 3.41) after 6 months, but no effect was demonstrated after 12 months of intervention.

3) Stratified analysis by smartphone app function

The results of the stratified analysis by smartphone app functions are shown in Fig. CQ7-3. Regarding the functions including BP recording, educational content, and

Fig. CQ7-3 Differences in office SBP (after 6 months of intervention, per application function). (Adapted from ref. [516]). [App Features] Educational Content: A feature that promotes behavior change through education and motivation. Feedback: A feature that enables sharing of data such as BP with healthcare institutions, allowing users to receive feedback from healthcare providers (e.g., Certified Cardiovascular Disease Prevention Educator, hypertension specialists). This also includes automated feedback based on user-recorded data, generated by AI or predefined rules.

Communication: A feature that allows interaction with healthcare professionals or other users

 Y. Ohya

communication between healthcare providers and other users, there was no clear difference in the antihypertensive effect between the group using these functions and the group not using them (smartphone app group vs. no smartphone app group). On the other hand, smartphone apps with functions that provided accurate BP readings via wireless connection to an upper arm cuff sphymomanometer tended to have a greater antihypertensive effect than other apps that do not have this function (BP lower by 5.42 mmHg vs. by 1.85 mmHg, P for interaction= 0.047).

4) Cost-effectiveness

The cost-effectiveness of one of the selected RCTs was analyzed, where the cost per QALY improvement was reported to be 1,199,880 yen [364].

5) Safety

There was no evidence of an increase in adverse events (compared to the control group) by using the smartphone app.

Conclusion

Intervention using a smartphone app significantly reduced office SBP by 2.76 mmHg after 6 months of intervention (vs. no app use). In healthy individuals, SBP was reduced after 3 months, but no effect was demonstrated after 6 months. In hypertensive patients, SBP was reduced at 3 and 6 months, but no effect was demonstrated after 12 months. In the evaluation of smartphone apps by function, the antihypertensive effect tended to be greater in those that obtained accurate BP values via wireless connection to a sphygmomanometer.

Literature search

A literature search was conducted using PubMed, Cochrane Library, and ICHUSHI, and each article was independently screened by two pairs of researchers (seven pairs in total) to extract articles applicable to this CQ.

Q 3 Is it necessary to further reduce the target salt intake for hypertensive patients in Japan from <6 g/day?

* This Guideline sets the salt reduction target for hypertensive patients at <6 g/day, but BP can be expected to be further lowered by a target lower than <6 g/day. When practicing salt reduction, it is important to ensure that the intake of energy, protein, fat, carbohydrate, and other necessary nutrients are in proportion to the patient's age, sex, and physical activity level. There is no need to lower the salt reduction target below 6 g/day, if this cannot be ensured.

Explanation

1) Antihypertensive effect of salt reduction

It is well known that excessive salt intake is a risk factor for increasing BP and the development and progression of CVD; many intervention trials and meta-analyses have demonstrated the antihypertensive effects of salt reduction. The guidelines advocate a salt reduction target of <6 g/day for hypertensive individuals (see section 1. Salt restriction, in this chapter). However, lowering BP by salt reduction is dose-dependent, and the American College of Cardiology/ American Heart Association (ACC/AHA), based on the DASH-Sodium study, has set a salt reduction target of <3.8 g/day for both the general adult population and hypertensive individuals [394]. On the other hand, the ESC/ESH has set a target for hypertensive patients at less than 5 g/day [183]. WHO recommends a target of less than 5 g/day for adults, including the general population [83]. In other words, epidemiologically, further reduction of BP can be expected by lowering the salt reduction target from <6 g/day.

2) Problems in lowering the salt reduction target

According to the 2023 National Health and Nutrition Survey, the dietary salt intake of the Japanese population remains high, at 10.7 g/day for men and 9.1 g/day for women [517], making the promotion of salt reduction at the national level an important issue. In Health Japan 21 (the third term), the target of salt intake was reduced from 8.0 g/day in the second phase to 7.0 g/day (by FY2032) [82]. On the other hand, the Dietary Reference Intakes for Japanese for the general population (2025) [415], sets the target salt intake at <7.5 g/day for men and 6.5 g/day for women. The energy requirement for adults aged ≥18 years in this standard are 1850–3150 kcal/day for men and 1,450–2,650 kcal/day for women, depending on the physical activity level, and the energy nutrient ratio consisting of P (protein), F (fat) and C (carbohydrate) (PFC). The recommended PFC balance consists of P: 13–20%, F: 20–30%, C: 50–65%. Thus, it is not easy to achieve a salt reduction of <6 g/day while ensuring the energy requirement and PFC ratio, considering the current dietary habits of Japanese people. A study evaluated salt intake 10 times in a mean observation period of 7.7 years with salt reduction instruction and 24-h urine collection in 186 hypertensive patients. The results showed only 7% of men and 19% of women achieved this target more than five times. Since body weight is a major determining factor of salt intake, it is considered more difficult for men with a high energy intake and those with a high body weight to achieve the goal of salt reduction [518].

The Consortium for Healthy Eating and Food Environment is working to certify "Healthy Eating and Food Environment" [Smart Meal® a nutritionally balanced meal] for restaurants, take-home meals and office meal service. In consideration of taste and feasibility, the amount of salt

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equivalent is set at <3.0 g for "average meal (<450,-650 kcal)" and <3.5 g for "larger meal (620,-850 kcal)," although, the "average" meal can be set at <2.5 g and "larger meal, at <3.0 g/day, as options to promote salt reduction [519]. In terms of daily diet, for example, a 70-year-old person with "normal" physical activity level needs to eat 2350 kcal/day for men and 1850 kcal/day for women, which is their energy requirement, while maintaining an appropriate PFC ratio and a sustainable and satisfying diet with <6 g/day of salt. This is not an easy level to achieve, and requires the use of low salt processed foods and seasonings, as well as various innovations in the cooking process. In actual clinical practice, the risk from disadvantages such as low nutrition, frailty, and sarcopenia should be avoided by prioritizing salt reduction, and there is no need to lower the salt reduction target further than <6 g/day unless guidance and support can be obtained from a registered dietitian or other specialist.

Conclusion

Salt reduction is dose dependent, and a further reduction in salt intake below 6 g/day can be expected to result in further reduction of BP. However, it is not easy to reduce intake further while maintaining energy requirements and other nutrients in the daily diet, so unless guidance is available from a registered dietitian or other specialist, there is no need to reduce salt intake further than <6 g/day.

Q 4 Is Na reduction guidance based on Na intake with estimation by spot urine testing, effective for Na reduction and BP management in hypertensive patients?

$\bullet$ There are individuals for whom Na reduction can be achieved with guidance based on Na intake estimation using spot urine. $\bullet$ The effectiveness of Na reduction guidance for BP control is currently unknown.

Commentary

1) Na reduction and intake estimation method

There are several methods for assessing Na intake, one of which is using spot urine samples. There are reports that Na reduction guidance using this method has improved the Na intake of subjects [133, 520–523], and the evidence for this method is increasing.

Because urinary Na excretion is subject to diurnal variation and dietary influences, estimation using spot urine is not as reliable as the 24-h urine method, which is considered the gold standard. However, the estimated Na excretion correlates well

with the measured Na excretion in the 24-h urine method, and the estimation using the spot urine Na test is simple and repeatable, making it a valuable tool in general clinical practice. The amount of Na excretion (i.e. Na dietary intake) decreases with repeated assessment and instruction [524]. When Na reduction guidance is provided using the Na intake as estimated by spot urine, repeated measurement and evaluation of trends in individual patients and presentation of the results to individuals are expected to enhance the effect of such guidance. However, in previous reports [520–522], not only the estimated Na intake by the spot urine Na test was presented, but Na reduction guidance was used in conjunction with a Na check sheet [525]. There is a report that Na reduction was also possible by a combination of guidance and Na self-measurement, using an electronic Na sensor estimating intake using nocturnal urine [526]. Although there are individuals for whom Na reduction can be achieved by guidance using estimates from the spot urine Na test, there may be limitations to guidance based solely on Na intake estimation using spot urine, considering that Na reduction can be even more effective with the use of supplementary tools.

2) BP management by Na reduction

The antihypertensive effect of Na reduction has been demonstrated in previous intervention studies [76, 392, 527]. Therefore, if effective Na reduction can be achieved through guidance, using Na intake estimated from the spot urine Na test, it is theoretically possible to also lower BP. However, the effect is not constant with respect to lowering BP [520, 521, 523, 526], and its effectiveness cannot be concluded. Results from intervention trials suggest that a reduction of 1 g/day of Salt (NaCl) lowers BP by an average of about 1.0/0.5 mmHg in hypertensive individuals [527, 528]. Because of the lack of reports, it is unclear how many g/day of NaCl reduction can be achieved by guidance using the spot urine Na test and how much of a BP lowering effect it has. Furthermore, since many factors other than Na intake are involved in BP regulation [529], BP control with Na reduction guidance alone is likely insufficient.

Conclusion

Although the reliability of Na intake estimation using the spot urine Na test is not high, it is simple and has the advantage of repeated measurement; together with Na reduction guidance, it may be possible to reduce Na intake. Further reduction of Na intake can be expected if other tools are used in combination with the spot urine method. Although Na reduction can be expected to lower BP, more evidence needs to be accumulated, and at this point, the effectiveness of Na reduction guidance based on Na intake estimation using the spot urine Na test is not clear.

Y. Ohya

Q 5 Is the spot urine Na/K ratio measurement effective for Na reduction and BP management? What is its target value?

$\bullet$ An optimal target value for urinary Na/K ratio in healthy Japanese is less than 2; this corresponds to the target amount of Na and K in the dietary reference intakes for Japanese. However, a target value of less than 4, which corresponds to less than the average value, is set as the feasible target. $\bullet$ The spot urine Na/K ratio can be measured easily and inexpensively at health checkups and healthcare institutions throughout Japan. We anticipate that the urinary Na/K ratio will be further utilized for BP control as an indicator of Na reduction and increased K intake.

Commentary

This section is based on the consensus statement of the Working Group on Urinary Sodium (Na)/Potassium (K) Ratio (Na/K Ratio) of the JSH published in 2024 [404]. The urinary Na/K ratio is the ratio of the Na concentration (mmol/L) to the K concentration (mmol/L) excreted in urine. Since approximately 90% of ingested Na and 70-80% of ingested K are excreted in urine [530], the urinary Na/K ratio can objectively evaluate the ratio of Na and K intake from the diet [404]. It can be assumed that the higher the urinary Na/K ratio, the higher the BP, since excessive Na intake and insufficient K intake independently increase BP. In fact, a positive association between the urinary Na/K ratio and BP has been found in a large study of the Japanese population [401, 403, 531, 532]. It has also been reported that the urinary Na/K ratio is more strongly associated with BP than either urinary Na or urinary K alone [531, 533].

The urinary Na/K ratio is an index that shows significant day-to-day and diurnal variability within individuals, due to physiological mechanisms and dietary influences [404]. The most accurate method (gold standard) for assessing urinary Na/K ratio is to calculate it from 24-h urine samples over multiple days [404]. However, this is time-consuming and labor-intensive, making it difficult to perform on a routine basis. In a Japanese study, the mean values of urinary Na/K ratios calculated from the spot urine samples collected at different times throughout 4–7 days showed a high correlation and agreement with the mean values of urinary Na/K ratios calculated from 24-h urine samples during 7 days [534, 535]. In light of this finding, the consensus statement of JSH strongly recommends that the mean value be calculated from measurements of spot urine samples at different times on four or more days per week [404]. However, if evaluation using a single spot urine is unavoidable, such as medical examinations, it may be desirable to use the urine from the second

urination event after waking up (urine collected around 9:00 a.m.) [404]. However, there is insufficient knowledge on the appropriate evaluation method of the urinary Na/K ratio using single spot urine, and further studies are needed.

Although it is desirable to have a specific target value for the urinary Na/K ratio for decision-making in clinical and health guidance settings, no such value has been established. In response to the recent progress in epidemiological studies on the urinary Na/K ratio, the consensus statement of the JSH states [404] that the optimal target value for healthy Japanese individuals is less than 2, which meets the target amount of both Na and K in the Dietary Reference Intakes for Japanese (2020 edition) of the Ministry of Health, Labor and Welfare [398] A value of less than 4, which is below the average value in several Japanese populations, was proposed as an achievable goal [398, 402, 531]. By setting two target values, it is considered that dietary habits can be improved step by step. Noteworthy however, these targets are not applicable to patients with specific diseases as further data is necessary for such assessment [404].

To date, there is only one report of an RCT examining the effectiveness of spot urine Na/K ratio measurement for Na reduction and BP management [406]. Therefore, the scientific basis is not sufficient at this stage, and further accumulation of knowledge is needed. On the other hand, when community health checkups have used a spot urine Na/K ratio measuring device, the results were quickly returned with information on Na reduction and increased K intake, and a significant decrease in the urinary Na/K ratio and BP levels were observed at the subsequent health checkup [536]. This suggests that the combination of the single-spot urine Na/K ratio measurement and health guidance under certain conditions of urine collection, such as at the time of health checkups, may be effective for Na reduction and BP control.

The urinary Na/K ratio can be easily measured at health checkup centers and healthcare institutions (including physicians' offices) throughout Japan at low cost and with less burden compared to blood sampling. We anticipate that the urinary Na/K ratio will be further utilized as an indicator of Na reduction and increased K intake for BP management.

Chapter 8. Drug therapy

[POINT 8]

1. The effect of antihypertensive drugs on CVD is largely determined by the degree of antihypertensive effect, rather than the class of drug.

2. Long-acting di�hydropyridine CCBs, ARBs, ACE inhibitors, low-dose thiazide diuretics, and β-blockers are the major antihypertensive drugs (antihypertensive drug group 1: G1). An appropriate drug should be

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selected as the initial monotherapy, taking into account the characteristics of each drug, as well as any compelling indications, contraindications, and conditions requiring special precautions for the use.

3. If monotherapy with a major antihypertensive drug fails to achieve the target BP, therapy should immediately be stepped up sequentially to dual (STEP 2) and, if necessarily, to triple (STEP 3) combination regimens, with careful monitoring for possible side effects and adverse events.

4. For individuals diagnosed with grade I hypertension (140-159/90-99 mmHg) at high risk or grade II/III hypertension (160/100 mmHg or higher) at the initial visit, initiation of therapy with dual antihypertensive agents (STEP 2) may be considered, particularly when early achievement of target BP is desirable.

5. In antihypertensive combination therapy STEP, CCBs and RAS inhibitors, which are well-tolerated and frequently used, are designated as G1a antihypertensive drugs. Low-dose thiazide diuretics and β-blockers, major antihypertensive drugs that are underutilized for conditions where they should be administered in Japan, are designated as G1b antihypertensive drugs. These drugs are used from monotherapy in STEP 1. After the two-

drug combination therapy (STEP 2), G1 antihypertensive drugs (an ARNI, MR antagonists) may also be used.

6. As a general principle, thiazide diuretics should be included in the three-drug combination therapy (STEP 3). If the BP target is not achieved with the three-drug combinations, lifestyle modifications should be tried, and if necessary, consider referral to a hypertension specialist.

7. In principle, antihypertensive drugs should be administered once a day. It is important to maintain a low BP level throughout the 24-h period.

8. Antihypertensive therapy STEP should be advanced with careful attention to the declaration of any side effects and adverse events, aiming to achieve the BP target within several months. However, in patients at a high risk for CVD, achieving the BP target within a few weeks should be considered, including initiation of dual antihypertensive therapy.

9. Combination therapy with different classes of antihypertensive drugs has a greater effect than doubling a single dose. Half dose combination therapy provides greater antihypertensive effects and a lower incidence of side effects (adverse events) than the usual single dose.

||Compelling indication|Contraindication|Conditions requiring special precautions for the use| |---|---|---|---| |Long-acting dihydropyridineCCBs a|Cerebrovascular disease Left ventricular hypertrophy Angina pectoris||| |ARB/ACE inhibitors|Cerebrovascular disease Left ventricular hypertrophy Post myocardial infarction HFrEF c|ARB/ACE inhibitors: Pregnancy ACE inhibitors: Angioedema, Special membrane-based apheresis/dialysisf|Renal artery $stenosis^{h}$ Hyperkalemia| |Thiazide $diuretics^{b}$|Cerebrovascular disease CDW with proteinuria/ microalbuminuria|Conditions in which sodium and potassium are clearly reduced|Gout Impaired glucose tolerance Pregnancy| |β blocker|Angina $pectoris^{d}$ Post myocardial infarction HFrEF a|Asthma ($β_{1}$ non-selective and αβ-blockers) Severe tradycardia Untreated pheochromocytoma/paraganglioma$^{g}$|Asthma ($β_{1}$ selective) Chronic obstructive pulmonary disease ($β_{1}$ selective) Impaired glucose tolerance| ||Thoracic aortic aneurisme|||

^a Benzothiazepine CCB, diltiazem, is reported to have a preventive effect on CVD events. However, it is not included as a major antihypertensive agents, due to the lack of evidence for combination therapy beyond STEP 2 (see Fig. 8-1). Nevertheless, it may be used from Step 1 in conditions such as angina pectoris

$^{b}$Thiazide-type diuretics include thiazide diuretics (hydrochlorothiazide, trichlormethiazide, etc.) and thiazide-like diuretics (indapamide, etc.)

$^{c}$Administration should be started at a low dose, and the dose should be carefully gradually increased

$^{4}$Caution is needed in patients with coronary artery spasm

$^{e}$There is evidence of the rate of aneurysm enlargement slowing and improvement of prognosis in thoracic aortic aneurysms caused by Marfan syndrome, but administration is also considered appropriate in other thoracic aortic aneurysms

$^{f}$Refer to "Section 3. 3) ACE inhibitors in this chapter

$^{8}$Combination with αβ-blockers or administration of αβ-blockers is necessary

hContraindicated in cases of bilateral renal artery stenosis

Y. Ohya

|Group|Antihypertensive Drugs|Features|| |---|---|---|---| |GI|a • Long-acting dihydropyridine CCBs • RAS inhibitors (ARB, ACE inhibitor) b • Low-dose thiazide diuretics$^{b}$ • β-blockers (bisoprolol, carvedilol, • ARNI • MR antagonist|• Major antihypertensive drugs • Select from antihypertensive treatment STEP 1ª according to the condition • Presence of evidence for prevention of cerebrovascular events in hypertension|a • Excellent tolerability| |G2|• ARNI • MR antagonist|• These drugs may be selected at STEP 2 or 3 according to the condition • No evidence for prevention of cerebrovascular events in hypertension|b • Currently, their use in appropriately indicated conditions remains limited, and more active administration is desired.| |G3|• α-blockers • Hydralazine • Central sympathetic nerve inhibitors, etc.|• Used for resistant hypertension and special conditions||

ªSee Fig. 8-1

ᵇTrichloromethiazide 0.5 to 1 mg, hydrochlorothiazide 6.25 to 12.5 mg, indapamide 0.5 to 1 mg equivalent

10. Simplification of prescribing through the use of combination drugs improves adherence and BP management.

1. Principles of antihypertensive drug selection

The higher the BP level and the more developed the hypertensive organ damage, the more difficult it becomes to achieve the target BP level by lifestyle modification alone, and consequently antihypertensive drug therapy is required. Lowering BP with antihypertensive drugs can reduce the incidence of CVD. A meta-analysis of large clinical trials has shown that this effect is independent of the class of drug and is proportional to the magnitude of BP reduction [306, 537, 538]. Antihypertensive drugs should be selected based on the characteristics of the drugs as well as contra-indications and precautions, and in consideration of the patients' concomitant medical conditions.

1) Major antihypertensive drugs

The major antihypertensive drugs are those that have been shown to inhibit CVD using a single drug. There are five classes: long-acting dihydropyridine CCBs, ARBs, ACE inhibitors, low-dose thiazide diuretics, and β-blockers (including αβ-blockers) (Table 8-1) [306, 537, 538]. These are referred to as antihypertensive drug group G1 (G1 antihypertensive drugs) in JSH2025 (Table 8-2). Since there are compelling indications, contraindications, and conditions that should be noted for each of these drugs, antihypertensive drugs should be selected in consideration of these indications.

Among the major antihypertensive drugs, CCBs and RAS inhibitors (ARBs and ACE inhibitors) are well tolerated, and have a high usage rate in clinical practice in Japan [539]; these were selected as G1a in the antihypertensive

drug group in the STEP for antihypertensive drug therapy. In addition to the compelling indications, the selection of CCBs should be considered for older adults, possible pregnancy, and for those whose blood tests are required before drug selection, but cannot be immediately confirmed (e.g. high-risk patients with renal dysfunction or electrolyte abnormalities, suspected secondary hypertension). For young and middle-aged individuals (excluding women of childbearing potential), RAS inhibitors should be considered (сOLUMN 8-1).

COLUMN 8-1

How to select a G1 Antihypertensive Drug when there are no compelling indications in STEP 1

* Long-acting dihydropyridine CCBs

* Older adults

$\bullet$ Possibility of pregnancy

$\bullet$ In the situation where blood tests are necessary but the results are not immediately available. (e.g., high-risk patients for kidney dysfunction or electrolyte abnormalities, or suspected secondary hypertension)

$\bullet$ ARB/ACE inhibitors

* Young adults/middle-aged adults (excluding women of childbearing potential)

$\bullet$ Low-dose thiazide diuretics

$\bullet$ Excessive salt intake

* Salt-sensitive hypertension

$\bullet$ β-blockers

$\bullet$ Hypertension reflecting increased sympathetic activation (young adults, tachycardia tendency, stress-induced hypertension)

* High cardiac output hypertension

The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and...

Low-dose thiazide diuretics (thiazide diuretics and thiazide analogues) and β-blockers, despite being the major antihypertensive agents, remain underused in clinical practice in Japan; they should be prescribed more appropriately from STEP 1 [539]. Therefore, these should be specifically categorized as antihypertensive drug group G1b (Table 8-2). Low-dose thiazide diuretics are expected to be effective for hypertension associated with excessive sodium intake and increased salt sensitivity, in addition to other compelling indications. Thiazide diuretics account for as low as 10% of antihypertensive prescriptions in Japan [539], which may be related to the fact that the control rate of hypertension in Japan is only about 25%. Thiazide diuretics are suitable for use in combination with RAS inhibitors or CCBs, and their active use is recommended. There was concern about metabolic side effects, such as elevated blood glucose levels, but the incidence of such effects can be suppressed when used in low doses [540].

Fig. 8-1 Antihypertensive drug

Fig. 8-1 Antihypertensive drug therapy STEP for hypertension: How to use antihypertensive drugs to achieve target BP. *1 For older adults aged ≥75 years or those with impaired kidney function (CKD stage ≥4, eGFR < 30 mL/min/1.73 m$^{2}$), treatment is generally started with half the standard dose of a single agent. *2 ARNI and ACE inhibitors should not be used concomitantly. When switching from an ACE inhibitor to ARNI, a washout period of at least 36 h should be taken. As stated in the package information, ARNI should generally not be administered as the first agent. *3 Loop diuretics should be used in patients with an eGFR <30 mL/min/1.73 m$^{2}$. *4 ARNI or MR antagonists can also be used because of their sodium excreting properties. *3 Refer to Chapter 11, "Poorly controlled hypertension"

from an ACE inhibitor to ARNI, a washout period of at least 36 h should be taken. As stated in the package information, ARNI should generally not be administered as the first agent.

STEP 2 Combination of two G1 antihypertensive drugs are achieved in the end of a 25th level of 35th level of 45th level of 65th level of 75th level of 85th level of 95th level of 100th level of 110th level of 120th level of 130th level of 140th level of 150th level of 140th level of 140th level of 140th level of 140th level of 140th level of 140th level of 140th level of 140th level of 140th level of 140th level of 140th level of 140th level of 140th level of 140th level of 140th level of 140th

Three-drug combination therapy with G1 antihypertensive drugs and G2 antihypertensive drugs

For antihypertensive treatment in compelling indications, the β-blockers used are the β₁ highly selective bisoprolol and the αβ-blocker carvedilol, both of which have established usefulness and safety [541–544]. In addition to compelling indications, β-blockers are also effective in hypertension in young adults, hypertension with tachycardia tendency, stress-induced hypertension, and high cardiac output hypertension, which reflects increased sympathetic nervous system activity. There are some reports suggesting an increased risk of diabetes and a weaker effect on protecting organ damage and CVD events, particularly in older adults, compared with other major antihypertensive agents [545]. However, these findings are [argely derived from certain β-blockers, such as atenolol [see Section 3. 5) β-blockers (including αβ-blockers) in this chapter].

2) STEP of antihypertensive drug treatment

The ultimate goal of antihypertensive treatment is to prevent the onset of CVD, and the target BP should be achieved and then maintained. At present, however, only

 G1 Antihypertensive drugs: Long-acting dihydropyridine-type CBs, ARB/ACE inhibitors, thiazide-type diuretics (low dose), β-blockers

 $\bullet$ Select with consideration of compelling indications

* If target BP cannot be achieved, step up treatment as early as possible

STEP 2

Combination of two G1 antihypertensive drugs G2 antihypertensive drugs may also be used depending on the patient's condition

G2 Antihypertensive drugs: ARNI*2, MR antagonists

 $\bullet$ Use fixed-dose combination tablets to minimize the number of tablets needed daily

$\bullet$ If target BP cannot be achieved, step up treatment as early as possible. However, as a general rule, increase the dosage of each drug to the standard dosage, except for thiazide diuretics

Three-drug combination therapy with G1 antihypertensive drugs and G2 antihypertensive drugs

In principle, thiazide-type diuretics 3 4 should be used

 * Confirm medication adherence

* Consider adding a thiazide diuretic if not already being administered

Reassess lifestyle modifications and medication adherence, identify any problems with medical therapy, and take appropriate measures.$^{5}$ Consider referring to a hypertension specialist

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about half of those taking antihypertensive drugs achieve the target [546]. Less than 40% of patients are able to achieve their target BP with monotherapy [547]. It is important to start the drug therapy appropriately, and if the effect is insufficient, to proceed sequentially with the STEPs of antihypertensive drug therapy without delay, while paying attention to side effects and adverse events. Also, providing patients with an explanation of the necessity of achieving the BP goal, and ensuring their understanding is critical for successful attainment of the target (Fig. 8-1).

Antihypertensive therapy is initiated with a single major antihypertensive drug (G1 antihypertensive) (STEP 1 of antihypertensive drug therapy). If a condition with a compelling indication exists, the corresponding drug should be selected (Table 8-1). For patients aged 75 years or older or those with reduced renal function (CKD stage 4 or higher, eGFR less than 30 mL/min/1.73 m$^{2}$), treatment should be initiated with half the standard dose of a single drug, with subsequent gradual upitration. If side effects occur or if the antihypertensive effect is negligible, the drug should be switched to another class of an antihypertensive drug. If monotherapy fails to achieve the target BP, two-drug combination therapy (STEP 2) should be initiated immediately. At the initial visit, in patients with degree II or III hypertension (160/100 mmHg or higher) or high-risk degree I hypertension (140-159/90-99 mmHg), treatment may be started with a two-drug combination (STEP 2), if necessary, after comprehensive consideration of the difference from the target BP, tolerability to the rate of BP reduction, complications and other factors. In such cases, the dose should be determined given consideration that a two-drug combination therapy at half the standard dose of each agent provide superior BP reduction with fewer adverse events compared with monotherapy at the standard dose (COL-UMN 8-2). If the two-drug combination at half the standard dose is ineffective, the dose of each drug should be increased to the usual dosage.

COLUMN 8-2

Antihypertensive drug combination therapy and fixed combination drugs

In the European and American guidelines, it is recommended to initiate antihypertensive treatment with two-drug combination therapy [1,2]. In addition, in recent years, it is reported that initiation of treatment with a fixed-dose combination tablet of four classes of antihypertensive drugs (CCB, ARB, thiazide diuretic, and β-blocker) at quarter doses is superior in lowering BP compared to initiation with a standard dos

e of ARB monotherapy [3]. Also, it is reported that starting with a fixed-dose combination tablet of 3 different

Table (continued)

COLUMN 8-2

classes of drugs (CCB, ARB, and thiazide diuretic) at quarter doses not only achieves lower BP levels but also reduces the risk of major CVD events, compared to starting with a standard dose of CCB monotherapy [4]. JSH2025 also recommends initiation of antihypertensive treatment with two-drug combination therapy (STEP 2) in high-risk grade I hypertension and grade II/III hypertension (Fig. 8-1). However, when the difference between baseline BP and the target BP is small, or when there are concerns about the tolerability to rapid BP reduction or complications, starting with a low dose (e.g. half dose of CCB + half dose of ARB) may be an option from the viewpoint of efficacy and safety. In Japan, the use of a fixed-dose combination tablet as the initial antihypertensive therapy is not approved under health insurance coverage. This is an important issue to be discussed in the future.

1) Whelton PK, et al. Hypertension. 2018; 71: 1269–324. PMID: 29133354

2) Mancia G, et al. J Hypertens. 2023; 41: 1874–2071.

PMID: 37345492

3) Chow CK, et al.; QUARTET Investigators. Lancet. 2021; 398: 1043–52. PMID: 34469767

4) Oji DB, et al. JAMA. 2024; 332: 1070-9. PMID: 39215620

In STEP 2, two G1 antihypertensive drugs are combined, but G2 antihypertensive drugs may also be administered, depending on the patient's clinical condition (Fig. 8-1, Table 8-2). G2 antihypertensive drugs have no evidence of preventing CVD in hypertension but have evidence for BP-lowering effects such as potency and long duration of action. They include ARNI and mineralocorticoid receptor (MR) antagonists. Both are useful for hypertension associated with fluid retention, excessive salt intake, and salt sensitivity. ARNI is indicated not only for hypertensive patients with heart failure (heart failure stage C/D) but also for those with asymptomatic heart disease (heart failure stage B pre-cardiac failure). In principle, ARNI should not be administered as the first drug as indicated in the package insert. ARNI is cleaved in the body into valsartan and sacubitril, resulting in dual effects; the former has ARB action, while the latter has multiple actions, such as the enhancing effects mediated by increased levels of endogenous natriuretic peptide [see Section 3. 7) ARNI in this chapter]. Switching from ARB or CCB monotherapy to ARNI is considered STEP 2. Combination of a CCB and an ARNI is regarded as a two-drug combination in STEP 2, but

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from the pharmacological perspective it is equivalent to STEP 3 in terms of the three different mechanisms of antihypertensive action. In STEP 2, it is essential to select MR antagonists with a low risk of side effects (adverse events), such as sex hormone-related side effects, hyperkalemia, and renal impairment [see "Section 3. 6) MR antagonist" in this chapter]. Among MR antagonists, eplerenone is contraindicated in hypertensive patients with moderate renal impairment or indiabetic patients with albuminuria/proteinuria.

If the target BP is not achieved in STEP 2, the patient proceeds to a combination of three drugs with different mechanisms of action (STEP 3). This combines drugs, with vasodilatory effects (CCBs, RAS inhibitors, ARNI), with medications that promote sodium excretion (principally thiazide-type diuretics, or ARNI or MR antagonists). If eGFR is less than 30 mL/min/1.73 m$^{2}$, a loop diuretic is used instead of a thiazide diuretic. If BP control is inadequate, medication adherence should be assessed. In patients not receiving a thiazide diuretic, the addition of a thiazide diuretic should be considered. If the target BP cannot be achieved even after these interventions, the patient is regarded as having poorly controlled hypertension; management and treatment strategies, including lifestyle modification, medication adherence, confirmation of concomitant medications, and selection and dosage of antihypertensive drugs, should be reassessed (see Chapter 11), and when necessarily, referral to a hypertension specialist is recommended.

In antihypertensive drug therapy, it is important to simplify the prescription in order to maintain medication adherence in the long term. For this reason, once daily dosing is preferrable. After STEP 2, the number of tablets should not be increased so far as it is possible, by the use of fixed-dose combination tablets. To prevent CVD, in addition to achieving the target office BP, it is also important to achieve the nocturnal and morning BP targets. Therefore, long-acting drugs should be selected. If morning or nocturnal hypertension is observed in home BP or 24-h ABPM, the once-daily morning administration of antihypertensive drugs may be modified to an evening dosing or divided into two doses (morning and evening), or added a dose can be added in the evening or before bedtime (see Q7).

Regarding the rate of BP reduction, it is desirable to achieve the target BP within a few months by following the antihypertensive therapy STEP, while avoiding side effects and adverse events. Especially for older adults with impaired renal function and BP regulation, avoid rapid lowering of BP and be aware of unexpected hypotension. In contrast, in patients at a high CVD risk, because the degree of BP reduction within 1-3 months after the start of treatment influences the incidence of CVD [548], achieving the target BP within a few weeks, including initiation of two-

drug combination therapy, should be considered. Before starting treatment, it is important to clearly present the final BP target to the patient and to specifically explain that the target will be achieved within one to several months.

3) Drug interactions

Drug interactions include pharmacodynamic interactions (no change in drug concentration in blood, but a weakening or potentiation of drug effect due to interaction at the site of action, such as receptors) and pharmacokinetic interactions (weakening or potentiation of drug effect due to changes in absorption, distribution, metabolism, and excretion of the drug). The former examples include potentiation of anti-hypertensive effects by concomitant use of a diuretic and an RAS inhibitor, suppression of cardiac function by concomitant use of a β-blocker and a non-dihydropyridine CCB, and elevation of serum potassium levels by concomitant use of an ARB/ACE inhibitor and an MR antagonist. A combination of diuretics, ACE inhibitors, ARBs, and β-blockers, along with non-steroidal anti-inflammatory drugs (NSAIDs), may attenuate the anti-hypertensive effects of these medications. Furthermore, concomitant use of diuretics, RAS inhibitors, and NSAIDs may cause a decline in renal function (COLUMN 8-3). In such cases, a change from NSAIDs to acetaminophen (1 g once daily, up to 4 g daily in Japan) is recommended.

��元字 8-3

Triple whammy to avoid: RAS inhibitors + diuretics + NSAIDs

RAS inhibitors and diuretics are the recommended combination of antihypertensive drugs, but the additional use of NSAIDs with them is a dangerous combination known as a triple whommy. It could be associated with the risk of acute kidney injury and impaired renal function. Older hypertensive patients, patients with heart failure, or those with impaired renal function require special attention to triple whammy.

Pharmacokinetic interactions are often mediated by the drug-metabolizing enzyme CYP3A4 for which approximately 60% of drugs could be the substrate, and by the transporter P-glycoprotein which acts in concert with it. Grapefruit juice, for example, inhibits those effects. Dihydropyridine CCBs are metabolized via this pathway, but they generally have a wide range of safe and effective blood concentrations, and except for azelnidipine (the blood concentration of which increases by about 3-fold and should be used with caution), increases in blood concentrations are minor [549]. Inhibition of these effects rarely results in serious adverse effects (adverse events). However, drugs

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that induce the CYP3A4 enzyme or other metabolic enzymes (rifampicin, phenobarbital, carbamazepine, etc.) may cause a remarkable decrease in the blood concentration and subsequently loss of effect when used concomitantly. In particular, hypertension emergencies and cases of treatment-resistant hypertension, whilst taking rifampicin, have been reported. It should be noted that CYP3A4 also metabolizes some anticancer drugs, and concomitant use with such drugs may enhance not only the antihypertensive effect but also that of the anticancer effect [550].

4) Dose reduction and discontinuation

BP shows a seasonal variation, rising in winter and falling in summer, but there are large differences among individuals. In patients with markedly increased BP in winter or markedly decreased BP in summer, appropriate intensification or dose reduction of antihypertensive drugs is recommended, to decrease the risk of CVD and adverse effects due to hypotension, respectively [492]. When BP is stably controlled at a low level, some patients may wish to reduce or discontinue their medication, but careful judgment is required, because a reduction or withdrawal of antihypertensive medication could result in a sudden increase in BP, which can lead to an increased risk of developing CVD. Even when BP is stable at a low level, BP rises again in 3 out of 4 patients upon drug withdrawal [551]. Patients who can be withdrawn for a long period of time usually meet the following situations of being treated with low doses of a single drug, having no organ damage, and having a thoroughly improved lifestyle. Even in such patients, if withdrawal is attempted, home BP monitoring is essential to watch the relapse of hypertension. For more information on drug reduction and withdrawal in frail patients, see "Chapter 10, 11. Older adults, 4) Polypharmacy".

2. Combination therapy

Two or three drugs are often used in combination to achieve target BP. Evidence has accumulated from large clinical trials showing that strict control of BP with a combination therapy leads to a further reduction in CVD events. There is evidence in high-risk patients in particular, that starting with a combination therapy is superior to monotherapy in achieving target BP promptly and maintaining BP control over the long term (Q6). JSH2025 recommends that patients with hypertension more than grade II, or patients with grade I hypertension who are at high risk of developing CVD, as soon as possible should be started on combination therapy to reduce the risk of developing CVD. The high sodium intake and aging of the Japanese population have led to a

large number of hypertensive patients with fluid retention. On the other hand, many patients also suffer from coronary artery disease, heart failure, and renal dysfunction, requiring a variety of treatment options that take into account comorbidities. In light of this situation, JSH2025 proposed a new antihypertensive therapy incorporating ARNI and MR antagonists which can well help to improve fluid retention (Fig. 8-1).

1) Merits of combination therapy

The preventive effect of antihypertensive treatment on CVD depends solely on the degree of BP reduction. A meta-analysis, comparing the antihypertensive effects according to the half-dose, standard dose, and double-dose CCBs, ACE inhibitors, ARBs, thiazide diuretics, and β-blockers, found no differences between drugs, and the antihypertensive effect of half-dose and double-dose compared to standard dose was -20% and +20%, respectively for all drugs [552]. The effects of the combination of each drug were additive. On the other hand, adverse effects (adverse events) increased in a dose-dependent manner with CCBs, thiazide diuretics, and β-blockers, but the risk was minor with any of the drugs at half-dose. The frequency of dry cough, seen with ACE inhibitors, was not dose dependent. ARBs had few adverse effects. Thus, half-dose combination therapy has the advantage of minimizing the incidence of side effects (adverse events) and increasing the antihypertensive effect about 1.6 fold compared to regular single-drug dosing.

2) Combination methods

(1) ARB/ACE inhibitor + CCB

A meta-analysis including 60 RCTs comparing the effects of this combination with those of 2 or 3 different combinations, showed that the combination of ARB/ACE inhibitor + CCB was superior to all other combinations in renal protection. It had less adverse effects on lipid and glucose metabolism, and was more effective in reducing CVD mortality [553]. Therefore, this is the most recommended combination therapy.

(2) CCB + diuretic

In a meta-analysis of four RCTs comparing the effects of this combination with diuretics + β-blockers, diuretics + ARBs, diuretics + placebo, CCBs + ARBs or CCBs + β-blockers, the combination of CCBs + diuretics had a similar reduction in total mortality and CVD mortality, but had significantly less myocardial infarction and stroke compared to other combinations [554]. Although this combination is rarely prescribed in clinical practice, it could be used more often in older hypertensive adults who are prone to fluid retention.

(3) ARB/ACE inhibitor + diuretic

This combination has also demonstrated efficacy as a combination therapy. There is evidence that all-cause mortality is reduced in patients aged 80 years and older

The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and...

[316] and recurrent stroke is prevented in patients with previous stroke, with the addition of a diuretic to an ACE inhibitor [555].

(4) ACE inhibitor + ARB

This combination was initially noted to be more effective in improving proteinuria than increasing doses of the single agents. However, a large RCT in patients at high risk for vascular events or diabetes mellitus revealed a high incidence of adverse events such as worsening renal function, hyperkalemia, and hypotension, with no difference in efficacy in preventing the development of CVD [556, 557]. Therefore, this combination is considered to cause more harm than benefit. It is not recommended in JSH2025, and it is no longer recommended worldwide.

(5) CCB + ARB/ACE inhibitor + diuretic

The combination of these three drugs lowers both office BP and 24-h BP more than the combination of any two of these drugs, while the incidence of adverse events remains the same [558]. Therefore, if BP cannot be controlled with two drugs, the combination of these three drugs is recommended.

(6) Others

ARNI has been reported to safely double the target BP achievement rate when used in combination in hypertensive patients who cannot achieve target BP with a CCB alone [559]. However, there are no reports evaluating the efficacy or adverse events of concomitant use with thiazide diuretics. Thus, when using these drugs in combination, caution is required. In HFpEF patients with treatment-resistant hypertension, ARNI is effective in lowering BP with or without MR antagonists [560].

MR antagonists have been used in combination with CCBs, diuretics, RAS inhibitors, and β-blockers in treatment-resistant hypertension or hypertension with heart failure. In treatment-resistant hypertension, spironolactone has been reported to show significantly greater anti-hypertensive effects than bisoprolol or doxazosin [561].

3) Fixed combination drugs

Simplified prescription, by reducing the number of tablets taken through the use of fixed combination drugs, is useful for improving adherence. Combination drug therapy improves adherence [562], long-term as well as short-term BP control [563, 564], and prognosis [564, 565], greater than two-drug therapy. In Japan, there are currently combination drugs consisting of an ARB and a CCB, an ARB and a diuretic, and a fixed-dose combination of an ARB, a CCB, and a diuretic. These combinations should be used effectively. Fixed dose combination of two drugs exist in various combinations ranging from half to double the dosage, so they should be selected according to the situation. Although Japanese public insurance does not permit the administration of combination drugs as the initial medication, we would like to promote them in STEP 1 of

antihypertensive treatment, especially for low-dose combination drugs, to take advantage of the efficacy of these combination drugs. This is expected to contribute to prompt BP management, especially in patients with hypertension of grade II or higher and those at high risk.

3. Characteristics and main side effects of antihypertensive drugs

1) CCBs

CCBs bind to Ca channels on cell membranes and inhibit Ca ion influx into cells, mainly by relaxing vascular smooth muscle, thereby lowering BP. In particular, long-acting DHP-based CCBs are widely used as antihypertensive drugs [566–568]. Non-DHP CCBs are classified into benzothiazepines (BTZ) and phenylalkylamines, but BTZ is used as an antihypertensive drug in Japan, while verapamil, a phenylalkylamine, is used for tachyarrhythmia and is not covered by insurance in Japan. Some CCBs have subtype Ca channel inhibitory activity, such as N- and T-type Ca channels, in addition to L-type Ca channels, but their main action is against L-type Ca channels.

Amlodipine, currently the most frequently used anti-pervertensive drug, has a long half-life in blood and a long duration of action, slow onset of effect, and is less likely to cause reflex sympathetic activation or RAS activation [569]. Nifedipine was the first CCB to be developed, and its long-acting formulation is widely used as a major anti-hypertensive agent. Short-acting nifedipine is a fast-acting and potent antihypertensive, but its use is limited because of the reflex sympathetic activation associated with BP reduction, which may increase myocardial oxygen consumption. Oral administration of nifedipine capsule contents should not be used in patients with an impending hypertensive emergency, as excessive hypotension can induce reflex tachycadia and ischemic stroke.

Long-acting DHP-type CCBs suppress left ventricular hypertrophy and the development of atherosclerosis, have little effect on glucose, lipid, and electrolyte metabolism, and are superior in preserving organ blood flow, making them a first choice for older adults and patients with complicated organ damage. In addition, its low variability in BP and stable antihypertensive effect have been shown to reduce the incidence of heart disease and death from cardiovascular events [221, 570, 571].

Known side effects of DHP-based CCBs include hypotension, palpitations, headache, hot flashes, facial flushing, edema, as well as gingival thickening and constipation. Edema occurs because arterioles dilate while venules do not, leading to an increase in capillary pressure.

The only BTZ-type CCB is diltiazem. Although diltiazem is a weak peripheral vasodilator, it strongly suppresses the stimulatory conduction system, especially

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atrioventricular nodal conduction, and increases coronary blood flow. Diltiazem is indicated for essential hypertension (mild to moderate) and vasospastic angina. Diltiazem is contraindicated in patients with congestive heart failure, atrioventricular block of degree II or greater, and sick sicus syndrome. Also, caution should be exercised in older adults with underlying heart disease and in patients receiving digitalis or β-blockers.

2) ARBs

ARBs are the most commonly used antihypertensive agents, along with CCBs [572, 573]. Like ACE inhibitors, ARBs are also referred to as RAS inhibitors. ARBs exert their antihypertensive effects by inhibiting the binding of angiotensin II (AII) to angiotensin type 1 (AT1) receptor, thus blocking the strong AII-induced vasoconstriction, fluid retention and sympathetic nerve activity. The type 2 (AT2) receptor, which antagonizes the cardiovascular effects of AT(1) receptors, is assumed to be stimulated by the administration of ARBs [574].

ARBs have also been shown to be organ-protective, and have been used as first-line agents in patients with heart, renal, and cerebral organ complications and diabetes [573, 575]. Most of their organ-protective effects are, however, derived from their antihypertensive effects [576]. Together with ACE inhibitors, they have demonstrated usefulness in the treatment of heart failure. The efficacy as an antihypertensive drug has been demonstrated for ACE inhibitors. Although not clearly different in their efficacy as antihypertensive agents from that of ACE inhibitors, the rate of discontinuation is low because of the minimal coughing as a side effect [556, 573]. The efficacy of ARBs is mostly the same class effects, but losartan has a uric acid-lowering effect. Prescribing combination drugs as adjunctive therapy including ARBs is increasing, and simplifying prescribing by using them without excessive lowering BP is believed to improve adherence and BP control [575].

ARBs are well-tolerated with a low incidence of adverse effects regardless of the dose. However, they are contra-induced in women who are pregnant or may be pregnant. Evidence regarding use during lactation is insufficient, therefore it should generally not be used. ARBs should be administered with caution to patients with severe hepatic impairment. In principle, ARBs are contraindicated in patients with bilateral renal artery stenosis or unilateral renal artery stenosis in a single kidney, since they can cause rapid deterioration of renal function. ARBs are also semi-contraindicated in cases of fluid loss or severe sodium deficiency. In older patients and patients with CKD (especially those already with reduced renal function and an eGFR of less than 30 mL/min/1.73 m$^{2}$), renal function may deteriorate, so the drug should be started cautiously, at low doses. After starting on the drug, eGFR and serum potassium should be measured within 2–4 weeks, and monitoring

should be continued thereafter. If eGFR falls by 30% or more of the previous value or serum potassium rises to 5.5 mEq/L or higher, it should be discontinued and a nephrologist or hypertension specialist consulted.

3) ACE inhibitors

ACE inhibitors were the first RAS inhibiting drugs to be developed and have been shown to be effective in many RCTs. They inhibit angiotensin II production and also enhance the renin-angiotensin-kinin-prostaglandin system in the powerful RAS, thereby contributing to the anti-hypertensive effect. The antihypertensive effect of ACE inhibitors alone is considered to be comparable to or slightly weaker than that of ARBs, but their efficacy in reducing CVD events and overall mortality in hypertensive patients is considered equivalent to that of ARBs [577]. ACE inhibitors activate the fibrinolytic system and inhibit the coagulation system. A meta-analysis of BPLTTC studies demonstrated that ACE inhibitors significantly reduce the risk of coronary artery disease [537]. In diabetic patients, they reduce the risk of myocardial infarction and all-cause mortality [578]. Also, ACE inhibitors and ARBs, as RAS inhibitors, suppress progression to end-stage renal disease in patients with CKD [579, 580]. ACE inhibitors also demonstrate efficacy in reducing CVD events and overall mortality [580].

The maximum dosage of ACE inhibitors is set at lower doses in Japan compared to Europe and America. Therefore, their antihypertensive effect is weaker than that of ARBs, and their use as an antihypertensive drug is less common in Japan than in Europe and America. This is due to their side effect of dry cough caused by increased bra- dykinin action, which is more common in East Asians, including the Japanese [581]. On the other hand, a pre- ventive effect against aspiration pneumonia caused by induced coughing has been proposed [582]. An important side effect is angioedema. It is contraindicated to use during apheresis with an adsorber using dextran sulfate- immobilized cellulose, tryptophan-immobilized polyvinyl alcohol, or polyethylene terephthalate or with sodium acrylonitrile methally sulfonate membranes, because it has been reported to cause shock and anaphylaxis-like symp- toms. Cilazapril should not be used in patients with cirrhosis of the liver accompanied by ascites, as it may cause excessive hypotension. In patients with renal impairment, ACE inhibitors should be administered in low doses as most are renally excretory. The other side effects and precautions are basically the same as those for ARBs, but contra- indicated in women who are pregnant or could be pregnant. For breastfeeding women, avoid immediate use after delivery; thereafter, it may be used with caution.

4) Diuretics

Diuretics, especially low-dose thiazide diuretics, have long been the first-line drugs for antihypertensive treatment,

The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and...

and there is much evidence showing their efficacy in reducing the incidence of CVD and improving prognosis [538, 567, 583, 584]. Thiazide diuretics decrease circulating blood volume by inhibiting sodium reabsorption in the distal tubule, but in the long term, they lower BP by decreasing peripheral vascular resistance. The thiazide diuretics are classified into two types of diuretics: thiazide diuretics, such as trichlormethiazide and hydrochlorothiazide, and thiazide analogues, such as indapamide [585, 586]. Comparisons between thiazide diuretics and thiazide analogues have been studied, but no differences in CVD outcomes were observed [586]. Thiazide diuretics alone have been reported to reduce CVD events, and they are inexpensive and cost-effective [584]. In fact, they are often used in combination with other drugs, and the prescription rate of diuretics is high in large clinical trials [342].

Thiazide diuretics are used as antihypertensive agents in patients with eGFR ≥ 30 mL/min/1.73 m$^{2}$. In patients with severely impaired renal function or end-stage renal failure (eGFR less than 30 mL/min/1.73 m$^{2}$), loop diuretics are administered first; they exert their diuretic effect by inhibiting NaCl reabsorption in the ascending limb of Henle's loop. Compared to thiazide diuretics, loop diuretics have a stronger diuretic effect but a weaker antihypertensive effect. In CKD, the addition of a thiazide diuretic to a loop diuretic may have an antihypertensive effect [587].

Diuretics can be widely used. They are particularly effective in hypertensive individuals with increased sodium sensitivity, such as older adults, hyporeninemic hypertension, CKD associated hypertension, and diabetes mellitus. They are also effective in hypertension with difficulty in reducing sodium, hypertension associated with fluid overload such as edema, treatment-resistant hypertension, and have excellent preventive effects on heart failure [342, 567, 588]. In the COPE study in Japanese subjects, thiazide diuretics were shown to be useful in preventing stroke as concomitant therapy with CCBs [589].

Thiazide diuretics may be administered in low doses (generally, half the dose, although the equivalent of one-fourth the dose is available in fixed-dose combinations) to achieve good antihypertensive effects with fewer side effects [588]. Specific examples include trichlormethiazide 0.5 to 1 mg, hydrochlorothiazide 6.25 to 12.5 mg, and indapamide 0.5 to 1 mg. In addition, concomitant use with other classes of antihypertensive drugs increases their antihypertensive effect, but concomitant use with β-blockers for lowering BP is not recommended due to their adverse effects on glucose and lipid metabolism. In addition, it has been reported that concomitant use with RAS inhibitors is superior in improving proteinuria [590].

The adverse effects of diuretics include electrolyte abnormalities such as hyponatremia, hypokalemia, and

hypomagnesemia [591, 592], renal dysfunction (decreased eGFR), excessive hypotension during summer due to seasonal BP changes, and adverse effects on the metabolic system such as impaired glucose tolerance, hyperuricemia and hypertriglyceridemia [588]. Electrolyte abnormalities are overlooked unless specifically measured. Prevention of hypokalemia is important to reduce mortality in hypertensive patients [592]. For the prevention of hypokalemia, concomitant use of ACE inhibitors or ARBs, or concomitant use of potassium preparations or MR antagonists, as well as guidance on the intake of citrus fruits with a high potassium content, are recommended. If hypokalemia is observed, causes other than diuretics should be determined as necessary. Photosensitivity and thrombocytopenia are serious adverse reactions, although their incidence is low.

5) β-blockers (including αβ-blockers)

β-blockers lower BP primarily by decreasing cardiac output and inhibiting renin secretion from the kidneys, and secondarily by decreasing central sympathetic outflow. Individual β-blockers differ substantially in β₁ selectivity, presence or absence of α-blockade, intrinsic sympathometric activity, lipophilicity/hydrophilicity, duration of action, and effects on glucose and lipid metabolism. Therefore, the choice of drug should be made with utmost consideration.

Compelling indications for using β-blockers include HFrEF, post-myocardial infarction, angina pectoris due to organic coronary artery stenosis, aortic dissection, and thoracic aortic neurysm. In addition, they are effective for hypertension in young adults with increased sympathetic activity, tachycardic hypertension, stress-induced hypertension, hyperdynamic (high-cardiac output) hypertension such as that seen in hyperthyroidism, hyperreninemic hypertension, and hypertensive patients with tachycardic atrial fibrillation.

Bisoprolol and carvedilol—agents with established efficacy and safety—are recommended for antihypertensive treatment in patients with compelling indications for heart disease and tachycardic atrial fibrillation [593–596]. In hypertension without compelling indications, β-blockers have been shown to adversely affect glucose and lipid metabolism and to be inferior to other major anti-hypertensive classes in preventing target-organ damage and CVD. These findings derive primarily from studies using conventional β-blockers, such as atenolol. αβ-blockers and lipophilic β-blockers have been reported to have fewer glucose- and lipid-metabolizing side effects than hydrophilic β-blockers (e.g., atenolol) [597–599]. In addition, long-acting agents are desirable as antihypertensive drugs. Therefore, carvedilol (an αβ-blocker) and bisoprolol (a lipophilic, highly β₁-selective β-blocker), both of which are long-acting, may be useful; however, future clinical trials comparing long-term outcomes among β-blockers in

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hypertension are needed. Labetal, an αβ-blocker, can be used in pregnant women with hypertension and in women planning pregnancy [600, 601]. In addition to the oral formulation, a transdermal patch of bisoprolol is available and is indicated for tachycardic atrial fibrillation and hypertension.

Contraindications or conditions requiring caution with β-blockers include bronchial asthma, severe bradycardia, atrioventricular block of degree II or greater, and pheochromocytoma/paraganglioma without adequate α-blockade. In bronchial asthma, non-selective β-blockers and the αβ-blocker carvedilol are contraindicated. However, in patients with HFrEF or the aforementioned coronary artery disease who also have bronchial asthma or chronic obstructive pulmonary disease (COPD), cautious use of bisoprolol—a highly β₁-selective agent—with close monitoring for respiratory symptoms is recommended.

Accordingly, recognizing that the choice of β-blocker should vary by disease state, the appropriate use of β-blockers in patients with hypertension should be promoted. In particular, among the compelling indications—such as HFrEF and the post-myocardial infarction state—their efficacy in improving prognosis and reducing cardiovascular events is well established; therefore, β-blockers should be continued as long as possible with careful monitoring for tradycardia and hypotension. Tailoring therapy to each patient's condition is essential, and consultation with a cardiologist is advisable, especially when β-blockers are used in hypertensive patients with heart disease.

β-blockers, whether used as monotherapy or in combination with diuretics, may adversely affect glucose and lipid metabolism [602–605]. Therefore, when employing two-drug antihypertensive therapy that includes a β-blocker, combining the β-blocker with a non-diuretic agent may be more appropriate than pairing it with a diuretic.

6) MR antagonists

These drugs antagonize aldosterone-induced MR activation in the distal kidney tubule and conjugated collecting kidney tubule, suppressing urinary potassium excretion and promoting sodium excretion, resulting in antihypertensive effects. They can be classified into two types, spironolactone and eplerenone, which have steroidal skeletons, and esaxerone, which is a non-steroidal type. For treatment-resistant hypertension, further BP lowering effects can be expected with the addition of low to moderate doses (e.g. 25-50 mg/day) of spironolactone [606, 607]. It is also used as the key drug in the pharmacotherapy of PA [608]. Numerous RCTs have shown that spironolactone and eplerenone improve prognosis after heart failure or myocardial infarction [609–611] and are one of the standard treatments for HFrEF [612]. Eplerenone should be used with caution in chronic heart failure and hypertension, as its

dosage and administration differ. When added as a second drug to a CCB or RAS inhibitor, which are the main anti-hypertensive drugs, eplerenone has an antihypertensive effect equivalent to that of an additional thiazide diuretic [613]. Eplerenone is contraindicated in diabetic patients with albuminuria or proteinuria and in hypertensive patients with moderate renal dysfunction (30 mL/min/1.73 m$^{2}$ ≤ eGFR<60 mL/min/1.73 m$^{2}$). However, esaxerone and spironolactone can be administered if attention is paid to renal function and serum potassium levels. On the other hand, a double-blind study showed that additional administration of eplerenone in hypertensive patients with CKD without diabetes mellitus, who were taking ARBs, had an antihypertensive effect and decreased albuminuria [614]. Eplerenone and esaxerone have fewer sex hormone-related adverse events than spironolactone. Both MR antagonists may cause hyperkalemia in combination with RAS inhibitors, renal dysfunction, or heart failure, and timely monitoring of serum potassium levels is important during the course of treatment.

7) ARNI

ARNI is a 1:1 monocomplex of sacubitril, a prodrug of sacubitrilat with a neprilysin inhibitor, and valsartan, which blocks angiotensin II type 1 (AT1) receptors. Neprilysin is a degrading enzyme of the natriuretic peptide system as well as various substances [615]. Sacubitril is metabolized to sacubitrilat, which increases endogenous natriuretic peptides by inhibiting neprilysin [616]. The antihypertensive effect of ARNI is thought to be a dual effect of the activation of endogenous natriuretic peptide function and AT1 receptor blockade [615].

Natriuretic peptide increases the GFR in the kidneys by dilating afferent arterioles, constricting efferent arterioles, and relaxing the mesangium. It also inhibits sodium and water reabsorption in the intramedullary collecting ducts and promotes natriuresis. In peripheral arteries and capillary vessels, natriuretic peptide increases cGMP in vascular smooth muscle and promotes vasodilation. Sacubitril alone increases angiotensin II activity since sacbitrilat also inhibits angiotensin II degradation and it antagonizes the anti-hypertensive effect of natriuretic peptides. The combination of sacubitril and valasertan is thought to produce significant antihypertensive effects by offsetting the angiotensin II-activating effect of sacubitril.

In patients with mild to moderate essential hypertension, ARNI has a significantly greater antihypertensive effect than valsartan or olmesartan [616–619]. Although it has a diuretic effect, it does not increase uric acid levels; rather, it is likely to decrease them, possibly due to its unique effects on renal function [620]. In a meta-analysis of 10 RCTs, the safety and tolerability of ARNI did not differ from those of the placebo [621]. Even in hypertensive patients with CKD,

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ARNI did not worsen renal function and produced a significant reduction in BP relatively safely [622, 623]. When switching from an ACE inhibitor, allow at least 36 h between doses to avoid the risk of angioedema.

8) Others

(1) α-blockers

α-blockers selectively block α-1 adrenergic receptors on the smooth vascular muscle and block the stimulation of these receptors by noradrenaline released from sympathetic nerve terminals, thereby dilating blood vessels and lowering BP. It has been shown to improve insulin resistance and have a positive effect on glucose and lipid metabolism. Because orthostatic hypotension is likely to occur with a first dose as an episode, start with lower doses and titrate up.

(2) Centrally acting sympatholytic drugs

These agents exhibit antihypertensive effects by stimulating α-2 adrenergic receptors in the rostral ventral lateral medulla, the sympathetic control center, thereby suppressing sympathetic activity. Adverse effects such as orthostatic hypotension, drowsiness, weakness, thirst, and impotence are observed, and withdrawal symptoms may occur after abrupt discontinuation of methyldopa. Methyldopa can be used safely in pregnant women [624] but hyperprolactinemia and amenororhea may occur, so caution is required.

(3) Classic vasodilators

Hydralazine acts directly on the smooth vascular muscle of peripheral arteries to dilate the vessels, thereby lowering BP [625]. It is fast-acting and used in hypertensive emergencies. It is safe to use in pregnant women. Caution should be exercised with side effects such as tachycardia, headache, palpitations, angina pectoris, systemic lupus erythematosus-like symptoms, hepatitis, and paralytic ileus.

Q 6 In patients with grade III hypertension (severe hypertension) or high-risk hypertension, is it appropriate to initiate antihypertensive therapy as combination therapy?

* In high-risk patients, prognosis is improved from prompt achievement of target BP.

$\bullet$ In high-risk patients, prognosis is improved from prompt achievement of target BP.

$\bullet$ For prompt achievement of target BP, starting anti-hypertensive therapy with a combination therapy is more effective than monotherapy.

$\bullet$ Combination therapy has a higher rate of achieving target BP than monotherapy at regular follow-up visits. This is one of the factors contributing to improved prognosis.

Explanation

According to global hypertension treatment guidelines, combination therapy for antihypertensive treatment is the

mainstream approach for patients with grade II or higher hypertension or high-risk hypertension, not only in Western countries but also in East Asian countries [183, 626–628]. Starting with monotherapy is permitted in only a few guidelines.

1) High risk patients and the importance of rapid achievement of target BP

In a post-hoc analysis of the VALUE trial targeting high-risk patients, the group that achieved target BP within six months had a lower risk of CVD compared to the group that achieved their target later [629]. Furthermore, this trial demonstrated that even BP at one month after treatment initiation was associated with future CVD risk [548]. This suggests that rapid achievement of target BP, preferably within a few weeks, is important for reducing the risk of CVD events in high-risk patients.

2) Achieving rapid target BP and the limitations of monotherapy

BP is regulated by multiple systems, and inhibiting one regulatory system often activates compensatory mechanisms that attempt to buffer BP reduction. Therefore, inhibiting two pressor pathways simultaneously can suppress compensatory responses to one antihypertensive pathway, potentially leading to faster and more reliable BP reduction. In fact, compared to monotherapy, combination therapy has been reported to achieve faster BP reduction [630], enable earlier attainment of target BP, and improve outcomes [631]. As the major hypertension treatment guidelines worldwide recommend BP targets <130/80 mmHg, high risk patients with BP ≥140/90 mmHg should initiate combination therapy to achieve target BP more rapidly. A meta-analysis based on RCTs of various antihypertensive drugs (CCBs, β-blockers, diuretics, ACE inhibitors, ARBs) reported that the SBP reduction with single-drug therapy at standard doses was not significantly different among the drugs, with an average reduction of 9.1 mmHg [552]. In patients with grade III hypertension (≥180/110 mmHg), the difference from the target BP (130/80 mmHg) is 50/30 mmHg lower, making it nearly impossible to achieve it with monotherapy, so combination therapy should be initiated from the start. Note that exclusion of secondary hypertension is mandatory in patients with grade III hypertension. Additionally, white-coat hypertension, which rarely presents with extreme white-coat phenomenon, exists; therefore, confirming that out-of-office BP is in the hypertension range before starting the treatment is important.

3) Long-term BP target achievement rate

Results from post-hoc analyses of RCTs in high-risk patients and large observational studies indicate that the rate of achieving BP targets at clinic visits over a certain period is associated with a prognosis with better outcomes

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observed in patients with more frequent BP control [632, 633]. Therefore, it is important to maintain BP below the target level at each clinic visit. When comparing the one-year target BP achievement rates between patients who started combination therapy and those who started monotherapy, the combination therapy group had a higher rate [634]. This is likely due to the higher incidence of clinical inertia in the monotherapy group, where patients are often observed without being stepped up to combination therapy [564]. Starting with combination therapy allows for effective BP management without increasing the number of medications by adjusting the dose of each drug or using combination agents when further dose escalation is needed. This also helps maintain adherence, ultimately leading to higher target BP achievement rates.

7 Can prognosis be improved by adjusting the time of administration (chronotherapy), taking into account the action of the drug?

$\bullet$ The effect of bedtime administration of antihypertensive drugs on the prevention of CVD events is limited, and no clear conclusions have been reached. $\bullet$ Tailored therapy for morning or nocturnal hypertension is acceptable after consultation with the patient.

Commentary

1) Evidence for chronotherapy

Early morning hypertension and nocturnal hypertension assessed by ABPM and home BP have been shown to be associated with CVD events. The currently available anti-hypertensive medications often have an antihypertensive effect that does not persist for 24 h. If early morning or evening BP is high by HBPM or ABPM, it may be possible to control BP elevation in the early morning by taking antihypertensive medications in the evening, dividing them into two doses (morning and evening), or adding an additional dose in the evening. In this case, the conventional oral treatment is not sufficient to control BP elevation in the early morning. Therefore, the clinical practice is to give antihypertensive drugs in the evening to correct early morning or nocturnal hypertension that is poorly controlled with conventional medical therapy.

Although a meta-analysis reported that nocturnal anti-hypertensive medication reduces CVD risk [635], subsequent studies indicated that some trials were highly biased [636–638], and the 2022 ISH position paper stated that bedtime administration of antihypertensive medications should not be uniformly recommended [639]. The 2023 ESH guideline also noted concerns about quality of the research on bedtime administration and about decreased adherence in taking bedtime medication. They also stated

that bedtime administration should be considered in cases of multiple drug use (with the exception of diuretics and other drugs not suitable for bedtime administration), taking into consideration the patient's wishes [183].

A recent clinical study has reported a new finding. In the TIME trial, there was no significant difference in the primary outcome between the evening and morning dosing groups, and there was no difference in safety either [640]. Furthermore, real-world data from the Spanish ABPM registry showed no significant difference in all-cause or cardiovascular mortality between the morning and bedtime dosing groups [641]. In the HARMONY trial, there was no significant difference in the 24-h mean SBP between the morning and evening dosing groups, with the nighttime SBP being 1.68 mmHg lower in the evening dosing group compared to the morning group [642]. In the TIME study, some subjects had their HBPM, and morning SBP was 17.7 mmHg lower in the evening group, while evening SBP was 1.06 mmHg higher [640]. When correcting morning hypertension or other hypertension with chron-otherapy in actual clinical practice, the degree of anti-hypertensive reduction at the target time is expected to be greater than in these studies, and the results of these large clinical studies are not directly applicable. Clinical trials comparing the timing of antihypertensive medication administration, such as BED-MED [643] and BedMed-Frail [644], do not specifically address antihypertensive medication before bedtime for morning and nighttime hypertension and do not provide answers for individual treatment.

2) Circadian rhythm and the possibility of future chronotherapy

A workshop at the U.S. National Heart, Lung, and Blood Institute has discussed bridging the gap between evidence and real-world clinical practice in BP circadian rhythms [645]. The RAS has diurnal variations, and the use of ACE inhibitors, ARBs, and other drugs, such as chronotherapy administered before bedtime is expected to inhibit atherosclerosis [646], and it has been reported to reduce hypertensive organ damage [647].

Chronotherapy may be useful for BP morning surge, nocturnal hypertension, and renal disease [648]. We cannot conclude that chronotherapy is useful in these cases if there is no verification of its event-suppressing effect. However, tailored therapy for morning and nocturnal hypertension may be considered if the patient agrees with it.

Conclusion

Although we do not uniformly recommend chronotherapy with antihypertensive drugs for hypertensive patients at present, tailored therapy for morning or nocturnal hypertension is acceptable after consultation with the patient.

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Chapter 9. Diagnosis of hypertension-mediated organ damage and treatment of hypertension

[POINT 9a]

[Cerebrovascular disease]

1. In the hyperacute phase (within 24 h of onset) and the acute phase (within 2 weeks of onset) of ischemic stroke, when thrombolytic therapy or mechanical thrombolysis is not indicated, careful antihypertensive treatment should be considered. But this should be only in cases of persistent hypertension exceeding 220 mmHg SBP and 120 mmHg DBP, in cases of aortic dissection, acute myocardial infarction, heart failure, renal failure, or other complications. Significant hypotension (shock) should be promptly corrected with intravenous fluids and antihypertensive drugs.

2. For patients with ischemic stroke in the subacute or chronic phase (after 2 weeks of onset), the target BP is <130/80 mmHg. However, patients with severe bilateral carotid artery stenosis, occlusion of the main cerebral artery, or unassessed vessels, should be treated on an individual basis.

3. In the acute phase of intracerebral hemorrhage, SBP should be lowered to <140 mmHg as soon as possible. The lower limit should be maintained above 110 mmHg. An SBP drop of >90 mmHg is not recommended to avoid renal dysfunction associated with rapid antihypertensive therapy. In the chronic phase of intracerebral hemorrhage, the target BP should be <130/80 mmHg. If the risk of recurrent intracerebral hemorrhage is high, a target BP of <120/80 mmHg should be considered.

4. In mild to moderate subarachnoid hemorrhage due to ruptured cerebral aneurysm, between the onset of

|||Conditions to treat|Target BP level|Antihypertensive drugs| |---|---|---|---|---| |Hyperacute $phase^{a}$ (Patients with ischemic stroke in whom thrombolytic therapy is indicated)|Within 4.5 h after onset of ischemic stroke|SBP ≥185 mmHg or DBP ≥110 mmHg|During thrombolytic therapy and within 24-h after thrombolytic therapy: SBP <180/105 mmHg, 85-90% of the pretreatment value|Micro-dose drip infusion of CCBs such as nicardipine| |(After mechanical thrombectomy for ischemic stroke)|Within 24-h after onset of ischemic stroke|SBP≥180 mmHg|<180 mmHg|| |Acute phase (Within 2 weeks after onset)|Ischemic stroke|SBP > 220 mmHg or DBP > 120 mmHg|85% of the pretreatment value|Micro-dose drip infusion of CCBs such as nicardipine, or oral drugs (CCBs, ACE inhibitors, ARBs or diuretics)| ||Intracerebral hemorrhage|SBP≥140 mmHg|SBP<140 mmHg$^{b}$ and SBP> 110 mmHg|| ||Subarachnoid hemorrhage mild to moderate (from the onset of ruptured cerebral aneurysm until the treatment of cerebral aneurysm)|SBP≥160 mmHg|SBP<160 mmHg$^{c}$|| |Subacute phase/ Chronic phase (≥2 weeks after onset)|Ischemic stroke|SBP≥130 mmHg|<130/80 mmHg$^{d}$|Oral drugs (CCBs, ACE inhibitors, ARBs or diuretics)| ||Intracerebral hemorrhage, subarachnoid hemorrhage|SBP≥130 mmHg|<130/80 mmHg$^{e}$||

ªRefer to "Chapter 16, 1. 4) Acute cerebrovascular diseases"

ᵇIn patients in whom increased intracranial pressure is expected due to a severe condition, it must be considered that cerebral perfusion pressure may reduce with a decrease in BP, causing acute kidney injury or deteriorating symptoms; therefore, BP reduction should be performed with caution

^a In patients in whom increased intracranial pressure is expected due to a severe condition or in those with acute ischemic stroke or cerebrovascular spasm, cerebral perfusion pressure may reduce with a decrease in BP, causing deteriorating symptoms; therefore, BP reduction should be performed with caution

^dRefer to CQ8. BP should be lowered slowly. In cases of bilateral carotid artery stenosis or cerebral main artery occlusion, be careful not to lower excessively. For those having bilateral carotid artery stenosis or cerebral main artery occlusion, or for those whose vessels have not been evaluated, individualized management is necessary

^e Refer to CQ8. In cases with a high risk of recurrent intracerebral hemorrhage, consider more strict BP management with a target BP <120/80 mmHg

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subarachnoid hemorrhage and aneurysm treatment, SBP should be lowered to <160 mmHg.

5. Antihypertensive drugs recommended in the hyperacute phase of cerebrovascular disease include micro-dose drip infusion of nicardipine, diltiazem, nitroglycerin or nitroprusside. However, early timing after the initiation of infusion, these should be switched to oral antihypertensive drugs. Sublingual nifedipine should not be used because it can cause rapid hypotension.

6. The recommended oral antihypertensive drugs for patients with cerebrovascular disease are CCBs, ACE inhibitors, ARBs, and diuretics.

1. Cerebrovascular diseases

In Japan, cerebrovascular diseases account for a large proportion of the hypertensive organ disorders, and in combination with the aging of the population structure, there is an increasing number of patients with cerebrovascular diseases, especially ischemic stroke. A large proportion of patients with cerebrovascular disease have hypertension in the acute phase, and the first question is how to manage BP. In ischemic stroke, as a rule, BP should not be lowered except under special conditions. In the hyperacute phase, during reperfusion therapy (thrombolytic therapy and endovascular therapy), antihypertensive therapy should be considered. Furthermore, hypertension is the most important risk factor for recurrence in patients with cerebrovascular disease; thus, hypertension must be controlled to prevent recurrence. In hypertensive patients with cerebrovascular disease, the target BP should be determined based on the clinical presentation, time since onset, severity of disease, age, and antithrombotic medication use (Table 9-1). It is also important to control BP in older hypertensive patients with asymptomatic cerebrovascular disease, which is known to occur at a high rate in such patients.

1) Acute phase

In patients with suspected acute stroke, head imaging should be performed promptly to diagnose ischemic stroke, intracerebral hemorrhage, or subarachnoid hemorrhage. In acute ischemic stroke, as a general rule, do not lower BP and immediately refer to a specialized clinical department such as neurology or neurosurgery. In acute intracerebral hemorrhage, BP lowering may be considered before urgent referral to a specialized department.

(1) Target BP

① Ischemic stroke

The latest large scale RCT has shown that lowering SBP to 130–140 mmHg during emergency transport of stroke patients was associated with an increased risk of poor outcomes in ischemic stroke and transient cerebral ischemia

(TIA) [649]. In ischemic stroke, in general, BP should not be lowered except under special conditions. The Japan Stroke Society (JSS) Guideline 2021 for the Treatment of Stroke (revised in 2023) [235] states that during the acute phase, if thrombolytic therapy or mechanical thrombectomy is not performed, treatment to lower BP can be performed carefully for patients with continuous SBP>220 mmHg or DBP>120 mmHg, or for patients with aortic dissection, acute myocardial infarction, heart failure, or renal failure [235, 650, 651]. The ESH/ESC Hypertension Guidelines [652] recommend that antihypertensive drug therapy should be started immediately after diagnosis for patients with TIA, and within a few days after diagnosis for patients with ischemic stroke. However, the optimal BP target remains unclear. In severe hypotension (shock), prompt care with intravenous fluids and vasopressors is recommended [235, 650].

② Intracerebral hemorrhage

The latest large scale RCT has shown that the reduction of SBP to 130–140 mmHg during emergency transport for intracerebral hemorrhage was associated with fewer poor outcomes [649]. Therefore, BP lowering therapy should be conducted earlier in cases of intracerebral hemorrhage. The JSS Guideline for the Treatment of Stroke (2023 Revision), states that high BP should be lowered to SBP <140 mmHg as early as possible during the acute phase, and maintaining the lower limit above 110 mmHg should be considered. The use of intensive BP lowering therapy, resulting in an SBP reduction of more than 90 mmHg, is not recommended to avoid acute kidney injury associated with antihypertensive therapy [235, 653, 654].

A multicenter observational study in Japan demonstrated that it is safe to reduce SBP to 120–160 mmHg with nicardipine intravenous infusion [655]. Large RCTs such as INTERACT2 [656], ATACH-2 [657], and SRs [651, 658–660] have demonstrated that intensive BP lowering therapy in the acute phase of intracerebral hemorrhage inhibits hematoma expansion. The effects on mortality and major functional disability at 3 months have not been proven; however, the consensus of experts is to recommend rapid BP reduction within 2 h of onset as the ideal approach [651]. However, excessive BP reduction has been associated with an increased risk of cardiac and renal complications [653, 654].

Regarding intracerebral hemorrhage in patients taking warfarin, maintaining PT-INR<1.3 and SBP<160 mmHg within 4 h has been reported to be associated with suppression of hematoma expansion [661].

③ Subarachnoid hemorrhage

In subarachnoid hemorrhage, preventing rebleeding is crucial, and adequate sedation and pain control are recommended. The effectiveness of BP management in reducing the risk of rebleeding has not been established [662]. In

The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and...

subarachnoid hemorrhage caused by a ruptured cerebral aneurysm, if SBP exceeds 180–200 mmHg from onset to management of the aneurysm, the American Stroke Association guidelines recommend gradual BP reduction [663]. However, hypotension must strictly be avoided with a mean BP <65 mmHg and frequent neurological assessment during BP reduction is recommended. Previous guidelines set the target values at <160 mmHg or <180 mmHg, but the latest guidelines do not specify a target BP. The JSS Guideline for the Treatment of Stroke (2023 Revision) [235] states that reducing SBP to <160 mmHg is appropriate for mild to moderate patients. Data supporting the efficacy of intravenous nicardipine as an antihypertensive drug in the acute phase of subarachnoid hemorrhage have been reported and are worth considering [664, 665]. Additionally, in severe cases where increased intracranial pressure is anticipated, or in cases with concomitant acute ischemic stroke or cerebral vasospasm, caution is warranted, as BP reduction may lead to decreased cerebral perfusion pressure and exacerbate symptoms.

(2) Pharmacological therapy

Drugs should be selected for their rapid onset of action and ease of dose adjustment, regardless of the clinical subtype of cerebrovascular disease. CCBs such as nicardipine or diltiazem, or nitroglycerin or nitroprusside (nitrate drugs) administered as a micro-dose drip intravenous infusion are recommended [666]. Importantly, sublingual administration of nifedipine capsules should not be used due to the risk of causing a sudden decrease in BP. Furthermore, intravenous antihypertensive therapy should be kept as short as possible and quickly switched to oral therapy [235]. Oral antihypertensive drugs include CCBs, ARBs, ACE inhibitors, and diuretics [666].

(3) Other

Early rehabilitation is necessary for improving ADL in stroke patients; however, when performing bedside rehabilitation, attention should be paid to fluctuations in BP that this may cause.

2) Chronic phase

Patients with a history of cerebrovascular disease are known to have a high rate of recurrence. The most significant risk factor is hypertension and controlling this is of utmost importance to prevent recurrence. Since 1990, several large-scale studies have been conducted to investigate the association between recurrence prevention of cerebrovascular disease and BP [374, 555, 667–671], with SRs also available [672–678]. Antihypertensive therapy significantly reduces the recurrence of all subtypes of cerebrovascular diseases, non-fatal ischemic stroke, myocardial infarction, and all vascular events.

(1) Target BP

① Ischemic stroke

The PROGRESS study [555] found that in patients with a history of stroke, adding perindopril or the diuretic indamide to conventional therapy reduced BP from 147/86 mmHg to approximately 138/82 mmHg and reduced stroke recurrence by 28%. Other reports [668] also showed that in the diuretic group, SBP decreased by 5 mmHg and DBP by 2 mmHg, resulting in a 29% reduction in stroke recurrence. Furthermore, a subgroup analysis of the PROGRESS study [679] demonstrated that patients with better BP control (SBP around 120 mmHg) had lower rates of intracerebral hemorrhage and ischemic stroke.

According to Rothwell et al. [680], BP reduction to SBP ≤140 mmHg significantly increased the risk of cerebrovascular events in patients with symptomatic bilateral carotid artery stenosis (70% or greater), but it did not increase the risk in patients with unilateral carotid artery stenosis. Additionally, in the WASID study [681], among cases of symptomatic intracranial artery (internal carotid artery, middle cerebral artery, vertebral artery, or basilar artery) stenosis, in cases with severe stenosis (≥70%), BP levels were not associated with the risk of ischemic cerebrovascular disease. However, in cases with moderate stenosis (<70%), the risk of ischemic cerebrovascular disease was elevated when SBP was ≥160 mmHg. Yamauchi et al. [682] compared BP and stroke recurrence during follow-up in patients with symptomatic atherosclerotic occlusion of major cerebral arteries using PET to assess the presence or absence of perfusion defects. They found that in the group with perfusion defects, the risk of recurrence was high with� concluded that evaluating the presence or absence of perfusion defects is important for BP management. Thus, it is considered that hemodynamics differ between cases of vascular stenosis and occlusion, and there is limited evidence regarding the relationship between BP levels and the risk of ischemic cerebrovascular disease in cases such as unilateral internal carotid artery occlusion or basilar artery occlusion. Therefore, individualized management is necessary in cases of cerebral trunk artery occlusion or severe stenosis.

The PRoFESS study [683] classified patients with ischemic stroke within 120 days of onset into four groups based on SBP: 120–130 mmHg, 130–140 mmHg, 140–150 mmHg, and ≥150 mmHg, and administered anti-hypertensive therapy for an average of 2.5 years. Compared with the group controlled to 130–140 mmHg, the groups with BP<120 mmHg and ≥140 mmHg showed an increased rate of stroke recurrence.

In SPS3 [374], there was no difference in the primary endpoint (ischemic stroke + intracranial hemorrhage) in the chronic phase of lacunar infarction between conventional

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BP control (SBP 130–149 mmHg) and compelling BP management (SBP <130 mmHg). There was no significant difference in ischemic stroke, while intracerebral hemorrhage occurred in 16 cases (0.29% per year) in the conventional group and in 6 cases (0.11% per year) in the intensive group, showing a significant reduction in the intensive group.

The PROGRESS study [684] showed that in patients with a history of stroke or TIA who were taking any antithrombotic drugs, BP lowering therapy reduced the incidence of intracranial hemorrhage. In the BAT study [685] that included a prospective registry of patients in Japan taking antithrombotic drugs for the prevention of recurrent cerebrovascular disease or heart disease, the incidence of intracranial hemorrhage was higher, particularly in those with a history of cerebrovascular disease. Additionally, there was a lower incidence of intracerebral hemorrhage with a lower BP at the time of onset or at the end of observation, with a threshold of 130/81 mmHg [686]. In a subgroup analysis of CSPS2 [687], the rate of incidence for intracerebral hemorrhage was higher in the aspirin group than in the cilostazol group at all SBP levels, and it was significantly higher at levels >140 mmHg. This suggests that BP management is particularly important when prescribing aspirin.

In the RESPECT study [373], for patients with a target SBP of <120 mmHg compared to a target SBP <140 mmHg, within 3 years of stroke onset there was a significant reduction of 91% for incidence of intracerebral hemorrhage, and a reduction trend of 27% for stroke recurrence. Pooled analysis of RESPECT study with SPS3 [374], PAST-BP [688], and PODCAST [689], showed BP reduction with a target SBP of <120–130 mmHg compared with a target SBP of <140 mmHg or <150 mmHg showed a 22% reduction in stroke recurrence.

In JSH2025, the BP target in patients with a history of ischemic stroke is set at <130/80 mmHg, which is consistent with the stroke treatment guidelines [235]. For patients with bilateral carotid artery stenosis or occlusion of the major cerebral arteries, caution is advised against excessive BP reduction. During treatment, if patients report symptoms such as dizziness, unsteadiness, fatigue, head-ache, numbness, weakness, decreased mental alertness, or worsening of neurological symptoms, there is a possibility of cerebral circulatory insufficiency due to the lowering of BP, and a reduction or change in antihypertensive medi- cation may be necessary. Particular caution is warranted in cases of brainstem artery stenosis or occlusion, as impaired cerebral circulation autoregulation may persist for more than three months [690, 691].

② Intracerebral hemorrhage

In hypertensive intracerebral hemorrhage, recurrence is more common in cases with poor BP control [692–696].

Regarding the prevention of intracerebral hemorrhage recurrence, there are reports that the lower the DBP, the lower the recurrence [692], and these recurrences are lower for a DBP of <90 mmHg [693]; however, the evidence level is low. In the PROGRESS study, which included chronic cerebrovascular disease cases with 11% of intracerebral hemorrhage, antihypertensive therapy reduced the incidence of intracerebral hemorrhage by half in all patients with a history of stroke [555] and also reduced the incidence of stroke by half in patients with a history of intracerebral hemorrhage [697]. In a subgroup analysis of PROGRESS [679], unlike in patients with ischemic stroke, antihypertensive therapy was effective for preventing recurrence in patients with intracerebral hemorrhage if SBP was ≥120 mmHg. Within the range of 112–168 mmHg, as BP was lower, the incidence of intracerebral hemorrhage decreased. Additionally, antihypertensive therapy significantly reduced (77%) the incidence of intracerebral hemorrhage associated with amyloid angiopathy [698].

In JSH2025, in accordance with the stroke treatment guidelines [235], it is considered appropriate to set a BP target of <130/80 mmHg in patients with a history of intracerebral hemorrhage. However, for patients at high risk of intracerebral hemorrhage recurrence, it is considered acceptable to consider more strict BP management with a target of <120/80 mmHg (see CQ8). When assessing the risk of recurrent intracerebral hemorrhage, consider the presence of microbleeds, use of antithrombotics, age, and other factors.

③ Subarachnoid hemorrhage

There is no evidence regarding BP targets in a history of subarachnoid hemorrhage, therefore, apply the same guidelines as for intracerebral hemorrhage.

(2) Pharmacological therapy

The PROGRESS study [555] showed that the combination of ACE inhibitors and diuretics may help reduce the recurrence rate of cerebrovascular diseases and prevent the onset of dementia. The MOSES study [671] showed that with ARBs compared to CCBs, despite a similar BP reduction for both groups, the primary endpoint (all-cause mortality, all CVD events) and the cerebrovascular events among the secondary endpoints, were significantly lower with ARBs. The ONTARGET study, which evaluated mortality from vascular accidents including stroke and hospitalization for heart failure (in patients with high-risk vascular disease including stroke) [556], demonstrated the non-inferiority of ARBs compared to ACE inhibitors, and further showed that the benefits of combination therapy were not outweighed by the disadvantages (angioedema).

Considering the above evidence, JSH2025 recommends CCBs, ARBs, ACE inhibitors, and diuretics for the

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treatment of hypertension in patients with a history of stroke, regardless of the clinical subtype of stroke. These medications do not reduce cerebral blood flow during BP reduction (excluding excessive BP reduction). Additionally, it is advisable to select antihypertensive medications which take into account the presence of comorbidities such as diabetes, metabolic syndrome, and chronic kidney disease.

3) Asymptomatic cerebrovascular diseases

Most asymptomatic cerebral infarctions are small infarcts similar to lacunar infarcts and are considered a small vessel disease, with hypertension and aging as the primary risk factors. Hypertension is also the primary risk factor for cerebral white matter lesions [236, 699–701]. Furthermore, asymptomatic intracerebral hemorrhage or microbleeds are often detected by T2*-weighted MRI and have garnered attention [702-704]. The presence or progression of these lesions is an independent risk factor for the onset of cerebrovascular disease and cognitive decline [236, 699, 705-709].

In principle, patients with asymptomatic cerebral infarction or intracerebral hemorrhage should follow the target BP levels and effective antihypertensive drugs for patients with a history of stroke. However, more intensive antihypertensive therapy is desirable, based on the results of the CT sub-study of the PROGRESS study [710]. Asymptomatic cerebral infarction, along with white matter lesions in the cerebral cortex, serves as an indicator of organ dysfunction. Non-dipper, riser, or morning surge patterns in 24-h BP are risk factors [199, 711–713]. Maintaining BP throughout the day and managing morning BP are important.

On the other hand, asymptomatic carotid artery stenosis and unruptured cerebral aneurysms are also frequently identified, and it has been established that these conditions constitute a high-risk group for the onset of cerebrovascular diseases. Regarding asymptomatic carotid artery stenosis, prior to initiating antihypertensive therapy it is important to evaluate the indication of surgical treatment. Intensive antihypertensive therapy is recommended in cases where there is a family history of subarachnoid hemorrhage, or an unruptured cerebral aneurysm is detected.

Additionally, during the asymptomatic phase, patients often experience significant anxiety regarding the pathophysiology and the treatment options of cerebrovascular diseases, therefore, thoroughly informed consent is critically important.

[Point 9b]

【Cardiac hypertrophy】

1. Hypertension treatment that reduces cardiac hypertrophy improves prognosis. 2. Sustained and adequate BP reduction is the most important factor in reducing cardiac hypertrophy; all

major antihypertensive drugs are effective. In particular, RAS inhibitors and CCBs are superior in reducing hypertrophy.

【Coronary artery disease】

1. In patients with coronary artery disease, BP reduction to <130/80 mmHg is required for the secondary prevention of coronary artery disease, as well as for the prevention of heart failure and stroke.

2. In hypertensive patients with angina pectoris due to organic coronary artery stenosis, CCBs or β-blockers without intrinsic sympathomimetic activity are recommended as the first-line drugs.

3. The first-line drugs for coronary vasospastic angina are CCBs.

4. In patients with old myocardial infarction (particularly those with reduced left ventricular ejection fraction), β-blockers, RAS inhibitors/ARNI, and MR antagonists improve prognosis.

【Heart failure】

1. In patients with heart failure, antihypertensive drugs are used not only to lower BP, but also to improve QOL and prognosis.

2. With hypertensive patients, strict BP control with major antihypertensive agents prevents the onset of heart failure.

3. For heart failure with reduced left ventricular ejection fraction, the standard treatment is combination therapy with RAS inhibitors (switching to ARNI) + β-blockers + MR antagonists + SGLT2 inhibitors. This reduces mortality and improves prognosis. In cases of low cardiac function or hypotension, due to the risk of heart failure worsening, the initiation, dose adjustment, or discontinuation of these agents should be determined by a cardiologist.

4. In heart failure with preserved ejection fraction (HFpEF), adequate BP control is important. To prevent hospitalizations due to heart failure, SBP should be reduced to <130 mmHg while confirming tolerability. SGLT2 inhibitors have also demonstrated improved outcomes in HFpEF patients.

【Atrial fibrillation】

1. Strict BP control to achieve SBP <130 mmHg is effective for preventing new-onset atrial fibrillation.

2. The preventive effect of RAS inhibitors on atrial fibrillation onset is unclear in terms of primary prevention in hypertensive patients. However, they are considered effective for suppressing the new onset

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of atrial fibrillation and preventing recurrence in patients with left ventricular hypertrophy or heart failure.

3. In patients with atrial fibrillation, strict BP control is desirable in conjunction with appropriate anticoagulant therapy and heart rate control.

【Valvular heart disease】

1. Hypertension is a major risk factor for the onset and progression of valvular heart disease. As this disease progresses, it increases the risk of serious cardiac events such as heart failure and atrial fibrillation in the future.

2. Optimal BP management method varies depending on the type of valvular disease and coexisting conditions. However, to date the clinical evidence focusing on BP management in patients with valvular disease is insufficient.

3. Given the advancements in surgical and catheter-based treatments for valvular heart disease, establishing appropriate BP management method in this population is essential.

2. Heart diseases

The heart is an important target organ for hypertension. Increased systolic and diastolic pressure loads lead to myocardial remodeling, such as cardiac hypertrophy and myocardial interstitial fibrosis, as well as small vessel remodeling, including coronary endothelial injury, medial smooth muscle hypertrophy, and epicardial fibrosis. Furthermore, in combination with risk factors such as dyspidemia, diabetes mellitus, and smoking, coronary artery atherosclerosis is accelerated. The progression of myocardial remodeling and coronary artery atherosclerosis can lead to coronary artery disease, heart failure, arrhythmias, and sudden death. To reduce the incidence, progression, and mortality of heart diseases, it is important to adequately and sustainably lower BP (Table 9-2) [100, 304-306, 308, 541, 612, 714, 715].

1) Cardiac hypertrophy

Hypertension is one of the main causes of cardiac hypertrophy, which occurs when increased cardiac workload leads to thickening of the heart muscle. Cardiac hypertrophy is a risk factor in heart failure, and regression of cardiac hypertrophy through antihypertensive therapy reduces the incidence of cardiovascular events [716, 717]. In a sub-analysis of the CASE-J study, lowering SBP to below 130 mmHg reduced the incidence of cerebrovascular and cardiovascular events to levels comparable to those

without heart failure, in patients with hypertension and heart failure [718]. In an additional analysis of SPRINT, lowering SBP to below 120 mmHg suppressed the onset of heart failure and reduced its severity [719]. Sustained and adequate BP reduction is the most important factor for heart failure regression, and all major antihypertensive drugs are effective. A meta-analysis comparing the effects of heart failure regression showed that RAS inhibitors and CCBs were highly effective, while β-blockers were less effective [247, 720]. Additionally, recent reports have shown that adding MR antagonists suppressed heart failure [721], and ARNI significantly reduced the left ventricular myocardial mass index compared to ARBs [722].

2) Coronary artery disease

(1) Target BP

Hypertension is a major risk factor for coronary artery disease [340], and regardless of the type of antihypertensive drugs, lowering BP can reduce the risk of death from coronary artery disease [723]. In particular, long-acting CCBs, ACE inhibitors, and ARBs are expected to be effective in preventing the onset of coronary artery disease and cardiovascular events [670, 724–730]. To prevent the onset and progression of coronary artery disease, appropriate BP management, treatment of risk factors and other comorbidities are essential. For example, antithrombotic (antiplatelet) therapy, lipid profile correction with statin-based drugs, cessation of smoking, and appropriate exercise are important for primary and secondary prevention in patients with coronary artery disease. In addition, it is necessary to work closely with a cardiologist to evaluate cardiac function, coronary artery stenosis, and myocardial ischemia, and to carefully consider the appropriateness of coronary revascularization.

There is already substantial evidence supporting the effects of primary and secondary prevention with anti-hypertensive therapy for coronary artery disease. The benefits of strict treatment for BP have been demonstrated in the SPRINT trial [342]. The STEP trial compared a standard BP management targeting SBP of 130–150 mmHg and a strict BP management targeting 110–130 mmHg in 60 to 80 years old Chinese hypertensive patients. The strict BP management group showed a 26% reduction in the incidence of composite CVD events defined as stroke, acute coronary syndrome, acute heart failure, coronary revascularization, atrial fibrillation, and cardiovascular death compared to the standard BP management group. The risk of acute coronary syndrome was also reduced by 33% in the strict BP management group [317]. These findings demonstrate that strict BP management reduces the risk of CVD events, including coronary artery disease, in older East Asians, providing important insights for our aging society in Japan.

The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and...

Table 9-2 Treatment of hypertension in patients with heart disease

|Cardiac hypertrophy|To achieve regression of cardiac hypertrophy, a sustained and sufficient decrease in BP is necessary.RAS inhibitors or long-acting CCBs are the first line drugs.| |---|---| |Coronary artery disease|Target BP should be <130/80 mmHg. First line drugs for angina pectoris related to organic stenosis of the coronary artery: β-blockers and long-acting CCBs First-line drugs for coronary vasospastic angina: CCBs| |Old myocardial infarction|Standard drug therapy: ACE inhibitors (ARBs if intolerable) in combination with β-blockers Patients with severe systolic dysfunction: Switch from RAS inhibitors to $ARN^{a},$ MR antagonists$^{b}$Relief of congestion: Diuretics should be added. Cases in which a decrease in BP is insufficient despite standard medical therapy with gradually increased maximum tolerated doses: A long-acting CCB is added.| |Heart failure|Prevention Adequate BP reduction is necessary to prevent heart failure. Target BP should be <130/80 mmHg Major antihypertensive agents (ACE inhibitors or ARBs, β-blockers, CCBs, thiazide diuretics) suppress the onset of heart failure In patients with diabetes: Administer SGLT2 inhibitors$^{c}$ HFrEF Although there are many normo- or hypotensive patients, antihypertensive drugs should be used to improve the QOL or prognosis and prevent heart failure hospitalization, in addition to BP control. Individualized treatment in accordance with the condition or comorbidities is important; therefore, the target BP cannot be set. Standard medical therapy: Combination therapy with an ACE inhibitor (or an ARB if intolerant of ACE inhibitors. ARBs if intolerant; switch to ARNI if ineffective$^{d}$), a β-blocker$^{d}$, an MR antagonistb and SGLT2 inhibitors$^{c}$ Cases in which a decrease in BP is insufficient (despite standard medical therapy at gradually increased maximum tolerated doses under the adequate use of a diuretic), a long-acting CCB is added. Alim for SBP <130 mmHg with major antihypertensive agents (ACE inhibitors or ARBs, β-blockers, CCBs, thiazide diuretics). Administer SGLT2 inhibitors regardless of the presence of type 2 diabetes$^{c}$ Cases of inadequate BP control: Switch from RAS inhibitors to $ARNI^{a}$, add MR antagonists$^{b}$ New-onset prevention: BP to an SBP of <130 mmHg is effective. Prevention of the new onset of atrial fibrillation in patients with cardiac hypertrophy or heart failure: Antihypertensive drug therapy with an RAS inhibitor Patients with atrial fibrillation: In addition to adequate anticoagulant therapy and heart rate control, an SBP of <130 mmHg should be targeted.| |a Atrial fibrillation|“New-onset prevention: BP to an SBP of <130 mmHg is effective. Prevention of the new onset of atrial fibrillation in patients with cardiac hypertrophy or heart failure: Antihypertensive drug therapy with an RAS inhibitor Patients with atrial fibrillation: In addition to adequate anticoagulant therapy and heart rate control, an SBP of <130 mmHg should be targeted.|

Furthermore, placebo-controlled trials such as HOPE, ACTION, and CAMELOT have demonstrated that strict BP control reduces the risk of cardiovascular events and may also inhibit the progression of coronary artery plaque and promote its regression [670, 726, 728, 731].The intensive treatment group (BP reduction to BP ≤135 mmHg) was associated with a 15% reduction in heart failure incidence and a 10% reduction in stroke incidence, primarily driven by the further intensive treatment group (BP reduction to BP ≤130 mmHg) [715]. Also, in a meta-analysis of coronary artery disease without hypertension (<140/90 mmHg), BP lowering therapy reduced stroke by 23%, myocardial infarction by 20%, heart failure by 29%, cardiovascular mortality by 17%, and overall mortality by 13% [732].

DBP influences coronary blood flow, so an excessive reduction in DBP can be considered as it may increase the risk of coronary events [733]. However, in patients with low DBP the increase in cardiac events in coronary artery disease is predominantly due to residual ischemia. The safety of BP lowering can be enhanced by coronary revascularization, as demonstrated by sub analyses of the INVEST and CREDO-Kyoto cohort-1 studies [734–736]. Furthermore, an SR for CQ7 in JSH2019 found that in patients with coronary artery disease and SBP of <130 mmHg, coronary revascularization and heart failure were reduced in patients with a DBP<80 mmHg compared to those with a DBP of ≥80 mmHg [737]. Based on these findings, the BP target for patients with coronary artery disease and hypertension should be set at <130/80 mmHg.

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(2) Angina pectoris

Angina pectoris can be classified into two types: that is caused by organic narrowing of the coronary arteries due to atherosclerosis, and that is caused by coronary vasospasm associated with endothelial dysfunction. In Japan, the incidence of vasospastic angina is higher than in Western countries. Angina caused by organic coronary artery stenosis often occurs during physical exertion when myocardial oxygen demand increases (exertional angina), and both β-blockers and CCBs (including non-dihydropyridine derivatives) are thought as effective [738, 739]. On the other hand, coronary vasospastic angina, which is influenced by the autonomic nervous system, can occur in the early morning or at rest, and CCBs with vasodilatory effects are the first-line drugs [740–742]. Additionally, while β-blockers are generally considered to carry a high risk of exacerbating coronary vasospastic angina, in cases where organic stenosis coexists with coronary vasospasm, β-blockers may be necessary, and their administration is recommended in combination with CCBs.

The antianginal effect of β-blockers primarily depends on reducing myocardial oxygen consumption through decreased heart rate and reduced myocardial contractility; therefore, medications without intrinsic sympathomimetic activity should be selected. If BP management is inadequate, CCBs or RAS inhibitors may be added.

(3) Old myocardial infarction

Following myocardial infarction, the selection of anti-hypertensive medications is important not only for BP management but also for the prevention of cardiovascular events and improvement of long-term prognosis. β-blockers without intrinsic sympathimetic activity significantly reduce the risk of recurrent myocardial infarction and sudden death [743, 744]. In cases of myocardial infarction or acute coronary syndrome (within 3 years of onset) with impaired left ventricular systolic function, β-blockers (carvedilol, bisoprolol) should be initiated for secondary prevention. However, recent reports suggest that in myocardial infarction patients with left ventricular ejection fraction (LVEF) maintained at 50% or higher, β-blockers may not affect overall mortality or myocardial infarction recurrence rates [745]. Therefore, the necessity of initiating or continuing β-blockers in cases with preserved LVEF after myocardial infarction should be determined by consultation with a cardiologist. In myocardial infarction with reduced LVEF (40% or less), RAS inhibitors suppress the progression of left ventricular remodeling (ventricular dilatation, myocardial hypertrophy, and interstitial fibrosis), reduce cardiac events such as heart failure and sudden death, and improve survival [746–749]. In cases of impaired cardiac function following myocardial infarction, adding MR antagonists to standard therapy (RAS inhibitors + β-blockers + diuretics) may improve prognosis [750, 751].

Among RAS inhibitors, ARNI is a good option for cases requiring more substantial BP reduction or those with heart failure (particularly left ventricular systolic dysfunction). In cases of coronary artery disease with treatment-resistant hypertension, where BP management remains inadequate despite the use of multiple antihypertensive agents, renal denervation, which involves ablating the sympathetic nerves around the renal arteries, may emerge as a promising treatment option in the future [752].

3) Heart failure

The Japanese Circulation Society (JCS)/Japanese Heart Failure Society (JHFS) 2025 Guideline on Diagnosis and Treatment of Heart Failure presents the following classification of the stages of the progression of heart failure. Stage A (at risk of heart failure), in which there are no heart failure symptoms nor structural/functional cardiac abnormalities, or no increase in blood biomarkers (natriuretic peptide and troponin), despite the presence of heart failure risk factors such as hypertension, diabetes mellitus, obesity, chronic kidney disease, and so on. Stage B (pre-heart failure), in which there is no sign of heart failure despite the presence of structural/functional cardiac abnormalities, elevated intracardiac pressure, or elevated biomarkers (natriuretic peptide and troponin). Stage C, symptomatic heart failure, and Stage D, advanced heart failure [543]. Hypertension is the most common underlying disease of heart failure [753], so it is important to initiate early therapeutic intervention in Stages A/B which are without heart failure symptoms, to prevent the onset of heart failure. Additionally, hypertension is a risk factor in the worsening of heart failure at all heart failure stages and is an independent predictor of heart failure readmission. Thus, strict BP management is necessary even after the appearance of heart failure symptoms and the progression to heart failure Stage C/D.

(1) Heart failure stage A/B

To prevent progression from heart failure risk, stage A/B to symptomatic heart failure (stage C), the management of hypertension is important [543]. It is necessary to understand that the risk of state of heart failure is also a risk for other CVD complications. A meta-analysis of RCTs on antihypertensive therapy showed that a 10-mmHg reduction in SBP reduces the incidence of heart failure by 28%, regardless of comorbidities [100]. To date, however, there are no RCTs on BP targets for the primary prevention of heart failure in hypertensive patients. The aim is for a target BP of <130/80 mmHg in accordance with target BP in general CVD prevention. Preventing coronary artery disease and inhibiting left ventricular hypertrophy [754, 755] are important in preventing onset of heart failure in hypertensive patients. A meta-analysis of large RCTs showed that major antihypertensive drugs (ACE inhibitors, ARBs, thiazide diuretics, long-acting dihydropyridine CCBs, and β-blockers) reduced the incidence of heart failure in

The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and...

hypertensive patients compared to the control group [306, 307]. All these major antihypertensive drugs demonstrated left ventricular hypertrophy regression effects [756, 757], which are considered to contribute to the reduction in heart failure onset.

Furthermore, results of a network meta-analysis of the effects of antihypertensive drugs in hypertensive patients, suggest that diuretics and RAS inhibitors have particularly strong effects in inhibiting heart failure onset [758]. The efficacy of thiazide diuretics in the primary prevention of heart failure has been demonstrated in Cochrane meta-analyses [316, 342, 759–761]. However, caution is necessary regarding renal dysfunction (eGFR decline) and electrolyte abnormalities, particularly hypokalemia [592, 762]. Therefore, the use of antihypertensive diuretics for BP reduction should be limited to low doses, and the combination with RAS inhibitors is recommended to enhance BP lowering effects and to correct hypokalemia.

Additionally, although SGLT2 inhibitor is not classified as antihypertensive agents, they have been proven to have natriuretic and antihypertensive effects, and they also reduce the occurrence of cardiovascular events including heart failure. Therefore, the SGLT2 inhibitor should be considered for hypertensive patients with diabetes.

(2) Heart failure stage C/D

Stages C and D are stages of heart failure, and particularly with Stage C, antihypertensive therapy aims to stabilize hemodynamics during acute decompensated heart failure and to prevent recurrence of acute exacerbations. Heart failure is broadly classified into HFrEF (left ventricular ejection fraction <40%) and heart failure with preserved ejection fraction (HFpEF, left ventricular ejection fraction ≥50%). Hypertension is closely associated with both types of heart failure, and antihypertensive therapy depending on the specific condition of heart failure is necessary.

In HFrEF patients, BP is often normal or low, and the use of antihypertensive medications is primarily aimed at suppressing heart failure readmission and improving the prognosis, rather than lowering BP. ACE inhibitors are recommended to be administered to heart failure patients from stage A, because they are demonstrated to inhibit readmission and to improve the prognosis in HFrEF patients. Furthermore, ARBs should be administered to these patients who are intolerant to ACE inhibitors. β-blockers (carvedilol and bisoprolol) improve prognosis and reduce hospitalization in HFrEF patients with stage B onwards, regardless of the presence of heart failure symptoms [593–595], so they should be administered to all HFrEF patients regardless of disease severity. Additionally, MR antagonists have shown to improve outcomes in patients with HFrEF and post-myocardial infarction by

many RCTs [611, 750, 763], and both spironolactone and eplerenone also have demonstrated to improve outcomes in HFrEF patients [609, 751]. Based on the accumulation of recent clinical evidence [543, 764–767], combination therapy with four classes of HFrEF medications—switching from ACE inhibitor or ARB to ARNI, β-blockers, MR antagonists, and SGLT2 inhibitors (dapagliflozin and empagliflozin)—are recommended as basic treatments [543]. It is important to initiate these medications at low doses and titrate to the maximum doses as quickly as can be tolerated [768]. If BP doesn't reach the target level (below 130/80 mmHg) despite the use of diuretics for the treatment and prevention of organ congestion in patients, long acting dihydropyridine CCBs are recommended for lowering BP [769, 770].

In initiation of these HFrEF medications, caution should be exercised regarding worsening heart failure, hypotension, bradycardia (especially by β-blockers), and impaired renal function. Treatments with these HFrEF medications should be initiated at a low dose, such as 1/4 to 1/2 of the standard dose, and gradually increased with careful monitoring. In cases of using HFrEF patients with low cardiac function or hypotension, the decision of initiation, dose adjustment, or discontinuation of these heart failure drugs should be made by a cardiologist. The above-mentioned antihypertensive drugs are necessary for improving prognosis of HFrEF even if BPs in these patients are low or normal, and discontinuation of these drugs might worsen prognosis in HFrEF patients [771]. Therefore, decision on reduction or discontinuation of these medications should be made with caution.

On the other hand, in HFpEF patients, based on the results of CQ 9 in the JSH guidelines, target SBP for preventing heart failure hospitalization is <130 mmHg. Although large-scale clinical trials using ACE inhibitors, ARBs, β-blockers, MR antagonists, and ARNI did not improve mortality [772-777], CHARM-Preserved, TOP-CAT, and J-DHF reduced heart failure hospitalization in HFpEF patients [772, 775, 776, 778]. Thus, due to the variety of phenotypes and the diversity of HFpEF, the effects of antihypertensive drugs for HFpEF have not been obtained consistent results, and antihypertensive drug selection should be tailored to individual pathophysiological conditions and individities in HFpEF [543]. Recently, the large clinical studies using SGLT2 inhibitors, EMPEROR-Preserved (empagliflozin) [789] and DELIVER (dapagliflozin) [780] demonstrated the effectiveness in HFpEF patients regardless of complication of diabetes, and these two SGLT2 inhibitors have expanded new indication for HfpEF in clinical use.

In both HFEF and HFpEF patients, diuretics are effective for improving symptoms such as dyspnea on exertion and edema caused by organ congestion. However, while

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loop diuretics are useful for reducing organ congestion not only in acute decompensated heart failure but also in chronic heart failure, there is no evidence that loop diuretics improve outcomes of heart failure patients. Instead, through the risk of hypokalemia and the activation of sympathetic nervous and RA system [781], diuretics have a possibility of worsened prognosis of heart failure patients [782–785]. So, overusage of diuretics should be avoided. Additionally, when combined use of loop diuretics with SGLT2 inhibitors, caution is warranted for enhancement of natriuresis [786]. In other words, when adding SGLT2 inhibitors to heart failure patients receiving diuretics, patient education should be provided regarding symptoms due to intravascular dehydration, and the dose of diuretics should be adjusted or reduced as appropriate [787].

4) Atrial fibrillation

Hypertension is a major risk factor for the onset of atrial fibrillation (see "Chapter 1, Section 1. 3) Heart failure/Atrial fibrillation"), but studies such as the SPRINT trial have reported that reducing SBP to below 130 mmHg can suppress the onset of new atrial fibrillation [788, 789].

Among antihypertensive drugs associated with the prevention of atrial fibrillation onset, in a meta-analysis of RCTs, RAS inhibitors showed no clear effect [790, 791]. However, in hypertensive patients with a history of atrial fibrillation, RAS inhibitors were effective in suppressing recurrence [791]. Additionally, they are considered to have a high efficacy in patients with concomitant left ventricular hypertrophy or heart failure [790–792]. Furthermore, observational studies and meta-analyses of RCTs, targeting patients after catheter ablation, suggested the preventive effect of RAS inhibitors on recurrence [793]. In a meta-analysis of RCTs targeting HFrEF, β-blockers were also effective in preventing the new onset of atrial fibrillation [794].

The risk of stroke, arterial embolism, and all-cause mortality, in patients with atrial fibrillation, increases in a BP dependent manner [337, 338]. In a subgroup analysis of the PROGRESS study in patients with atrial fibrillation, BP lowering therapy reduced cardiovascular events by 38% [795]. In a subgroup analysis of the SPRINT trial in patients with atrial fibrillation, SBP reduction to below 120 mmHg reduced CVD events by 24%, but the difference was not statistically significant [796]. A meta-analysis of RCTs in patients with or without atrial fibrillation demonstrated that a 5 mmHg reduction in SBP was associated with a 9% reduction in CVD events, regardless of atrial fibrillation status [797]. Furthermore, while appropriate anticoagulant therapy is necessary for patients with atrial fibrillation, strict BP management is also desirable to reduce hemorrhagic complications associated with anticoagulant use [798, 799] (see "Chapter 10, Section 6, Patients taking antithrombotic drugs"). Clear evidence supporting SBP reduction to below

130 mmHg is awaited from ongoing trials such as the CRAFT study [800].

Regarding medications associated with the suppression of CVD events in patients with atrial fibrillation, meta-anyses of RCTs suggest the efficacy of RAS inhibitors [801]. Also, for heart rate control in patients with atrial fibrillation, β-blockers (bisoprolol, carvedilol) are used as first-line drugs [802], but in cases where β-blockers are contraindicated, non-dihydropyridine CCBs should be considered.

5) Valvular heart disease

(1) Pathophysiological association

Although the mechanisms vary among individual valvular heart diseases, elevated BP and hypertension are closely associated with the pathophysiology of valvular heart disease [803, 804]. Elevated BP increases afterload on the left ventricle, leading to left ventricular hypertrophy and myocardial remodeling, and also imposes mechanical stress on cardiac valves, resulting in valvular dysfunction. The effects of elevated BP on heart valves differ depending on the type of valvular disease. For example, aortic stenosis is known to progress more rapidly in the presence of hypertension. Elevated BP itself, as well as the mechanical stress it imposes on the aortic valve, is believed to induce atherosclerosis and calcification of the aortic valve, leading to valve stenosis over the long term. In contrast, in aortic valve insufficiency, systolic hypertension accompanied by increased pulse pressure is observed due to increased cardiac output.

(2) BP management

In hypertension treatment guidelines in Europe and the United States, the importance of BP management in patients with valvular heart disease is emphasized [183, 626]. In patients with valvular heart disease, appropriate BP management is essential to reduce the risk of cerebrovascular events and heart failure. If left untreated, hypertension can accelerate the progression of valvular heart disease and increase the risk of subsequent cardiac events. The importance of lifestyle modifications (non-pharmacological treatment) such as salt restriction, maintaining optimal body weight, and physical activity goes without saying. However, when selecting pharmacological treatment, ACE inhibitors and ARBs (including ARNI) are considered effective for managing hypertension and valvular heart disease, as they not only lower BP and reduce cardiac afterload but also inhibit the progression of myocardial remodeling. CCBs and diuretics may also be used depending on the condition. In particular, patients with valvular disease are classified as Stage B (risk stage) in heart failure treatment guidelines, thus appropriate BP management is important to prevent progression to Stage C/D (symptomatic heart failure stage). From the perspective of heart failure prevention, it is also important for patients with

The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and...

valvular heart disease or those who have been identified with heart murmurs during health checkups to receive regular follow-up care from a cardiologist. While BP management is essential in the treatment of valvular heart disease, evidence is limited about the optimal BP management for valvular heart disease [805–808]. At present, the consensus is that treatment should be initiated with general BP reduction targets for hypertension in patients with mild valvular heart disease. Further, patients with moderate to severe valvular heart disease, or those who have undergone valvular heart surgery, should be regularly co-managed by a cardiologist. The cardiologist should set appropriate BP targets and select antihypertensive medications based on the patient's condition.

(3) Future challenges

In clinical practice the importance of BP management in the treatment of valvular heart disease is strongly recognized. Improved BP control in patients with aortic valve insufficiency or mitral valve insufficiency often results in a reduction in the severity of valvular disease as assessed by echocardiography. This is also observed in cases of mitral valve repair following mitral valve repair surgery. However, BP reduction must be approached with caution in patients with severe aortic stenosis who have experienced syncope. In particular, vasodilators such as nitrates, which reduce preload, should be avoided. Invasive treatments for valvular disease, such as transcatheter aortic valve implantation (TAVI) for aortic stenosis and transcatheter mitral valve repair for mitral regurgitation, are expected to increase. BP management in cases where such treatments are performed is an urgent issue. As the population ages, the number of cases with valvular heart disease is expected to increase. Therefore, it is essential to accumulate clinical data for patients with valvular heart disease and establish the appropriate methods of BP management.

【POINT 9c】

【Kidney disease】

1. Hypertension is commonly associated with chronic kidney disease (CKD). Renal parenchymal hypertension is suspected when renal impairment precedes hypertension, and urine protein levels of ≥1 g/day (or 1 g/gCr), glomerular hematuria of ≥2+, or red blood cell casts are present.

2. Hypertension associated with CKD often presents with abnormalities in the diurnal BP rhythm, such as the absence of nocturnal BP reduction, and it is associated with an increased risk of CVD. Strict BP management, including management of the diurnal rhythm, is required.

3. In CKD patients with proteinuria, treatment should be initiated when BP is ≥130/80 mmHg. If BP is ≥140/90 mmHg, antihypertensive medication should be

initiated immediately. However, if BP is 130-139/80-89 mmHg, lowering BP by lifestyle modifications may be attempted for up to one month.

4. Lifestyle modifications include restricting salt intake to <6 g/day, maintaining a healthy weight, and engaging in exercise therapy. This should be performed in a safe environment, taking into account the patient's renal function, age, and background.

5. Target BP: For patients with proteinuria, a target of <130/80 mmHg is recommended. For non-diabetic patients without proteinuria, individualized management should be considered, balancing the benefits and risks, and taking into account renal function and age. Particular attention should be paid to the rate of BP reduction in older patients aged 75 years or older to avoid excessive BP lowering.

6. First-line drugs: For patients with proteinuria, RAS inhibitors are recommended. For patients without proteinuria, RAS inhibitors, long-acting dihydropyridine CCBs, or thiazide diuretics are recommended.

7. Improvement in proteinuria is closely associated with the prevention of progression to end-stage renal disease, and it is important to reduce urine protein levels as much as possible.

8. For management of BP in hemodialysis patients, measurements of BP generally used are other than those made in the dialysis room.

9. In hemodialysis patients, the benefits of using antihypertensive drugs targeting specific mechanisms for many outcomes cannot be proposed at this time.

3. Kidney disease

1) Chronic Kidney Disease (CKD) and renal parenchymal hypertension

Kidney is a vital organ involved in regulating BP. CKD, characterized by kidney dysfunction such as proteinuria and impaired kidney function (eGFR <60 mL/min/1.73 m$^{2}$) that persists for more than three months, is often associated with the development of hypertension [253, 809]. Hypertension caused by renal artery stenosis is referred to as renal vascular hypertension, while hypertension induced by renal disease is termed renal parenchymal hypertension, with the latter accounting for approximately 2–5% of all hypertensive patients [810, 811]. However, hypertension associated with CKD is not always the renal parenchymal hypertension. The combination of CKD and essential hypertension, or nephroscclerosis caused by hypertension, is not strictly a renal parenchymal hypertension. The diagnosis of renal parenchymal hypertension requires confirmation of renal impairment preceding hypertension. If various urinary findings such as proteinuria, hematuria, or various casts are

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Table 9-3 Target BP and recommended antihypertensive drugs for patients with chronic kidney disease

|||Target BP|First-line drugs|Second-line drugs (combination drugs)| |---|---|---|---|---| |Without proteinuria|Diabetes (-)|<130/80 mmHg (Generally, individualized management is required)|RAS inhibitors, CCBs, thiazide diuretics|Select from other first-line drugs| |Without proteinuria|Diabetes (+)|<130/80 mmHg||| |With proteinuria||<130/80 mmHg|RAS inhibitors|CCBs (CVD high risk) Thiazide diuretics (fluid retention, morning hypertension)|

* Proteinuria: diagnosed to be present if more than mild proteinuria (≥0.15 g/cr)

For diabetes mellitus, diagnosed positive if ≥30 mg/gCr, based on microalbuminuria

* In older adults aged 75 years or older with suspected nephrosclerosis (severe atherosclerosis and negative proteinuria), CCB is the first-line drug

$\bullet$ In patients with an eGFR <30 mL/min/1.73 m$^{2}$ or in older adults aged 75+ years, RAS inhibitors should be initiated at a low dose. In older adults aged 75+ years with an eGFR <30 mL/min/1.73 m$^{2}$, there is a high likelihood of underlying renal ischemia. Even in cases with positive proteinuria, it is safer to initiate treatment with CCBs and confirm that there is no worsening of kidney function before switching to RAS inhibitors. If kidney function worsens with CCBs, consulting a nephrologist is advisable

* In CKD patients without diabetes mellitus and negative proteinuria, monitor for adverse events such as worsening renal function. Then cautiously proceed to reduce BP to below 130/80 mmHg, with an intermediate target of below 140/90 mmHg. However, individualized management based on renal function and age is necessary. In CKD patients with proteinuria, even in older adults aged 75 years or older, aim for BP below 130/80 mmHg whenever possible, but first try to achieve BP below 140/90 mmHg. If there are no adverse events such as ischemic symptoms in the brain/heart/dickneys, acute kidney injury, or hypotension-related symptoms (dizziness, vertigo), and if tolerability is judged to be acceptable, aim for BP below 130/80 mmHg

* If eGFR is <30 mL/min/1.73 m$^{2}$, switch from thiazide-type diuretics to loop diuretics. However, do not use loop diuretics as the first-line drug. Under loop diuretic therapy, thiazide diuretics may be effective even with an eGFR of <30 mL/min/1.73 m$^{2}$, but caution is required regarding renal function when using diuretics in combination

* As for CCBs, long-acting dihydropyridine CCBs (a major antihypertensive drug) should be used

present prior to the onset of hypertension, the likelihood of renal parenchymal hypertension is high. In cases where past test findings or history are unclear, current urinary findings should be referenced. If urine protein of 1 g/day (or 1 g/gCr) or more, or glomerular hematuria of 2+ or more, or red blood cell casts are present, renal parenchymal hypertension should be suspected, and referral to a nephrologist is recommended [253].

(1) Pathophysiology

In CKD, salt-sensitive hypertension, which worsens with increased salt intake, is common. In salt-sensitive hypertension, both systemic BP and glomerular BP are elevated. Glomerular hypertension is a risk factor for glomerulosclerosis and must be suppressed for long-term renal protection. Additionally, salt-sensitive hypertension often presents with abnormal diurnal variations, such as the absence of nocturnal BP reduction [812], which are risk factors for CVD. Furthermore, as renal function declines, sleep apnea syndrome is more likely to develop [813], contributing to the progression of severe hypertension. Therefore, strict BP management over a 24-h period is required in hypertension complicated with CKD.

Among CKD without proteinuria, nephroscclerosis is particularly common in older adults. In nephroscclerosis, salt sensitivity to BP is not elevated in the early stages, but as renal arteriolar sclerosis progresses, some glomeruli

undergo ischemic stiffness, leading to a reduction in the number of functional nephrons. As a result, sodium excretion function decreases, resulting in the development of salt-sensitive hypertension.

(2) Antihypertensive therapy

Regardless of whether it is renal parenchymal hypertension or not, hypertension associated with CKD exacerbates kidney damage and further worsens hypertension. To break this vicious cycle, strict BP management, including diurnal variations, is necessary. In particular, hypertension combined with CKD and proteinuria is classified as the highest risk level (Risk Level 3), and treatment should be started at ≥130/80 mmHg. If BP is ≥140/90 mmHg, anti-hypertensive medication should be initiated immediately. However, if BP is 130-139/80-89 mmHg, lifestyle modifications to lower BP may be attempted for up to one month. The goal of BP management in CKD patients is to prevent the onset of CVD and to delay the progression of CKD to end-stage kidney disease (ESKD). To achieve this, appropriate BP targets and the selection of antihypertensive medications are necessary. Table 9-3 shows the target BP and recommended antihypertensive drugs for CKD patients with hypertension.

① Target BP

In CKD with proteinuria, given the high risk of CVD and the expectation that adequate BP control can reduce urine

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protein levels, a BP target of <130/80 mmHg is recommended. In the absence of proteinuria, careful consideration should be given to adverse events such as worsening renal function, and BP should be cautiously lowered to below 130/80 mmHg, with 140/90 mmHg as an intermediate target. Notably however, individualized management based on renal function and age is necessary. In patients with diabetes, the target BP is <130/80 mmHg even in the absence of proteinuria. In all cases, BP management should be performed while monitoring for signs of hypotension or dizziness associated with intensive lowering of BP. Particularly in elderly patients with renal arteriosclerosis, there is a high likelihood of underlying atherosclerotic coronary artery disease or peripheral artery disease, so sufficient consideration must be given to the potential for reduced organ perfusion associated with the lowering of BP.

② Lifestyle modifications

In CKD, sodium excretion impairment leads to fluid overload, contributing to the elevation of BP. Thus, salt reduction is the principle, with a daily salt intake of <6 g. Additionally, salt reduction is expected to enhance the BP-lowering effect and proteinuria-reducing effect of RAS inhibitors [814, 815]. However, excessive salt reduction is not recommended because it may lead to reduced food intake and dehydration. Efforts should be made to improve obesity when present, as it increases salt sensitivity to BP through insulin resistance. Even in CKD patients with an eGFR of <60 mL/min/1.73 m$^{2}$, including dialysis patients, exercise therapy is reported to lower BP and central BP, improve cardiopulmonary function, and enhance QOL [816]. Exercise therapy for CKD patients should be conducted in a safe environment after thoroughly understanding the patient's clinical background.

③ Pharmacological therapy

In CKD with moderate or severe proteinuria (≥0.15 g/ gCr, or albuminuria ≥30 mg/gCr in diabetes), there is a high likelihood of the presence of glomerular hypertension requiring treatment. The first-line treatments for this are RAS inhibitors that dilate efferent arterioles and reduce glomerular BP (see CQ11). The renal protective effects of RAS inhibitors are greater in cases with impaired renal function, and their efficacy can be confirmed by a reduction in proteinuria. Improvement in proteinuria is strongly associated with the prevention of ESKD and CVD, so it is important to reduce proteinuria as much as possible. However, achieving BP targets is often difficult with RAS inhibitors alone, so CCBs or thiazide diuretics should be added to achieve adequate BP control. In cases of stage III hypertension or high CVD risk, CCBs, which have a reliable antihypertensive effect and are expected to increase organ blood flow, are used in combination. In contrast, in cases where fluid volume remains excessive despite salt restriction, thiazide diuretics are used in combination;

however, in cases of impaired renal function (CKD stage G4–G5: eGFR <30 mL/min/1.73 m$^{2}$), switch to or add loop diuretics. In patients where the addition of a diuretic to ARBs is desirable, consider switching to fixed-dose combinations or ARNI to avoid increasing the number of medications.

In patients with impaired renal function, particularly in elderly patients aged 75 years or older, RAS inhibitors are often withheld or discontinued. This is due to concerns about the risk of hyperkalemia or the need for earlier initiation of renal replacement therapy, even if proteinuria is positive. However, recent reports increasingly recommend continuing RAS inhibitors without discontinuation, even in patients with severe renal impairment. In hypertensive patients with CKD stage G4 or G5, discontinuation of RAS inhibitors did not result in a significant difference in renal function at 3 years [817]. Among patients in the same stage who discontinued RAS inhibitors, the risk of renal replacement therapy was significantly reduced (8.3%), but the risk of all-cause mortality (13.6%) and major cardiovascular events (11.9%) increased [818]. A meta-analysis including these two studies also reported that discontinuing RAS inhibitors in CKD patients significantly increased the risk of all-cause mortality and cardiovascular events [819]. Additionally, a study that followed 6,065 Japanese CKD patients who discontinued RAS inhibitors due to hyperkalemia or acute kidney injury found that patients who resumed RAS inhibitors within one year had significantly fewer kidney events (initiation of renal replacement therapy, eGFR reduction ≥50% or to <5 mL/min/1.73 m$^{2}$) within one year. In addition, composite kidney outcome (initiation of kidney replacement therapy, a ≥50% decline in eGFR, or kidney failure [eGFR <5 mL/min/1.73m$^{2}$]) and the overall mortality rate were significantly lower (14% and 32%), with no difference in the incidence of hyperkalemia [820]. In this study, there was no difference in outcomes between patients aged 70 years or younger and those over 70 years, suggesting that RAS inhibitors should be administered to CKD patients who are eligible, even if elderly. Therefore, in patients with CKD stage G4, G5, or aged 75 years or older, RAS inhibitors should be initiated at a low dose, and rapid dose reduction or discontinuation should be considered if renal function worsens or hyperkalemia occurs. However, in elderly patients aged 75 years or older with CKD stage G4 or G5, there is a higher likelihood of underlying renal ischemia. Thus, even in cases with proteinuria, it is safer to start with CCBs and confirm that there is no worsening of renal function due to the lowering of BP before switching to RAS inhibitors. If renal function deteriorates despite CCBs, referral to a nephrologist is recommended. Table 9-4 summarizes precautions for administering RAS inhibitors to patients with renal dysfunction and measures to take if serum potassium levels rise. If target BP is not achieved,

Y. Ohya

Table 9-4 Precautions for administering RAS inhibitors to patients with renal dysfunction, and measures to take in case of elevated serum potassium levels

<Precautions> If possible, start with the minimum dose (or half the dose) before administering diuretics Perform electrolyte and renal function tests (BUN, serum Cr, serum potassium, etc.) within 2-4 weeks Continue the treatment (regularly monitor electrolytes and renal function) if an increase of serum Cr within 30% of baseline (or 1.0 mg/dL), or if serum potassium remains below 5.5 mEq/L If there is a further increase, refer to a nephrologist (collaboration is important) <Causes to consider if kidney function worsens> * Renal artery stenosis (especially bilateral) * Oral medications that reduce renal blood flow (e.g., NSAIDs or cyclosporine) * Heart failure * Dehydration (especially in older adults during the summer. Also note, dehydration could be due to loss of appetite or diarrhea) * Urinary tract abnormalities (e.g., hydronephrosis) <Precautions when adding MR antagonists> * Contraindicated in patients with serum potassium levels exceeding 5.0 mEq/L or those receiving potassium supplements or potassium-sparing diuretics (e.g., triamterene) Before additional administration, measure serum potassium levels (within 2 weeks after initiation, and if possible, 4 weeks later). Continue monitoring serum potassium levels regularly thereafter. * Start with the minimum dose as a general rule; however, in patients with moderate or severe renal impairment or diabetes mellitus, the risk of hyperkalemia is particularly high, so consider starting with the minimum dose. * If serum potassium is >5.0 but <5.5 mEq/L, reduce dosage. If serum potassium is ≥5.5 but <6.0 mEq/L, consider reducing the dosage or discontinuing treatment. If serum potassium is ≥6.0 mEq/L, discontinue immediately and consider referral to a specialist. <Measures to take when serum potassium levels rise during administration of RAS inhibitors or MR antagonists> Reduce or discontinue the causative drug and promptly refer to a nephrologist, if possible. However, the following measures may help lower serum potassium levels: * Ensure adequate fluid intake, followed by administration of diuretics (thiazide diuretics, loop diuretics) * Restrict potassium intake * Take action to prevent constipation * Administration of potassium binders (cost-effectiveness is important: expensive medications should be reserved for emergencies) * Review concomitant medications (some potassium binders may have reduced efficacy when used with magnesium- or aluminum-containing antacids or laxatives) * Correction of acidosis (Diabetic Kidney Disease). It has formerly been translated into Japanese as "diabetic kidney disease," but in October 2023, both the Japanese Society of Nephrology and the Japanese Diabetes Society revised the term to "diabetes-related kidney disease", replacing the previous term "diabetic kidney disease (in Japanese language)". This concept encompasses all conditions where diabetes, diabetes-related pathologies, comorbidities, or treatment effects contribute to CKD, regardless of severity, and includes diabetic nephropathy, which is kidney damage mostly caused by diabetes. Typical diabetic nephropathy follows a course where long-term inadequate blood glucose control leads to glomerular hyperfiltration, microalbuminuria, overt proteinuria, and nephrotic sta, leading to progressive decline in renal function, while cases with rapid decline in renal function at the normal to microalbuminuria stage (rapid/fast decliner) and cases with rapid decline in renal function at a certain stage (nonlinear decliner) are also included. (Diabetic Kidney Disease (4th) pertentent) and 3, 2, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3, 3,

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As antidiabetic agents, SGLT2 inhibitors (canagliflozin, dapagliflozin, empagliflozin), which have evidence of renal protective and cardiovascular protective effects, are recommended for compelling administrations [824]. Higher efficacy is observed in patients with higher urine protein (or albumin) levels; however, these agents should not be initiated in patients with an eGFR <15 mL/min/1.73 m$^{2}$or for those on dialysis.

3) Chronic maintenance dialysis

There was a times when hypertension guidelines in other countries no longer included recommendations for patients receiving hemodialysis, but there has been a resurgence of interest in this area in the 2020s. An RCT (BID trial) that compared the CVD prevention effects and the safety of strict BP lowering, versus standard BP lowering using pre-dialysis BP as an indicator, found no significant differences between the two groups [825]. However, BP measured outside the dialysis unit was associated with mortality [826], so it is recommended that traditional pre-dialysis BP be used as the reference to assess the stability of hemodynamics during dialysis session. Home BP should be the basis for diagnosing hypertension and determining treatment targets. Some guidelines or consensus documents propose a target home BP ≤135/85 mmHg or office BP ≤140/90 mmHg [827, 828]. However, due to limited accumulated evidence in Japan and variability in clinical presentations among patients, it is currently considered inappropriate to define specific numerical targets. In clinical practice, BP targets should be individualized, ensuring the prevention of hemorrhagic complications and heart failure, maintenance of internal shunt blood flow, and avoidance of intradialytic hypotension. The basic treatment remains the same as before, correction of excessive salt intake and appropriate setting and management of dry weight (target body weight). Regarding the selection of antihypertensive medication considering complications, while there are reports of partial outcome improvements with various antihypertensive drugs, the accumulation of evidence is limited compared to other conditions. This is due to the high proportion of patients already taking multiple anti-hypertensive medications when starting dialysis. In peritoneal dialysis and post-kidney transplant patients, management should be guided by guidelines corresponding to the CKD stage, where BP fluctuations associated with treatment are minimal.

【POINT 9d】 【Vascular diseases】

1. Strict BP management is important for aortic aneurysms, with a target of <130/80 mmHg as a general rule.

2. In chronic aortic dissection, strict BP management targeting ≤130/80 mmHg is recommended.

3. Strict BP management is important for peripheral arterial disease as the treatment goal is not only to improve ischemic symptoms, but also to prevent CVD events which frequently coexist.

4. In cases such as heart failure or coronary artery disease, where β-blockers are indicated, their administration should also be considered.

4. Vascular diseases

1) Aortic diseases

(1) Aortic aneurysm

Aortic aneurysms are often asymptomatic, so they are frequently incidentally discovered during health screenings or physical examinations. Once ruptured, the mortality rate is exceptionally high [829–831].

Strict BP management is important for aortic aneurysms, and it is generally recommended to maintain BP <130/80 mmHg [832, 833]. Regarding antihypertensive drugs, β-blockers have been reported to slow the rate of aneurysm enlargement and improve prognosis in patients with Marfan syndrome [834], but in abdominal aortic aneurysms, β-blockers have been reported to have no effect in reducing aneurysm growth rate [835]. There is also no evidence that other antihypertensive drugs inhibit enlargement in abdominal aortic aneurysms [836, 837], so the choice of antihypertensive drugs should be made considering other comorbidities. Smoking is a risk factor for the enlargement and rupture of abdominal aortic aneurysms, and smoking cessation counseling is important for patients with aneurysms [838–840]. Additionally, CT scans are useful in diagnosing and monitoring the size of aneurysms, and regular CT scans should be performed to monitor the size. If the trend is towards enlargement, surgical intervention should be considered at an appropriate time [833].

(2) Aortic dissection

Most chronic aortic dissection patients have been treated for acute aortic dissection, but asymptomatic aortic dissection may occasionally be discovered incidentally. It is reported that good BP management reduces the incidence of re-dissection to approximately one-third [841] and strict BP management with a target BP <130/80 mmHg is recommended [832]. β-blockers have been reported to reduce dissection-related complications and suppress aneurysm enlargement [842, 843]. Regular CT follow-ups to monitor the rate of aneurysm enlargement and diameter are recommended, with surgical intervention considered at an appropriate time [833].

For acute aortic dissection, refer to "Chapter 16, Section 1. Hypertensive emergencies and urgencies".

2) Peripheral Arterial Disease (Arteriosclerotic obliterans)

Y. Ohya

Most common is lower extremity obstructive atherosclerosis. Hypertension is a risk factor equivalent to diabetes [844], and approximately 5% of hypertensive patients in Japan have an ABI of <0.9 [845]. Although ischemic symptoms have been improved with advances in revascularization therapy, the object of treatment is not only to improve ischemic symptoms, but also to prevent the onset of CVD events, which frequently coexist.

The cornerstones of basic therapy for systemic atherosclerosis are the treatment of risk factors and lifestyle modification. Strict BP management is often ineffective in improving lower extremity ischemic symptoms, but it is important in preventing the onset of CVD events, along with risk factor management. This includes the cessation of smoking [846, 847]. There is no preferred antihypertensive drug for lower extremity ateriosclerotic obliterans [848, 849]. β-blockers have been recognized to be associated with the worsening of lower extremity ischemia symptoms, but RCTs in patients with intermittent claudication showed no significant worsening of symptoms or prognosis [850–852], so they are not contraindicated. β-blockers should be considered in patients with concomitant ischemic heart disease [853]. In studies in diabetic patients, the incidence of CVD was shown to be lower in the intensive BP lowering group (mean BP 128/75 mmHg) compared to the placebo group (137/81 mmHg) [846], and the incidence of lower limb amputation or death in diabetic patients was strongly correlated with SBP [854, 855]. Therefore, the appropriate target BP and antihypertensive drugs should be selected based on whether cautious administration or active treatment are required, and contraindications, as well as the presence of comorbidities.

Exercise therapy does not improve ABI, but it has been shown to improve claudication symptoms and QOL and increase the patient's maximum walking distance [856-858]. In cases where exercise therapy and drug therapy do not provide sufficient efficacy for claudication symptoms, revascularization should be considered. In severe cases, percutaneous vascular angioplasty or surgical revascularization may be necessary, so referral to a specialist is recommended.

5. Cognitive impairment

1) Association with BP

Hypertension is a risk factor for vascular dementia [42, 626, 859, 860], but it is also associated with vascular abnormalities in Alzheimer's disease [42, 859, 860]. Furthermore, based on the concept of the neurovascular unit, which integrates vascular and neural systems [861], associations between hypertension, causing structural and functional abnormalities in cerebral blood vessels, and Alzheimer's disease have been reported

[42, 626, 859, 860, 862]. Additionally, a significant proportion of dementia in older adults is influenced by vascular disorders that accumulate over the lifespan [863]. Hypertension may serve as a risk factor for dementia in older adults [864]. The relationship between BP, cognitive function, and dementia is complex; it is influenced by various factors such as age, duration of hypertension, and anti-hypertensive medication [42, 865]. In particular, the influence of age is significant, with hypertension in younger adults being associated with cognitive decline in midlife [866], and as demonstrated in numerous observational studies, hypertension in midlife is a risk factor for cognitive decline in late life [42, 44, 626, 859, 860, 867]. Hypertension is a modifiable potential risk factor for dementia [868, 869]. Therefore, hypertension in midlife should be actively treated from the perspective of dementia prevention [42, 626, 859–861].

To date, the relationship between dementia and BP in late life is inconsistent, and not only hypertension but also hypotension is associated with dementia [867, 870, 871]. Reports suggest that the association between low BP and cognitive decline or brain atrophy in older adults depends on the presence of hypertension in middle age [860, 872], and the inconsistent association between BP and cognitive function in late life may be attributed to the interactive effects of BP in midlife and late life.

Abnormal BP variability, rather than average BP, has also been shown to be associated with cognitive decline [868, 873–875], as well as orthostatic hypotension [876, 877] and symptomatic latent orthostatic hypotension [878], and nighttime BP non-dipper or riser [879] have been reported. Additionally, in Japan’s Ohasama Study [51] and the Hisayama Study [52], increased day-to-day BP variability has been associated with cognitive decline and the onset of dementia.

2) Primary prevention of dementia

In hypertensive patients without a history of cerebrovascular disease [880] or in older hypertensive patients [881], and in those with a history of ischemic stroke or TIA [678] it is reported that antihypertensive therapy does not prevent dementia or cognitive decline. However, recent meta-analyses have reported that antihypertensive therapy reduces the risk of dementia and cognitive decline [867, 882–884]. Reports have been published on the effects of CCBs or RAS inhibitors [885], ARBs [886, 887], and it has been suggested that ACE inhibitors and ARBs may be more effective as they have a lower blood-brain barrier permeability compared to those with higher permeability [888], and reports indicate that the effects among the classes are unclear [889, 890]. Furthermore, the evidence level is currently low regarding whether strict BP management reduces the risk of cognitive decline or dementia [891]. Furthermore, there is limited evidence supporting the initiation of

The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and...

antihypertensive therapy in patients with elevated BP based on cognitive decline [892]. On the other hand, there is no clear evidence that discontinuing antihypertensive medications can suppress cerebral blood flow reduction and thereby inhibit the onset of dementia [893].

Since trials in hypertensive patients have shown lower rates of dementia onset, long-term observation of a large number of cases is necessary to prove that antihypertensive drugs suppress the onset or progression of dementia [868]. Furthermore, the fact that dementia is associated with many factors other than hypertension is considered to be the reason why most studies have not reached clear conclusions [868].

Therefore, while there is no definitive evidence that antihypertensive therapy prevents dementia or preserves cognitive function in older hypertensive patients, there is some hope for its efficacy in inhibiting the onset of dementia. Given that there is no evidence that antihypertensive therapy worsens cognitive function in older hypertensive patients without dementia, antihypertensive therapy should be considered [626].

3) Antihypertensive treatment in hypertension with dementia

In a study, 35% of older adults with hypertension have a mild cognitive impairment (MCI) level of latent cognitive decline [894], and it has been reported that older patients with poor adherence to antihypertensive medication have a three-fold higher risk of developing dementia [895]. In older hypertensive patients, it is advisable to always consider the possibility of cognitive decline, refer to medication adherence status, and perform a three-word delayed recall assessment during outpatient visits.

Evidence on the efficacy of antihypertensive therapy in patients with hypertension and dementia is limited. Two meta-analyses examining progression from MCI to dementia found that hypertension was not a significant risk factor [896, 897]. However, observational studies suggest that treatment of hypertension may inhibit progression from MCI to Alzheimer's disease [898]. In addition, observational studies of patients with MCI have shown that the rate of progression to dementia was significantly lower, and cognitive decline was suppressed in users of centrally acting ACE inhibitors and ARBs [899]. Furthermore, there are reports that the rate of progression from MCI to dementia is lower in users of ARBs than in users of ACE inhibitors [900].

In patients with Alzheimer's disease, cognitive decline was suppressed by controlling atherosclerotic risk factors, including antihypertensive drugs [901]. In a follow-up study of patients with Alzheimer's disease, those who took antihypertensive drugs had less cognitive decline than those who did not [902]. In clinical trials conducted in Japan, it has been reported that RAS inhibitors suppressed cognitive decline in Alzheimer's disease patients [903–905].

There is limited evidence regarding the target BP for patients with dementia and hypertension. Patients with Alzheimer's disease have a higher risk of orthostatic hypotension [906], and there are reports that with the combination of ACE inhibitors and diuretics, falls associated with orthostatic hypotension are more common [907]. Furthermore, in observational studies of patients with MCI and Alzheimer's disease taking antihypertensive medications, significant cognitive decline was observed in the group with daytime low BP (SBP ≤128 mmHg) [908]. It has been suggested that reduced cerebral perfusion due to excessive BP lowering may contribute to cognitive decline [909, 910], and caution is needed regarding excessive BP reduction. Regarding the usefulness of discontinuing or reducing antihypertensive medications in older hypertensive patients with dementia, as stated in Q7 of JSH2019, there is insufficient evidence to establish optimal BP targets [284]. However, as described in "Chapters 10 and 11. Older adults, 2) Frailty, need for care, end-of-life", it is suggested that the benefits of antihypertensive therapy diminish and adverse events become more likely with the decline in physical and mental function in older adults aged 75 years or older. This section proposes categorizing older adults 75 years or older based on their functional status and administering antihypertensive therapy accordingly, and the same approach is recommended for patients with dementia. Additionally, in patients with hypertension and dementia, poor medication adherence significantly impacts BP management, making the involvement of family members and healthcare staff in medication management crucial.

CQ 8 Should target BP level for hypertensive patients with a history of stroke be <130/80 mmHg?

$\blacktriangleright$ For hypertensive patients with a history of stroke, we strongly recommend implementing antihypertensive therapy to achieve SBP <130 mmHg to prevent recurrent CVD events. However, caution is advised regarding the potential occurrence of adverse events associated with BP reduction.

[Recommendation strength 1, Evidence strength A, Consensus rate 100%]

Summary of evidence

Stroke recurrence [373, 374] or major cardiovascular events [367], SBP changes [688], infarct volume changes [911], cognitive function [689], and changes in mean white matter diffusion rate [912] were the primary outcomes, and seven RCTs comparing an intensive BP lowering group with a standard BP lowering group in patients with a history of stroke were identified [913]. One trial included intracerebral hemorrhage in the history of stroke [373], and one trial

Y. Ohya

![StudyRR(95%CIIntensive BP controStandard BP controlEventTotalEventTotal11815011519SPS3.20131470.81(0.641.02)02662633PAST-BP.20160.14(0.012.72)141342PODCAST.20170.34(0.043.15)159521Park JM et al.20180.88(0.06,13.74)RESPECT.201939633526300.75(0.501.11)PRESERVE.20213553561.02(0.214.83)Overall0.79(0.65,0.96)Heterogeneity:72=0.00,12=0.00%,H2=1.00Test of 1= 0j: Q(5)=2.09,p=0.840.1110Recurrent stroke (target BP: intensive BP lowering vs. standard BP lowering).(Adapted from ref. [913]\n](1/parseimages/figuree1ae252e7543471e91aaf46789c37841_0_1.png) included hemorrhagic stroke [689]. Two trials [373, 374] reported stroke outcomes separately as ischemic stroke and hemorrhagic stroke, and one trial [689] reported stroke outcomes separately as ischemic stroke and hemorrhagic stroke.

Explanation

The target BP for the intensive BP lowering group was BP<120/80 mmHg [373], SBP<120 mmHg [367, 911], <125 mmHg [689, 912], or <130 mmHg [374, 688]. The target BP for the standard antihypertensive group was BP <140/90 mmHg [373], SBP <140 mmHg [367, 688, 699, 911], 130 -140 mmHg [912], or 130-149 mmHg [374]. In individual trials, the efficacy of strict BP lowering, including the prevention of stroke recurrence, was not demonstrated.

1) Stroke recurrence rate

The target BP for the active BP lowering group was a BP in 1 case of <120/80 mmHg [373], 1 case of SBP <120 mmHg [911], 2 cases of <125 mmHg [689, 912], 2 cases of <130 mmHg [374, 688]. In this meta-analysis, the incidence of stroke recurrence was significantly lower for the intensive BP lowering group (162/2555) compared to the standard BP lowering group (209/2,562) (RR 0.79 [95% CI 0.65 to 0.96]) (Fig. CQ8-1). Additionally, no significant heterogeneity was observed ($I^2=0\%$; publication bias, $P=0.405$). In the analysis stratified by ischemic stroke and hemorrhagic stroke, in the four studies reporting ischemic stroke [373, 374, 689, 911] no statistically significant reduction were shown in the intensive BP lowering group (151/2,234) compared to the standard BP lowering group (175/2,243) (RR 0.87 [95% CI 0.71–1.08], $I^2=0\%$; publication bias, $P=0.569$) (Fig. CQ8-2). In contrast, in the three studies [373, 374, 689] that reported intracerebral hemorrhage (including hemorrhagic stroke), there was a

significant reduction in the intensive BP lowering group (8/2175) compared to the standard BP lowering group (28/2191) (RR 0.33 [95% CI 0.15 to 0.74], $I^2 = 0\%$; publication bias, $P = 0.898$) (Fig. CQ8-2).

2) CVD

A pooled analysis was conducted on the incidence of CVD, defined as circulatory disease, stroke, and fatal car-diovascular disease, including one trial with a target BP <120/80 mmHg [373], 2 trials with a target SBP <120 mmHg [367, 911], 1 trial with a target SBP<125 mmHg [689], and 2 trials with a target SBP<130 mmHg [374, 688]. The intensive BP lowering group (409/4020) had a significantly lower incidence of CVD (RR 0.86 [95% CI 0.76 to 0.97], $I^2 = 0\%$; publication bias, $P = 0.157$) compared with the standard BP lowering group (event rate/total number of patients, 477/4008), (Fig. CQ8-3).

3) Cardiovascular death

One trial with a strict BP lowering group with a target SBP <120 mmHg [911], one trial <125 mmHg [689], and two trials <130 mmHg [374, 688] were included for the analysis. The results were 43/1876 (event count/total patient count) in the standard BP reduction group and 37/1867 in the intensive BP reduction group, with no significant difference between groups (RR 0.88 [95% CI 0.57 to 1.35], $I^2=0\%$).

4) All cause mortality

One trial with an intensive BP lowering group with a target BP <120/80 mmHg [373], two trials with target SBP <125 mmHg [689, 912], and two trials with target SBP <130 mmHg [374, 688] were included for the analysis, and the results were 144/2,510 (event count/total patient count) in the standard BP lowering group and 141/2496 in the intensive BP lowering group, with no significant difference between groups (RR 0.99 [95% CI 0.79 to 1.24], $I^2 = 0\%$).

The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and...

 

5) Hypotension-related symptoms*

As an assessment of adverse effects, the occurrence of syncope (fainting) and dizziness consistent with hypotensive symptoms was evaluated. One trial in the active BP lowering group had a target BP of <120/80 mmHg [373], one trial a target SBP <120 mmHg [911], and one trial a target SBP <125 mmHg [912], and 2 trials of target SBP<130 mmHg [374, 688]. These were pooled and analyzed. The intensive BP lowering group (91/2418) showed a significant increase in hypotension related symptoms (RR 1.30 [95% CI 1.00 to 1.68], $I^2=0\%$), compared to the

standard BP lowering group (event rate/total number of patients, 71/2443).

6) Renal impairment

The results of one trial with an intensive BP lowering group of a target BP <120/80 mmHg [373], one trial with a target SBP <125 mmHg [912] were pooled and analyzed. There was a trend toward an increase in renal impairment in the intensive BP lowering group (7/688) compared to the standard BP lowering group (event rate/total patient count, 1/686), but no statistically significant difference between groups was observed (RR 4.86 [95% CI 0.84 to 28.27], $I^2=0\%$).

Y. Ohya

Summary

In hypertensive patients with a history of CVD, BP management of a target SBP 120-130 mmHg significantly reduced the risk of stroke recurrence, intracerebral hemorrhage, and CVD (see Table 9-1). However, symptoms of hypotension also significantly increased. Only one randomized trial included the DBP in the criteria [373].

Literature search

Eight SR committee members independently searched PubMed, the Cochrane Library, and ICHUSHI for relevant literature and extracted papers relevant to this CQ.

Footnotes

*In the meta-analysis of hypotension-related symptoms, when both syncope and dizziness were reported, syncope was prioritized. In reference [374], severe adverse events "orthostatic syncope" and a side effect potentially related to BP lowering "dizziness when standing up" were reported, and "orthostatic syncope" was adopted in the meta-analysis.

CQ 9 Does BP management targeting an SBP <130 mmHg in HFpEF reduce all cause death, CVD deaths/ events, or heart failure hospitalization?

$\blacktriangleright$ BP management targeting an SBP <130 mmHg is strongly recommended in HFpEF. However, caution is advised regarding the occurrence of adverse events associated with BP reduction.

[Recommendation strength: 1; Evidence strength: C; Consensus rate: 100%]

Summary of evidence

Six RCTs were included with all-cause mortality, cardiovascular mortality, CVD, heart failure hospitalization, renal dysfunction, hypotension, and serious adverse events as primary outcomes. This targeted patients with HFpEF satisfying the following criteria: ① RCTs were conducted after 2012 (the year the ESC heart failure guidelines defining HFpEF as LVEF ≥ 50% were published). ② RCTs with interventions including BP reduction to SBP <130 mmHg, various antihypertensive medications, or strict heart failure management. ③ RCTs where significant BP

![A. All Cause Mortality\nStudy\nExperimental Events Total Control Events Total Risk Ratio\nRBC Ratio\n[0.12; 71.85]\n[0.13; 130]\n[0.14; 130]\n[0.15]\n[0.16]\n[0.17]\n[0.18]\n[0.19]\n[0.10]\n[0.11]\n[0.12]\n[0.13]\n[0.14]\n[0.15]\n[0.16]\n[0.17]\n[0.10]\n[0.11]\n[0.11]\n[0.11]\n[0.11]\n[0.11]\n[0.11]\n[0.11]\n[0.11]\n[0.11]\n[0.11]\n[0.11]\n[0.11]\n[0.11]\n[0.11]\n[0.11]\n[0.11]\n[0.11]\n[0.11]\n[0.11]\n[0.11]\n[0.11]\n[0.11]\n[0.11]\n[0.11]\n[0.11]\n[0.11]\n[0.11]\n[0.11]\n[0.11]\n[0.11]\n[0.11]\n[0.11]\n[0.11]\n[0.11]\n[0.11]\n[0.11]\n[0.11]\n[0.11]\n[\n](1/parseimages/figurecf23b91c524047a4baab03503e94ae5e_0_12.png) The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and...

![A. CVD\nStudy\nExperimental Events Total Control Events Total Risk Ratio [95%CI]\n#SPRINT Aldo-DHF 15 213 21 209 PARAMOUNT 9 149 12 152 TOPCAT 58 505 70 499 STRONG-HF 32 177 35 170 Common effect model 1074 Random effects model Heterogeneity : I2=0%, Tau2=0, P=0.95 0.5 1 2 0.51 2 R [95%CI]\n##B. HF Hospitalization\n###Study\n####Experimental Events Total Control Events Total Risk Ratio [95%CI]\n####PARAGON-HF 690 2407 797 2389 0.86 [0.79; 0.94]\n####PARAMOUNT 4 149 6 152 0.86 [0.79; 0.94]\n#####STRONG-HF 12 177 23 170 0.88 [0.20; 2.36]\n############################################################################################################################################################################################################################################################################\n](1/parseimages/figurec6c325ab46a34a1e9806e099a6f427a1_0_1.png) reduction was observed after treatment in the intervention group and post-treatment BP reached SBP <130 mmHg (including estimated values). Ⓐ A follow-up period of ≥6 months. The 6 RCTs included two trials which evaluated the efficacy of MR antagonists [914, 915], two trials which evaluated the efficacy of ARNI [777, 916], one trial which is the follow up study of the SPRINT trial evaluating the efficacy of strict BP control [917], and a trial evaluating the efficacy of strict heart failure management [918]. Additionally, the SR added two meta-analysis papers [919] including one which validated the same CQ as in the previous JSH2019 and a review article on BP management in HFepEF patients [920]. In total eight papers [777, 914–921].

This meta-analysis did not include RCTs that used BP management targeting SBP <130 mmHg, therefore, the evidence level was lowered from an indirect perspective. For hospitalizations from heart failure and all-cause mortality, where suppression effects or trends were demonstrated in BP management targeting an SBP <130 mmHg, many of the trials were largely weighted and had limitations from an indirect perspective. Also, most of the trials included in this meta-analysis defined HFpEF as having an LVEF of 40–45%, so it is important to note that they also included heart failure with mid-range ejection fraction (HFmrEF: LVEF 41–49%).

Explanation

BP management targeting SBP <130 mmHg in HFpEF demonstrated a significant reduction in heart failure hospitalization and a trend toward reduced all-cause mortality. However, an increase in hypotension was observed, although no increases in deterioration of renal function or severe adverse events were noted.

1) All-cause mortality

BP management with SBP <130 mmHg in HFpEF reduced all-cause mortality by 26% compared with BP management with SBP ≥130 mmHg, although the trend was not statistically significant (RR 0.74 [95% CI 0.53 to 1.04], P=0.083) (6 trials, Fig. CQ9-1A) [777, 914–918]. Heterogeneity was moderate ($I^2 = 50$%). In a sensitivity analysis excluding the follow-up trial of SPRINT, a quasi-RCT [917], no significant change was observed (RR 0.72 [95% CI 0.46 to 1.11], $I^2 = 59$%). Additionally, in an analysis excluding PARAGON-HF [777], a significant reduction in all-cause mortality was observed (RR 0.63 [95% CI 0.47 to 0.84], $I^2 = 0$%).

In subgroup analyses by antihypertensive drug class and intervention method (e.g., intensive therapy), significant mortality reduction was observed with MR antagonists, including Aldo-DHF [914] and the subgroup analysis of

Y. Ohya

A. Hypotension

![Study Experimental Events Total Control Events Total Risk Ratio [95%CI] Weight Weight (Common) Weight (Random) PARAMOUNT 28 149 27 152 STRONG-HF 8 177 0 170 PARAGON-HF 380 2407 257 2389 Common effect model 2733 Random effects model Heterogeneity: P=55%, Tau$^{2}$=0,0139, P=0,11 0.01 0.1 1 10 100 B. Serious Adverse Events Experimental Experimental Events Total Risk Ratio 195 PARAMOUNT 22 149 30 152 ARAMOUNT 231714.06 [1.26; 1.68] 100.0% Random effects model Heterogeneity: P=55%, Tau$^{2}$=0,0139, P=0,11 0.01 1 10 100 B. Serious Adverse Events Development 2948 Random effects model Heterogeneity: P=15%, Tau$^{2}$=0,0139, P=0,11 0.01 0.1 1 10 100 B. Serious Adverse Events Development 2948 Experimental Experimental Method Control Control Control Control Control Control Control Control Control Control Control Control Control Control Control Control Control Control Control Control Control Control Control Control Control Control Control Control Control Control Control Control Control Control Control Control Control Control Control Control Control Control Control Control Control Control Contr\n](1/parseimages/figure154cb0a507084751a2f97fa21db6ba18_0_2.png) B. Serious Adverse Events

 Fig. CQ9-3 Adverse events (Achieved SBP: <130 mmHg [intervention] vs. ≥130 mmHg [control]). (Adapted from ref. [921])

TOPCAT which included treatment-resistant hypertension [915] (RR 0.67 [95% CI 0.47 to 0.93]).

2) CVD mortality

BP management which targeted an SBP <130 mmHg in HFepEF did not affect the risk of CVD mortality (RR 0.73 [95% CI 0.47 to 1.14], P = 0.163) (4 trials, Fig. CQ9-1B [777, 915, 917, 918]. Heterogeneity was moderate ($l^2 = 56\%$).

3) CVD events

BP management which targeted an SBP <130 mmHg in HFpEF did not significantly affect the incidence of CVD events (RR 0.83 [95% CI 0.67 ~ 1.03], P = 0.098) (5 trials, Fig. CQ9-2A) [914–918]. Heterogeneity was mild ($I^2$ = 0%).

4) Heart failure hospitalization

BP management which targeted an SBP <130 mmHg in HFpEF reduced heart failure hospitalizations by 20%, with a statistically significant reduction (RR 0.80 [95% CI 0.69 to 0.93], P=0.005) (5 trials, Fig. CQ9-2B) [777, 915–918]. Heterogeneity was mild ($I^2$ = 0%). Subgroup analyses and sensitivity analyses were conducted in the same way as all-cause mortality, and BP management of SBP<130 mmHg was observed to reduce heart failure hospitalizations in every analysis.

5) Decline in renal function

Decline in renal function was not affected by BP management which targeted an SBP <130 mmHg in HFpEF (RR 0.97

[95% CI 0.42 to 2.29], P=0.953) (4 trials) [777, 914, 916, 918]. Heterogeneity was high ($I^2=86\%$). A sub-analysis focusing on intervention studies using ARNI [777, 916] showed that BP management which targeted an SBP <130 mmHg reduced the decline in renal function by 49%, with a significant inhibitory effect, and heterogeneity disappeared (RR 0.51 [95% CI 0.34 to 0.77], P=0.002; $I^2=0\%$).

6) Hypotension

BP management which targeted an SBP <130 mmHg in HFpEF increased the risk of hypotension by 39% (RR 1.39 [95% CI 1.09 to 1.78], P=0.007) (3 trials, Fig. CQ9-3A) [777, 916, 918]. Heterogeneity was moderate ($I^2$ = 55%). However, among the three trials included in the meta-analysis, only the PARAMOUNT trial explicitly reported symptomatic hypotension [916], while the other two trials [777, 918] included the number of events labeled as "Hypotension" or "SBP <100 mmHg" in the analysis, necessitating consideration of non-direct outcomes. In a sub-analysis of the ARNI intervention study [777, 916] focusing on patients who achieved SBP 120–130 mmHg, BP management resulted in a 35% increase in hypotension, which was statistically significant (RR 1.35 [95% CI 1.03 to 1.79], P=0.03; $I^2$=39%).

7) Serious adverse events

BP management which targeted an SBP <130 mmHg in HFpEF did not increase the risk of serious adverse events (RR 0.92 [95% CI 0.78 to 1.08], P=0.295) (4 trials,

The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and...

Fig. Q9-3B) [777, 914, 916, 918]. Heterogeneity was mild ($l^2 = 15\%$). Subanalyses by intervention method or baseline BP (SBP ≥130 mmHg) also did not show an increase in serious adverse events. Note that the breakdown of serious adverse events included death and heart disease, and three [777, 916, 918] of the four papers included in the meta-analysis [777, 914, 916, 918], explicitly defined "serious adverse events" in the text, and the definitions of events were generally consistent. However, in the Aldo-DHF study, "all hospitalizations" were included as serious adverse events in the analysis [914].

Summary

BP management which targeted an SBP <130 mmHg in HFpEF demonstrated a significant reduction in heart failure hospitalization and a trend toward reduced all-cause mortality, but it increased the incidence of hypotension. However, it did not increase serious adverse events or show a decline in renal function.

Literature search

Four SR committee members independently conducted literature searches in PubMed, the Cochrane Library, and ICHUSHI to identify relevant papers for this CQ.

CQ 10. Is antihypertensive treatment which targets a BP of <130/80 mmHg recommended for hypertensive patients with CKD?

$\blacktriangleright$ Antihypertensive treatment which targets a BP <130/80 mmHg is strongly recommended for hypertensive patients with CKD. However, it is important to be mindful of potential adverse events associated with BP reduction.

[Recommendation strength 1, Evidence strength A, Consensus rate 100%]

Summary of evidence

The JSH 2019 recommends a target BP of <130/80 mmHg for hypertensive patients with CKD who are proteinuria positive, and a target BP of <140/90 mmHg for those who are proteinuria negative, to reduce cardiovascular events and mortality. However, BP lowering therapy targeting an SBP <130 mmHg may increase the risk of adverse events due to BP reduction. Clarifying whether BP reduction targeting 130/80 mmHg improves outcomes in hypertensive patients with CKD is an important clinical challenge.

An RCT was conducted to evaluate the efficacy of antihypertensive therapy targeting SBP <120-130 mmHg or DBP <80 mmHg in men and women aged 18 years or older, diagnosed with CKD and hypertension (excluding patients on dialysis, those in the acute phase of stroke, or those in the acute phase of cardiovascular disease). A total of 9 RCTs were included (AASK [922], ACCORD-BP [923], CRHCP [924], ESPRIT [367], and MDRD [925], REIN-2 [926], SPRINT [927], STEP [317], and SPS3 [928]) and a meta-analysis was conducted [929] (ACCORD-BP [923] using hazard ratio data in the meta-analysis). Beneficial outcomes showed a trend toward reducing all-cause mortality and the incidence of cerebrovascular events. Harmful outcomes were not increased, including the incidence of serious adverse events. However, caution is necessary regarding hypotension due to the intensified lowering of BP.

After the analysis, the BPROAD trial [376] was reported, and then we urgently conducted an additional analysis. The results for composite CVD events remained unchanged.

 Fig. CQ10-1 All-cause mortality (target SBP: <120-130 mmHg [intervention] vs. <130-150 mmHg [control]). (Adapted from ref. [929])

Y. Ohya

|Study|Year|More intensive BP control|Less intensive BP control|Weight|Risk ratio (95%CI) Random-effects model||| |---|---|---|---|---|---|---|---| |Study|Year|Events|Total|Weight|Risk ratio (95%CI) Random-effects model|Events|Total| |Cardiovascular events|||||||| |$AASK^{5}$|2002|71|540|78|554|0.93 (0.69-1.26)|| |$ACCORD^{26*}$|2023|-|-|-|-|7.1%|0.70 (0.40-1.21)| |$ESPRIT^{20}$|2024|52|337|61|340|19.2%|0.86 (0.61-1.21)| |$SPRINT^{28*}$|2017|112|1330|131|1316|37.9%|0.85 (0.67-1.08)| |$SPS3^{29*}$|2019|39|247|30|227|11.3%|1.20 (0.77-1.86)| |Overall||274+|245+|300+|2437+|100.0%|0.89 (0.77-1.03)|

Heterogeneity: Tau-squared = < 0.001, P = 0.0%

Test for overall effect Z = 1.52 (p = 0.13)

![0.25\n0.50\n0.50\n1.00\n2.00\n4.00\nFavors more intensive\nBP control\n[929])\n](1/parseimages/figure0bfe016478de4637a20229439d2a91fe_0_4.png) |Study|Year|More intensive BP control|Less intensive BP control|Weight|Risk ratio (95%CI)|||| |---|---|---|---|---|---|---|---|---| |Study|Year|Events|Total|Weight|Risk ratio (95%CI)||Events|Total| |50% reduction in eGFR/GFR||||||||| |$AASK^{5}$|2002|82|540|82|554|78.5%|1.03 (0.77-1.36)|| |$ACCORD^{26*}$|2023|-|-|-|-|4.2%|0.50 (0.15-1.70)|| |$CRHCP^{19}$|2023|8|268|10|241|7.5%|0.72 (0.29-1.79)|| |$SPRINT^{28*}$|2017|10|1330|12|1316|9.0%|0.83 (0.36-1.90)|| |$STEP^{18}$|2021|1|99|1|97|0.8%|0.98 (0.06-15.4)|| |Overall||101+|2237+|105+|2208+|100.0%|0.95 (0.74-1.22)||

Heterogeneity: Tau-squared = < 0.001, P = 0.0%

Test for overall effect Z = 0.40 (p = 0.69)

 Hypertension treatment targeting SBP <120–130 mmHg showed a trend toward reducing risk compared with treatment targeting SBP <130–150 mmHg, although the difference was not statistically significant (RR 0.87 [95% CI 0.76 to 1.00], P = 0.050).

Explanation

In creating the search formula,

P (patient): (=) Men and women aged 18 years or older with CKD and hypertension (regardless of diabetes status; patients on dialysis, those in the acute phase of stroke, and those in the acute phase of cardiovascular disease were excluded).

I (intervention): Antihypertensive treatment targeting BP <130/80 mmHg.

C (comparison): Antihypertension treatment targeting BP<140/90 mmHg or higher.

O (outcome): primary endpoints included all-cause mortality, 50% reduction in GFR or doubling of serum creatinine, progression to end-stage renal disease, composite cardiovascular events, serious adverse events, and hypotension.

Finally, we evaluated the efficacy of antihypertensive therapy targeting SBP <120-130 mmHg or DBP <80 mmHg in patients aged 18 years or older with CKD and hypertension, based on nine RCTs: AASK [922], ACCORD-BP [923], CRHCP [924], ESPRIT [367], MDRD [925], REIN-2 [926], SPRINT [927], STEP [317], and SPS3 [928]. Limitations of this meta-analysis include slight differences in the definitions of P (CKD) and O (each outcome), and the inability to stratify by the presence or absence of proteinuria due to the lack of data for CKD stage A1 (A1 and eGFR <60 mL/min/1.73 m$^{2}$).

1) All-cause mortality

Hypertension treatment which targeted an SBP < 120-130 mmHg showed a trend toward reducing the risk of all-cause mortality compared with SBP < 130-150 mmHg, although the difference was not statistically significant (RR 0.81 [95% CI 0.65 to 1.00], P=0.051, Fig. CQ10-1 ). The funnel plot results suggested a low likelihood of publication bias.

2) Composite CVD events Hypertension treatment which targeted SBP < 120-130 mmHg showed a trend toward reducing the risk of composite CVD events compared with SBP < 130-150 mmHg, although the difference was not statistically significant (RR 0.89 [95% CI 0.77 to 1.03]). Publication bias was negative (Fig. CQ10-2 ).

3) GFR reduction by 50% or doubling of Cr There was no significant difference in the risk of GFR reduction by 50% or doubling of Cr between antihypertensive treatment targeting SBP < 120-130 mmHg and SBP < 130-150 mmHg (RR 0.95 [95% CI 0.74 to 1.22]). Publication bias was negative (Fig. CQ10-3 ).

4) End-stage kidney disease (ESKD)

4) End-stage kidney disease (ESKD)

There was no significant difference in the risk of ESRD between antihypertensive treatment targeting an SBP of < 120-130 mmHg and < 130-150 mmHg (RR 0.92 [95% CI 0.75 to 1.14]). Publication bias was negative.

5) Adverse events

5) Adverse events

In a subgroup analysis of the SPRINT trial, there was no significant difference in the risk of serious adverse events between antihypertensive therapy targeting SBP < 120 mmHg and < 140 mmHg (RR 0.97 [95% CI 0.90 to 1.05]). Since only one study was included in the meta-analysis for this outcome, a funnel plot analysis could not be performed.

6) Hypotension

6) Hypotension

In a subgroup analysis of the SPRINT trial, BP-lowering therapy targeting an SBP < 120 mmHg showed a trend toward an increased risk of hypotension compared with therapy targeting an SBP < 140 mmHg, although the difference was not statistically significant (RR 1.33 [95% CI 0.88 to 2.01]). Since only one study was included in the meta-analysis for this outcome, a funnel plot analysis could not be performed.

Summary

Summary

In patients aged 18 years or older with hypertension and CKD, a comparison was made between the outcomes from antihypertensive therapy targeting BP of < 140/90 mmHg with < 130/80 mmHg. The lower target showed beneficial outcomes, reducing all-cause mortality and the incidence of cardiovascular events. There were no increases in adverse outcomes, such as a 50% reduction in GFR, progression to end-stage renal disease, or serious adverse events. However, caution is needed regarding hypotension associated with intensified lowering of BP.

Additionally, since the BPROAD trial [376] was reported after the analysis, an additional analysis was conducted. The results for composite cardiovascular events remained unchanged. Hypertension treatment targeting SBP below 120-130 mmHg showed a trend toward reducing the risk of cerebrovascular events compared with hypertension treatment targeting SBP below 130-150 mmHg, although the difference was not statistically significant (RR 0.87 [95% CI 0.76 to 1.00], P=0.050).

Literature search

Literature search

Four SR committee members independently conducted literature searches in PubMed, Medline Web, and the Cochrane Library, extracted 806 documents through primary screening (titles and abstracts), excluded 762 documents based on exclusion criteria, and performed secondary screening (full text) of 44 documents. The results of this process yielded nine documents relevant to the current CQ, which were used for the meta-analysis.

CQ 11. In hypertensive patients with non-diabetic CKD and proteinuria, is the first-line antihypertensive drug an RAS inhibitor (ARB, ACE inhibitor)? In hypertensive patients with non-diabetic CKD without proteinuria, is the first-line antihypertensive drug an RAS inhibitor?

► In hypertensive patients with non-diabetic CKD and proteinuria, RAS inhibitors are recommended as the firstline antihypertensive drug.

[Recommendation strength-1, Evidence strength -A, Consensus rate -100%] ► For hypertensive patients with non-diabetic CKD without proteinuria, one of the following is suggested as the first-line drug: RAS inhibitors, CCBs, or thiazide diuretics.

[Recommendation strength -2, Evidence strength -C, Consensus rate -100%】

Summary of evidence

Summary of evidence

With proteinuria:

With proteinuria:

A screening of literature published after the period covered by JSH2019 did not identify any intervention studies or observational studies eligible for evaluation. In JSH2019, a meta-analysis of 29 RCTs showed that RAS inhibitors had a significant proteinuria-reducing effect and inhibited the progression of kidney failure in patients with CKD without diabetes (with proteinuria: ≥0.15 g/day [or 0.15 g/gCr]). Regarding hyperkalemia, although the incidence rate was low, a significant increase was observed with RAS inhibitors. No significant differences were observed between RAS inhibitors and other antihypertensive drugs in terms of all-cause mortality, CVD, hypotension, or acute kidney injury.

The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and. . .

References

Without proteinuria:

A meta-analysis of three RCTs showed no significant effect of RAS inhibitors on renal events or CVD events in patients with non-diabetic CKD without proteinuria.

Explanation

1) CQ Setting

Similar to CQ10 in JSH2019, this CQ also divided the population into two groups—those with proteinuria and those without—and conducted an SR. Note that in this CQ,proteinuria was defined as ≥0.15 g/day (0.15 g/gCr) or albuminuria as ≥30 mg/day (30 mg/gCr). Outcomes were set as 1) renal events and 2) cardiovascular events.

2) SR included trials

A literature search was conducted on PubMed, Cochrane Library, and ICHUSHI from September 8, 2017, to May 1,2024, and relevant papers that met the criteria of this CQ were extracted. For studies targeting hypertensive patients with non-diabetic CKD, we included RCTs with a diabetes prevalence of ≤30% and a hypertension prevalence of≥50%. Out of 1,677 papers, four were selected for the review after primary and secondary screening. Among them, three were excluded due to factors such as focusing mainly on diabetic patients or being of non-RCT design,resulting in one paper being selected [930]. Although the

ALLHAT trial lacked information on proteinuria, considering that existing guidelines cite trials as evidence for CKD patients without proteinuria, we extracted cases from the ALLHAT trial with GFR <60 mL/min/1.73 m2 and nondiabetes, and combined them with cases from the AASK trial with urine protein ≤0.22 g/gCr to conduct an exploratory meta-analysis [931–933].

3) Analysis targeting non-diabetic CKD (with proteinuria)

In this SR, no new papers were identified for the metaanalysis; therefore, the results of the SR from 2019 JSH

[934] are reprinted as follows. Regarding the progression of kidney failure, a meta-analysis of 18 RCTs that defined outcomes as progression to end-stage kidney failure or a doubling of serum creatinine levels (or equivalent indicators) found that RAS inhibitors significantly suppressed the progression of kidney failure (Fig. CQ11-1, RR 0.63 [95%CI 0.52 to 0.75]). Regarding proteinuria, a meta-analysis of 23 RCTs showed that RAS inhibitors consistently and significantly reduced the value of urine protein (mean difference: vs. control group: by 0.42 g/day [95% CI 0.26 to

0.58]). Regarding all-cause mortality and the incidence of CVD, no significant differences were observed, possibly due to the small number of events in the included RCTs(RR 0.77 [95% CI 0.51 to 1.16]). Regarding adverse outcomes, hyperkalemia showed a significant increase,

Fig. CQ11-1 Kidney events (non-diabetic CKD with proteinuria). (Adapted from ref. [934])

Y. Ohya

Abstract

although the incidence rate was low (RR 2.01, 95% CI 1.07 to 3.77). No significant effects were observed on hypotension or acute kidney injury.

Abstract

Among CKD patients taking RAS inhibitors, the STOP-ACEi trial is an RCT that evaluated the significance of discontinuing RAS inhibitors [817]. In this trial, patients (36% had diabetes) with an eGFR of < 30 mL/min/1.73 m 2 who were receiving ACE inhibitors or ARBs were randomized to either continue RAS inhibitors or discontinue them. The primary endpoint, eGFR at 3 years, was 13.3 ± 0.6 mL/min/1.73 m 2 in the continuation group and 12.6 ± 0.7 mL/min/1.73 m 2 in the discontinuation group, indicating that discontinuation of RAS inhibitors did not demonstrate a protective effect on renal function. The median urine protein/creatinine ratio in the patients enrolled in this trial was 960 mg/gCr (interquartile range 230-2089), and no heterogeneity was observed in the prespecified subgroup analyses based on the presence or absence of diabetes.

Abstract

Considering the above results, while caution is warranted regarding the risk of hyperkalemia, the benefits outweigh the risks, and RAS inhibitors are recommended as the firstline antihypertensive drug for patients with non-diabetic CKD (with proteinuria).

Abstract

4) Analysis targeting non-diabetic CKD (without proteinuria)

Abstract

Only one study was deemed appropriate for inclusion in the meta-analysis in this SR [930], thus an exploratory meta-analysis was conducted using this RCT, the AASK trial targeting hypertensive nephrosclerosis, and the ALL-HAT trial targeting hypertensive patients at risk of coronary artery disease [931] [932][933] . Note that the study population in the AASK trial was limited to patients with a urine protein/ creatinine ratio of 0.22 g/gCr or less, and in the ALLHAT trial, to patients without diabetes and with an eGFR of < 60 mL/min/1.73 m 2 . Although these populations did not always include solely patients with negative proteinuria, they are estimated to include a significant proportion of patients with hypertensive nephrosclerosis, a form of CKD

characterized by relatively low proteinuria. As a result, the RR for renal events was 1.13 (95% CI 0.84 to 1.51, Fig. CQ11-2 ), and the RR for CVD events was 1.10 (95% CI 0.99 to 1.22), indicating no superiority of RAS inhibitors. Although the population for the meta-analysis was estimated to include a relatively large number of patients with hypertensive nephrosclerosis and low urine protein levels, there are issues regarding indirectness in relation to this CQ, and caution is required in interpreting the results. Additionally, no RCTs were identified that could be used for meta-analysis of the adverse outcomes of hyperkalemia, acute kidney injury, and hypotension. In the trials included in the meta-analysis, CCBs or thiazide diuretics were used as comparators for RAS inhibitors, and no superiority of RAS inhibitors over other medications was demonstrated in patients with non-diabetic CKD (without proteinuria). Therefore, we propose that RAS inhibitors, CCBs, or thiazide diuretics be considered as first-line antihypertensive drugs.

Literature search

Literature search

A literature search was conducted on PubMed, Cochrane Library, and ICHUSHI, from September 8, 2017, to May 1, 2024, and papers relevant to this CQ were extracted from the search results.

Chapter 10. Management strategies for comorbidities and life stages The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and. . .

References

of 130-139/80-89 mmHg, lifestyle modifications should be attempted for a period not exceeding one month. 3. For the selection of antihypertensive drugs for hypertensive patients with diabetes, the method of using antihypertensive drugs for high-risk grade I hypertension and grades II and III hypertension should be adhered. 4. In hypertensive patients with diabetes who have microalbuminuria or proteinuria, individualized management is required, and administration of RAS inhibitors (ARBs or ACE inhibitors) should be considered for preventing the progression of DKD

of 130-139/80-89 mmHg, lifestyle modifications should be attempted for a period not exceeding one month. 3. For the selection of antihypertensive drugs for hypertensive patients with diabetes, the method of using antihypertensive drugs for high-risk grade I hypertension and grades II and III hypertension should be adhered. 4. In hypertensive patients with diabetes who have microalbuminuria or proteinuria, individualized management is required, and administration of RAS inhibitors (ARBs or ACE inhibitors) should be considered for preventing the progression of DKD

1. Diabetes mellitus

1. Diabetes mellitus

It has been reported that the prevalence of hypertension in patients with diabetes is about twice as high as that in patients without diabetes and that the prevalence of diabetes in hypertensive patients is 2-3 times higher than that in nonhypertensives [935] . A pathogenic relationship between type 2 diabetes and hypertension has been suggested, and both diseases are associated with obesity and insulin resistance as common background factors. In hypertensive patients with diabetes, strict BP management in addition to lifestyle modifications and proper blood glucose control are important for prevention and improvement of diabetic complications such as microvascular and macrovascular diseases. In hypertensive patients with diabetes, the treatment should be initiated at BP ≥130/80 mmHg. If BP is ≥140/90 mmHg, antihypertensive treatment should be immediately initiated. If BP is in the range of 130-139/ 80-89 mmHg, lifestyle modifications to lower BP may be attempted for a period not exceeding one month. The target BP for hypertensive patients with diabetes remains unchanged as < 130/80 mmHg for office BP and < 125/75 mmHg for home BP based on the results of CQ12.

According to CQ12, there was no significant difference in the risk of cardiovascular events and mortality between RAS inhibitors (ACE inhibitors, ARBs), CCBs and thiazide diuretics. However, the effects of antihypertensive agents on insulin sensitivity, glucose metabolism and lipid metabolism should be considered at the selection of drugs. RAS inhibitors (ACE inhibitors, ARBs) and long-acting dihydropyridine CCBs have been reported to improve insulin sensitivity without affecting lipid metabolism [548, 936] . Furthermore, in comparison of the three drugs, ARBs and ACE inhibitors have been reported to have superior efficacy for preventing new onset of diabetes compared to CCBs [548, 584, 724] . As other drugs, β-blockers may reduce hypoglycemic symptoms in patients with diabetes. It has also been reported that diuretics and β-blockers reduce insulin sensitivity and increase triglyceride levels, which are unfavorable effects on glucose and lipid metabolism.

For the selection of antihypertensive drugs in hypertensive patients with diabetes, according to the antihypertensive treatment STEP (see Chapter 8, Fig. 8-1 ), the method of using antihypertensive drugs for high-risk grade I hypertension, grade II hypertension and grade III hypertension should be adhered. In hypertensive patients with diabetes who have microalbuminuria (≥30 mg/gCr) or proteinuria (≥0.15 g/gCr), the administration of RAS inhibitors (ARBs or ACE inhibitors) should be considered for preventing the progression of DKD as an individualized management. In hypertensive patients with diabetes who have no microalbuminuria or proteinuria, antihypertensive drugs are selected from RAS inhibitors, CCBs, low-dose thiazide diuretics, and β-blockers by the consideration of indication in specific conditions. If the effect of BP lowering is insufficient, the increase in the dose of drugs and/or a combination therapy using two or three drugs should be considered (see "Chapter 8, Section 2. Combination therapy").

【POINT 10b】 【Obesity】 1. The prevalence of hypertension is high in obese individuals. 2. In hypertensive patients with obesity, a reduction of body weight ≥3% by diet and exercise therapies can significantly reduce BP.

2. Obesity

2. Obesity

Obese individuals have a 2-3 times higher prevalence of hypertension compared to non-obese individuals, [937] .

Hypertension is more common in subjects who have gained body weight, especially in the period of young adulthood and middle age. The pathology of hypertension associated with obesity includes activation of sympathetic nervous system, sodium retention/salt sensitivity, and insulin resistance/hyperinsulinemia. Obese subjects may have sleep apnea syndrome, which can also cause or exacerbate hypertension (see "Chapter 10, Section 4, Sleep Apnea Syndrome"). In obese individuals with a large upper arm circumference, the measurement of BP using a standard cuff may overestimate values of BP.

The BP-lowering effect of weight loss is well established, and a meta-analysis of large-scale clinical trials showed that a weight loss of 4-5 kg resulted in a significant BP reduction [432] . In an interventional study using specific health checkups and health guidance, a significant reduction of BP was observed in Japanese individuals receiving active support who lost ≥ 3% of their body weight over one year Y. Ohya

References

. For BP treatment in hypertensive patients with obesity, the initiation of weight loss through diet and exercise therapies is the first step. If BP remains uncontrolled after lifestyle modulations, drug treatment is started.

The selection of antihypertensive drugs should be followed by the standard method since obesity is not included in compelling indications. The use of ARBs and ACE inhibitors may be generally recommended because of the perspective of improving glucose metabolism and insulin resistance. It has been shown that diuretics and β-blockers reduce insulin sensitivity and that α-blockers have glucose and lipid metabolism-improving effects although the evidence for organ protection is unclear. In the CASE-J study conducted in Japan [724] , the use of ARBs was associated with a significant reduction in new onset of diabetes compared to the use of CCBs, and the inhibitory effect of ARBs was particularly pronounced in obese subjects with a BMI of ≥ 25 kg/ m 2 . In the ACCOMPLISH study [939] , the use of CCBs demonstrated a significant efficacy in reducing cardiovascular events compared to the use of diuretics. However, in patients with obesity (BMI ≥ 30 kg/m 2 ), the effects of CCBs and those of diuretics were equivalent. Therefore, the addition of a longacting CCB or a thiazide-type diuretic is considered to use in hypertensive patients with obesity who do not achieve adequate BP by treatment with ARBs or ACE inhibitors. The thiazide-type diuretics have minimal metabolic effects at a half of the standard dose. On the other hand, in patients with severe obesity, bariatric surgery for weight loss and metabolic improvement may improve hypertension. The J-SMART study using 322 Japanese patients with severe obesity (mean BMI 43.7 kg/m 2 ) who underwent laparoscopic sleeve gastrectomy showed that there was an average weight loss of 36 kg after 2 years with a 41.8% improvement in BP control for hypertensive patients [940] .

【POINT 10c】 【Dyslipidemia】 1. Hypertensive patients with dyslipidemia are classified as risk category II, corresponding to at least a moderate risk level. 2. The target for lipid management is determined using the Hisayama Score, taking into account SBP, the presence or absence of impaired glucose metabolism, and other factors. 3. Lifestyle modifications should be implemented regardless of risk level, while pharmacological treatment should be considered in patients at high risk.

3. Dyslipidemia

3. Dyslipidemia

Hypertension with dyslipidemia is a common condition encountered in internal medicine practice. Hypertension is a major cause of CVD and related mortality; however, hypertensive patients with additional risk factors exhibit even higher morbidity and mortality rates [941] . The INTERHEART study demonstrated that when hypertension is accompanied by other conditions such as dyslipidemia, type 2 diabetes and smoking, the risk of cardiovascular events increases more than 20-fold, compared to hypertension alone [942] . Therefore, treating BP alone is of limited efficacy, and comprehensive management of risk factors is recommended. Elevated total cholesterol and LDL cholesterol increase the risk of future CVD incidence and mortality [324, [943] [944] [945] [946] [947] . A meta-analysis of 11 cohort studies in Japan, EPOCH-JAPAN, demonstrated a synergistic effect of BP and total cholesterol on coronary artery disease mortality [948] . In the Hisayama Study, an increase in LDL cholesterol levels was associated with an increased RR of coronary heart disease and atherothrombotic ischemic stroke [944, 949] . The Japan Atherosclerosis Society (JAS) Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2022 [950, 951] adopt the score from the Hisayama Study for absolute risk assessment, aiming for more comprehensive management of risk factors.

Patients with hypertension complicated by dyslipidemia are classified as risk category II, corresponding to at least a moderate risk level; however, the target BP for treatment does not differ based solely on the presence or absence of dyslipidemia (see Chapter 6). In contrast, lipid management targets are determined using the Hisayama Score from the JAS Guidelines for Prevention of Atherosclerotic Cardiovascular Diseases 2022, considering SBP, the presence of impaired glucose metabolism, and other factors to assess risk and set the target values [950, 951] . For the treatment of hypertensive patients with dyslipidemia, regardless of risk level, non-pharmacological interventions should be implemented. These include smoking cessation, energy intake control, dietary modifications, alcohol consumption control, and improvements in physical activity and exercise. Among dietary modifications, the DASH (Dietary Approaches to Stop Hypertension) diet has been shown to be effective in lowering BP and LDL cholesterol [952, 953] . Pharmacological therapy combining antihypertensive agents and statins has been demonstrated to significantly reduce the risk of CVD [954] [955] [956] [957] . In patients with hypertension complicated by dyslipidemia whose BP is < 140/90 mmHg, lifestyle modification should be reinforced. However, in cases where elevated BP coexists with cardiovascular disease or other high-risk conditions, antihypertensive drug therapy should be considered (for risk assessment and treatment strategies, see Chapter 6). CCBs, ARBs, and ACE inhibitors do not affect lipid metabolism, while α-blockers exert a modestly favorable effect on lipid metabolism.

The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and. . .

References

1. Obstructive sleep apnea syndrome (OSAS) is one of the most common causes of secondary hypertension and is also an underlying condition contributing to poorly controlled hypertension, including treatmentresistant hypertension. Therefore, it is essential to diagnose and treat OSAS appropriately in the management of hypertension. 2. Continuous positive pressure breathing (CPAP) therapy for OSAS modestly lowers BP. Its BP-lowering effect is significant in severe OSAS and uncontrolled hypertension, and maintaining or improving CPAP adherence enhances the BP lowering effect. 3. In hypertensive patients with OSAS, initiate salt reduction and weight loss, in conjunction with CPAP (as appropriate under insurance coverage), with antihypertensive treatment conducted over 24 h, including nocturnal BP.

4. Sleep apnea syndrome

4. Sleep apnea syndrome

Sleep apnea is broadly classified into the obstructive type (OSA), which is associated with physical airflow restriction in the upper airway during inhalation during nocturnal sleep, and central type, which is related to abnormalities in the respiratory center. The latter is rare in hypertensive patients without severe heart failure, so this section focuses primarily on OSA. Approximately 30% of hypertensive patients have OSAS, and approximately 50% of OSAS patients have hypertension. OSAS is one of the causes of hypertension and it is the most common factor in secondary hypertension [958] , thus, the appropriate diagnosis and treatment of OSAS are extremely important, not only for BP management, but also for the prevention of cardiovascular events.

The mechanisms underlying BP elevation in OSAS involve a complex interplay of the following factors: 1) hypoxemia associated with apnea, 2) repeated episodes of rapid reoxygenation that occurs when apnea resolves, 3) excessive activation of the sympathetic nervous system due to fluctuations in intrathoracic pressure associated with respiratory effort, 4) endothelial dysfunction, 5) activation of the renin-angiotensin-aldosterone (RAA) system, 6) increased oxidative stress and inflammation [959, 960] . In hypertension associated with OSA, in addition to daytime BP elevation, nocturnal hypertension (non-dipper/riser type) is commonly observed, and particularly, the prolonged excessive activation of the sympathetic nervous system during the night may contribute to the development of morning hypertension or treatment-resistant hypertension [961, 962] . Therefore, it is important to consider OSAS not only in patients with typical OSAS symptoms such as snoring during sleep or daytime sleepiness but also in those with early morning hypertension or treatment-resistant hypertension. Furthermore, during the recovery phase following OSAS apnea episodes, significant BP surges may occur, leading to increased nocturnal BP variability and potentially triggering nocturnal cardiovascular events. Moreover, intermittent hypoxemia associated with OSAS, as assessed by the oxygen desaturation index (ODI), is more strongly associated with hypertension and BP surges than the apnea hypopnea index (AHI) [963, 964] .

OSAS is a disease closely associated with lifestyle factors, and it is important to improve lifestyle behavior (treatment of obesity, cessation of smoking, moderation of alcohol consumption, especially the prohibition before bedtime) with CPAP therapy implemented appropriately, based on the individual [965] . Multiple meta-analyses have demonstrated the modest BP lowering effects of CPAP therapy, particularly in populations < 60 years, those with poorly controlled BP at the start of CPAP therapy (including treatment-resistant hypertension), and those with severe decreases in oxygen saturation during sleep [966, 967] . Also, a meta-analysis of studies with an observation period of less than three months showed limited BP lowering effects of CPAP [968] , but implementing CPAP therapy for 4 h or more per night was associated with a greater reduction in early morning BP [969] , suggesting the importance of maintaining and improving CPAP adherence. Concurrently, weight loss achieved through lifestyle modifications focused on dietary therapy enhances the BP lowering effect of CPAP [970] .

Evidence regarding target BP in hypertension with OSAS remains insufficient [971], but it is desirable to manage BP over 24 h, particularly strict suppression of nocturnal hypertension ( < 120/70 mmHg), given the characteristic features of this condition [972] . In patients with inadequate BP control despite CPAP, antihypertensive drugs may be added. However, there is no clear evidence regarding the efficacy of specific antihypertensive drugs, so selection should be based on other comorbidities and the patient's condition.

5. Hyperuricemia/Gout

5. Hyperuricemia/Gout

【POINT 10e】

【POINT 10e】

【Hyperuricemia/Gout】 1. Hyperuricemia frequently coexists with hypertension and has been associated with renal dysfunction and an increased risk of cardiovascular events. Therefore, uric acid control should be considered in managing hypertension.

Y. Ohya

References

2. Hyperuricemia is diagnosed when the serum uric acid level is > 7.0 mg/dL, and lifestyle interventions should be initiated such as weight loss, restriction of purine, fructose, and alcohol intake, and regular aerobic exercise. 3. In patients with hypertension and a serum uric acid level of ≥8.0 mg/dL, consider initiating uric acid lowering therapy with a target serum uric acid level of ≤6.0 mg/dL 4. When selecting antihypertensive drugs, prioritize agents that have a favorable effect on uric acid metabolism.

Hyperuricemia frequently coexists with hypertension, and it has been shown that for every 1 mg/dL increase in the serum uric acid level, the prevalence of hypertension increases by 13-20% [973, 974] . Even asymptomatic hyperuricemia has been reported to be an independent predictive factor for both new-onset hypertension [975] and the progression from pre-hypertension to hypertension [976] . Additionally, several intervention studies have demonstrated that uric acid lowering therapy reduces BP [977, 978] . Mendelian randomization analyses and metaanalyses have also shown an association between uric acid and hypertension [979] , highlighting the need to consider uric acid control in hypertension management. In contrast, there is a debate regarding the direct preventive effects of treatment for hyperuricemia on the onset of CVD; further evidence is needed. Hyperuricemia is a cause of both the onset and recurrence of gout [980] , and it is a risk factor for the onset of CVD [981, 982] . This makes the management of hyperuricemia important from the perspective of the prevention of gout [983] .

In the Guideline for the Management of Hyperuricemia and Gout (3rd edition) by the Japanese Society of Gout and Uric & Nucleic Acids, hyperuricemia is defined as a serum uric acid level of > 7.0 mg/dL and instructions on changes to lifestyle are recommended (Fig. 10-1 ) [984] . Specifically, these include weight loss through appropriate energy intake, the restriction of purine/fructose/alcohol consumption, and regular aerobic exercise. Further recommendations include the consumption of alkaline foods and a moderate intake of fluids to promote uric acid excretion, ensuring a urine output of 2000 mL/day or more, if underlying conditions such as heart failure do not coexist.

In hypertensive patients with hyperuricemia, consider initiating uric acid-lowering therapy when the serum uric acid level is ≥8.0 mg/dL, with a target of maintaining levels of ≤6.0 mg/dL (Fig. 10-1 ). However, evidence remains inconclusive regarding the efficacy of treatment to prevent CVD events. Uric acid-lowering medications include uric acid synthesis inhibitors (xanthine oxidase inhibitors: febuxostat, allopurinol, topiroxostat) and uricosuric drugs (benzbromarone, probenecid, dapagliflozin). When using uricosuric drugs, urine alkalinization is also recommended to prevent urolithiasis.

In patients with hyperuricemia and hypertension, it is important to consider uric acid metabolism when selecting antihypertensive drugs. Diuretics (thiazides, loop diuretics) and β-blockers increase uric acid levels. CCBs, ACE inhibitors, and most ARBs do not significantly affect uric acid metabolism. However, some ARBs (losartan, irbesartan) and ARNI (sacubitril/valsartan) have uric acid-lowering effects and may be suitable for patients with hypertension and hyperuricemia. There are reports that the combination of losartan and CCBs reduces the risk of the onset of gout [985] . Hypertension complicated by obesity, metabolic abnormalities, or chronic kidney disease is prone to treatment resistance, and combination therapy, including thiazides, is often necessary to achieve target BP. Special caution is also required regarding the presence of hyperuricemia. The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and. . .

References

Abstract

【POINT 10f】 【Patients on antithrombotic drugs】 1. Strict BP management is necessary for patients taking antithrombotics (antiplatelet drugs, anticoagulants), because hypertension is a risk factor for intracranial hemorrhage.

6. Patients taking antithrombotic drugs

6. Patients taking antithrombotic drugs

There is an increase in the use of antiplatelet drugs for the secondary prevention of atherosclerotic diseases (such as transient ischemic attacks, ischemic stroke, coronary artery disease, peripheral artery disease, and carotid atherosclerosis) and oral anticoagulants to prevent the onset of cardioembolic stroke and deep vein thrombosis. The use of antithrombotic drugs increases the risk of hemorrhagic complications, particularly intracranial hemorrhage [986, 987] . The risk of bleeding is further increased by the dual antiplatelet therapy (DAPT) with aspirin and thienopyridine-class antiplatelet drugs, initiated early after drug-eluting stent therapy or in the early stages of noncardioembolic stroke. This is also the case for combined antithrombotic therapy with antiplatelet drugs and oral anticoagulants for atherosclerotic diseases complicated by atrial fibrillation [685, [987] [988] [989] [990] [991] [992] [993] [994] [995] .

Hypertension is a risk factor for intracranial hemorrhage in patients receiving antithrombotic therapy, so strict BP management is important. In a subgroup analysis of the J-CAD registry study of coronary artery disease, a risk of intracranial hemorrhage increased with an SBP elevation using DAPT or an antiplatelet plus oral anticoagulants, compared with using antiplatelet monotherapy [996] . In a subgroup analysis of the PROGRESS study of patients taking antithrombotic drugs, the mean BP decreased by 8.9/ 4.0 mmHg in the active drug group compared to the placebo group, and the incidence of intracranial hemorrhage decreased by 46% [684] . In the BAT prospective observational study of Japanese patients taking antiplatelet drugs or warfarin, BP levels during treatment were correlated with the incidence of intracranial hemorrhage. The BP cutoff value for predicting intracranial hemorrhage was 130/81 mmHg [686] . Additionally, in the SPS3 study, which compared the BP-lowering effects of targeting SBP < 130 mmHg versus 130-149 mmHg in patients with lacunar infarction (receiving either aspirin monotherapy or aspirin plus clopidogrel), the group achieving a BP < 130 mmHg had a 19% lower incidence of all strokes and a 63% significantly lower incidence of hemorrhagic stroke [374] . At present, the evidence is insufficient, but careful BP reduction, targeting < 130/80 mmHg should be considered to prevent intracranial hemorrhage in hypertensive patients taking antithrombotics, while monitoring for ischemic symptoms or findings in the brain, heart, and kidneys. In patients with a history of intracerebral hemorrhage while taking antithrombotics, more strict BP management with a target of < 120/80 mmHg may be considered [373] (For patients combined with ischemic stroke, see "Chapter 9, Section1. Cerebrovascular diseases"; for patients combined with atrial fibrillation, see "Chapter 9, Section 2. 4) Atrial fibrillation").

7. Cancer patients

7. Cancer patients

【POINT 10g】

【POINT 10g】

【Cancer Patient Management】 1. Hypertension is one of the most common complications in cancer patients, and the relationship between cancer and hypertension is bidirectional. 2. Hypertension associated with cancer treatment is observed with many anticancer therapy, and appropriate BP management should be initiated early to ensure the continuation of cancer treatment. 3. BP management should be conducted after anticancer therapy, including late-onset hypertension in cancer survivors, in collaboration with oncologists, cardiologists, nephrologists, primary care physicians, outpatient pharmacists, and other relevant professionals.

1) Relationship between cancer and hypertension: Oncological Hypertension (Onco-Hypertension [997])

1) Relationship between cancer and hypertension: Oncological Hypertension (Onco-Hypertension [997])

Hypertension is one of the most common comorbidities in cancer patients and occurs at a high rate alongside heart failure and thrombosis among cancer therapy-related cardiovascular toxicities [997] [998] [999] [1000] . Hypertension and cancer development have a bidirectional relationship, sharing common risk factors such as aging, smoking, physical inactivity, obesity, and diabetes, as well as shared pathogenic mechanisms including vascular endothelial dysfunction, oxidative stress, and inflammatory states [183, 997, [1001] [1002] [1003] [1004] . Furthermore, a significant association between hypertension and the onset of renal cell carcinoma [1004] and colorectal cancer [1005, 1006] has been reported.

2) Cancer therapy-related hypertension Cancer therapy-related hypertension is observed in many cancer treatments [183, [998] [999] [1000] [1001] [1002] [1003] [1004] . Antihypertensive therapy should be initiated early, and the content of cancer treatment should follow the guidelines of the Common Terminology Criteria for Adverse Events (CTCAE; version 5.0) established by the U.S. National Cancer Institute (NCI) and the Cancer Therapy Evaluation Program (CTEP) [1007] . Of particular note, anti-angiogenic agents may Y. Ohya

References

cause vascular endothelial damage, microvascular damage, atherosclerotic changes, and nephrotoxicity in a dosedependent manner, leading to BP elevation and proteinuria shortly after treatment initiation. Furthermore, longterm administration may lead to serious complications such as myocardial infarction, ischemic stroke, and peripheral arterial occlusive disease [1008] [1009] [1010] [1011] . Other agents, including BTK inhibitors, proteasome inhibitors, platinumbased agents, alkylating agents, calcineurin inhibitors, BRAF/MEK inhibitors, RET inhibitors, PARP inhibitors, mTOR inhibitors, hormone therapy, and radiation therapy, have been reported to increase BP [183, 1000 BP [183, -1004]] .

Appropriate BP management is important for cancer patients in terms of avoiding hypertensive emergencies, preventing the onset of CVD, and maintaining optimal cancer treatment. Prior to initiating cancer treatment, stratify the risk of cardiovascular events to predict the onset of hypertension and consider appropriate cancer treatment methods. After initiating cancer treatment, monitor BP using home and 24-h HBPM. The BP at the time antihypertensive therapy is initiated and the target BP may vary, depending on the clinical scenario of the cancer patient [1000], thus collaboration with the cancer treatment physician is necessary. In general, antihypertensive therapy is initiated when office BP is ≥140/90 mmHg, but in cases of concomitant atherosclerotic diseases, chronic kidney disease, diabetes, etc., consideration should be given to lowering BP to < 130/80 mmHg. However, if BP is ≥180/110 mmHg, or if a hypertensive emergency [1012] is present, consider discontinuing or modifying the cancer treatment. Regarding the selection of antihypertensive medications, in general the guidelines for the use of antihypertensive drugs for High-Risk Grade I hypertension and Grade II and III hypertension should be followed (Chapter 8, 1,2) Antihypertensive Therapy STEP). Be mindful of BP fluctuations associated with cancer-specific disease-related functional impairments, nutritional deficiencies, pain, anxiety, and other systemic conditions. Ensure patient-centered care while paying attention to drug interactions and excessive BP lowering [183, [1000] [1001] [1002] [1003] [1004] .

3) BP management after cancer treatment In some reported cases BP decreases after the completion of anticancer therapy. However, there are also cases, particularly among pediatric and AYA-generation cancer survivors, where hypertension develops as a late complication due to endocrine disorders or cardiovascular toxicity [1013] [1014] [1015] [1016] . After the completion of cancer treatment, BP management should be conducted with a target BP of 130/ 80 mmHg, taking into consideration the life prognosis [1000] . BP management for cancer survivors is a long-term process, requiring collaboration among oncologists, cardiologists, nephrologists, primary care physicians, and outpatient pharmacists.

【POINT 10h】 【Bronchial asthma and COPD】 1. Non-selective β-blockers and αβ-blockers are contraindicated in patients with hypertension and bronchial asthma. 2. ACE inhibitors are associated with the side effect of persistent dry cough. Distinguishing between a cough caused by bronchial asthma and that induced by ACE inhibitors is often difficult. Therefore, their use is not recommended in hypertensive patients with bronchial asthma. 3. CCBs, ARBs, and low doses of diuretics are permissible in hypertensive patients with bronchial asthma. 4. In hypertensive patients with COPD, CCBs, ACE inhibitors, ARBs, and low doses of thiazide diuretics may be used. 5. In hypertensive patients with COPD, the use of β-blockers is permissible, but β 1 -selective β-blockers should be used.

【Liver disease】 1. In hypertensive patients with severe liver dysfunction, liver-metabolized antihypertensive drugs may increase blood concentrations; therefore, dose adjustment is necessary. 2. Non-selective β-blockers and carvedilol may reduce the risk of gastrointestinal bleeding and mortality in patients with cirrhosis. 3. ACE inhibitors and ARBs may inhibit liver fibrosis and improve prognosis.

8. Other diseases

8. Other diseases

1) Bronchial asthma and obstructive pulmonary disease Bronchial asthma and COPD are both chronic inflammatory airway diseases, characterized by obstructive airway disease. Bronchial asthma is defined as "a disease characterized by chronic inflammation of the airways, variable airway narrowing, and clinical symptoms such as wheezing, dyspnea, chest tightness, and cough" [1017], primarily involving allergic airway inflammation. In contrast, COPD is a "lung disease caused by long-term exposure to harmful substances, such as tobacco smoke, characterized by airflow obstruction on pulmonary function tests" [1018] ; it is a slowly progressive chronic inflammatory lung disease. This chronic inflammation is suggested to be associated with hypertension. Hypertension is the most common comorbidity in COPD patients [1019] . Due to a history of longterm smoking, these patients often have concomitant

The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and. . .

References

coronary artery disease or peripheral artery disease [1020] , making BP management particularly important.

It is unclear whether salt intake affects bronchial hyperresponsiveness. However, salt restriction does not have adverse effects on bronchial asthma or COPD. Aerobic exercise is recommended for both bronchial asthma patients [1021] and COPD patients [1022] . However, caution is advised in cases of exercise-induced bronchial asthma. In recent years, a condition known as bronchial asthma and COPD overlap (ACO) has been proposed [1017] . Different approaches are necessary when selecting antihypertensive medications for asthma and COPD.

(1) Bronchial asthma CCBs relax bronchial smooth muscles and alleviate bronchoconstriction, making them appropriate for hypertensive patients with bronchial asthma [1023] . ACE inhibitors have a side effect of persistent dry cough, which is difficult to distinguish from exacerbation of bronchial asthma, and its occurrence can worsen asthma control. Therefore, though not contraindicated, ACE inhibitors are not recommended [1024] . ARBs may reduce airway hyperresponsiveness [1025] and are suitable for use in hypertensive patients with bronchial asthma. β-blockers antagonize β2 receptors in bronchial smooth muscle, and thereby increase airway resistance. Therefore, non-selective β-blockers are contraindicated in patients with bronchial asthma. If β 1 -selective β-blockers must be used in cases of heart failure or arrhythmias, they should be initiated at the lowest possible dose, while closely monitoring the patient's condition. αβ-blockers, which act as non-selective β-blockers, are generally contraindicated. Low doses of thiazide diuretics are generally considered safe for use, as they have no significant effect on the respiratory system. However, in cases where high doses of β2 agonists or steroids are administered for bronchial asthma, caution is required regarding hypokalemia [1026] .

(2) COPD CCBs, ACE inhibitors, ARBs, and low doses of thiazide diuretics have not been shown to worsen COPD or increase mortality, and their use is generally acceptable. However, when using thiazide diuretics, caution is necessary regarding hypokalemia, similar to bronchial asthma, and use should be limited to low doses to avoid increasing sputum viscosity [1027] . Β-blockers have been reported to be safe and improve outcomes in COPD patients with concomitant coronary artery disease or heart failure [1028] . If β-blockers are necessary for the treatment of complications, start with a low dose of β 1 selective β-blockers.

2) Liver disease In severe cirrhosis, BP tends to decrease due to changes in hemodynamics and blood levels of physiologically active substances [1029] , but if hypertension is present, standard antihypertensive therapy should be administered. In cirrhosis, delayed activation of prodrugs or increased blood concentrations of drugs metabolized by the liver may occur. Therefore, caution is necessary when administering livermetabolized antihypertensive drugs, such as by reducing the dose or extending the dosing interval. In cases of edema or ascites, secondary aldosteronism may be present, and spironolactone, an MR antagonist, is often administered regardless of the presence of hypertension. Serum electrolyte concentrations should be monitored [1030] . Methyldopa and labetalol have a high incidence of drug-induced liver injury and should not be administered to patients with liver dysfunction.

Non-selective β-blockers such as propranolol have been reported to reduce portal pressure, thereby lowering the risk of gastrointestinal bleeding and mortality in patients with cirrhosis [1031] . Recently, the use of carvedilol has also been recommended [1032] . In contrast, diuretics such as hydrochlorothiazide, furosemide, and chlorthalidone (no longer available in Japan) may precipitate hepatic encephalopathy through their rapid diuretic effects in patients with cirrhosis and should be used with caution. ACE inhibitors and ARBs have been reported to potentially inhibit the progression from chronic hepatitis to cirrhosis and improve the prognosis of patients with cirrhosis [1033] . However, liver-metabolized ARBs such as telmisartan are contraindicated in patients with severe liver dysfunction. Additionally, cilazapril is contraindicated in cirrhosis patients with ascites, due to increased blood levels of active metabolites, which may cause severe hypotension.

【POINT 10i】 【Women】 1. BP varies by sex and in women may be influenced by sex-specific physiological conditions and medication use. 2. In the management of hypertension in women of reproductive age, it is important to identify and appropriately treat secondary hypertension before conception and treat both hypertension and the underlying condition adequately. Patients should be informed that RAS inhibitors are contraindicated during pregnancy. 3. There is a tendency for BP to rise rapidly during perimenopause.

9. Women's life stages 1) Sex differences and hypertension In general, women have shorter stature, shorter arterial trees, and smaller hearts and blood vessels than men. As a result, they tend to have higher heart rates, reduced cardiac contractility, and earlier arterial pulse wave reflection, Y. Ohya

References

which increases central SBP rather than central DBP. Consequently, women have lower brachial BP and central DBP compared with men, making them more susceptible to microvascular complications [1034] [1035] [1036] [1037] [1038] [1039] . Among common cardiovascular risk factors, the effect of obesity on BP is greater in women than in men [1034] . Leptin gene polymorphisms are particularly associated with hypertension in postmenopausal women, and this association remains significant even after adjusting for BMI [1040] . On the other hand, the association between plasma leptin levels and hypertension has been reported to disappear after adjusting for BMI [1040] . Components of the RAS, such as ACE2, angiotensin 1-7, AT 2 receptors, and Mas receptors (MAS1 proto-oncogene, G protein-coupled receptors) are more strongly expressed than men [1041, 1042] . These components counteract the vasoconstrictive and sodiumretentive effects mediated by AT₁ receptors, contributing to vasodilation and natriuresis [1042] . Women have lower sympathetic nervous system sensitivity compared with men [1043], however, this varies across the menstrual cycle and increases after menopause [1043, 1044] . In addition, salt sensitivity is higher in women [1045] .

Estrogen has cardioprotective effects, reducing oxidative, ischemic and hypertensive stress, while promoting peripheral and coronary artery dilation and inhibiting the development of atherosclerosis [1046] . However, it may have adverse effects on the vascular walls of older women or at certain pharmacological doses [1047] . The age-related decline in estrogen is associated with increased salt sensitivity [1048] . Progesterone has been linked to endothelium cell injury mediated by leptin via MR receptors in premenopausal obese women [1049] , and it may be associated with salt sensitivity [1050] .

In addition to traditional cardiovascular risk factors such as an unhealthy lifestyle, obesity, insulin resistance, and low birth weight [1051], several female-specific conditions are associated with hypertension. These include early or late menarche (U-shaped curve phenomenon) [ 2) Preconception care Preconception care is a life-course approach that promotes physical, psychological, and social health and wellbeing in sexuality and reproduction [1065] . It targets all young people, regardless of their future family plans, with the goal of contributing to the health of both the individual and the next generation [1066] [1067] [1068] . The National Center for Child Health and Development has developed and published a "Precon Check Sheet" on its website to encourage individuals to begin taking proactive steps toward health from an early age (Table 10-1) [1069] .

Pregnancies complicated by chronic hypertension are considered high-risk [1070] . Although the optimal prepregnancy BP levels for improving maternal and fetal outcomes have not yet been clearly established, appropriate control of hypertension and underlying comorbidities before conception is essential (Table 10-2) [1071] . Interconception care also serves as preconception care for the next pregnancy and plays a crucial role in reducing the risk of complications in subsequent pregnancies.

3) After menopause The average age of menopause in Japan is approximately 50 years. Age-adjusted analyses show that BP rises more steeply in women than in men, with this trend becoming particularly pronounced after menopause [1035, [1072] [1073] [1074] [1075] [1076] . The risk of CVD rises markedly after menopause and generally occurs several years later than in men [1077] . Reports suggest that women are at an increased risk of CVD even at lower BP levels compared to men. [1035] .

【POINT 10j】 【Adolescence】 1. For the prevention of CVD, BP management for hypertensive young adults should be conducted in accordance with the guidelines for adults. The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and. . .

References

10. Adolescence

10. Adolescence

Young adults in their mid-teens to early twenties are physically equivalent to adults, so adult BP classifications are used to evaluate BP, and treatment guidelines are also based on those for adults. The incidence of essential hypertension is lower in younger individuals, and when considering the causes of hypertension in young adults, secondary hypertension such as renal vascular hypertension or chronic kidney disease should be considered. From a hemodynamic perspective, increased sympathetic nervous activity leads to elevated cardiac output and peripheral vascular resistance, and due to high arterial wall elasticity, DBP is often elevated. BP elevation is often associated with genetic predisposition, as well as factors such as obesity, salt intake, stress, and physical inactivity, thus lifestyle modifications are important [1078] . In mild hypertension without organ damage or cardiovascular or renal disease, the risk is low to moderate, and there is limited evidence of improved prognosis with antihypertensive drug therapy. However, the increased lifetime risk of CVD is clear, therefore, treatment should be similar to that for adults [1079, 1080] .

【POINT 10k】 【Older adults: clinical conditions and characteristics of complications】 1. Hypertension characterized by systolic hypertension significantly increases in older adults. 2. Adverse events from antihypertensive treatment are more likely to occur due to increased BP variability in older adults. 3. Individualized antihypertensive treatment strategies based on the patient's background should be considered for those ≥75 years. 4. We propose determining the antihypertensive treatment strategy based on categories classified according to health and functional status in older adults aged ≥75 years (Table 10-4 ). 5. The initial dose of antihypertensive drugs is generally started at half the standard dose and it is gradually increased in those aged ≥75 years. 6. Avoid a prescribing cascade due to adverse events from antihypertensive drugs. 7. Polypharmacy increases the risk of adverse events in hypertensive older adults. 8. Implement polypharmacy management strategies through interprofessional collaboration among physicians, pharmacists, nurses, and other healthcare professionals. 9. When reducing the dosage of antihypertensive drugs, reduce one at a time, while monitoring BP levels. 10. Exercise is recommended within the nonpharmacological therapy management of frail older

References

adults and dietary therapy should have limits so as not

to reduce appetite.

11. Be mindful of the increased risk of falls associated

with antihypertensive drugs in frail older adults.

12. Hypertension treatment for patients with dementia and

hypertension should be individually determined and

based on the category classified according to health

and functional status. (Table 10-4).

13. For hypertension with cognitive impairment or

dementia, antihypertensive treatment should take into

account the increased risk of falls and reduced

adherence to taking medication.

14. Evidence is limited for antihypertensive treatment in

older adults requiring long-term care or at the end

of life.

11. Older adults

1) Characteristics

(1) Definition of older adults

Recent data indicates that older adults in Japan are becoming physically younger, and the Japan Federation of Gerontological Societies and the Japan Geriatrics Society have proposed revising the definition of an older adult from≥65 years to ≥75 years [1081]. After the age of 75 years,conditions such as frailty and dementia tend to increase,which can influence the treatment. Individuals aged 65 to 74 are classified as an age group where hypertension increases,

but antihypertensive treatment is administered similarly to those <65 years. Those aged ≥75 are classified as an age group where antihypertensive therapy are determined individually based on patient background. For those aged 65–74 years with significant functional decline, antihypertensive treatment is managed similarly to those aged ≥75 years.

With the evidence on hypertension treatment, it has become possible to avoid uniform categorizing of older adults by age. Accordingly, the guidelines minimize references to"older adults" and instead focus on individual characteristics associated with aging.

(2) Epidemiology

Japan is one of the world's most super-aged societies,with 29.1% of the population aged 65 or older and 16.1%aged 75 or older [1082]. The prevalence of hypertension increases with age, 63% of those aged 65–74 years and 74%of those aged ≥75 years have hypertension [1083].

(3) Age-related changes

The characteristics of hypertension in older adults, and the main causes and conditions associated with it are shown in Table 10-3.

① Impact on hypertension

In older adults, the physiological hardening and loss of elasticity of the blood vessels centered around the aorta lead to isolated systolic hypertension, where only SBP rises.

Another factor contributing to the increase in hypertension in older adults is increased salt sensitivity, where SBP rises more easily with salt intake.

② Increased BP variability

Table 10-4 Category classification based on health and functional status and BP guidelines for older adults aged ≥75 yearsa

Category 1

Patients who can maintain

ADL independently and

attend outpatient visits on

their own

Category 2

Patients with impaired instrumental ADL

requiring assistance for outpatient visits

Category 3

Patients who have difficulty

attending outpatient visits and have impaired basic ADL

Category 4

Patients at the end of life

General condition

From healthy to frail From frailty to requiring care

Needing care

End-of-life

Instrumental ADLb

Maintained

impaired

Severely impaired

Basic ADLc

declining

impaired

Severely impaired

Target BP <130/80 mmHg

SBP <140 mmHg

SBP<130 mmHg (set individually according to complications, etc).

SBP <150 mmHg

Complications may require further BP reduction through individual assessment, but avoid reduction below 120 mmHg

Individual judgment

(Guideline: SBP 140–160 mmHg)

Other notes Same treatment guidelines as for non-older patients

Consider reducing antihypertensive medication if SBP is <120 mmHg

Consider gradual reduction or

discontinuation of antihypertensive medications (Do not initiate treatment in untreated cases)

aThe hypertension management guidelines for older adults aged 65 to 74 years with impaired health or functional status is to follow this table

bActivities requiring more complex and numerous tasks, such as shopping, meal preparation, medication management, financial management, and using public transportation (assessed by the Lawton scale, etc.)

cBasic ADL (e.g., mobility, stair climbing, bathing, toilet use, eating, and dressing) (assessed using the Barthel Index, etc.)

The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and. . .

Decreased elasticity of large blood vessels is a factor contributing to increased BP variability. Also, reduced arterial baroreceptor reflex, decreased sympathetic nervous system responsiveness (such as β-receptor dysfunction), and reduced skeletal muscle mass also contribute to increased BP variability. Pathological conditions associated with symptoms or adverse events related to increased BP variability include orthostatic hypotension and postprandial hypotension. Additionally, an increase in white-coat or masked hypertension is a characteristic of older adults.

③ Increase in cardiovascular and renal complications In addition to the increase in stroke and ischemic heart disease, left ventricular wall hypertrophy-induced impaired diastolic function contributes to the rise in hypertensive heart failure (primarily heart failure with preserved ejection fraction [HFpEF] ). Atrial fibrillation, a complication of hypertension, also increases with age. Furthermore, the progression of chronic kidney disease (CKD), primarily caused by nephrosclerosis, significantly impacts the management of hypertension in older adults.

④ Impacts on antihypertensive treatment Adverse events associated with antihypertensive treatment are more common in older adults. Falls caused by BP fluctuations are common adverse events in the early stages of taking antihypertensive medication, and impaired musculoskeletal function, such as physical frailty, sarcopenia, and osteoporosis, can lead to severe outcomes due to fractures. Adverse events such as electrolyte abnormalities caused by antihypertensive diuretics or RAS inhibitors, and lower leg edema caused by CCBs also increase with age. Decreasing adherence due to cognitive decline is another condition requiring attention.

(4) Points to note during diagnosis and treatment ① BP measurement Considering the increased incidence of white coat or masked hypertensions, clinical management based on out of office BP, mainly with home BP, is recommended. For the diagnosis of orthostatic hypotension, a standing test (Schönlein test) is necessary, but there is a more simple risk assessment which can be performed by measuring BP reduction (SBP ≥20 mmHg and DBP ≥10 mmHg) 1 min after standing from a supine position [1084] . For symptoms such as dizziness after meals, postprandial hypotension should be suspected, and evaluation should be conducted through postprandial BP measurement at home or ABPM.

② Target BP For older hypertensive patients aged ≥75 years with tolerable BP, the SBP target is < 130 mmHg. However, individual judgment is required if physical or mental functional decline is suspected (see CQ14).

③ Non-pharmacological therapy Combined exercise therapy involving walking and resistance training is strongly recommended. Weight loss is generally not recommended for older adults aged ≥75 years unless obesity significantly impacts daily living (e.g., lower limb joint pain). Salt reduction is effective in older adults, but care should be taken to avoid appetite suppression.

④ Antihypertensive treatment For individuals aged ≥75 years or those aged 65-74 years with severe functional decline, except in emergencies, initiate antihypertensive medication at half the standard dose and gradually increase the dose while monitoring for adverse effects. The decision on antihypertensive therapy for older adults aged ≥75 years should be based on their functional status, as outlined in the following section.

2) Frailty, need for care, and end-of-life care (1) Definition of frailty Frailty is a condition in which physical, psychological, and social vulnerabilities increase and resilience to stress decreases in older adults. However, the definition of older adults classified as frail varies depending on the method of evaluation. In JSH2025, frailty is defined as a state positioned between healthy and requiring care, which can be restored to a healthy state through intervention. Based on this definition, the Japanese version of the frailty criteria (J-CHS criteria) includes the following ① Weight loss: Unintended weight loss of ≥2 kg over 6 months, ② Muscle strength decline: Grip strength < 28 kg (man), < 18 kg (woman), ③ Fatigue: Feeling tired for no apparent reason in the past 2 weeks, ④ Decreased walking speed: Walking speed < 1.0 m/s (or "no" to the question "Can you cross the crosswalk before the traffic light changes?"), ⑤ Decreased physical activity: 1. Do you engage in light exercise or calisthenics? 2. Do you engage in regular exercise or sports? Answer "No, not even once a week" to both questions.

If three or more of the five items apply, the individual is classified as "Frail". If one or two items apply, they are classified as "Pre-frail". If none apply, they are classified as healthy, "Robust" [1085].

(2) Frailty and the need for care As shown in CQ14, in SPRINT, the benefits of intensive BP lowering were demonstrated regardless of the severity of frailty assessed by the Frailty Index* in the disability accumulation model [1086] . Since the general profile of older adults eligible for RCTs includes the ability to go out independently and attend outpatient visits, it is recommended to actively achieve BP targets in older adults with these levels of physical function. On the other hand, there is limited evidence supporting the benefits of antihypertensive treatment for frail older adults with impaired ADL. An observational study in France (PARTAGE study) involving nursing home residents aged ≥80 years reported that participants with SBP < 130 mmHg who took two or more antihypertensive drugs had poorer survival outcomes compared to those who did not [1087] . However, no studies have demonstrated that hypertension is a risk factor for poor Y. Ohya

References

outcomes in frail older adults, suggesting that the riskbenefit ratio of intensive antihypertensive treatment may reverse during the transition period between frailty and frailty-related disability.

* The frailty index is a method for quantitatively assessing the severity of frailty on a scale from 0 to 1, and it differs from the frailty assessment method defined in (1).

(3) End-of-Life

Currently, in Japan, it is estimated that antihypertensive medications are often continued without a clear reason in many older adults and terminally ill cancer patients who have reached the end of life. There are few studies examining the significance of hypertension at the end of life, and there is a possibility that antihypertensive treatment may be harmful. It is strongly suggested that hypertension at the end of life does not act as a poor prognostic factor, based on reports linking hypertension and the need for longterm care.

(4) Categorization of older adults and antihypertensive treatment

Considering the impact of the aforementioned health and functional status on the risk-benefit ratio of antihypertensive treatment, we propose recommendations for treatment goals of antihypertensive therapy in older patients aged ≥75 years based on the category classification shown in Table 10-4.

However, when revising antihypertensive treatment according to the category classification, there is a possibility of exacerbating comorbid conditions such as heart failure or CKD. Therefore, when reducing the dose of antihypertensive drugs, it is necessary to proceed cautiously while monitoring changes in symptoms and laboratory values.

(5) Points to note in the management of frail hypertensive patients

The following points are considered important in addition to routine care during daily clinical practice. These points are also applicable to healthy patients aged ≥75 years.

① Risk of fall assessment

In frail patients, an increased risk of falls and fractures occurs, particularly at the initiation or titration of antihypertensive therapy, due to orthostatic hypotension and impaired mobility. Therefore, standing BP assessment and screening for orthostatic hypotension via a questionnaire should be performed. Additionally, adequate explanation regarding fall risk is necessary when prescribing antihypertensive drugs.

② Cognitive function assessment

The above-mentioned J-CHS criteria do not include an assessment of cognitive function. However, since cognitive decline and physical frailty often progress simultaneously,cognitive function tests or referral to a specialist is recommended when cognitive impairment, such as pathological memory loss, is suspected.

③ Non-pharmacological therapy

Dietary therapy, including sodium reduction, is effective,but it is important to perform it within a range that does not reduce appetite. Exercise combining aerobic exercise such as walking and resistance exercise is recommended. It is important to monitor body weight to prevent weight loss.

④ Pharmacological therapy

As with the general population aged ≥75 years, first-line drugs should be initiated at half the usual dosage, with gradual titration based on symptoms and BP levels.

3) Cognitive Impairment and Dementia

This section outlines key points for treating hypertension in patients with concomitant cognitive impairment or dementia. For evidence-based hypertension treatment in patients with dementia and hypertension, refer to “Chapter 9, Section 5.3) Antihypertensive treatment in hypertension with dementia”.

(1) Target BP

Since patients with dementia are generally excluded from RCTs of antihypertensive treatment, it is not possible to apply evidence of intensive antihypertensive treatment to patients with hypertension and dementia. As dementia progresses, instrumental ADL and basic ADL decline.

However, in patients with dementia, ADL decline may progress while physical function remains preserved.

Therefore, we propose that BP targets for patients with dementia be determined individually, referencing the category classification in Table 10-4.

(2) Considerations for antihypertensive therapy

① Fall risk

Orthostatic hypotension has been reported to increase in dementia conditions such as Alzheimer's disease and Lewy body dementia [1088, 1089]. Also, due to impaired attention and motor function, the risk of falls increases, thus particular caution is necessary, including risk assessment,such as measuring BP upon standing, especially when initiating new antihypertensive medications.

② Medication Adherence

Cognitive decline in older hypertensive patients has been reported to be associated with poor medication adherence[1090–1092], therefore it is also necessary to consider cognitive decline when poor adherence is observed in older adults. To improve adherence, efforts such as reducing the number of antihypertensive medications as much as possible through the use of combination therapies, using singledose packaging, and consulting with caregivers to monitor medication management are also required.

4) Polypharmacy

Polypharmacy refers to a situation where the risk of adverse events increases due to the use of multiple drugs(typically five or more types).

(1) Impact on hypertension treatment

① Interactions between antihypertensive drugs and other medications

The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and. . .

Interactions between antihypertensive drugs and other drugs may weaken efficacy or exacerbate side effects (refer to "Chapter 15, Section 4. Drug-induced hypertension").

② Effects on BP Control Drug-induced hypertension may be caused by licoricecontaining herbal medicines, NSAIDs, etc.BP lowering can be due to α-blockers in cases of urinary disorders (such as benign prostatic hyperplasia), and orthostatic hypotension, among others.

③ Reduced medication adherence Polypharmacy may reduce medication adherence, leading to inadequate BP lowering effects.

(2) Management and improvement methods ① Adjustment of overall medication a. Routine review of medication Routine review of the medications currently being taken, focusing on potentially inappropriate medications (PIMs) and potentially prescribing omissions (PPOs) [1093] . Consider switching medications that affect BP management to alternative drugs.

b. Use of unit-dose packaging and combination medications

The use of unit-dose packaging or combination medications improves adherence and reduces the risk of adverse events.

② Adverse events Avoid situations where additional oral medications are prescribed due to adverse events caused by antihypertensive medications (prescription cascade) (Table 10-5 ).

③ Reduction in antihypertensive drugs An RCT reported that reducing one dose did not worsen the management of BP in an 80-year-old hypertensive patient taking more than 2 doses of antihypertensive drugs. When reducing the dosage of antihypertensive drugs, reduce one at a time while monitoring BP levels [1094] .

④ Interprofessional collaboration Interprofessional collaboration among physicians, pharmacists, nurses, and other professionals is essential for addressing polypharmacy.

CQ 12 Is antihypertensive treatment targeting of BP < 130/80 mmHg effective for preventing the incidence and mortality of CVD in hypertensive patients with diabetes mellitus? ► Antihypertensive treatment targeting of BP < 130/80 mmHg is strongly recommended in hypertensive adults with diabetes.

[Recommendation strength -1, Evidence strength -B, Consensus rate -100%]

Summary of evidence

Summary of evidence

A meta-analysis was conducted to evaluate intensive BP control targeting an SBP of < 130 mmHg or a DBP of < 80 mmHg in hypertensive patients with diabetes aged ≥18 years using a total of 8 RCTs (HOT [1095] , ABCD [1096] , ACCORD [366] , SPS3 [374], J-DOIT3 [1097] , RESPECT [373] , STEP [317], and ESPRIT [367] ) (intervention/control: 8042/8091 individuals). Since the J-DOIT3 was a multifactorial intervention study for not only BP but also levels of glucose and lipids, it may have a greater therapeutic effect than antihypertensive treatment alone. Therefore, outcomes were analyzed by using dataset with and without the J-DOIT3 study. In both analyses including and excluding the J-DOIT3 study, there was a significant reduction in the risk for composite cardiovascular events and stroke. On the other hand, there was a trend, but not statistically significant, toward reduction in the risk for coronary artery disease in the intensive BP lowering group. In addition, there was no significant difference in the reduction of the risk for all-cause mortality or cardiovascular mortality between intensive and control BP lowering groups regardless of the absence and presence of the J-DOIT3 study. In the risk for serious adverse events, there was a significant increase in the intensive BP control group compared to the control group in the ACCORD study. However, the difference was disappeared when the J-DOIT3 study was included. Due to the high heterogeneity between the two trials, the reliability of the results regarding the risk of serious adverse events with intensive BP control considered to be limited.

After conducting the meta-analysis, since the BPROAD trial [376] was reported, an additional analysis including the BPROAD trial was conducted. The results of composite cardiovascular events and stroke remained unchanged and showed a significant reduction in the risk. The results of allcause mortality and cardiovascular mortality also remained unchanged and showed no significant difference in the risk. On the other hand, there was a significant reduction in the risk for coronary artery disease after the addition of the BPROAD trial. In contrast, there was no significant increase in the risk for adverse events after the addition of the BPROAD trial.

Explanation

Explanation

In creating the search formula, the PICO system was used:

References

P (patient): hypertensive men and women with diabetes aged ≥18 years I (intervention): antihypertensive treatment with a target BP of < 130/80 mmHg.

C (comparison): antihypertensive treatment with a target BP of < 140/90 mmHg or higher. O (outcome): primary endpoints included composite cardiovascular events, coronary artery diseases, stroke, allcause mortality, cardiovascular mortality and adverse events.

After screening candidate papers, a meta-analysis was conducted to evaluate intensive BP control targeting an SBP of < 130 mmHg or a DBP of < 80 mmHg in hypertensive patients with diabetes aged ≥18 years using a total of 8 RCTs (HOT [1095] , ABCD [1096] , ACCORD [366] , SPS3

[374], J-DOIT3 [1097] , RESPECT [373] , STEP [317] , and ESPRIT [367]) (intervention/control: 8,042/8,091 individuals). Since the J-DOIT3 was a composite intervention trial targeting not only BP but also levels of blood glucose and lipids, the meta-analysis was conducted in two ways using dataset excluding the J-DOIT3 and that including the J-DOIT3. The results of the primary endpoints are shown below.

1) Composite cardiovascular events Intervention of targeting a BP < 130/80 mmHg significantly decreased the risk for composite cardiovascular events in both analyses excluding the J-DOIT3 (RR 0.844 [95% CI 0.732-0.972]) and including the J-DOIT3 (RR 0.848 [95% CI 0.760-0.947]) (Fig. CQ12-1 ). The results of the funnel plot (Egger test) suggested a low likelihood of publication bias (excluding J-DOIT3: P=0.137, including J-DOIT3: P= 0.079).

2) Coronary artery disease In both analyses excluding the J-DOIT3 (RR 0.833, 95% [0.675-1.027]) and including the J-DOIT3 (RR 0.814 [95% CI 0.663-1.000]), there was no significant difference in the risk for coronary artery disease between the intervention and control groups (Fig. CQ12-2 ). The possibility of publication bias was considered to be low (excluding J-DOIT3: P= 0.324, including J-DOIT3: P= 0.077).

3) Stroke In both analyses excluding the J-DOIT3 (RR 0.780 [95% CI 0.629-0.966]) and including the J-DOIT3 (RR 0.705 [95% CI 0.541-0.918]), the intervention group showed a significant reduction in the risk for stroke compared to the control group (Fig. CQ12-3 ). Publication bias was suggested to be negative (excluding J-DOIT3: P=0.999, including J-DOIT3: P=0.697).

4) All-cause mortality

4) All-cause mortality

In both analyses excluding the J-DOIT3 (RR 0.720 [95% CI 0.430-1.205]) and including the J-DOIT3 (RR 0.835 [95% CI 0.587-1.187]), there was no significant difference in the risk for all-cause mortality between the intervention and control groups (Fig. CQ12-4 ). There was a high heterogeneity (excluding J-DOIT3: I 2 = 71.7%, including: I 2 = 61.9%). The possibility of publication bias was suggested (excluding J-DOIT3: P < 0.001, including J-DOIT3: P = 0.191).

5) Cardiovascular mortality Since cardiovascular mortality was not included in the J-DOIT3, the analysis was conducted by using only data from studies without the J-DOIT3. There was a high The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and. . .

References

heterogeneity (I 2 = 71.0%). There was no significant difference in the risk for cardiovascular mortality between the intervention and control groups (RR 0.618 [95% CI 0.295 to 1.293]) (Fig. CQ12-5 ). Publication bias was suggested to be negative (excluding J-DOIT3: P = 0.217).

6) Adverse events The analysis was limited to the ACCORD after excluding the J-DOIT3, and the intervention group showed a significant increase in the risk for adverse events ). However, when the J-DOIT3 was included, the result became non-significant (RR 1.544 [95% CI 0.584-4.084]) (Fig. CQ12-6 ). The number of studies was small, heterogeneity was high (I 2 = 93.9%), and publication bias could not be assessed. Additionally, since data on "hospitalization due to heart failure" and "hospitalization due to cardiovascular diseases other than heart failure" were unavailable, the analyses could not be performed.

Summary

Summary

In hypertensive adults with diabetes aged ≥18 years, intensive BP control targeting < 130/80 mmHg significantly reduced the risk for composite cardiovascular events and stroke compared to BP control targeting higher values of BP. The intervention group had an increased risk for adverse events compared with the control group. However, the number of studies included in the analysis was small, and the heterogeneity was high.

In this meta-analysis [1098], there were various definitions of "composite cardiovascular events". In some trials, not only coronary artery disease, stroke, cardiovascular death but also fatal arrhythmia, acute heart failure and carotid endarterectomy with variations were included. Additionally, since data on angina pectoris was not available, the number of patients with angina pectoris was not included in the analysis for "coronary artery disease". Furthermore, since data on "hospitalization due to heart failure" and " hospitalization due to other than heart failure" were not available, further verification will be needed. Additionally, although intensive BP control group showed a trend of increasing the risk for adverse events, the number of studies included in the analysis was very small and heterogeneous. Further verification using a large sample size would be required.

Since the BPROAD trial [376] was reported after conducting the meta-analysis, additional analyses were urgently conducted. The results of composite cardiovascular events and stroke remained unchanged and showed a significant risk reduction by intensive BP management. The results of all-cause mortality and cardiovascular mortality remained unchanged and showed that there was no significant difference in the risk between the intensive and control groups. In contrast, after the addition of the BPROAD trial, the results of risk for coronary artery disease became significant, and those for adverse events became nonsignificant.

Literature search

Literature search

Five SR committee members independently conducted literature searches in PubMed, Ichushi-Web and the Cochrane Library. They extracted 1308 documents as the first screening (title and abstract), excluded 1030 documents based on exclusion criteria, and performed a second screening (full text) of 278 documents. As a result, 8 documents relevant to this CQ were used for the metaanalysis [1098] .

References

Abstract

CQ 13 Does treatment with RAS inhibitors for hypertensive patients with diabetes improve the incidence and mortality of CVD events compared to the treatment with CCBs or thiazide diuretics? ► In the treatment of hypertensive patients with diabetes, there was no superiority observed in RAS inhibitors, and the use of RAS inhibitors, CCBs, and thiazide diuretics is weakly recommended.

Abstract

[Recommendation strength -2, Evidence strength -B, Consensus rate -100%]

Summary of evidence

Summary of evidence

A literature search for relevance to this CQ identified 12 eligible RCTs. A meta-analysis of outcomes including composite cardiovascular events, all-cause mortality, stroke, myocardial infarction, and end-stage kidney disease (ESKD) found no evidence that RAS inhibitors demonstrated event-preventing effects compared to CCBs or thiazide diuretics in hypertensive patients with diabetes.

Explanation 1) Basis of the CQ In JSH2019, the incidence or mortality from cardiovascular diseases, renal dysfunction (doubling of serum creatinine levels and ESKD), and all-cause mortality were evaluated as outcomes, based on the question of CQ12 "Should ARBs or ACE inhibitors be prioritized over CCBs or thiazide diuretics in antihypertensive therapy for hypertensive patients with diabetes?" There was no evidence to recommend RAS inhibitors as the first-line therapy over other antihypertensive drugs. In this SR, five outcomes including composite CVD events*, all-cause mortality, stroke, myocardial infarction, and ESKD were evaluated. The efficacy of RAS inhibitors was compared with that of CCBs and thiazide diuretics for these outcomes. Stratified analysis was also conducted for RCTs that mentioned the presence or absence of albuminuria [1099] .

*Acute myocardial infarction or unstable angina, stroke, heart failure death/hospitalization,/acute aortic dissection/ aneurysm death/hospitalization, other cardiovascular deaths 2) Studies included in the SR A literature search was conducted in PubMed, the Cochrane Library, and Medline Web up to August 15, 2024, and papers relevant to this CQ were extracted from the search results. A total of 21,589 papers were screened. After primary and secondary screening, 12 RCTs were included in the meta-analysis [932, 1096, [1100] [1101] [1102] [1103] [1104] [1105] [1106] [1107] [1108] [1109] .

3) SR results For composite cerebrovascular events, the RR was 0.93 (95% CI 0.81-1.07), and there was no significant difference in the incidence risk between RAS inhibitors, CCBs, and thiazide diuretics (Fig. CQ13-1 ). Similarly, for all-cause mortality (RR 1.00 [95% CI 0.92-1.08], Fig. CQ13-2 ), stroke (RR 1.14 [95% CI 1.00-1.31]), and myocardial infarction (RR 0.64 [95% CI 0.32-1.22]), no differences were detected between RAS inhibitors, CCBs, and thiazide diuretics. Similar results were observed in subgroup analyses stratified by the presence or absence of albuminuria data and in analyses restricted to patients with albuminuria of ≥30 mg/gCr.

Based on the above, if equivalent BP-lowering effects can be achieved, there is no evidence to support recommending RAS inhibitors as the first-line drug for hypertensive patients with diabetes. Therefore, the use of RAS inhibitors, CCBs, and thiazide diuretics is weakly recommended.

Literature search

Literature search

PubMed, Cochrane Library, and Medline Web were searched from June 1, 2024, to August 15, 2024, and papers relevant to this CQ were extracted from the search results. The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and. . .

References

CQ 14 Is a target SBP of < 130 mmHg recommended for older adults aged ≥75 years ? Does the target BP vary depending on the presence or absence of mental or physical functional decline in older adults ? ► A target SBP of < 130 mmHg is strongly recommended for patients aged 75 years or older, if well tolerated. However, individual judgment is required if cognitive or physical functional decline is suspected. [Recommendation strength 1, Evidence strength A, Consensus rate 95.5%]

CQ 14 Is a target SBP of < 130 mmHg recommended for older adults aged ≥75 years ? Does the target BP vary depending on the presence or absence of mental or physical functional decline in older adults ? ► A target SBP of < 130 mmHg is strongly recommended for patients aged 75 years or older, if well tolerated. However, individual judgment is required if cognitive or physical functional decline is suspected. [Recommendation strength 1, Evidence strength A, Consensus rate 95.5%]

Summary of evidence

Summary of evidence

BP-lowering treatment for hypertension in drug therapy for hypertension in older patients aged ≥75 years, targeting an SBP of < 130 mmHg was associated with a reduction in composite cardiovascular events, all-cause mortality, and cardiovascular mortality compared with targeting a higher SBP. This did not increase incidences of serious adverse events.

There was no evidence supporting the modification of target BP based on the presence or absence of diabetes, coronary artery disease, stroke history, chronic kidney disease, or frailty.

Therefore, in older adults aged ≥75 years, antihypertensive therapy targeting an SBP of < 130 mmHg is beneficial in terms of improving life prognosis and preventing the onset of cerebrovascular disease. However, there are no RCTs targeting older adults with impaired physical or mental function, such as those requiring longterm care or those with dementia, and therefore this evidence cannot be applied to such individuals. Therefore, while we strongly recommend targeting an SBP of < 130 mmHg in older adults aged ≥75 years who tolerate the therapy, individual judgment is strongly recommended in cases where impaired physical or mental function is suspected.

Explanation 1) Basis of the CQ

Explanation 1) Basis of the CQ

In JSH2019, based on an SR, BP lowering therapy targeting an SBP of < 140 mmHg was recommended for older hypertensive patients aged ≥75 years. However, following the publication of large-scale RCTs such as STEP [317] and ESPRIT [367] after 2019, which evaluated the efficacy of stricter BP control, JSH2025 conducted another SR to verify the appropriateness of an SBP target of < 130 mmHg for individuals aged 75 years or older [1110] . Outcomes included composite cardiovascular events, all-cause mortality, cardiovascular mortality, stroke, and serious adverse events.

2) Studies included in the SR

The RCTs with published results for participants aged 75 years or older were SPS3 [1111] , SPRINT [1112], and INFINITY [369] , for a total of three studies. In RESPECT [373] , results for a subgroup of participants aged 70 years or older were reported, but data for those aged 75 years or older were extracted from the database. To ensure that the evidence applies to the older hypertensive individuals, the results were extracted in accordance with the SR [1113], three additional RCTs (PODCAST [689] , STEP [317] , and ESPRIT [367] were included, as they provided data on older hypertensive patients aged ≥70 years.

3) Efficacy of BP reduction in older hypertensive patients with SBP < 130 mmHg A meta-analysis of four trials (including subgroup analyses) targeting individuals aged 75 years or older found that BP-lowering therapy targeting an SBP of < 130 mmHg did not increase the risk of serious adverse events compared with therapy targeting a higher SBP, while reducing the risk of composite cardiovascular events (RR 0.61 [95%CI 0.40 to 0.94], P=0.03), all-cause mortality (RR 0.72 [95% CI 0.56 to 0.93] , P=0.01), and cardiovascular death (RR 0.55 [95% CI 0.35 to 0.88], P=0.01) compared with antihypertensive therapy targeting a higher SBP. In contrast, there was no reduction in stroke (RR 0.75 [95% CI 0.48 to 1.19], P=0.22). Serious adverse events (RR 1.00 [95% CI 0.93 to 1.08], P=0.97) did not increase (Fig. CQ14-1 ). The results of a meta-analysis of seven studies with sub-analyses, including three studies targeting patients aged ≥70 years, were similar (Fig. CQ14-2 ). Additionally, the BPROAD trial targeting patients with type 2 diabetes and hypertension was reported after the analysis [376] . When the sub-analysis results for patients aged 80 years or older from this trial were added to the four trials targeting patients aged 75 years or older (including sub-analyses) mentioned above and meta-analyzed, active BP lowering therapy significantly reduced composite cardiovascular events compared with standard BP lowering therapy (RR 0.63 [95% CI 0.44 to 0.90], P=0.01).

4) Should target BP be adjusted based on the presence of comorbidities, frailty, or impaired mental/physical function?

We then examined whether target BP should be adjusted based on the presence of comorbidities. No RCTs were identified that could verify the efficacy of BP-lowering therapy targeting SBP < 130 mmHg in patients with diabetes, coronary artery disease, stroke history, or chronic kidney disease. A report that classified SPRINT participants aged 75 years or older into fit, less fit, and frail based on the Frailty Index found no significant differences in event reduction effects between groups [1112] . Therefore, we conclude that there is currently no evidence supporting the modification of BP targets based on the presence or severity of comorbidities or frailty.

Y. Ohya

References

However, the RCTs included in this SR generally excluded nursing home residents and patients with dementia, therefore the evidence obtained in this study cannot be applied to older adults with significantly impaired mental and physical function. Recommendations for antihypertensive therapy in older adults aged ≥75 years classi-fied by health and functional status are described in Chapter 10, Section 11, Older adults.

Literature search

Four SR committee members independently conducted literature searches in Ovid MEDLINE, the Cochrane Library,and Medline Web, extracted 594 documents as the first screening (titles and abstracts), excluded 495 documents based on exclusion criteria, and performed a second screening (full text) of 99 documents. As a result, seven documents relevant to the current CQ were selected, and a meta-analysis was conducted.

Chapter 11. Poorly controlled hypertension

【POINT 11a】

【Individual Factors Contributing to Poorly controlled Hypertension】

1. The condition of poorly controlled hypertension is when the target BP is not achieved despite lifestyle modification and appropriate, adequate antihypertensive medication.

2. If an improvement in BP is not observed, even after identifying individual factors contributing to poor control and implementing appropriate measures, refer to "Chapter 12. Resistant hypertension."

1. Factors

When the target BP is not achieved in patients with hypertension despite lifestyle modification and appropriate,adequate antihypertensive drug therapy, the condition is considered poorly controlled. The factors contributing to this and the corresponding strategies are summarized in Table 11-1. Hypertension that remains poorly controlled despite the use of three antihypertensive drugs from different classes, including a thiazide-type diuretic, is referred to as treatment-resistant hypertension. However, if poorly controlled hypertension persists, despite implementing the various measures outlined in this section, refer to “Chapter 12. Resistant hypertension."

Fig. CQ14-2 Outcomes of older adults (≥70 years) (target SBP <130 mmHg in [intervention group] vs. standard BP lowering [control group]). (Adapted from ref. [1110])

Fig. CQ14-1 Outcomes in older adults (≥75 years) (targeting SBP <130 mmHg [intervention group] vs. standard BP lowering [control group]).

(Adapted from ref. [1110])

The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and. . .

In cases of poorly controlled hypertension, it is important to consider the underlying factors and implement appropriate measures. In the early stages of treatment, when communication with the patient and treatment adherence are not yet well established, it is essential to verify the accuracy of home BP measurements and records, and confirm the occurrence of side effects associated with the initiation and adherence of antihypertensive medication. Even if appropriate drugs are selected and administered at adequate doses, the patient's treatment status is considered to be poorly controlled if BP targets are not achieved. Concurrently, it is necessary to assess whether further evaluation or intervention is required regarding lifestyle factors,drug interactions, the possibility of secondary hypertension,and psychosocial factors such as stress.

European and US hypertension treatment guidelines[183, 1114] identify the following as contributing factors to poorly controlled hypertension: non-adherence to drug treatment, lifestyle issues (excessive salt intake, lack of exercise, excessive alcohol consumption, smoking), obesity,stress, secondary hypertension (including sleep apnea), drug interactions, and problems accessing medical care. In survey studies targeting Japanese hypertensive patients, the following factors have been identified: inadequate home BP measurement, poor medication adherence, lifestyle disorders, stress and psychosocial factors, the presence of secondary hypertension, and inappropriate drug treatment

[1115]. To address these factors and considered key to improvement, are accurate home BP measurement and recording, education of patients, promotion of

Table 11-1 Factors contributing to poorly controlled hypertension and countermeasures Factors

Countermeasures

Inappropriate BP assessment

Measurement environment

• Accurately measure and record home BP

• Conduct ABPM

• Confirm that the patient is seated, the room temperature is appropriate, the patient has urinated, not bathed recently or consumed alcohol (if different, note the details in the memo section)

Inappropriate cuff use

• Verify the size of the rubber cuff of the BP monitor (the width should be at least 40% of the upper arm circumference, and the length should encircle at least 80% of the upper arm circumference)

Incomplete records

• Verify the number of measurements and that all have been recorded

Pseudohypertension

• Be cautious of advanced arteriosclerosis

Inappropriate lifestyle behaviors

Excessive salt intake

• Check daily salt intake (use a salt intake checklist, etc.)

Obesity (excessive energy intake) • Repeat guidance on energy intake restrictions and physical activity

Excessive alcohol consumption • Advise on ethanol intake (20–30 mL/day or less) and liver rest days (dry days)Lack of exercise

• Advise reducing sedentary activity time, combining aerobic exercise (min. 30 min) with low-intensity resistance training per day

Psychological factors, decline in QOL or ADL

• Actively listen and verify the relationship between self-reported symptoms and BP values

• Conduct a Comprehensive Geriatric Assessment (CGA) [1125]

• Provide stress management programs and psychological counseling

• Strengthen mental health support (in collaboration with occupational physicians)

• Implement yoga and mindfulness programs

Decreased medication adherence • Monitor for dementia or side effects

• Utilize medication packaging and medication calendars, and collaborate with pharmacists

• Consider financial issues

Inappropriate medication therapy • Discontinue medications that affect BP, such as NSAIDs or licorice (Glycyrrhiza)

• Confirm that appropriate drug selection is made based on complications or organ dysfunction

• Combine low doses of antihypertensive drugs using different mechanisms of action

• Consider the use of thiazide diuretics, MR antagonists, or ARNI

• Consider the timing of drug administration based on the duration of efficacy

• Take into account salt sensitivity and fluid overload

Presence of secondary hypertension • Confirm the presence or absence of sleep apnea syndrome

• Conduct screening paying attention to typical symptoms and findings

• Refer patients to a hypertension specialist or consult with one

Communication with patients, SDM,

and adherence

• Practice coaching theory

• Respect the patient's autonomy (implement SDM)

• Discuss the bill for lifestyle disease management fees and utilize treatment plans

• Promote interdisciplinary collaboration among healthcare staff, including registered dietitians and certified cardiovascular disease prevention educators

Y. Ohya

psychological support, and clarification of multifactorial causes. Among these, home BP measurement is particularly important, as accurate measurement and recording of all values can improve medication adherence and BP control

[1116].

After home BP measurement the next factor to confirm is adherence to medication [1117]. This requires the use of single-dose packaging or combination drugs and collaboration with the patient's regular pharmacy. To accurately identify the reasons for missed or interrupted doses,it is essential to listen to the patient's perspective and address any questions or concerns. It is necessary to provide sufficient explanation about the significance of hypertension management and treatment, set BP targets(recording in a BP diary is recommended), present treatment options, and engage in SDM with the patient.

The creation of a treatment plan required to calculate the cost of lifestyle-related disease management is a good example of SDM, and the introduction of hypertension treatment apps is also expected to be helpful. Regular follow-up and support by medical care staff are important in ensuring continuation of the treatment and in achieving BP targets. Strategies should be considered to help sustain long-term BP treatment. In cases where medical care visits are interrupted, guidance from public health nurses during health checkups or reminders from pharmacists at the patient's regular pharmacy can serve as triggers for resuming treatment.

Lifestyle modifications are a consistent mainstay of BP treatment and should always be reviewed when drug treatment reaches a plateau [1118]. If poor hypertension control is suspected to be due to excessive salt intake, estimate the daily salt intake using a checklist or spot urine tests, and provide specific guidance on how to reduce salt intake and cooking methods. Collaboration with registered dietitians and certified cardiovascular disease prevention educators is effective for obesity control, by providing guidance on both salt intake and energy intake. For excessive alcohol consumption, verify the type and alcohol content of beverages consumed and advise moderation or abstinence. Physical inactivity is also an important factor; considering the long periods of sedentary behavior among Japanese, increasing physical activity, including daily living activities, is essential. Recommended exercises include a combination of 30 min of aerobic exercise and low-intensity resistance training per day.

Secondary hypertension should also not be overlooked as a potential underlying factor. Pay close attention to the severity of hypertension, characteristic symptoms, andfindings, and conduct screening within the scope of what is feasible. In cases where diagnosis is difficult or refractory hypertension is suspected, referral to a hypertension specialist is recommended.

Finally, confirm that the combination, dosage, and duration of action of antihypertensive medications are appropriate.

Fluid retention-type or salt-sensitive hypertension is commonly observed in cases of poor control. If poor control persists despite combination therapy with ARBs and CCBs(including fixed-dose combinations), switching to or adding thiazide diuretics, ARNI, or MR antagonists is recommended.

Combining lower doses of antihypertensive drugs with different mechanisms of action is more effective than combining high doses of the same drug [1119]. If BP targets cannot be achieved at specific times of the day, adjust the timing of drug administration according to the duration of action.

2. Measures

1) Accurate BP measurement

To determine whether BP is poorly controlled, it is essential to accurately measure and record BP both in the office and at home. In particular, it is mandatory to confirm the accuracy of home BP measurements and records, which are taken frequently and have good reproducibility [1120].

To this end, confirm that the cuff is the appropriate size and properly positioned, that measurements are taken after urination and while seated, and data selection based on selfjudgment or excessive measurement frequency is not occurring. Utilizing the memo section of the BP diary to record BP when there are changes in daily life or symptoms is also an effective measure. Reports indicate that patients tend to increase measurement frequency or record only low values based on self-judgment [1121]. If there is a significant discrepancy between office BP and home BP,consider using BP management applications, recording data via communication functions, or checking data stored on the home BP monitor. If possible, ABPM may also be useful.

2) Consideration of QOL

Hypertension treatment must avoid impairing patients'QOL and ADL. A comprehensive analysis of the relationship between QOL and BP control in hypertensive patients

[1122] revealed a tendency for poor BP control in patients with lower QOL. Similarly, impaired ADL has been shown to contribute to poor BP control due to physical inactivity and reduced self-management ability [1123]. In contrast,reports indicate that poor BP control leads to a decline in QOL regardless of the presence or absence of chronic kidney disease (CKD). More specifically, symptoms such as dizziness, lightheadedness, palpitations, fatigue, and lower leg edema, which are commonly observed in older adults shortly after the initiation of antihypertensive treatment,have been observed in meta-analyses to contribute to a decline in QOL [1124]. For increases in BP medication careful consideration of the dosage and timing is necessary.

In older adults, it is recommended to conduct a comprehensive geriatric assessment (CGA) [1125] before initiating

The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and. . .

BP treatment, to evaluate cognitive function, frailty, and sarcopenia [1126].

3) Medication adherence

Adherence by patients is also important when proceeding with antihypertensive treatment. In patients with treatmentresistant hypertension, 23–65% are reported to have poor adherence [1127]. In a study investigating BP control and its factors, the physician's attitude toward treatment was identified as the most significant factor [958]. Furthermore,inadequate explanation leading to insufficient patient acceptance of treatment, or the physician's failure to recognize the side effects of antihypertensive drugs, can contribute to poor medication adherence.

(1) Factors contributing to poor adherence

The main factors include: ① lack of knowledge about medications, ② concerns about side effects, ③ complex medication schedules, ④ financial burden, ⑤ insufficient understanding of the disease, and ⑥ poor lifestyle habits. It is important to assess these factors appropriately and implement individualized strategies tailored to the patient.

(2) Strategies for Improvement

To improve medication adherence, the following strategies are effective: ① education on the importance of medication, ② simplification of the number of doses (e.g., use of once-daily combination medications), ③ appropriate management and explanation of side effects, ④ use of medication reminders (e.g., smartphone apps), ⑤ obtaining family cooperation, encouragement and regular monitoring of medication adherence. It is important to combine these strategies and tailor them to the patient's lifestyle and values.

4) Communication with patients

The success of hypertension treatment requires a good relationship between healthcare providers and patients. A shift from the traditional concept of "compliance" to a more patient-centered approach called "concordance" is important.

(1) Concept

Concordance is an approach in which healthcare providers and patients decide on a treatment plan on an equal footing and proceed with treatment based on mutual agreement. This concept aims to respect the autonomy of patients and encourage their active participation in treatment.

(2) Effective Communication

To achieve concordance, it is essential to establish effective communication between healthcare providers and patients, focusing on the following six points: ① Listen carefully to the patient and approach them with empathy, ②Avoid medical jargon and explain in terms the patient can understand, ③ Understand and respect the patient's values and life circumstances, ④ Present treatment options and select the most appropriate method together with the patient, ⑤ Address the patient's questions and concerns

thoroughly, ⑥ Conduct regular follow-ups and share progress in treatment. (Conversation Example 1)

Conversation Example 1:

A 50-year-old woman (Ms. A) with poorly controlled hypertension

Doctor:Ms. A, how has your blood pressure been recently?

Ms. A: Actually, when I measure it at home, it's around 140–150 mmHg...

Doctor: I see. It doesn't seem to be reaching the target range. How do you feel about these results?

Ms. A: Honestly, I’d like it to go down a bit more. But I’m hesitant about increasing the medication...

Doctor: I understand how you feel. There are other options besides increasing medication, such as improving your lifestyle. Let's work together to find the best approach for you.

(3) Adjusting for poorly controlled hypertension

For patients with poorly controlled hypertension, it is important to communicate with them, paying particular attention to the following five points: ① Identify the causes of inadequate BP control together with the patient, ② Propose specific lifestyle modification measures and set achievable goals, ③ If a change in medication is necessary,explain the reasons and expected effects in detail, ④Address concerns about side effects honestly and discuss countermeasures together, ⑤ Emphasize the importance of regular follow-up visits and commit to ongoing follow-up(Conversation Example 2).

Conversation Example 2:

70-year-old man (Me. B)

Doctor: Mr. B, your blood pressure is still high. Is there anything you can think of that might be causing this?

Mr. B: Actually, I feel more tired when I take the

medication... and sometimes I forget to take it.

Doctor: I see. Fatigue could be a side effect. Changing the class of drug or the dosage may help alleviate those

symptoms. Additionally, I recommend keeping a blood pressure diary to record your condition on the days you take the medication and days you forget. This will help us better understand the medication's effectiveness and any potential side effects.

In this approach, the following three points are emphasized in the conversation: ① Sincere response to the patient's concerns (side effects), ② Proposal of specific measures

Y. Ohya

(medication change, BP diary), ③ Promotion of patientparticipatory symptom monitoring.

Improving communication and medication adherence based on patient concordance are extremely important in managing poorly controlled hypertension. By combining these elements appropriately, patient-centered, effective hypertension treatment can be achieved, ultimately leading to improved QOL and the prevention of cardiovascular events. The Proper Use of Medicines Council has created a video that clearly explains the concepts of communication and concordance with patients, which may be helpful [1128] .

5) Clinical inertia Considering the advancements in diagnostic methods for hypertension and the development of antihypertensive medications, BP management should have become easier. However, the proportion of patients with appropriately controlled BP remains low, posing a significant issue. One contributing factor is clinical inertia [1129] . Conditions such as hypertension, diabetes, and dyslipidemia are characterized by the absence of noticeable symptoms, and patients rarely initiate treatment changes on their own. Therefore, it is essential for physicians to promptly diagnose, evaluate, and propose optimal treatment options.

(1) Diagnostic inertia, therapeutic inertia Clinical inertia is used as a cautionary term directed at healthcare providers. It can be divided into two categories, diagnostic and therapeutic inertia, as follows: ① diagnostic inertia, which refers to "physicians or other healthcare providers hesitating to diagnose or delaying the diagnosis of poor BP control in patients" or "failing to investigate the causes of resistant or treatment-resistant hypertension," and ② therapeutic inertia, which refers to "physicians hesitating to initiate or change drug therapy (change medication, adjust dosage, or add medication) when BP exceeds recommended target values.". If inadequate BP management persists, due to clinical inertia, it can ultimately have a negative impact on life prognosis and the onset of cardiovascular disease, so sufficient attention is necessary.

Epidemiologically, it is known that many hypertensive individuals are unaware of their condition. This represents a state of diagnostic inertia, necessitating social intervention. Additionally, it is important to raise awareness in clinical practice to avoid missing secondary hypertension; however, information on its prevalence is limited. In contrast, it is well-established that therapeutic inertia significantly contributes to low BP control rates [1130, 1131] . A Dutch study showed that 10% of hypertensive patients were "hypertensive patients with poor BP control despite treatment with one or two antihypertensive drugs," and 87% of these patients were in a state of therapeutic inertia [1132] . In the SPRINT trial, therapeutic inertia was reported in 50.8% of patients [1133] . A retrospective cohort study in Japan suggested that approximately 40% of patients were in a state of therapeutic inertia [1134] . The differences in these proportions are due to variations in the methods used to define therapeutic inertia in each study. However, it is clear that a significant proportion of patients are in a state of therapeutic inertia.

(2) Factors On the healthcare provider side, factors contributing to clinical inertia include the large number of patients, limited consultation time, issues with patient compliance, and insufficient knowledge and enthusiasm among physicians regarding hypertension management. Factors reported as contributing to therapeutic inertia include the absence of antihypertensive medication, non-adherence to the guidelines, the use of multiple antihypertensive drugs, and short consultation periods [1134] . Additionally, physicians may perceive that measured BP does not accurately reflect patients' actual BP (e.g., not measuring home BP and attributing white coat phenomenon to clinic BP alone). Expectations of effects from lifestyle changes, concerns about complications from BP reduction (e.g., excessive hypotension, falls, fractures, stroke), and assumptions about poor patient adherence are also likely contributing factors.

Factors associated with patients prone to therapeutic inertia include BP close to the target BP, diabetes, and advanced age, as well as a long history of hypertension treatment [1135] .

(3) Approaches Strategies for improving clinical inertia include, first and foremost, enhancing physicians' knowledge about the strong association between hypertension and the risk of CVD, as well as the efficacy of BP management. To achieve this, it is essential to promote the widespread adoption of treatment guidelines. Since hypertension care is primarily provided by healthcare facilities that do not specialize in hypertension, it is important to promote collaboration between hypertension specialists and general practitioners, as well as the dissemination and implementation of hypertension treatment guidelines. Additionally, public awareness campaigns targeting patients and the general population, along with educational programs for healthcare professionals involved in hypertension care (including physicians, nurses, pharmacists, registered dietitians, clinical laboratory technologists) and public health nurses are crucial. Furthermore, ensuring appropriate and timely feedback from physicians, appropriate BP measurement and the promotion of home BP measurement by patients are important. In addition, improving patients' knowledge and interest in BP management may help suppress clinical inertia. In fact, educational programs for general practitioners and patients have been reported to be effective [1136] . Additionally, maintaining appropriate communication with patients and setting common goals between

The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and. . .

References

patients, their families, and the medical team about the treatment approach is also considered important [1137] . In this way, clinical inertia can be addressed by improving patients' attitudes toward treatment [1138] . Recently, a cardiovascular disease prevention strategy, combining these three approaches (Measure Accurately, Act Rapidly, and Partner With Patients: MAP) has been proposed, and it has been shown to contribute to improved BP control and reduction in therapeutic inertia [1139, 1140] . Notably however, it has been pointed out that antihypertensive medications are insufficiently used. In a large-scale European study, half to two-thirds of patients were receiving monotherapy [1135, 1141] , and only 36% switched to combination therapy after three years of treatment [564] . In patients with poor control, combination therapy is often used when changing treatment from monotherapy, and its use has been proposed as a useful strategy to address therapeutic inertia [1135] . Furthermore, setting incentives for healthcare providers based on the number of patients achieving good BP control may also be useful in improving therapeutic inertia [1142] . Combining these approaches is expected to reduce clinical inertia and improve BP management in the general population.

Note that when clinical inertia occurs, other CVD risk factors may increase, such as cholesterol and blood glucose. Clinical inertia can occur in various clinical settings due to many factors, so healthcare providers should regularly reflect on whether any form of inertia is present in their daily clinical practice.

6) Exercise therapy Chapter 7 outlines lifestyle modifications for hypertension. The importance of exercise is undeniable, in addition to salt reduction, healthy eating patterns, maintaining a healthy weight, moderate alcohol consumption, and smoking cessation. Therefore, it is considered important to reinforce lifestyle modifications to include exercise, even for patients with controlled hypertension, and particularly for those with poorly controlled hypertension. However, it is necessary to thoroughly assess the patient's overall CVD risk and confirm that they can safely engage in exercise, before initiating exercise therapy.

Several RCTs have reported the short-term BP-lowering effects of exercise in patients with resistant hypertension. In a study examining the effects of 45 min of aerobic exercise, BP decreased in a intensity-dependent manner immediately after exercise. This was following a single session of lightintensity exercise (50% of maximum heart rate) or of moderate-intensity (75% of maximum heart rate). However, only light-intensity exercise showed longer-lasting BP-lowering effects. Therefore, light-intensity exercise may be more beneficial for patients with resistant hypertension [1143] . In patients with resistant hypertension, combining aerobic and resistance exercises has also been reported to reduce BP for a longer duration than either exercise alone [1144] . Overall, short-term exercise has been shown to reduce BP [1145] , but notably, studies have reported that longer-term exercise demonstrates BP-lowering effects. A program of moderateintensity aerobic exercise (a treadmill exercise program), performed three times a week for 8-12 weeks, significantly reduced both SBP and DBP as measured by ABPM [1146] . Additionally, a study was made involving 1 hour of flexibility exercises and walking in a warm-water pool, three times a week for 12 weeks. This reported that daytime average BP, as measured by ABPM, decreased by 21 mmHg in SBP and 11 mmHg in DBP, while nighttime BP decreased by 15 mmHg in SBP and 8 mmHg in DBP [1147] . Furthermore, in a group receiving stretching and physical exercise guidance from a physical therapist and weekly text message information via mobile phone, there was a significant increase in physical activity levels with a decrease in BP [1148] . In addition to standard treatment, adding such exercise therapy has been shown in meta-analyses to significantly reduce BP levels assessed by ABPM, even in patients with treatment-resistant hypertension [1149] . Therefore, light-intensity exercise, such as moderate aerobic exercise (e.g., treadmill walking or brisk walking) with an intensity of approximately 50% of maximum heart rate, is considered useful in the management of BP for patients with poorly controlled hypertension. However, although various studies have been conducted, all studies were small scale and did not provide sufficient evidence. This is an area where further research is anticipated.

7) Psychological approaches It has been suggested that mental issues such as anxiety and stress related to hypertension and medication may increase BP and cardiovascular disease risk [1150, 1151] . Anxiolytics are effective for alleviating anxiety, but they have side effects and dependency issues, so long-term use is not recommended [1152] . Therefore, there is growing interest in the potential of non-pharmacological psychological approaches in improving BP. Psychological approaches may not only lower BP but also improve acceptance of hypertension as a disease, as well as adherence to lifestyle changes and medication, making them a potential option for patients with poorly controlled hypertension.

COLUMN 11-1

Mindfulness and BP

Mindfulness and BP

Yoga and meditation are practices aimed at calming the mind, and yoga can be considered a method that uses poses and breathing techniques to facilitate entering a meditative state. Meta-analyses have demonstrated the efficacy of yoga, suggesting it may serve as a useful Y. Ohya

References

COLUMN 11-1 alternative therapy to pharmacological treatments [1] [2] [3] . Additionally, yoga nidra (a meditation technique where participants relax in a lying position while following an instructor's guidance) has been shown to lower BP [4] . The program Stress Reduction Mindfulness is a type of meditation for chronic pain and stress [5] , and studies on its effects on BP are being conducted. Mindfulness is defined as "awareness that arises through intentional attention to the present moment," and involves training to "direct attention to breathing or bodily sensations and observe them as they are" through an 8-10 week intensive training program [5] . Also known as mindfulness yoga or mindfulness meditation, it has been shown to reduce stress and lower BP in RCTs and meta-analyses [6, 7] Anxiety-related hyperventilation, panic attacks (panic disorder), and pseudo-pheochromocytoma may present with episodic BP increases accompanied by symptoms such as

3. Transient increases in BP

3. Transient increases in BP

The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and. . .

References

tachycardia or palpitations. In these conditions, psychological factors are believed through significantly influence episodic BP increases, and controlling BP is often challenging with antihypertensive medications alone. Using a combination of anxiolytics/antidepressants [1163] , psychological therapy, behavioral therapy, and other mental health interventions provided by specialists should also be considered [1164] (refer to JSH2019, Q8).

Summary of evidence

Summary of evidence

A total of 61 RCTs involving 64,857 participants aged ≥18 years were identified through literature searches, comparing a team-based medical care intervention group (including physicians) with a control group (no intervention) using BP changes as an outcome measure.

The BP in the team-based medical care intervention group compared to the control group was reduced by 6.31 mmHg (95% CI 4.90 to 7.71) for SBP and by 3.11 mmHg (95% CI 2.28 to 3.94) for DBP, demonstrating a significant BP lowering effect. Furthermore, the team-based medical intervention reduced the proportion of patients with poorly controlled BP by 27% (RR 0.73 [95% CI 0.68 to 0.79]).

Even when the leader of the team-based medical care was a physician or other medical staff such as nurses or pharmacists, it consistently demonstrated significant BP reduction. Additionally, when the effects were analyzed by intervention duration (6 months or less, over 6 months to 1 year, or over 1 year) significant BP-lowering effects were observed in all periods.

Explanation

Explanation

In Japan, the proportion of hypertensive patients achieving BP targets (control rate) is low, which is a significant issue [284] . Team-based care has been reported to be associated with improved BP management compared to physician-only care [1153, 1154, 1157] . Therefore, the importance of teambased care, where multiple professionals (physicians, nurses, pharmacists, physician assistants, dietitians, social workers, and community health workers) collaborate to manage patients, has been emphasized over physician-only BP treatment. It is also recommended in the 2017 ACC/ AHA guidelines for hypertension and in the 2024 ESC guidelines for the management of elevated BP and hypertension [181, 626] . Interestingly, a recent meta-analysis investigating the effectiveness of BP management suggested that non-physician-led team-based care may be more cost-effective and beneficial than physician-led care [1154, 1159] .

In Japan, team-based care for hypertension generally does not function without physicians. Therefore, in JSH2025, an SR and meta-analysis were conducted to clarify the evidence for BP management by patient care teams including physicians. The outcome was changes in BP values, and subgroup analyses based on the structure of patient care teams (differences in the central roles within the team) and differences in the effectiveness of BP management based on treatment duration were also examined [1165] .

References

1) BP changes

1) BP changes

A meta-analysis of 57 RCTs targeting patients with hypertension and using office BP as an outcome measure found that, compared to the control group, SBP decreased significantly by 6.31 mmHg (95% CI 4.90 to 7.71) and DBP decreased significantly by 3.11 mmHg (95% CI 2.28 to 3.94). Additionally, in eight RCTs evaluating 24-h ABPM, team-based care resulted in significant reductions in SBP by 8.11 mmHg (95% CI 5.27 to 10.96) and DBP by 3.53 mmHg (95% CI 1.97 to 5.06).

2) Influence of professional roles In studies on team-based care for hypertension treatment, various professions have taken a leading role in interventions. In 6 RCTs led by physicians, SBP decreased significantly by 4.07 mmHg (95% CI 0.83 to 7.31), while in 22 RCTs led by pharmacists, it decreased by 5.74 mmHg (95% CI 4.38 to 7.10), and in 16 nurse-led RCTs it decreased by 5.79 mmHg (95% CI 3.88 to 7.69). These RCTs demonstrated BP-lowering effects comparable to those of physician-led team-based care (Table CQ15 -1). Community health workers (CHWs), who are common in developing countries, provide health promotion services to local residents on behalf of healthcare professionals; they also showed a trend toward BP reduction (8.02 mmHg [95% CI 0.07 to 16.10], P = 0.05) in team-based care. Additionally, in seven RCTs led by registered dietitians or without a clearly defined leader, a BP-lowering effect of 8.03 mmHg (95% CI 5.10 to 10.95) was also demonstrated. Thus, these results suggest that team-based healthcare is effective for hypertension, regardless of which professional leads the intervention, as long as they are involved in patient management.

3

) Effect of intervention duration

) Effect of intervention duration

We also examined the differences in effects based on the duration of intervention. A meta-analysis of 33 RCTs, where team-based medical intervention lasted 6 months or less, showed a reduction in SBP of 6.15 mmHg (95% CI 5.11 to 7.20), in 16 RCTs with an intervention period of 6 to 12 months, it was 4.77 mmHg (95% CI 2.77 to 6.77), and in 8 RCTs with an intervention period exceeding 1 year, it was 8.51 mmHg (95% CI 1.48 to 15.55), indicating a significant reduction in SBP. This confirms the presence of long-term stable BP-lowering effects.

Summary

Summary

In this SR and meta-analysis, team-based healthcare involving physicians demonstrated BP-lowering effects regardless of the profession of the team leader. Furthermore, since these effects were observed regardless of the intervention period, the usefulness of actively implementing team-based healthcare for BP management is clear. It is important to actively implement team-based healthcare to improve BP management rates in hypertension.

Literature search

Literature search

A comprehensive literature search was conducted using PubMed, the Cochrane Library, and Medline Web, and relevant RCTs and cluster RCTs up to May 2024 were extracted.

Q 8 Does BP treatment by board certified hypertension specialist physicians result in higher BP management rates compared to non-specialist physicians?

• Hypertension specialists have completed specialized training that enables them to understand the characteristics of office BP, home BP, and 24-h ABPM, to evaluate BP using appropriate methods, to understand the mechanisms behind individual cases of increases in BP, and are able to implement appropriate BP lowering measures taking into account organ damage and complications. Therefore, they are expected to achieve higher BP control rates than non-specialists.

Explanation

Explanation

There are no prospective controlled trials directly proving that BP management by hypertension specialists is superior, but retrospective studies support this finding.

In the Penn Hypertension Program, which examined the BP management status, one year after referral, 158 hypertensive patients who had poor BP control despite taking two or three antihypertensive medications. BP was reduced from 149/87 mmHg to 129/78 mmHg without increasing the number of antihypertensive medications [1166] . In this program, patients were referred to hypertension specialists. They were instructed in how to improve their lifestyle habits, with antihypertensive medications adjusted, based on their initial visit levels of PAC and plasma renin activity. Specifically, RAS inhibitors or β-blockers were prescribed for normal renin and normal aldosterone levels. For low renin and low aldosterone levels, diuretics were administered as they were considered indicative of salt-sensitive hypertension. For high aldosterone levels, MR antagonists were administered. This demonstrates that patient counseling by hypertension specialists and the selection of appropriate antihypertensive medications are effective in improving BP control.

In the Asia BP@Home Study, BP management status was investigated using home BP measurements in 1,443 hypertensive patients attending 15 specialized hypertension centers (11 countries/regions) in Asia. Among these patients, 68.2% had early morning SBP < 135 mmHg,

The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and. . .

References

indicating relatively good control [1167]. This management rate was superior to that of the J-HOP study in Japan

[1168], where many patients were treated by general practitioners.

A study investigating BP management in 122 patients referred from non-specialist physicians to the Hypertension Clinic at Guy’s Hospital and St. Thomas’ Hospital in London found that BP decreased from 149/92 mmHg to 140/86 mmHg, and the rate of achieving BP targets improved from 35% to 53%. In this study, many patients achieved BP reduction by switching to thiazide-type diuretics as antihypertensive medications [1169].

In Japan, it has been reported in the Japan Medical Association Primary Care Physician Clinical Database Study (J-DOME) that hypertension specialists provide more appropriate BP treatment and stricter salt restriction guidance compared to general practitioners [1170]. The home BP measurement rate was approximately 20% in general practitioner cases and approximately 70% in specialist cases, suggesting that "blood pressure management based on home blood pressure" recommended by JSH 2019 is being actively implemented. Additionally, the estimated daily salt intake was 9.3 ± 3.3 g in general practitioner cases and 8.6 ± 2.5 g in specialists’ cases.

A study of 1,469 hypertensive patients in Okinawa Prefecture revealed that good medication adherence with antihypertensive treatment from hypertensive specialists significantly increased the rate of achieving BP targets

[1171]. In that report, patients receiving treatment from hypertension specialists had a higher awareness of vegetable intake and salt reduction, with a BP target achievement rate of 56.7%, which was significantly higher than that (46.1%) among patients treated by nonspecialists.

Furthermore, in the PARADOX study conducted in Hokkaido, it was reported that hypertension specialists provided more detailed patient education and lifestyle modification counseling compared to non-specialists [1172].

Summary

Physicians who have completed specialized training such as hypertension specialists, are expected to achieve higher rates of BP control compared to treatment administered by other physicians.

Q 9 Does guidance provided by healthcare staff with specialized knowledge in hypertension treatment improve BP control compared to guidance provided by healthcare staff without such qualifications?

● Guidance provided by healthcare staff with specialized knowledge in hypertension, compared to guidance

provided by healthcare staff without, is expected to improve BP control.

Explanation

Guidance provided by medical staff is effective in improving BP management and has been shown to help patients achieve their BP management goals [1173].

Regarding training for healthcare staff, there are specialized programs such as the AMA MAP™ Hypertension program developed by the American Medical Association (AMA)and The Canadian Hypertension Education Program developed in Canada. Previous studies have shown that the implementation of these programs has strengthened accurate BP measurement techniques and patient-centered treatment and care, improved management response and healthcare staff capabilities with enhanced BP control in patients [1139, 1140, 1174, 1175]. The Hypertension Management Program (HMP) developed by the U.S. Centers for Disease Control and Prevention (CDC) emphasizes the importance of team-based care, improving staff BP measurement skills, and patient education, including home BP measurement [1176]. The BP control achievement rate among hypertensive patients approximately six months after the implementation of the HMP was 1.21 times higher than the achievement rate before the program was introduced

[1177]. Healthcare staff completing specialized training in hypertension treatment contributes to improved skills in guidance, patient education, and counseling quality, thereby deepening patients' understanding of BP management and gaining their consent. Additionally, healthcare staff with specialized knowledge tend to communicate more smoothly with patients, strengthen trust, and improve patient satisfaction. These results suggest that treatment effectiveness is increased and BP management is improved [1178].

In terms of cost-effectiveness, effective BP management by healthcare professionals who have undergone specialized training has been shown to contribute to reducing medical costs in the long term. It has been demonstrated that specialized BP management guidance by pharmacists reduces the incidence of cardiovascular diseases and saves $10,162 per person in medical costs[1179, 1180]. In Japan, the Certified Cardiovascular Disease Prevention Educator system was established in 2015 with the aim of cultivating professionals capable of effectively conducting therapeutic guidance. This guidance is for the improvement and/or prevention of lifestyle-related diseases, such as hypertension, which are the primary causes of cardiovascular diseases, as well as for the management of other risk factors. Under this system, a training curriculum has been developed to equip professionals with the latest knowledge and treatment

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methods for lifestyle-related diseases such as hypertension, as well as skills for evaluating and supporting lifestyle modification, enabling them to effectively address lifestyle-related diseases and implement preventive measures for cardiovascular diseases [1181] .

Guidance provided by medical staff with specialized knowledge in hypertension treatment is expected to improve BP management more effectively compared to guidance provided by medical staff without such qualifications. It is anticipated that the increasing involvement of medical staff capable of delivering such high-quality guidance will contribute to the suppression of CVD in Japan and the extension of healthy life expectancy among the population.

Summary

Summary

Guidance provided by healthcare staff with specialized knowledge in hypertension treatment is expected to improve BP management compared to guidance provided by unqualified healthcare staff, as it involves accurate BP measurement-based evaluations and improved patient education quality, leading to higher patient satisfaction and understanding.

Part 3. Management and Treatment of Secondary Hypertension and Special Conditions Chapter 12. Resistant hypertension

【POINT 12】

【POINT 12】

【Resistant hypertension】 1. Resistant hypertension is defined as a hypertension where the target BP is not achieved despite the use of three different classes of antihypertensive drugs, including diuretics. Approximately 14-16% of patients undergoing antihypertensive treatment do not achieve target BP, but these include such as white-coat hypertension, making it difficult to estimate the true prevalence of resistant hypertension. 2. True resistant hypertension, particularly refractory hypertension, is often associated with increased fluid volume and an activation of sympathetic nervous system. In chronic kidney disease (CKD), resistant hypertension may be accompanied with excessive fluid retention, but strict salt restriction is also effective in lowering BP. Other lifestyle factors such as obesity and alcohol consumption should be reevaluated and improved. 3. In antihypertensive treatment, multiple drugs with different mechanisms of action, including diuretics, are used in combination. When using antihypertensive drugs, principally long-acting agents should be used, and sufficient doses, including diuretics, should be administered. Additionally, the frequency and timing of administration can be considered in order to achieve stable BP control throughout the 24-h period. 4. MR antagonists are useful as additional antihypertensive drugs for resistant hypertension. 5. Renal denervation for resistant hypertension may become a new option for BP management in the future. 6. Appropriate BP management is particularly required, because they often have target organ damages and cardiovascular disease (CVD) risk factors. Moreover, secondary hypertension may be present, thus consultation with a hypertension specialist is recommended.

1. Definition and prevalence

1. Definition and prevalence

Many hypertensive patients remain uncontrolled despite undergoing antihypertensive treatment. Resistant hypertension is defined as the failure to achieve target BP despite the use of three different classes of antihypertensive drugs, including diuretics [626] . When target BP is achieved with four or more antihypertensive drugs, these patients are considered to be controlled resistant hypertension, because they have high risks of organ damage [626, 1182] . Antihypertensive drugs must be used at appropriate doses and regimens (maximum tolerated dose). Furthermore, if BP does not achieve < 140/90 mmHg despite the use of five or more drugs, including diuretics and MR antagonists, the condition is regarded as refractory hypertension [1183] [1184] [1185] . Resistant hypertension often involves patients with organ damage or those at a high risk of CVD, necessitating more appropriate management of hypertension [1186] [1187] [1188] . Patients with difficult-to-control BP are preferred to be referred to a hypertension specialist at an early stage. The diagnosis of true resistant hypertension requires the evaluation of out of office BP (24-h BP, home BP), confirmation of medication adherence, and exclusion of secondary hypertension. In patients whose BP does not reach target levels, these factors are often involved, thus appropriate evaluation and management are strongly required. For details, refer to "Chapter 11, Poorly Controlled Hypertension". The prevalence of resistant hypertension varies depending on diagnostic criteria, target BP values, and the population being studied. This prevalence is also significantly influenced by factors such as the clinical background of the patient, the use of appropriate antihypertensive medications and their doses, medication adherence, and target BP levels. Therefore, it seems difficult to estimate the prevalence of

The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and. . .

References

true resistant hypertension after adequately evaluating these factors. When evaluated based solely on BP values, the prevalence varies among reports but is generally reported to be approximately 14-16% of patients undergoing antihypertensive treatment [1189] . In contrast, analyses using data from the National Health and Nutrition Examination Survey (NHANES) in the United States found that applying the BP targets in the AHA/ACC guidelines [626] and the 2018 scientific statement from AHA [1182] (with BP targets of < 130/80 mmHg for those < 65 years or with diabetes, CKD, or high risk of CVD), 19.7% were classified as having resistant hypertension. This was an increase from 17.7% under the previous statement [1190, 1191] . Additionally, when white-coat hypertension was excluded using 24-h BP monitoring, the prevalence of resistant hypertension decreased from 12.2% to 7.6%, suggesting that there may be a higher prevalence of apparently treatment resistance [1192] . Furthermore, in the J-HOME study, which was investigated primarily by practicing physicians in Japan, 13% of patients had uncontrolled BP at home or in medical facilities, despite taking three or more medications [147] .Moreover, the proportion of patients with refractory hypertension resistant to antihypertensive treatment was low, ranging from 0.5-1.4% of patients undergoing antihypertensive treatment [1183, 1193] . As described in the following section, refractory hypertension may have different pathophysiological mechanisms compared with typical hypertension [1194] .

2. Factors and strategies

2. Factors and strategies

For patients exhibiting treatment-resistant or uncontrolled hypertension, it is necessary to identify the etiological factors to establish appropriate approaches. Since many patients appear to be apparently resistant hypertension, it is important to evaluate individual factors contributing to poor control of BP and respond appropriately (for details, refer to Chapter 11). This includes cases where BP values cannot be accurately evaluated due to factors such as use of a cuff that is too small or pseudohypertension. Other factors related to BP measurement such as white coat hypertension or the white coat phenomenon and poor medication adherence are included. Clinical inertia, medication adherence, and patient concordance are also important factors, and appropriate approaches should be taken after adequate evaluation (for details, refer to Chapter 11).

There are many factors that contribute to resistance to antihypertensive treatment. Lifestyle-related factors include excessive salt intake, obesity, and excessive alcohol consumption. Patient-related conditions such as sleep apnea syndrome and excessive fluid retention are also included. There are issues related to the combination, dosage, or duration of action of antihypertensive drugs. There is also the issue of intake of drugs or foods that elevate BP or reduce the efficacy of antihypertensive drugs and there is the possibility of the presence of secondary hypertension [1182] . Sleep apnea syndrome is reported to often coexist with resistant hypertension in over 80% of patients [962] ; therefore, screening should be considered if symptoms are suspected (refer to Chapter 11). Among secondary hypertension, primary aldosteronism and renovascular hypertension are relatively common and have high prevalence rates, thus they should always be considered. Additionally, BP may rise when NSAIDs, corticosteroids, traditional Chinese medicines containing licorice, glycyrrhizin preparations, oral contraceptives, cyclosporine, erythropoietin, or molecularly targeted drugs are used concomitantly. If these medications are involved in BP elevation, they could be withheld or reduced if possible; however, this is often difficult. In order to achieve BP in adequate levels, select appropriate antihypertensive drugs considering the mechanisms of increased BP and interaction of drugs.

In patients with excessive salt intake, inadequate use of diuretics, or impaired renal function, treatment resistance due to fluid overload is commonly found. The appropriate use of diuretics is effective in these conditions. In particular, loop diuretics should be used in patients with impaired renal function (eGFR < 30 mL/min/1.73 m 2 ). Additionally, even in cases of resistant hypertension of CKD or already treated with diuretics, strict salt restriction is also effective for BP control [1195, 1196] . If the duration of BP reduction is insufficient due to the inappropriate combination or dosage of antihypertensive drugs used, antihypertensive drugs with different mechanisms of action can be combined, and adequate doses of antihypertensive drugs, including diuretics, should be administered.

In patients with difficult-to-control BP despite improvement of various factors (e.g., refractory hypertension), it has been reported that activation of sympathetic nervous system and fluid retention induced by aldosterone excess are involved in BP elevation [1194] . Additionally, these patients frequently suffer from advanced organ damage and have high risks of CVD [1197] . In patients unresponsive to antihypertensive treatment, these pathophysiological conditions should be reconsidered and lifestyle issues (excessive salt intake, obesity, excessive alcohol consumption) should be strictly improved, while selecting antihypertensive drugs appropriate for the underlying condition and conducting treatment.

3. Treatment

3. Treatment

1) Pharmacological treatment

1) Pharmacological treatment

If diuretics are not being used, initiate their use; if already in use, adjust the dose and type as appropriate. For appropriate use and dosage of diuretics, refer to "Chapter 8, Y. Ohya

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Section 3. 4) Diuretics". In order to reduce BP, consider using higher doses than the usual recommended dose while paying attention to effects on electrolytes and metabolism. If the eGFR is ≥30 mL/min/1.73 m 2 , select a thiazide-type diuretic. If the eGFR is < 30 mL/min/1.73 m 2 , select a loop diuretic. Furosemide may require multiple daily doses due to its short duration of action, so longer-acting agents (e.g., torasemide) may be recommended.

In addition to diuretics, multiple antihypertensive agents with different mechanisms of action are considered in combination. When selecting antihypertensive agents, those with active indications are prioritized; CCBs and angiotensin receptor blockers (ARBs) or angiotensin-converting enzyme (ACE) inhibitors are commonly used. To reduce BP to target levels at all times of the day, long-acting agents are generally recommended at adequate doses. If BP remains uncontrolled despite the combination of three agents (a CCB, an ARB, or an ACE inhibitor, and a diuretic) at adequate doses, consider adjusting the timing of medication administration, such as changing from once daily in the early morning to twice daily in the early morning and evening. In resistant hypertension, insufficient duration of action of antihypertensive drugs can lead to periods of inadequate BP control. Evaluate BP at home in the early morning and evening, or assess diurnal BP variability using 24-h BP monitoring, and adjust not only the type of antihypertensive drug but also the timing of administration. Administration of antihypertensive drugs at bedtime has been shown to reduce 24-h BP and nighttime BP in patients with resistant hypertension, thereby improving the rate of achievement of BP targets [1198] . Furthermore, even among antihypertensive drugs of the same class or with similar mechanisms of action, there are some differences in magnitude and duration of antihypertensive effects among them [585, [1199] [1200] [1201] [1202] , thus consideration should be given to switching to a more effective antihypertensive drug even within the same class as needed.

Regarding combination therapy, the addition of MR antagonists is recommended as an adjunct medication because they can achieve effective BP reduction [561, 1203] (refer to Q10), but attention should be paid to increases in serum potassium levels. Switching from ARBs or ACE inhibitors to ARNI may also yield further BP reduction [1204] . When switching from an ACE inhibitor to ARNI, start administration at least 36 h after final administration of ACE inhibitors to avoid the risk of angioedema. On the other hand, if MR antagonists or ARNI are already used as part of antihypertensive treatment STEP 2 instead of diuretics, consider adding a diuretic first. Concomitant use of sympatholytic agents such as αβ blockers, α blockers, or β blockers can also be considered. In resistant hypertension, an activation of sympathetic nervous system is often observed [1194] , thus central sympatholytic agents such as guanabenz or methyldopa may be effective. Vasodilators, such as hydralazine, may also be used, but attention should be paid to the individual antihypertensive characteristics (such as the duration and magnitude of BP reduction) and specific side effects of each antihypertensive agent. In general, avoid duplicate administration of agents within the same class. However, concomitant use of two CCBs, or a combination of thiazide-type diuretics and loop diuretics could be considered. In patients with resistant hypertension in stage 4 CKD, the use of chlorthalidone (unavailable in Japan in 2008), a thiazide-like agent, has been reported to be effective combined with loop diuretics [587] . When using multiple or high doses of antihypertensive drugs, unexpected side effects or an acute drop in BP may occur, then treatment by a hypertension specialist is recommended in resistant hypertension.

2) Non-pharmacological treatment (renal denervation, etc.)

Since the publication of JSH2019, no new nonpharmacological treatments (device-based therapies) have been approved for hypertension treatment in clinical practice in Japan.* However, in addition to renal denervation discussed in CQ16, several device-based therapies are currently under development overseas with the aim of clinical implementation.

(*In August 2025, two devices for renal denervation received regulatory approval in Japan)

Baroreflex activation therapy (BAT) lowers BP by stimulating carotid sinus baroreceptors, which reduces heart rate and induces peripheral vasodilation. Clinical trials employing various BAT devices for treatment-resistant hypertension have been conducted, with some demonstrating BP-lowering effects, while others found no significant difference between the BAT and placebo groups [1205, 1206] . Several clinical trials are currently ongoing. Another approach targeting carotid sinus baroreceptors involves placing a stent near the carotid sinus to modify its shape and enhance baroreceptor sensitivity, thereby aiming to achieve BP reduction. In the first human trial, BPlowering effects were demonstrated [1207], and a clinical trial comparing this method with a placebo group is ongoing. Additionally, an approach to lower BP by ablating excessive activity of the carotid body is also under investigation [1208] . Regarding treatments targeting the regulation of baroreceptors common to these conditions, there is a tendency to focused on heart failure rather than hypertension, considering the relative severity of the disease.

Devices that artificially create iliac-femoral artery fistulas have demonstrated BP-lowering effects in clinical trials [1209] , but they are associated with complications such as high cardiac output and are currently not being developed for hypertension treatment.

The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and. . .

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Abstract

In clinical practice, there are a certain number of patients with treatment-resistant or refractory hypertension in whom target BP cannot be achieved despite appropriate pharmacological and non-pharmacological therapies, including lifestyle modifications. Although device-based therapies are likely to take time to be introduced in Japan, they may provide a new treatment option for hypertension depending on the outcomes of future clinical trials.

Abstract

CQ 16 Is renal denervation recommended for the treatment of resistant hypertension?

Abstract

► Renal denervation may become a new treatment option as an adjunctive therapy for resistant hypertension in the future.

Abstract

[Strength of Recommendation-2, Strength of Evidence-B, Consensus rate -100%]

Summary of evidence

Summary of evidence

Twelve RCTs comparing renal denervation with sham treatment for hypertension, using 24-h SBP reduction measured by ABPM as the primary outcome, were identified. No significant heterogeneity or publication bias was observed across studies. In both untreated and treated hypertensive patients, the renal denervation group showed a significant reduction in 24-h SBP compared to the sham treatment group.

Explanation

Explanation

Renal denervation, first applied in humans in 2007, was considered a novel treatment for hypertension and has subsequently been investigated in numerous clinical trials. While early proof-of-concept studies demonstrated significant BP lowering effects, the first sham-controlled RCT failed to reproduce these initial results. In recent years the trial design, technical aspects of the procedure, and the device were improved. Trials were also expanded the study population to include subjects with a wide range of hypertension profiles, from resistant hypertension to those untreated or those taking only one or two antihypertensive drugs. This CQ conducted an SR of randomized shamcontrolled trials published up to November 15, 2023 November 15, [1210]] . All 12 trials were included [1211] [1212] [1213] [1214] [1215] [1216] [1217] [1218] [1219] [1220] [1221] [1222] .

1) Reduction in 24-h BP by ABPM In the pooled analysis of all 12 trials, the renal denervation group showed a greater reduction in 24-h SBP of 2.81 mmHg (95% CI 1.53 to 4.09, P < 0.001) and DBP of 1.47 mmHg (95% CI 0.56 to 2.39, P = 0.002) compared with the sham treatment group. Significant heterogeneity was observed among trials for the results of the 24-h DBP outcome.

2) Reduction in Office BP

In the pooled analysis of all 12 trials, the renal denervation group showed a significantly greater reduction in office SBP of 4.95 mmHg (95% CI 3.54 to 6.37, P < 0.001) and office DBP of 2.79 mmHg (95% CI 1.90 to 3.67, P < 0.001), compared with the sham treatment group.

3) Reduction in daytime and nighttime BP by ABPM Compared with the sham treatment group, the renal denervation group showed significantly greater reductions in daytime SBP of 3.17 mmHg (95% CI 1.58 to 4.75, P < 0.001) and daytime DBP of 1.88 mmHg (95% CI 0.68 to 3.08, P = 0.002), as measured by ABPM. Nighttime SBP was reduced by 3.41 mmHg (95% CI 2.13 to 4.69, P < 0.001) and DBP was reduced by 1.61 mmHg (95% CI 0.17 to 3.05, P = 0.028), both being significantly lower in the renal denervation group. Significant heterogeneity was observed among trials for the daytime DBP outcome, and publication bias was suggested for nighttime SBP.

4) Reduction in home BP Data from five trials showed significantly greater reductions in home SBP of 4.64 mmHg (95% CI 1.84 to 7.44, P = 0.001) and home DBP of 2.28 mmHg (95% CI 0.26 to 4.30, P = 0.027) in the renal denervation group compared with the sham treatment group.

5) BP lowering effects according to antihypertensive medication status and device type

5) BP lowering effects according to antihypertensive medication status and device type

The effect of renal denervation on 24-h SBP and office SBP did not differ significantly between patients receiving antihypertensive medications and those not receiving medications. No significant difference was observed between radiofrequency and ultrasound renal denervation devices. When studies were divided into renal denervation device type, 1st-generation (up to Simplicity HTN-3) and 2ndgeneration (Simplicity HTN-3 and later), a trend toward greater reductions in 24-h and office SBP was observed with 2nd-generation renal denervation devices. However, this difference was not statistically significant.

This meta-analysis, using data from 12 randomized sham-controlled trials (2222 patients), demonstrated that renal denervation significantly reduced all BP parameters compared with sham treatment, in patients with resistant hypertension, poorly controlled hypertension, and untreated hypertension. These reductions were consistent regardless of device type, use of antihypertensive medication, or device generation, although heterogeneity and publication bias were noted in some outcomes. Oral antihypertensive drugs exhibit trough and peak effects, making it difficult to control 24-h BP. This limitation and the observed reduction in nighttime SBP suggest that renal denervation may have substantial clinical significance in reducing cardiovascular events in hypertensive patients.

In this study, renal denervation reduced office SBP by approximately 5 mmHg. A reduction of 5 mmHg in SBP, even in individuals with normal BP ( < 120 mmHg) or high-normal Y. Ohya

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BP (120-129 mmHg), regardless of the presence or absence of cardiovascular disease, has been reported to lower the risk of CVD by approximately 10%. Therefore, renal denervation may exert clinically significant BP-lowering effects.

Subgroup analyses demonstrated that the 24-h and office BP-lowering effects of renal denervation were consistent in patients, regardless of antihypertensive drug use. Although medication adherence is often a concern in renal denervation trials, these results support the BPlowering effect of renal denervation independent of antihypertensive drug use.

As of April 2025, renal denervation is not covered by public insurance in Japan. Regarding the international status of renal denervation, the 2023 ESH guidelines list renal denervation as a Class II treatment option for resistant hypertension, and as a Class I recommendation for patient selection: "The selection of patients for renal denervation should be made through a shared decision-making process based on objective and fully informed criteria." "Renal denervation should only be performed at experienced centers" [183] . In the United States, two renal denervation devices were approved by the FDA in November 2023 as adjunctive therapies for hypertension, and a statement regarding their use was issued by the ACC in August 2024 [1223] .

Summary

Summary

Renal denervation has demonstrated efficacy in reducing ABPM, home BP, and office BP compared with sham treatment in both untreated and treated hypertension. This SR did not limit its scope to resistant hypertension. It also emphasized that, even in resistant hypertension, nonpharmacological therapies focused on lifestyle modification and the continuation of antihypertensive medications remain essential. Given that renal denervation is not currently covered by public insurance in Japan (approved on August 2025), the response to this CQ is that renal denervation may become a novel treatment option as an adjunctive therapy for resistant hypertension in the future.

Literature Search

Literature Search

Two SR committee members independently searched PubMed and the Cochrane Library to extract articles relevant to this CQ.

Q 10 Is the addition of MR antagonists useful in the management of BP for treatment-resistant hypertension?

•

•

In treatment-resistant hypertension, the addition of MR antagonists is useful because it significantly reduces both office and ambulatory BP compared to the addition of α-blockers or β-blockers.

•

•

In patients with treatment-resistant hypertension and renal impairment [eGFR < 30 mL/min/1.73 m 2 ], the addition of MR antagonists is not recommended.

• When continuing MR antagonist therapy for treatmentresistant hypertension, regular monitoring of renal function and serum potassium levels is necessary.

Explanation

Explanation

For JSH2019, the following clinical question (CQ) was posed: "Should MR antagonists be recommended for treatment-resistant hypertension?" Treatment-resistant hypertension is defined as a condition in which BP does not decrease to target levels despite lifestyle modifications and appropriate doses of three antihypertensive medications (including diuretics), such as CCBs, ACE inhibitors/ARBs, and thiazide-type diuretics [1182] , and the efficacy of MR antagonists as an additional antihypertensive agent following these three agents was also evaluated.

Two meta-analyses [606, 607] of four RCTs [561, [1224] [1225] [1226] concluded that "the addition of MR antagonists is recommended" (strength of recommendation: 2, evidence: B). The addition of low-dose spironolactone (25-50 mg/day) in the treatment-resistant hypertensive patients showed a significant reduction in office SBP by 15.73 mmHg, office DBP by 6.21 mmHg, out of office SBP by 8.70 mmHg, and out of office DBP by 4.12 mmHg, compared with the control drugs such as placebo, doxazosin, and bisoprolol. Although there was a slightly higher rate of adverse events such as hyperkalemia (≧5.0 mEq/L) and renal failure in the spironolactone group compared to the control drugs, no significant differences were observed. It was suggested that adequate monitoring of serum potassium levels and renal function before and during treatment could manage these events. Studies evaluating the efficacy of eplerenone or esaxerenone for treatment-resistant hypertension are limited, and sufficient evidence has not yet been established. However, these agents are considered to have similar effects to spironolactone. Based on these results, the addition of MR antagonists is concluded to be useful for BP management in treatment-resistant hypertension.

However, when we revisit the patient populations of the four RCTs, one study targeted patients with treatmentresistant hypertension complicated by stage 2 and 3 CKD [1226] , and another study, the PATHWAY-2 trial [561] excluded patients with an eGFR < 45 mL/min/1.73 m2 and serum potassium > 4.5 mEq/L, suggesting that the efficacy of MR antagonists in patients with moderate to severe renal impairment and treatment-resistant hypertension has not been sufficiently validated.

The 2020 ISH guidelines [1227] recommend the use of MR antagonists only in patients with treatment-resistant

The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and. . .

References

hypertension and eGFR > 45 mL/min/1.73 m 2 and serum potassium < 4.5 mEq/L. Additionally, the ESH 2023 guidelines [183] also modify the recommendation for MR antagonists based on the level of renal dysfunction, specifying eGFR ≥30 mL/min/1.73 m 2 (preferably with eGFR ≥45 mL/min/1.73 m 2 and serum potassium ≥4.5 mEq/L) in patients with treatment-resistant hypertension. However, MR antagonists are generally contraindicated in patients with eGFR < 30 mL/min/1.73 m 2 .

In Japan, regarding MR antagonists used as antihypertensive agents, eplerenone is contraindicated in patients with moderate or severe renal impairment (creatinine clearance < 30 mL/min), and esaxerenone is contraindicated in patients with an eGFR of < 30 mL/min/1.73 m 2 or less. Therefore, it is considered appropriate to limit the use of MR antagonists as an additional treatment for resistant hypertension to patients with moderate renal impairment (eGFR ≥30 but < 60 mL/min/1.73 m 2 ). However, for spironolactone, if its benefits are deemed to outweigh the risks due to concomitant conditions, its use may be carefully considered even if eGFR is < 30 mL/min/1.73 m 2 , provided that renal function safety is closely monitored.

In 2021, the results of the AMBER trial, an RCT evaluating the efficacy of concomitant administration of the potassium-binding agent patiromer and spironolactone in patients with treatment-resistant hypertension and moderate (eGFR < 45 mL/min/1.73 m 2 ) or severe (eGFR < 30 mL/min/ 1.73 m 2 ) renal impairment, were reported [1228] . Even in patients with treatment-resistant hypertension and moderately advanced renal dysfunction at this level, the addition of low-dose potassium-binding agents and spironolactone (25-50 mg/day) resulted in a significant reduction in SBP of approximately 6-13 mmHg, and the incidence of adverse events such as further progression of renal dysfunction or hyperkalemia (≥5.5 mEq/L) were also suppressed. Therefore, in patients with moderate or severe renal dysfunction and treatment-resistant hypertension, the initial combination of MR antagonists and potassium-sparing diuretics may be beneficial, and further validation of this approach in Japan is anticipated.

Finally, based on the recommendations in JSH2025 to achieve BP targets by initiating antihypertensive treatment as early as possible and promoting the active use of combination treatment, the following conclusions are summarized. For patients who may exhibit treatment resistance from the onset of hypertension treatment (e.g., obesity, CKD, or concomitant sleep apnea syndrome), it is important to plan treatment with a combination of four antihypertensive drugs, including MR antagonists, while distinguishing whether or not the hypertension is true treatment-resistant hypertension; it is also important to promptly escalate antihypertensive treatment by adding additional antihypertensive drugs if BP targets are not achieved. Additionally, when continuing MR antagonist therapy, regular monitoring of renal function and serum potassium levels is necessary.

Chapter 13. Hypertension in peripartum women

1. Diagnosis of hypertension associated with pregnancy

1. Diagnosis of hypertension associated with pregnancy

If hypertension is detected during pregnancy, the condition is diagnosed as HDP [600, 1229] (Table 13 -1). HDP is classified as preeclampsia, gestational hypertension, superimposed preeclampsia, or chronic hypertension based on the timing of hypertension onset anf the presence or absence of proteinuria or findings suggestive of maternal or fetal organ damage into the following categories: Severe hypertension is defined as an SBP of ≥160

Y. Ohya

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2. Definition

2. Definition

Hypertension during pregnancy is called "hypertensive disorders of pregnancy (HDP)." HDP is classified into preeclampsia, gestational hypertension, superimposed preeclampsia and chronic hypertension. Method for BP measurement: 1. After the subject has remained still for 5 min or more and confirming that the cuff around the upper arm is at the heart level, BP is measured twice at an interval of 1-2 min in the sitting position. The average of two measurements is adopted. If the second BP reading differs by 5 mmHg or more from the first one, measurement is repeated several times until the reading becomes stable. The subject should be prohibited to take caffeine or smoke within 30 min before measurement. 2. During the first session of measurement, BP is measured on both of right and left upper arms. If the reading differs by 10 mmHg or more between two sides, the higher reading is adopted. 3. Measurement should use an automated sphygmomanometer of precision comparable to that of a mercury sphygmomanometer. Proteinuria: Positive urinary protein (urinary protein excretion 300 mg/day or more, or protein/creatinine ratio in random urine sample 0.3 mg/ mg･Cr or higher)

3. Subtyping by symptoms

3. Subtyping by symptoms

① Severity HDP is rated as severe if it falls under any of the following criteria. The category "mild" is not used, as a rule, because it can be misunderstood as indicating HDP without high risk.

1. Cases of preeclampsia, gestational hypertension, superimposed preeclampsia or chronic hypertension in which BP satisfies any of the criteria given below: SBP ≥160 mmHg DBP ≥110 mmHg 2. Cases of preeclampsia or superimposed preeclampsia in which maternal organ damage or uteroplacental dysfunction is present *Severity classification based on intensity of proteinuria is avoided.

4. Disease typing ① Preeclampsia (PE) 1. Hypertension with proteinuria occurring for the first time after week 20 of pregnancy but resolving within 12 weeks after delivery. 2. Hypertension having developed for the first time after week 20 of pregnancy, without proteinuria but having any of the below-listed problems resolving within 12 weeks after delivery i) Hepatic impairment without underlying disease (hepatic enzyme increased [ALT or AST > 40 IU/L], right hypochondrial or epigastric pain of persisting severity not responding to treatment and not allowing any other diagnosis)

ii) Progressive nephropathy (serum creatinine > 1.0 mg/dL, other renal diseases ruled out) iii) Stroke, neuropathy (intermittent convulsion, eclampsia, visual field defect, headache excluding primary headache) iv) Coagulopathy (HDP-associated thrombocytopenia [ < 150000/μL], disseminated intravascular coagulation, hemolysis) 3. Hypertension having developed for the first time after week 20 of pregnancy, without proteinuria but associated with uteroplacental dysfunction (fetal growth retardation [FGR] , abnormal umbilical artery flow pattern, still birth) ② Gestational hypertension (GH) Hypertension occurring for the first time after week 20 of pregnancy but resolving within 12 weeks after delivery and not falling under the definition of preeclampsia ③ Superimposed preeclampsia (SPE) 1. Hypertension occurring before pregnancy or by week 20 of pregnancy, along with any of hepatic/renal impairment (without proteinuria or underlying disease), stroke, neuropathy or coagulopathy emerging after week 20 of pregnancy. 2. Aggravation of pre-existing (before pregnancy or before week 20 of pregnancy) hypertension and proteinuria after week 20 of pregnancy. Either one or both aggravations are acceptable.

3. Hypertension emerging after week 20 of pregnancy in patients with pre-existing renal diseases that manifest solely as proteinuria. 4. Hypertension occurring before pregnancy or by week 20 of pregnancy, associated with uteroplacental dysfunction after week 20 of pregnancy ④ Chronic hypertension (CH) Hypertension occurring before pregnancy or by week 20 of pregnancy, without accompanying superimposed preeclampsia Notes 1. Pregnancy-induced proteinuria Refers to proteinuria first detected after week 20 of pregnancy and resolving within 12 weeks after delivery, but not included in disease typing.

2. Diagnosis of hypertension

2. Diagnosis of hypertension

Office BP sometimes does not reflect the real BP, as seen in cases of white coat hypertension or masked hypertension. Particularly in cases of chronic hypertension, it is advisable to conduct home BP measurement or ABP monitoring for diagnosis of white coat hypertension or masked hypertension and distinction from other accidental complications.

3. Related conditions ① Eclampsia

3. Related conditions ① Eclampsia

Convulsive seizure occurring after week 20 of pregnancy. Exclusion of epilepsy and secondary convulsion is essential. Eclampsia is classified into three types: eclampsia gravidarum, intrapartum eclampsia and puerperal eclampsia based on the timing of convulsive seizure. Eclampsia is

The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and. . .

References

mmHg or a DBP of ≥110 mmHg. In contrast, non-severe hypertension is defined as an SBP of ≥140 mmHg and/or a DBP of ≥90 mmHg. Regarding BP measurement, the oscillometric method has been validated as a BP measurement method for pregnant women, including those with gestational hypertension or preeclampsia [1230] . During pregnancy, both circulating plasma volume and cardiac output increase. However, due to factors such as a decrease in systemic vascular resistance from the early stages of pregnancy and the formation of placental circulation, BP physiologically decreases after conception [1231] ; it reaches its lowest point in the mid-pregnancy period, after which it begins to rise toward delivery [1232] . This has also been reported in home BP measurements [1233, 1234] . BP measurement methods and diagnostic criteria are the same as those in non-pregnant individuals. However, pregnancy-specific BP thresholds that take into account both maternal-fetal outcomes and physiological changes during pregnancy have not yet been established [600, 601, 1229, 1235, 1236] . Secondary hypertension is associated with worse maternal and fetal outcomes than essential hypertension [1237] . Prepregnancy screening and treatment are recommended, but if not performed, screening during pregnancy should be conducted within the scope of examinations considered feasible and safe during pregnancy.

In a prospective cohort study conducted in Japan, 30% of women who were suspected of having hypertension, based on office BP, during the first trimester of pregnancy were found to have white-coat hypertension [1238] . White-coat hypertension has been reported to be associated with poorer maternal and fetal outcomes compared with normal BP pregnancy, but better outcomes than pregnancies complicated by chronic hypertension [1239] , so continuous monitoring of BP trends is desirable even in cases of white-coat hypertension. However, the association between masked hypertension and maternal and fetal outcomes is uncertain [1240] .

2. Target BP

2. Target BP

In the management of HDP, it is essential to consider both maternal organ protection and maintenance of fetoplacental function. Due to the heterogeneity of clinical conditions, it is difficult to establish specific criteria for initiating antihypertensive treatment or setting BP targets, and management should be conducted in close collaboration with obstetric specialists. Previous reports have suggested an association between maternal death from stroke and preceding severe hypertension [1241, 1242] , and severe hypertension requires immediate BP reduction [600, 601, 1229, 1235, 1236] . The Japanese Society of Obstetrics and Gynecology guidelines [1229] recommend immediate BP reduction and hospitalization when SBP is ≥160 mmHg and/or DBP is ≥110 mmHg on multiple occasions. For chronic hypertension, recent large-scale clinical trials [1243, 1244] suggest initiating BP lowering at ≥140/90 mmHg [600, 601, 1236, 1245] , but target BP values cannot be established at this time.

3. Nonpharmacological treatment

3. Nonpharmacological treatment

A meta-analysis of observational studies found that a diet rich in fruits and vegetables is beneficial for preventing considered as convulsive seizure due to reversible angiogenic edema of the cerebral cortex, but edema can develop also in the occipital lobe or brainstem, resulting in various disorders of the central nervous system (CNS). ② HDP-associated CNS disorders Includes cortical blindness, posterior reversible encephalopathy syndrome (PRES), hypertension-associated cerebral hemorrhage and cerebrovascular spasm. ③ HELLP syndrome Develops during pregnancy or during or after delivery, associated with signs of hemolysis (LDH increased), hepatic impairment (AST increased) and thrombocytopenia but not attributable to any other accidental complication. Conditions presenting with only one of these signs/ symptoms are not described as HELLP syndrome. The diagnosis of HELLP syndrome should be based on the diagnostic criteria of Sibai.* ④ Lung edema HDP involves increased vascular permeability due to vascular endothelial dysfunction, often leading to edema. In severe cases, lung edema is also noted. ⑤ Perinatal cardiomyopathy Women having no history of heart disease can develop heart failure suddenly during pregnancy or puerperium, resulting in a fatal outcome in severe cases. HDP is an important risk factor for this condition.

References

preeclampsia; in contrast, a high total energy intake and low intake of magnesium and calcium are associated with preeclampsia [1246] . A network meta-analysis also suggested the efficacy of calcium supplementation and vitamin D [1247] . However, a Cochrane review concluded that there is insufficient evidence of calcium supplementation [1248] .

In the Birth and Three-Generation Cohort Study (TMM BirThree Cohort Study) in Japan, low intake of calcium and potassium [1249] and skipping breakfast [1250] were associated with HDP and preeclampsia, but the Japan Environment and Children's Study (JECS) found no association between calcium intake and preeclampsia [1251] .

An umbrella review of SRs and meta-analyses of intervention studies examining the preventive effects of physical activity found that supervised physical activity during early pregnancy was effective in preventing preeclampsia [1252] and that physical activity during pregnancy reduced the risk of preeclampsia [1253] . The effects of bed rest on preeclampsia remain unclear [1254] . Multiple pregnancies are risk factors for preeclampsia [1255] . However, a metaanalysis showed that multiple pregnancy reduction surgery in triplet pregnancies reduced the risk [1256] .

4. Pharmacological treatment 1) During pregnancy

4. Pharmacological treatment 1) During pregnancy

The selection of antihypertensive agents for the treatment of HDP is important. All antihypertensive agents cross the placental, so their effects on the fetus (teratogenicity in early pregnancy, fetal toxicity in mid-pregnancy and later) must be considered. RAS inhibitors including ACE inhibitor, ARB and ARNI have fetal toxicity [1257] [1258] [1259] and are contraindicated during pregnancy. Antihypertensive agents considered safe and appropriate for use during pregnancy include methyldopa, nifedipine, amlodipine, labetalol, and hydralazine. Recent reports [1260, 1261] have also suggested that maternal hypertension itself, regardless of antihypertensive agents use, is associated with specific morphological abnormalities.

(1) Methyldopa Methyldopa is a central sympathetic nerve inhibitor that can be used throughout pregnancy [600, 601, 1229, 1236, 1245] . It exerts minimal effects on uteroplacental circulation and fetal hemodynamics [1262] , and no adverse effects on the offspring were observed in a 7.5-year follow-up study [1263] . No increase in teratogenic risk has been reported with use during the first trimester [624] . Side effects include drowsiness and liver dysfunction in both mother and infant, which require caution.

(2) CCBs Previous studies have not shown an increase in teratogenicity with nifedipine use [1264, 1265] . In Japan, the contraindication for use during the entire pregnancy period was removed from the package insert in November 2022. Because the placental circulation lacks autoregulatory capacity, rapid or excessive BP reduction may lead to fetoplacental circulatory failure; therefore, sustained-release formulations are generally recommended. It has a high BPlowering effect and is recommended as an oral medication for severe hypertension [1266, 1267] . Additionally, the contraindication for amlodipine during all stages of pregnancy has been removed from the package insert. No increase in teratogenicity has been reported to date [1265, 1268, 1269] . When oral therapy is insufficient, intravenous agents may be required; in such cases, nicardipine-which offers favorable hemodynamic controllability-is recommended [600, 1229] .

(3) β-blockers The α-β blocker labetalol is safe for use throughout pregnancy [1270, 1271] . An increase in teratogenic risk with β-blockers is not currently considered to be a major concern [1272] [1273] [1274] ; however, associations with fetal growth restriction have been reported [1275, 1276] , particularly with atenolol [1277, 1278] . Therefore, the use of atenolol during pregnancy is not recommended unless there are no alternative medications available. It should be avoided in patients with bronchial asthma [1279] . In March 2024, the contraindications for carvedilol and bisoprolol were removed from the package insert.

(4) Hydralazine Hydralazine, a vasodilator, is less commonly used due to reports of difficulties in adjusting BP, inferior efficacy in lowering BP compared to other agents, and the increased side effects [1280] .

(5) Diuretics Some reports indicate that while circulating plasma volume decreases, there is no adverse effect on pregnancy outcomes [1281] . However, preeclampsia may worsen due to reduced circulating plasma volume and increased vascular permeability, so the recommendation for the use of diuretics is only when necessary in cases for the treatment of the underlying disease. At present, no increase in teratogenicity has been reported.

(6) RAS inhibitors Use of RAS inhibitors during the second trimester or later has been associated with fetal toxicity, causing fetal hypotension, reduced renal blood flow, and abnormalities in tubular dysgenesis. Fetal renal failure leading to decreased urine output and oligohydramnios may result in physical compression, causing pulmonary hypoplasia, limb contractures, and craniofacial deformities in the fetus [1259] [1260] [1261] . Regarding teratogenicity, some reports suggest an increased risk [1282] and some reports deny it [1283, 1284] . At present, no conclusive findings

The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and. . .

References

have been established; however, continued reports of increased teratogenicity [1285] have been made, and caution should be exercised regarding the use of these agents throughout pregnancy. If a woman using these agents becomes pregnant, oral administration should be discontinued immediately, and alternative therapy should be considered as appropriate. ARNI is expected to have similar effects, and its use during pregnancy is contraindicated.

(7) MR antagonists

Data on the use of these MR antagonists during pregnancy are still insufficient.

(8) Magnesium sulfate

Magnesium sulfate, when used for the prevention and management of eclampsia [600, 601, 1229, 1236, 1286],causes vasodilation of central and peripheral blood vessels,resulting in a decrease in BP [1287].

(9) Low-dose aspirin

In recent years, in the obstetric field, low-dose aspirin has been used from early pregnancy in women with a history of preeclampsia to reduce the risk of recurrence [1288].

However, in Japan, its use is contraindicated within 12 weeks of the expected date of delivery (after 28 weeks of pregnancy). It is not covered by the national insurance system for the prevention of preeclampsia, thus its use is off-label [1229].

2) Breastfeeding period

The breast milk/plasma drug concentration ratio (M/P ratio)and relative infant dose of various antihypertensive agents and their use during breastfeeding are shown in Table 13-2[1289–1291]. Most antihypertensive agents that can be used during pregnancy can also be used during breastfeeding. ACE

inhibitors, such as enalapril and captopril, are contraindicated during pregnancy because of their known fetotoxicity. However, these agents are minimally excreted into breast milk and are therefore considered acceptable for use during lactation.[600, 601, 1229, 1236, 1245]. Methyldopa is associated with postpartum depression and should be used with caution [1292]. Atenolol is excreted into breast milk at relatively high concentrations and is primarily eliminated via the kidneys;therefore, caution should be exercised when administering atenolol to breastfeeding mothers, particularly in cases involving newborns, preterm infants, or when the maternal dosage is high.

[1293]. Although Saireito is sometimes prescribed postpartum for its diuretic effect [1294], there is no evidence of an antihypertensive effect.

Regarding medication consultation services for use during pregnancy and breastfeeding, refer to your local “Japan Drug Information Institute in Pregnancy”.

5. Postpartum (short-term and long-term)

Preeclampsia is a systemic endothelial cell dysfunction caused by fetal-derived circulatory factors released from the placenta due to various reasons, leading to placental ischemia. [1295] Careful management is required for at least one week postpartum [1296]. BP typically decrease immediately after childbirth and then rise, reaching its peak 3–6 days postpartum in women with preeclampsia[1297–1299], and stabilizing approximately 3 weeks postpartum [1300]. HDP is a major risk factor for postpartum hypertension [1301] and is also associated with maternal mortality. In Japan, 11 of the 30 maternal deaths due to pregnancy-related hypertension in 2010–2015 occurred

Table 13-2 List of antihypertensive drugs that are considered safe for use during breastfeeding Class of drugs

M/P ratio

RID (%)

Breastfeeding

CCB

Nifedipine

Adalat

1.0

2.33.4

Possible

Amlodipine

Norvasc, Amlodin

1.4

1.724.32

Nicardipine

Perdipine

0.25

0.070.1

Diltiazem

Herbesser

1.0

0.87

Central agonist

Methyldopa

Aldomet

0.190.34

0.10.4

αβ-blocker

Labetalol

Trandate

0.82.6

0.20.6

β-blocker

Propranolol

Inderal

0.5

0.30.5

Atenolol

Tenormin

1.56.8

6.6

cautious

Vasodilator

Hydralazine

Apresoline

0.491.36

1.2

Possible

ACE inhibitor

Enalapril

Renivace

-

0.070.2

Captopril

Captopril

0.012

0.02

M/P Breast milk/plasma drug concentration, RID relative infant dose

RID indicates the proportion of the therapeutic dose of a drug that an infant would ingest through breast milk, serving as a guideline for the infant's drug exposure level. When the RID is ≤10%, breastfeeding can be considered acceptable. When the RID is ≤1%, breastfeeding is considered safe and poses no concern

(Source: Prepared based on refs. [1289–1291])

Y. Ohya

postpartum [1241] . However, there is limited evidence to establish clear management guidelines for postpartum hypertension [1302] . Breastfeeding has been reported to promote mother-infant bonding, reduce the risk of future obesity and diabetes in both mother and infant, and enhance the infant's immune defense and neurodevelopment. In cases of hypertension during breastfeeding, antihypertensive medication can generally be continued while maintaining breastfeeding. In Japan, BP reduction is recommended starting at 140/90 mmHg [1296] . If hypertension or abnormal urine test results persist for 12 weeks postpartum, consider the possibility of secondary hypertension or renal disease (e.g., nephritis), and perform appropriate differential diagnosis. Women who have had HDP have an estimated 1 in 5 risk of developing hypertension-related complications in subsequent pregnancies [601] . Women who have experienced pregnancy complications are at a higher risk of developing long-term maternal diseases, even beyond reproductive years. HDP carries a 1.8-to 6.7-fold higher risk of hypertension and 1.6-to 2.5-fold higher risk of cerebrovascular disease [1303] . Gestational diabetes has a 9.5-fold higher risk of type 2 diabetes [1304] and approximately a two-fold higher risk of cerebrovascular diseases [1305] . Preterm birth carries a 1.4-to 2.0-fold higher risk of cerebrovascular disease [1306] . Fetal growth restriction carries a 1.2-to 2.6-fold higher risk of cerebrovascular disease [1307, 1308] . All these patients should be informed about the future risk of developing these conditions and receive guidance on hypertension management, weight control, and the prevention of lifestyle-related diseases [1296] . Long-term followup is recommended [1309, 1310] . Recently, it has been reported that women with a history of preeclampsia can reduce the risk of recurrence by taking low-dose aspirin from the early stages of the subsequent pregnancy [1288] , and this advice is often communicated to women planning another pregnancy.

CQ 17 Does achieving a target BP of < 130/80 mmHg with drug treatment prevent maternal and fetal complications in non-severe hypertension in pregnancy?

►Evidence is insufficient regarding the efficacy of achieving BP levels below 130/80 mmHg through drug treatment in non-severe hypertension in pregnancy. Therefore, no recommendations are provided. 【Recommendation with held, Strength of evidence C, Consensus rate 100%】

Summary of evidence

Summary of evidence

In non-severe hypertension in pregnancy, pharmacological antihypertensive treatment significantly reduced the risk of BP worsening (progression to ≥160/110 mmHg), development of preeclampsia, and preterm birth (before 37 weeks) compared with no treatment. No significant increase in the risk of fetal growth restriction was observed with antihypertensive therapy. There was no significant interaction between antihypertensive intervention and BP worsening (progression to ≥160/110 mmHg), preeclampsia, or preterm birth (before 37 weeks) based on achieved BP levels. Among all outcomes examined, the only significant interaction by HDP subtype was observed for placental abruption.

Explanation

Explanation

Regarding BP management in HDP, a systematic review was conducted by the Japanese Society of Hypertension in 2022 to clarify target BP levels to prevent BP worsening, in non-severe hypertension [1311] . The results showed that antihypertensive treatment with BP-lowering medications for non-severe hypertension in pregnancy reduced the incidence of BP worsening, preeclampsia, severe preeclampsia, placental abruption, and preterm birth compared with placebo/no treatment, but increased the incidence of small-for-gestational-age infants. In these outcomes, achieving an SBP of < 130 mmHg reduced the risk of BP worsening by approximately two-thirds compared with achieving an SBP of ≥140 mmHg.

The guideline updated the above study and conducted a systematic review [1312] to determine that for non-severe hypertension in pregnancy, achieving a target SBP of < 130 mmHg with antihypertensive treatment is associated with improved maternal and fetal outcomes compared to achieving a SBP of ≥130mmHg. Maternal outcomes included BP worsening, eclampsia, preeclampsia, severe preeclampsia, HELLP syndrome, placental abruption, cesarean section, and adverse events. Fetal outcomes include neonatal death, stillbirth, NICU admission, low birth weight, preterm birth ( < 37 weeks, < 34 weeks) and small-for-gestational-age.

Following primary and secondary screening, a total of 40 RCTs were included. When comparing the BP-lowering treatment group (intervention group) with the placebo/no treatment group for each outcome, the intervention group showed a significant reduction in the risk of BP worsening, preeclampsia, and preterm birth before 37 weeks. The increased risk of small-for-gestational-age identified in the previous systematic review was not observed (Table CQ17 -1, 2).

For the outcomes where the risk was significantly reduced by the intervention (BP worsening, preeclampsia, and preterm birth before 37 weeks), we compared the results stratified by SBP levels achieved (≤129, 130-139, and ≥140 mmHg). Still, no significant interaction effects were observed based on BP levels (Fig. CQ17-1 ). The same

The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and. . .

References

results were observed when comparing DBP levels of < 80 mmHg and ≥80 mmHg.

In a sensitivity analysis, we stratified and analyzed the risk of each outcome (vs. placebo/no treatment) with pharmacological antihypertensive treatment according to the type of HDP; only the interaction for placental abruption was significant. Antihypertensive drug treatment significantly reduced the risk of BP worsening across all three subtypes. Additionally, in pregnancies complicated by chronic hypertension, it reduced the risk of BP worsening, as well as the risk of preeclampsia, severe preeclampsia, and placental abruption (Tables CQ17-3, 4 ).

This systematic review may have been significantly influenced by the results of large-scale clinical studies [1244] on chronic hypertension published since the previous systematic review.

Summary

Summary

HDP is a general term for a group of diseases with various pathophysiological conditions, and at present, there is insufficient evidence to establish BP criteria applicable in all cases. Therefore, for this CQ, due to limited evidence, this guideline withholds making a recommendation regarding the use of antihypertensive therapy to achieve BP below 130/80 mmHg in women with non-severe hypertension in pregnancy.

Literature search

Literature search

Three SR committee members independently searched PubMed, Ichushi-Web, and the Cochrane Library. They conducted an initial screening (title and abstract) of 1,172 records, excluded 180 duplicate studies and 930 articles based on exclusion criteria, and performed a secondary screening (full text) of 62 articles. As a result, 40 articles relevant to this CQ were selected for the metaanalysis.

Q 11 Is strict salt restriction necessary in preeclampsia?

• Strict salt restriction ( < 6 g/day) is not recommended as a non-pharmacological treatment for preeclampsia.

References

The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and. . .

References

Abstract

In CQ15 of JSH2019, an SR and meta-analysis was conducted on pregnant women with preeclampsia aged ≥18 years to examine the association between salt restriction and ① reduced maternal mortality, ② reduced proteinuria and preeclampsia, ③ reduced cesarean section rates, ④ increased incidence of hypotension, ⑤ reduced fetal and neonatal mortality, ⑥ increased preterm birth rates, and ⑦ increased low birth weight. The results showed no evidence of benefit from salt reduction for any of the outcomes, and no adverse effects were identified [284].

Abstract

In Japan, salt intake is generally higher than that in Western countries [1313], but it varies by age group. According to the National Health and Nutrition Survey published in 2019 by the Ministry of Health, Labor and Welfare, the average salt intake for adults was 9.3±3.6 g/ day, and 9.9±3.8 g/day for those aged 65 to 74 years old. In contrast, the intake is lower in those in their 20s (8.3 ± 3.3 g/day) and 30s (8.5 ± 3.3 g/day) [1314]. Additionally, the average adjusted 24 h urinary sodium excretion in Japanese pregnant women, at approximately 20 weeks of gestation, was reported to be 7.7 g/day [1315] and 8.6 g/day [1316] . In recent large-scale birth cohort studies such as the JECS and the TMM BirThree Cohort Study, salt intake was estimated based on dietary frequency surveys, yielding values of 7.2 g/day [1317] and 7.5 g/day [1249] , respectively. In both cohorts, salt intake itself was not associated with the risk of subsequent HDP.

Abstract

In general, in hypertensive patients, salt restriction reduces circulating blood volume, thereby lowering BP. However, in preeclampsia, circulating blood volume is already reduced, and further reduction through salt restriction may lead to decreased placental and renal blood flow [1318]. Chapter 14. Hypertension in Children 【POINT 14】 【Blood pressure (BP) Measurement and Evaluation】

1. BP in children should be measured using a cuff of appropriate size, with three consecutive measurements taken. The value used for evaluation should be either the average of the second and third measurements, or the third measurement alone. 2. Hypertension in children is diagnosed when BP measurements exceed reference values on three or more separate occasions. 3. Screening criteria are primarily used for diagnosing hypertension in population-based health screenings, whereas management criteria are applied in clinical practice where BP control is required. 4. The treatment goal for children and adolescents with hypertension is to achieve BP levels below the 90 th percentile of the BP distribution for healthy children. 5. For non-pharmacological therapy in children and adolescents, a low-sodium diet and regular physical activity of 30-60 min per session are recommended. 6. The first-line medications for pharmacological therapy are ACE inhibitors, ARBs, or CCBs.

1. Prevalence of hypertension

1. Prevalence of hypertension

The

2. BP measurement and reference values 1) Measurement Methods

2. BP measurement and reference values 1) Measurement Methods

BP should be measured in the right upper arm while the child is seated, using a cuff of appropriate size. Generally, 7 cm-wide cuff is recommended for ages 3-6, a 9 cm-wide cuff for ages 6-9, use, and a 12 cm-wide cuff (adult size) for ages 9 and above. However, cuff selection should be based on upper arm circumference rather than age whenever possible, ensuring that the width of the rubber bladder does not exceed 40% of the upper arm circumference and that the length encircles at least 80% of the upper arm circumference. Auscultatory BP measurement is preferred, but automated BP monitors using the oscillometric method may also be used. However, DBP tends to be lower when measured by oscillometry compared to auscultation [1327] .

When BP is measured consecutively, the values tend to decrease with each measurement [1320] . The JSH2019 recommends taking three or more consecutive measurements and using the average of two stable measurements [1319] . However, it is often difficult to determine two stable measurements in children. The ESH guidelines (ESH2016) Y. Ohya

References

recommend taking three measurements and using the average of the second and third measurements [1328] . The AAP 2017 guidelines recommend classifying BP as normal if the first measurement is below the 90th percentile for healthy children. If it is at or above the 90 th percentile, a second measurement should be taken, and the average of the first and second measurements for classification [1323] . In Japan, there are no significant differences between studies using the third measurement alone [1329] and those using the average of the second and third of three consecutive measurements [1320] . Therefore, the JSH2025 recommends three consecutive measurements and using either the average of the second and third measurements or the third measurement alone.

In population-based health screenings, BP measurement methods may be limited. In Japan, some reports have used the average of two consecutive measurements [1321] , while other have generally used a single measurement, but performed a second measurement only if the first value exceeded the reference, adopting the second value in such cases [1324] . When reporting BP, the specific measurement method used (i.e. type, number of measurements and value adopted) should be clearly stated. However, with a single measurement, it is not possible to accurately assess the distribution of BP.

2) Reference values In children, reference values are based on the 95th percentile values of BP distribution in healthy children. BP in children is strongly associated with height during periods of growth [1320] . Therefore, it is desirable to set BP reference values according to gender, age, and height percentile. AAP 2017 sets the reference values for children under 13 years of age [1323] , whilst ESH2016 sets the age cutoff at under 16 years [1328] . In Japan, although associations between BP and height have been reported in healthy children [1320] , the evidence is insufficient. Therefore, JSH2025 does not establish diagnostic criteria based on height percentile. Table 14 -1 presents the hypertension reference values by age and sex. Among healthy Japanese children, when BP is measured multiple times and evaluated according to the JSH2019 criteria, the prevalence of hypertension is approximately 0.1-5.5% [1320, 1321] . In contrast, in pediatric lifestyle disease prevention screenings conducted in various regions, hypertension is often diagnosed based on a single BP measurement, with a prevalence of approximately 3% [1322] . This threshold value has been adopted since JSH2000, and changing it could cause confusion in both medical and public health settings. Therefore, JSH2025 will continue to adopt the JSH2019 criteria. Hypertension in children will be diagnosed if BP exceeds the threshold value on three or more separate occasions [1330] .

3. Etiology and pathophysiology

3. Etiology and pathophysiology

The etiology of pediatric hypertension varies by age. In children aged 6 years or older, essential hypertension is predominant, whereas in children under 6 years of age, particularly those under 3 years, the likehood of secondary hypertension increases, with renal hypertension due to renal parenchymal disorders accounting for 60 80% of cases [1331, 1332] . Causes of renal parenchymal disorders include acute and chronic glomerulonephritis, as well as chronic kidney disease (CKD) resulting from congenital anomalies of the kidney and urinary tract (CAKUT) [1333] .

1) Lifestyle-related diseases (obesity) Obesity is the most important risk factor for childhood essential hypertension, and the prevalence of hypertension increases with the degree of obesity [1320, [1334] [1335] [1336] . The association between BP elevation and weight has been recognized since early childhood. A retrospective study of 18,618 children aged 2 -19 years found that BP increased with increasing BMI in all age groups, including those aged 2-5 year [1337] .

2) Excessive salt intake Excessive salt intake is also a significant factor in pediatric hypertension. A meta-analysis of children with unexplained BP elevation found that for every 1 g increase in daily sodium (Na) intake, SBP increased by 6.3 mmHg and DBP by 3.5 mmHg [1338] .

3) Low birth weight Abnormal birth history, including preterm birth and low birth weight, is a risk factor for hypertension and CVD in adulthood [1339, 1340] . In a prospective cohort study in Japan, low birth weight was associated with the prevalence of hypertension, diabetes, and CVD in adulthood [1341] . Additionally, a higher BMI in adulthood is associated with a higher prevalence of hypertension [1342] . Proposed mechanisms include long-term effects on BP regulation due to reduced sodium excretion capacity associated with decreased renal nephron number, activation of the RAS, and epigenetic changes such as DNA methylation caused by fetal stress [1343] .

Elementary school

Elementary school

First to third graders ≥130 ≥80

Fourth to sixth graders

≥135 ≥80

≥135 ≥80

Junior highschool Boys ≥140 ≥85

Girls

Girls

≥135 ≥80

≥135 ≥80

High-school ≥140 ≥85

The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and. . .

References

4. Clinical implementation of treatment 1) Evidence for intervention

4. Clinical implementation of treatment 1) Evidence for intervention

Several large-scale longitudinal cohort studies have clearly demonstrated that hypertension in children is highly likely to persist into adulthood [1344] [1345] [1346] . Furthermore, the presence of hypertension-related target organ damage, such as left ventricular hypertrophy, during childhood [1347] has been shown to increase the risk of adult-onset hypertension and cerebrovascular disease [1348] [1349] [1350] . Conversely, appropriate management of hypertension in children has been shown to improve existing target organ damage and reduce the risk of cerebrovascular disease [1351] [1352] [1353] . Thus, early diagnosis and intervention for pediatric hypertension are crucial for reducing long-term health risks and preventing complications, and are therefore recommended.

2) Treatment and management procedures The management procedures for pediatric hypertension are illustrated in Fig. 14-1 . In Japan, two sets of hypertension criteria have been established: screening criteria (Table 14 -1) and management criteria (Table 14-2) [1320] . After screening, using the screening criteria, multiple BP measurements based on the management criteria are performed to confirm the diagnosis, assess severity, and set management goals. ABPM or home BP measurements are useful for distinguishing between white coat hypertension and masked hypertension [1354] .

In recent years, BP values exceeding the 90th percentile, which are considered normal according to the AAP 2017 criteria [1323] , has been reported to be associated with target organ damage such as left ventricular hypertrophy [1345, 1355, 1356] , progression to adult hypertension, and CVD risk factors [1345, 1357] . Therefore, the treatment goal for pediatric hypertension should be to achieve BP below the 90th percentile to help prevent future CVDs. In cases where target organ damage is already present or in secondary hypertension, lower BP targets are recommended [1358] .

Accordingly, the JSH2025 guidelines have added the 90th percentile derived from measurements in the same population to the table of hypertension management criteria (Table 14-2) [1320] . The SBP 90th percentile and 95th percentile in these management criteria are nearly identical to the SBP 90 th percentile and 95th percentile at the 25th percentile height according to the AAP 2017 criteria, which corresponds to the average height of Japanese children (Table 14 -3). DBP is approximately 10 mmHg lower than the AAP 2017 reference values, which is attributed to differences in measurement methods (auscultatory method [AAP] vs. oscillometric automatic BP monitor [JSH] ). Since the JSH BP management criteria do not include standards for infants under 5 years of age, the AAP criteria (Table 14 -3), which include standards for children aged 1 year and older, are considered applicable.

3) Non-pharmacological therapy

References

(1) Dietary therapy Excessive sodium intake is associated with increased BP in children [1338] , and many studies have demonstrated the effectiveness of sodium restriction in managing pediatric hypertension [76, 1359] . A diet limits salt and fat intake while increasing consumption of potassium-rich fruits and vegetables and, dietary fiber is effective in managing both obesity and hypertension in children [76, 1359] .

Additionally, reducing sodium intake from infancy has been shown to suppress BP elevation during childhood [1360] , and the quality of diet at ages 56 years has been linked to BP status six years later [1361] , suggesting that early initiation of dietary therapy, including sodium reduction, is desirable.

(2) Exercise therapy Exercise therapy is essential for the prevention and management of obesity. For hypertension, aerobic exercises such as swimming, jogging, cycling, and dancing are recommended. Flexibility exercises, including yoga and stretching, are also beneficial. Regular physical activity for 30-60 min, three times per week (totaling 150 min or more weekly) is recommended [1356] .

(3) Sleep An SR examining the relationship between sleep duration in childhood and adolescence and CVD risk factors, found that short sleep duration in children is associated with increased BP, obesity markers, and insulin resistance [1362] . Regardless of gender, age, or obesity status, shorter sleep duration and later bedtimes have been reported to be associated with higher BP [1363] , highlighting the importance of ensuring adequate sleep quality and promoting stress reduction in the management of pediatric hypertension.

4) Pharmacological therapy Pharmacological therapy should be initiated when lifestyle modifications alone are insufficient or when hypertension-related organ damage is already present, or in cases of symptomatic hypertension or secondary hypertension (Fig. 14-1 ).

For antihypertensive medications, CCBs, ACE inhibitors, and ARBs, which have established efficacy and safety in children, are first-line drugs [1364] . In particular, ARBs have been shown to reduce the risk of CVD in children with The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and. . .

References

coexisting left ventricular dysfunction or CKD [1365, 1366] , as well as in children with CKD [1367, 1368] . However, RAS inhibitors have teratogenic potential, thus caution is warranted when prescribing them to postpubertal females.

Whenever feasible, antihypertensive medications covered by Japan's national health insurance should be selected (Table 14-4 ). All medications should be started at low doses followed by gradual titration and close monitoring for adverse events such as excessive BP reduction, headache, or hyperkalemia. If adverse effects occur or target BP is not achieved, treatment plans should be reassessed and adjusted accordingly. Additionally, combining pharmacological therapy with non-pharmacological interventions is generally more effective than either approach alone. Once BP is controlled, medications should be gradually reduced or discontinued, and non-pharmacological therapy should be resumed to monitor long-term progress.

In cases of secondary hypertension, treatment for the underlying condition should be provided concurrently. For curable conditions such as renovascular hypertension, definitive treatment should be prioritized whenever possible, even in pediatric patients [1369] .

Chapter 15. Secondary hypertension

Chapter 15. Secondary hypertension

Secondary hypertension is caused by a specific underlying etiology, which often differs significantly from essential hypertension in both pathophysiology and treatment approach. It is frequently treatment-resistant, making it difficult to achieve target BP with conventional treatment. Identification and treatment of the underlying cause can effectively lower BP and prevent or mitigate organ damage. Therefore, it is important to suspect secondary hypertension and establish an appropriate diagnosis [1370] . The prevalence of secondary hypertension is higher than previously thought, accounting for at least 10% of all hypertensive individuals. In particular, secondary hypertension due to primary aldosteronism is reported to account for 5-10% of hypertension cases [273] . Sleep apnea syndrome also represents a significant cause of secondary hypertension, and its prevalence is expected to increase with improvements in diagnosis.

Hypertension caused by renal parenchymal diseases is referred to as renal parenchymal hypertension, and its etiology involves factors such as increased fluid volume and activation of the RAS. This subtype accounts for a significant proportion of secondary hypertension, representing 25% of all hypertensive individuals [810, 811, 1371] . However, hypertension associated with chronic kidney disease (CKD) does not necessarily indicate renal parenchymal hypertension. It is important to distinguish it from the coexistence of CKD with essential hypertension or cases in which hypertension itself has caused renal damage (nephrosclerosis). For diagnosis, the presence of renal damage preceding hypertension is the key determinant (see "Chapter 9, 3. Kidney diseases").

Table 15 -1 lists the underlying diseases causing secondary hypertension, the findings suggestive of these diseases, and the tests necessary for differential diagnosis. The details of these underlying diseases causing secondary hypertension are discussed later, but several points should be noted here. In primary aldosteronism, hypokalemia and nocturia are characteristic findings, but are present in less than 50% of patients. Attention should be paid to medications for other diseases, as glycyrrhizin (licorice) and

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NSAIDs are well known to have pressor effects. Antidepressants and medications for Parkinson's disease not only raise BP but may also cause orthostatic hypotension and significantly increase BP variability. Recently, cases of drug-induced hypertension caused by cancer therapies have been increasing. Health supplements also warrant caution. Since patients rarely report their use voluntarily, physicians must actively inquire about supplement use during the medical history interview.

The possibility of secondary hypertension should always be considered in the management of all patients with hypertension, and it is important not to overlook suggestive findings and to perform appropriate tests. If secondary hypertension is suspected, the patient should be referred to a specialist.

【POINT 15a】

【POINT 15a】

【Primary aldosteronism】 1. In patients with hypertension, primary aldosteronism (PA) has a high prevalence and is associated with organ damage, making early diagnosis and treatment important. 2. In hypertensive patients, especially those with a high prevalence of PA (Table 15 -2), active screening should be performed, followed by functional confirmatory tests and if positive, diagnosis of the subtype and localization. 3. In unilateral PA, adrenalectomy is recommended as it may lead to resolution of the condition, normalization of BP, improvement of organ dysfunction, and the The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and. . .

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inhibition of progression. In bilateral PA or in cases where surgery is not indicated or desired, medical therapy centered on MR antagonists should be used

inhibition of progression. In bilateral PA or in cases where surgery is not indicated or desired, medical therapy centered on MR antagonists should be used

1. Primary aldosteronism (PA)

1. Primary aldosteronism (PA)

1) Diagnosis

1) Diagnosis

The prevalence of primary aldosteronism (PA) in hypertension is reported to be 5-10%, making it the most common type of secondary hypertension [273] . It is characterized by autonomous aldosterone secretion and low PRA; hypokalemia, being considered a hallmark sign traditionally, is present only in typical cases. The incidence of cerebrovascular disease, coronary artery disease, atrial fibrillation, heart failure, and peripheral artery disease, and other CVD is 2-5 times higher in patients with primary aldosteronism than in those with essential hypertension [273, [1372] [1373] [1374] [1375] . Additionally, PAC is closely associated with renal impairment in PA patients [1376] . PA presents with salt-sensitive hypertension, where PAC does not appropriately decrease even with excessive salt intake, and many cases exhibit treatment-resistant hypertension. The disease is broadly classified into two subtypes: unilateral lesions (typically aldosterone-producing adenoma [APA]) where adrenalectomy is feasible, and bilateral adrenal hyperplasia (idiopathic hyperaldosteronism [IHA] ) where pharmacological therapy is indicated. In unilateral lesions, many cases achieve biochemical cure with adrenalectomy, emphasizing the importance of early detection and appropriate treatment. Clinical guidelines have been published in Japan, the United States, and Europe [276, [1377] [1378] [1379] .

Among hypertensive patients, screening is recommended in groups with a high prevalence of PA (Table 15 -2) [276, 1377, 1378] . For PA screening, PAC (CLEIA method) and PRA or plasma ARC are measured simultaneously (take blood in the morning, draw at rest, while seated). In this screening PAC (pg/mL)/PRA (ng/mL/h) ratio (ARR) ≥200 or PAC (pg/mL)/ARC (pg/mL) ≥40, and PAC ≥60 pg/mL are considered positive [276, 1377] . However, until optimal cutoff values are established using the CLEIA method, an ARR of 100-200 (PAC/ARC: 20-40) is considered the "ARR borderline range," and if PAC is ≥60 pg/mL, it is provisionally considered positive, with treatment decisions made considering patient needs and clinical findings [276] .

Many antihypertensive drugs affect the renin activity and aldosterone levels (Table 15 -3), thus screening tests should preferably be performed before initiating oral therapy or after discontinuing the drug. MR antagonists increase both PRA and PAC, with the former having a greater impact, leading to a decrease in ARR. Therefore, a 4-week or longer drug holiday is recommended. For β-blockers, diuretics, ARBs, or ACE inhibitors, blood tests should be performed after discontinuing the medication for 2 weeks. However, if renin activity is suppressed (PRA ≦1 ng/mL/h) while taking antihypertensive medications other than β-blockers, screening may be possible. In contrast, when PRA is not suppressed (PRA > 1 ng/mL/h) and ARR is at the cutoff value threshold, it is recommended to replace the antihypertensive drug with a CCB or α-blocker and repeat the test after 2 weeks. In practice, screening tests are often possible without discontinuing or changing antihypertensive drugs, and it is most important to first confirm the current antihypertensive drugs before performing the screening test. In principle, a single measurement is used for diagnosis, but if the result is negative, retesting should be considered as appropriate, taking into account the antihypertensive medication and blood sampling conditions (early morning, fasting, after bed rest). PAC units differ depending on the assay kit, with both pg/mL and ng/dL being used, and the former value is 10 times that of the latter.

If the screening test is positive, at least one confirmatory test should be performed to demonstrate autonomous aldosterone secretion (Table 15 -4). The sensitivity and specificity of each test vary depending on the report; however, SRs and meta-analyses of the accuracy between tests have reported no significant differences in sensitivity or specificity between the captopril test and the saline infusion test [1380] . Note that in screening-positive cases meeting all of the criteria (hypokalemia ( < 3.5 mEq/L), elevated baseline PAC ( > 100 pg/mL), and renin below the detection The influence is less marked than that of ACE inhibitors and ARBs c Possibility of false positive results

Table 15 -2 Groups with a high prevalence of PA in hypertensive patients [276, 1377, 1378] • Hypertension with hypokalemia (including diuretic-induced)

• Hypertension in young adults ( < 40 years)

• Resistant hypertension

• Resistant hypertension

• Sustained BP of 150/100 mmHg or higher

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limit), then confirmatory tests may be omitted, and PA may be diagnosed definitively [276] . In the Japanese multicenter collaborative study JPAS/JRAS, the confirmatory tests may be omitted if PAC (CLEIA method) > 171 pg/mL and PRA ≤0.6 ng/mL/h [1381] . Captopril tests and oral salt loading tests can be performed as outpatient procedures. The furosemide upright test is physically demanding. The saline infusion test is performed in the supine position, takes a long time, and is not suitable for cases with impaired cardiac or renal function; however, there are reports that performing it in the seated position reduces false negatives [1382] . Of note, subclinical Cushing's syndrome is reported to coexist in over 20% of PA cases with adrenal tumors [1383] , and, if suspected, the dexamethasone suppression test is recommended.

For the diagnosis of PA subtypes and localization, there is no significant difference in sensitivity and specificity between CT and MRI in detecting adrenal adenomas. Therefore, CT examination (thin slice), which is easy to perform and cost-effective, should be performed first to evaluate adrenal lesions and to rule out malignant tumors [276] . In cases where adrenal venous sampling (AVS) is anticipated, contrast-enhanced dynamic CT (MDCT) is recommended to ensure accurate visualization of the adrenal veins for reliable AVS. Tumors of the adrenal gland in PA are often small (5 mm or less) and CT-negative. Additionally, even when a tumor is present in one adrenal gland, the likelihood of a non-functional tumor increases with age, thus caution is necessary. Therefore, AVS is essential when considering adrenalectomy. Adrenal scintigraphy has a high rate of false positives and false negatives and is not suitable for localization diagnosis.

During AVS, the use of ACTH stimulation is useful for determining the success of catheterization and the localization of lesions. AVS is an invasive procedure with technical challenges, such as a low success rate in the right adrenal vein, thus the decision to perform AVS should be made after thoroughly considering the suitability of surgery, the patient's preferences, and other factors, and it is recommended to perform the procedure at a specialized facility with experienced personnel. Additionally, as an indicator for localization determination using AVS, the lateralized ratio (LR: [aldosterone (A)/cortisol (C)] high side/[A/C] low side) > 4, and the contralateral ratio (CR: [A/C] low side/[A/C] inferior vena cava distal side) < 1 have been reported to be useful cutoff values. However, comprehensive judgment is necessary in borderline or discordant cases [276] . In contrast, reports have also described disease patterns where AVS can be omitted based on the analyses of multiple cases. The guidelines of the American and Japanese Endocrine Societies state that AVS can be omitted and localization diagnosis is possible in cases where the patient is under 35 years of age, has hypokalemia (serum potassium < 3.5 mEq/ L), elevated PAC, and a typical unilateral tumor (1 cm or larger) on CT [276, 1377 CT [276, , 1378 CT [276, , 1384]] .

2

) Treatment

) Treatment

The PA management protocol in routine clinical practice is shown in Fig. 15-1 . PA treatment varies depending on the type of lesion (unilateral or bilateral), and the prognosis should be evaluated based on improvement or resolution of hyperaldosteronism and hypokalemia (biochemical cure) and improvement or resolution of hypertension (clinical cure). In unilateral lesions, laparoscopic adrenalectomy is the first-line treatment, with biochemical cure expected in over 90% of cases postoperatively [1385] . However, the rate of BP normalization postoperatively ranges from 30% to 52%, depending on factors such as the duration and severity of hypertension, and the presence of essential hypertension [1378, 1386] ; this is particularly true in older adults, as a domestic multicenter study reported a rate of 18% [1387] . In cases where surgery is not indicated or desired, or in bilateral lesions, MR antagonists are used to ARR is calculated with PAC (CLEIA method) in the unit of pg/mL, but ARR 100200 is provisionally considered positive as a borderline range c However, PAC (CLEIA method) 12-60 pg/mL is considered the cutoff range and is provisionally positive d For inpatients, salt intake should be maintained at 10-12 g/day for 3 consecutive days e It should be confirmed that salt loading is sufficient

The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and. . .

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treat hypertension and hypokalemia. When BP control is difficult with an MR antagonist alone, CCBs, diuretics, or ACE inhibitors/ARBs are used in combination while monitoring serum potassium levels.

The differences in long-term prognosis between adrenalectomy and medical therapy are not necessarily clear, but adrenalectomy has been reported to be superior in preventing CVD mortality and new-onset atrial fibrillation [1388, 1389] . Two recent meta-analyses reported that adrenalectomy had a better prognosis than pharmacological therapy in terms of all-cause mortality and major cardiovascular events [1390, 1391] . Furthermore, in the metaanalysis conducted in the current study, adrenalectomy was found to be superior to pharmacological therapy in terms of preventing CVD events in patients with unilateral PA (CQ18). Of note, a retrospective cohort study has shown that if pharmacological therapy is used to adequately control BP and serum potassium levels, and the dose of MR antagonists is adjusted based on PRA non-suppression (≥1 ng/mL/h), the risk of CVD in patients with PA is equivalent to that of patients with essential hypertension [1392] .

Spironolactone has a high affinity for MR and exhibits strong MR antagonistic effects; however, due to its androgen receptor antagonistic effects and progesterone receptor stimulatory effects, it is associated with a high incidence of sex hormone-related side effects such as gynecomastia and menstrual irregularities. In contrast, eplerenone has a low affinity for MR and weak MR antagonist activity, but it has high MR selectivity and extremely few sex hormone-related side effects. However, it is contraindicated in patients with concomitant potassium-containing medications, microalbuminuria or proteinuria in diabetes, or moderate or severe renal impairment. Additionally, a new non-steroidal MR antagonist, esaxerenone, has been added, and its efficacy is anticipated. Esaxerenone has high MR selectivity but it is contraindicated in patients with severe renal impairment or in those receiving potassium supplements. In patients with moderate renal impairment or diabetes with albuminuria/ proteinuria, caution is advised when initiating treatment, starting with a low dose and monitoring for hyperkalemia.

【POINT 15b】 【Other major endocrine-related hypertension】 1. Cushing's syndrome is diagnosed by focusing on characteristic physical findings, measuring serum cortisol and ACTH levels, and performing a dexamethasone suppression test. Subclinical Cushing's syndrome should be distinguished from adrenal incidental tumors. 2. Pheochromocytoma and paraganglioma are suspected based on symptoms such as tachycardia and headache, episodic hypertension, or incidental adrenal tumors. Diagnosis is confirmed by measuring urinary catecholamines and their metabolites (metanephrine) and imaging studies. These conditions are potentially malignant and are definitively diagnosed as malignant when they exhibit metastasis to non-chromaffin tissue or local invasion. 3. Acromegaly, hyperthyroidism, and hypothyroidism present with characteristic physical findings, while primary hyperparathyroidism is often diagnosed due to hypercalcemia.

2. Other major endocrine causes of hypertension

2. Other major endocrine causes of hypertension

1) Cushing's syndrome Cushing's syndrome is broadly classified into ACTHindependent and ACTH-dependent types. The former

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includes narrowly defined Cushing's syndrome caused by adrenal adenomas or bilateral adrenal hyperplasia, while the latter includes Cushing's disease caused by pituitary ACTHproducing tumors (adenomas) and ectopic ACTHproducing tumors. Cushing's syndrome is characterized by autonomic and excessive secretion of cortisol, leading to hypertension and diabetes, and complications such as myocardial infarction, stroke, and venous thromboembolism contribute to the increased mortality rate of this condition [1393] [1394] [1395] [1396] . Hypertension is also strongly influenced by the mineralocorticoid effects of cortisol in addition to its glucocorticoid effects [1397, 1398] , and may lead to resistant hypertension with hypokalemia. Mineralocorticoid receptor antagonists are considered appropriate for hypertension associated with Cushing's syndrome, but comparisons with other antihypertensive agents are insufficient [1399] .

In diagnosis, attention is given to Cushing's signs, such as central obesity, moon face, buffalo hump, red skin stripes, thinning skin, hirsutism, and acne. Nonspecific findings include hypertension, diabetes, dyslipidemia, osteoporosis, urinary tract stones, and nail fungus. In routine blood tests, pay attention to eosinophilia, lymphocytopenia, and neutrophilia. Diagnosis is confirmed by elevated free cortisol levels in 24-h urine, absence of diurnal rhythm in serum cortisol levels, and failure of cortisol suppression on the dexamethasone suppression test (serum cortisol > 5 μg/dL on the morning after 1 mg oral administration) [1393] [1394] [1395] [1396] . Also distinguish between ACTHdependent and ACTH-independent forms based on the presence or absence of plasma ACTH suppression, with definitive diagnosis confirmed by imaging findings. Subclinical adrenal Cushing's syndrome, which involves autonomous cortisol secretion but lacks characteristic Cushing's signs, requires differential diagnosis when incidental adrenal tumors are present [1400] .

Treatment involves laparoscopic adrenalectomy for adrenal adenomas, transsphenoidal pituitary resection for Cushing's disease, and surgical resection of the primary lesion for ectopic ACTH-producing tumors. With adrenal subclinical Cushing's syndrome, if the tumor diameter is 4 cm or larger, and demonstrates a tendency for enlargement, surgery should be considered, or if obesity, hypertension or impaired glucose tolerance are present [1393, 1396] . In cases where surgery is difficult or insufficient improvement is achieved postoperatively, medical therapy with adrenal corticosteroid synthesis inhibitors (such as metyrapone) or sustained-release somatostatin analogues (such as pasireotide) that suppress ACTH production may be considered. Recently, oscilodrostat, an inhibitor of 11β-hydroxylase, which catalyzes the final step of cortisol biosynthesis, has been marketed and is expected to be a beneficial oral medication with fewer side effects. Although oscilodrostat is effective for controlling hypercortisolism, there is a risk of adrenal insufficiency during and after treatment, thus glucocorticoid replacement therapy should also be considered [1401] .

In patients with hypertension, if Cushing's signs, treatment-resistant hypertension, or concomitant diabetes and obesity are present, or if adrenal incidental tumors are detected, Cushing's syndrome should be suspected, and the patient should be referred to a specialist. In particular, it has been reported that undiagnosed subclinical Cushing's syndrome may be present in a significant number of cases of treatment-resistant hypertension [1402] , thus careful attention is required to avoid overlooking diagnoses.

2) Pheochromocytoma, paraganglioma Pheochromocytoma is a tumor originating from the adrenal medulla, while paraganglioma is a tumor originating from the paraganglion. Both are associated with hypertension and impaired glucose tolerance due to catecholamine excess. Approximately 10% of cases are extraadrenal, bilateral, multiple, or malignant, and it has been clarified that approximately 40% of cases exhibit genetic abnormalities, which were previously estimated to account for about 10%. Diagnosis and treatment should be based on the diagnostic criteria of the Japanese Society of Endocrinology [1403] and the American Association of Clinical Endocrinologists [1404] . When the tumor is metastatic, it is diagnosed as malignant pheochromocytoma; however, in recent years, this tumor itself has been reclassified from a benign entity to one with the potential for malignancy.

Symptoms such as headaches, palpitations, excessive sweating, pallor of the face and extremities, and episodic hypertension caused by catecholamine excess may suggest this tumor. Hypertensive crises may be triggered by exercise, stress, or defecation, and caution is required for hypertensive crises induced by metoclopramide or glucagon injection. Recently, there has been an increase in cases of adrenal incidental tumors discovered asymptomatically [1405] . Hypertension occurs due to catecholamine excess, often accompanied by tachycardia, and increased vascular tone leads to accelerated blood flow. As a screening test, measurement of serum catecholamine fractions (adrenaline, noradrenaline) and urine metanephrine fractions (metanephrine, normetanephrine) in an outpatient setting is usuful as a screening test. In patients with blood levels of adrenaline and noradrenaline exceeding three times the upper normal limit or a combined total of 2000 pg/mL or higher, or in patients with elevated levels of metanephrine and normetanephrine in urine at any time (more than three times the upper normal limit or 0.5 mg/gCr or higher), confirm an increase in catecholamine fractions in a 24-h urine collection (more than twice the upper normal limit) and an increase in metanephrine fractions (more than three times the upper normal limit) [1404] . Note that only one of the The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and. . .

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urine metanephrine and blood metanephrine fractions is covered by insurance, and simultaneous testing is not possible. Imaging studies show low signal intensity on T1weighted MRI and high signal intensity on T2-weighted MRI. For cases with unclear localization, multiple lesions, or to search for metastatic lesions, 123I-MIBG scintigraphy or 18F-FDG PET may be used.

As for pharmacological therapy, adrenergic receptor blockers that inhibit the action of catecholamines are wellsuited for this indication. β-blockers are used in combination for the treatment of tachycardia and arrhythmias, but their use alone is contraindicated because it enhances αadrenergic effects. α-blockers such as doxazosin should be administered prior to β-blockers. If BP remains uncontrolled with α-blockers alone, combination therapy with dihydropyridine CCBs or catecholamine synthesis inhibitors (methyldopa) may be effective (methyldopa is expensive and should be reserved for refractory cases). Surgical resection of the tumor is the primary treatment. Prior to surgery, administer α-blockers to manage BP, correct circulating plasma volume, and prevent crisis during surgery. To prepare for sudden increases in BP during surgery, intravenous fentanyl, an α-blocker, should be prepared. In cases of pheochromocytoma crisis, intravenous fentanyl is administered, and oral α-blockers are initiated once BP and pulse rate have stabilized. The greatest challenge is in malignant cases, where pathological differentiation is difficult, necessitating lifelong follow-up for recurrence and metastasis.

If typical symptoms such as paroxysmal hypertension or pallor of the face are present, or if an adrenal incidental tumor is detected, suspect pheochromocytoma and refer the patient to a specialist.

3) Others (1) Acromegaly Suspect acromegaly based on characteristic physical findings, such as enlargement of the extremities and protrusion of the forehead, with approximately 40% presenting hypertension. Diagnosis is confirmed by elevated blood levels of growth hormone (GH), insulin-like growth factor-1 (IGF-1), and impaired GH suppression ( > 0.4 ng/mL) during a 75-g OGTT, along with the presence of a pituitary tumor. Increased circulating blood volume and peripheral vascular resistance, enhanced renal epithelial sodium channel activity, increased sympathetic nervous system activity, and the presence of sleep apnea syndrome are the main pathophysiological mechanisms underlying hypertension in patients with this condition. The principle of treatment is transsphenoidal pituitary gland resection, combined with pharmacological therapy using somatostatin analogs, GH receptor antagonists, and dopamine agonists.

(2) Hyperthyroidism Elevated serum T3 levels lead to increased sympathetic β-receptor activity, resulting in increased heart rate and cardiac contractility, and presenting with systolic hypertension and increased pulse pressure. Hyperthyroidism can be suspected based on symptoms, such as palpitations, tremors, increased appetite, weight loss, goiter, and protruding eyeballs. Diagnosis is confirmed by measuring free T3, free T4, TSH, and TSH receptor antibodies (TRAb). Treatment includes administration of antithyroid drugs and β-blockers. Differential diagnosis from thyroid toxicity, such as painless thyroiditis is necessary, and referral to a specialist is recommended.

(3) Hypothyroidism Chronic thyroiditis (Hashimoto's disease) is the primary cause of hypothyroidism. Due to a decrease in thyroid hormone levels, there may be a reduction in cardiac output, cardiac contractility, and bradycardia, along with increased peripheral resistance and a decrease in endothelium-derived relaxing factor (EDRF), which can lead to hypertension. Non-specific symptoms such as fatigue, intolerance to cold, and hair loss, non-pitting edema, goiter, and dyslipidemia are the basis for diagnosis. Treatment involves replacement therapy with thyroid hormone T4 (levothyroxine) preparations.

(4) Primary hyperparathyroidism Approximately 40-65% of primary hyperparathyroidism cases present with hypertension, and involvement of the RAA system, impaired vasodilatory capacity of resistant vessels, and enhanced responsiveness to pressor hormones has been demonstrated. BP changes after parathyroid adenoma resection are reported to be inconsistent. Hypercalcemia, elevated intact PTH levels, hypercalciuria, and urinary tract stones may serve as diagnostic clues. Treatment involves the removal of the diseased parathyroid gland.

(5) Mineralocorticoid excess disorders other than PA This includes hypertension associated with genetic mutations, such as Liddle syndrome (refer to "Section 5. Hereditary hypertension" in this chapter), where plasma renin activity and aldosterone levels are normal to low, but hypertension develops due to excessive activation of the MR. Congenital adrenal hyperplasia (17α-hydroxylase deficiency, 11β-hydroxylase deficiency) and tumors producing deoxycorticosterone (DOC) cause hypertension and hypokalemia due to MR activation by DOC. Pseudoaldosteronism induced by traditional Chinese medicine occurs due to inhibition of 11β-hydroxysteroid dehydrogenase type 2 by licorice (glycyrrhizin), leading to MR activation by cortisol accumulated in the kidneys, resulting in hypertension and hypokalemia (refer to "Section 4. Drug-induced hypertension" in this chapter).

【POINT 15c】 【Renovascular hypertension (RVHT)】

Y. Ohya

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Abstract

1. RVHT is caused by the narrowing or obstruction of the renal arteries, accounting for approximately 1% of all hypertension cases. In middle-aged and older adults, atherosclerosis is the primary cause, while in younger individuals, fibromuscular dysplasia is the main cause. In cases of atherosclerosis, it often coexists with other vascular lesions such as coronary artery disease or atherosclerotic peripheral arterial occlusive disease. 2. Patients suspected of having RVHT include those with early-onset hypertension, severe hypertension, treatment-resistant hypertension, worsening hypertension, abdominal vascular bruit, bilateral renal size differences, and worsening renal function with RAS inhibitor therapy. 3. The diagnosis of RVHT is based on morphological diagnosis centered on imaging studies, with functional diagnosis used as an adjunct. Renal Doppler Ultrasound is useful as a screening tool for morphological diagnosis, and if this test is not feasible, MRA or CT angiography (CTA) should be considered depending on renal function. 4. In RVHT, combination therapy with RAS inhibitors,

Abstract

CCBs, and β-blockers is used to achieve target BP. However, the use of RAS inhibitors requires the following considerations:

Abstract

•

In unilateral cases, RAS inhibitors may be considered as they are beneficial for BP reduction, renal function preservation, and improved prognosis.

•

•

In bilateral cases, RAS inhibitors may cause rapid renal dysfunction and are generally contraindicated. 5. In fibromuscular dysplasia-related RVHT, the combination of percutaneous transluminal renal angioplasty (PTRA) and antihypertensive therapy yields high BPlowering effects and relatively good long-term outcomes, thus it should be actively considered. In atherosclerotic RVHT, the combination of PTRA and antihypertensive therapy has not been proven to provide superior treatment effects compared to antihypertensive therapy alone, thus its application is limited.

3. RVHT

3. RVHT

RVHT is caused by decreased arterial inflow to the kidney and is an important underlying In patients with hypertension, the prevalence of renovascular hypertension is estimated to be approximately 1%. The prevalence of renal artery stenosis varies depending on the cause and comorbid conditions. In an SR, the prevalence of atherosclerotic renal artery stenosis (stenosis rate of 50% or more) was 10%, 25%, and 33% in patients with hypertension complicated by coronary artery disease, atherosclerotic peripheral arterial occlusive disease, and abdominal aortic aneurysm, respectively [1407] . This increases with age and the presence of CVD [626, 1408] . Fibromuscular dysplasia is estimated to affect 0.4% of the general population and is more common in women [1409] .

Unilateral renal artery stenosis is common, but bilateral cases are also not uncommon. The preferred sites vary depending on the underlying disease, with atherosclerosis affecting the origin of the renal artery and fibromuscular dysplasia affecting the middle to distal segments [1410] . Fibromuscular dysplasia has subtypes such as intimal hypertrophy and medial hypertrophy, and may be associated with stenosis in coronary arteries, carotid arteries, and intracranial vessels [1411, 1412] .

1) Diagnosis

1) Diagnosis

The history and clinical signs suggestive of renovascular hypertension or ischemic nephropathy are shown in Table 15 -5. The diagnosis of renovascular hypertension is inferred based on the medical history and clinical signs, supported by morphological evaluation, and confirmed by treatment response. Therefore, diagnosis should be made considering the individual patient's background, the accuracy of the facility's tests, and the advantages and disadvantages of each diagnostic method. Diagnostic tests include morphological diagnostic methods, such as Renal Doppler Ultrasound, CTA, and MRA (Fig. 15 -2), and functional diagnostic methods, such as PRA, renal scintigraphy (renogram), and captopril-loaded PRA.

Renal Doppler Ultrasound has a high diagnostic accuracy (sensitivity 91-100%, specificity 82-91%) [1413, 1414] , is inexpensive, and allows for non-invasive evaluation, making it the first test to consider. It measures parameters such as peak systolic velocity (PSV) in the renal artery and the renal/aortic ratio (RAR = PSV at the origin of the renal artery/PSV in the abdominal aorta), and detects renal artery stenosis with a stenosis rate of 60% or higher, based on

The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and. . .

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criteria such as PSV > 200 cm/s, RAR > 3.5, and characteristic waveforms of arterial blood flow within the kidney. [1415, 1416] . However, this examination requires skill, and its accuracy depends on the operator's technical proficiency. The examination time is longer than that of other ultrasound examinations. Additionally, visualization of the renal artery may be difficult in cases of obesity or intestinal gas [1417] .

If Renal Doppler Ultrasound cannot be performed or if stenosis cannot be confirmed, consider evaluation using MRA or CTA. Contrast-enhanced MRA has a high accuracy (sensitivity 94-97%, specificity 85-93%) [1414] , but in cases of renal dysfunction (eGFR < 30 mL/min/1.73 m 2 ), it is generally not performed due to an increased risk of nephrogenic systemic fibrosis (NSF) [1418, 1419] . Noncontrast MRA, which does not use contrast agents, has been reported to have accuracy comparable to contrast-enhanced MRA [1420], but it requires more time and depends on the equipment used and the skill of the operator. Additionally, it cannot be performed on patients with metallic implants, and evaluation of renal arteries after stent placement is not possible. CTA has superior spatial and temporal resolution compared to MRA and angiography (sensitivity 64-96%, specificity 90-92%) [1414] , providing clear, high-quality images; however, it may overestimate stenosis in calcified lesions. Additionally, the use of iodine contrast agents and ionizing radiation poses risks of renal impairment and radiation exposure, thus the dosage of contrast agents should be determined considering renal function. [1421] . If stenosis is not clearly identified using Renal Doppler Ultrasound, MRA, or CTA, or if PTRA is considered, catheter-based aortic angiography or selective renal artery angiography of both sides may be considered.

PRA is a simple test, but it may not always be elevated in cases of bilateral renal artery stenosis. Additionally, approximately 20% of patients with renovascular hypertension have normal PRA levels, and elevations may be observed in some patients with essential hypertension [1422] . Compared to MRA or CTA, the diagnostic accuracy of captopril-loaded PRA and captopril-loaded renogram is somewhat inferior. However, a captopril-loaded renogram has the advantage of evaluating renal function and bilateral differences in renal blood flow. These functional diagnostic methods, which have been traditionally performed, are not suitable for screening based on comparisons with imagebased morphological diagnoses [626] and are recommended for use as adjunctive tests.

2) Treatment Treatment for renovascular hypertension includes drug therapy centered on antihypertensive agents, revascularization procedures such as PTRA or surgical bypass surgery, and nephrectomy. The treatment method is selected based on the patient's condition and underlying disease. Regardless of the treatment method chosen, regular monitoring of serum creatinine levels and Renal Doppler Ultrasound is necessary.

(1) Pharmacological therapy Although effective pharmacological therapy for renovascular hypertension has not been established, the drugs used in previous RCTs [1423, 1424] that evaluated the efficacy of PTRA were combinations of antihypertensive agents, statins, and aspirin. Combining these with smoking cessation and glycemic control in diabetes is considered effective [626] .

RVHT may exhibit treatment resistance, and achieving the target BP often requires the use of multiple antihypertensive medications, such as RAS inhibitors, CCBs, and β-blockers. Although there are no RCTs comparing the efficacy of antihypertensive drugs, RAS inhibitors (ACE inhibitors or ARBs) have been shown in many observational studies to improve life prognosis, CVD risk, and renal prognosis in renal artery stenosis. ACE inhibitors are

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associated with improved survival and renal outcomes regardless of PTRA use [1425] . Compared to other antihypertensive drugs, RAS inhibitors reduce the risk of heart failure hospitalization, dialysis initiation, and death [1426] . Therefore, RAS inhibitors should be considered in patients with hypertension due to unilateral renal artery stenosis. However, there are reports suggesting an association between the use of RAS inhibitors and acute kidney injury [1427] , thus treatment should be initiated at a low dose, with regular monitoring, and discontinued or switched to another antihypertensive agent if hypotension, rapid deterioration of renal function, or hyperkalemia occurs. Regarding bilateral renal artery stenosis, while there are reports indicating the tolerability and efficacy of RAS inhibitors [1428, 1429] , they may cause renal dysfunction [1430] and their safety has not been established, thus they are generally contraindicated.

Although evidence for other antihypertensive agents is limited, β-blockers are considered effective based on their mechanism of action, and reports indicate that the combination with low-dose aspirin may be effective [1431] . CCBs have minimal effects on the RAS, and α-blockers may also be used.

(2) Revascularization In fibromuscular dysplasia, PTRA is preferred unless technically difficult. The initial success rate of PTRA is high [1432] , and it offers greater BP-lowering effects compared to atherosclerosis, as well as the potential for reducing or discontinuing antihypertensive medications, making it worthy of consideration [1433] . BP lowering effects are greater in younger patients and those with a shorter history of hypertension, as demonstrated by metaanalyses [1434] . However, PTRA in fibromuscular dysplasia generally does not involve stent placement, resulting in a relatively high rate of restenosis [1435] .

The use of PTRA in patients with atherosclerotic renal artery stenosis has shown BP-lowering effects in non-RCT studies [1436, 1437] , however superior treatment effects compared to drug therapy alone have not been demonstrated in RCTs [1438] [1439] [1440] [1441] [1442] [1443] . Similarly, in four RCTs reported since 2009, no superior therapeutic effects were demonstrated in terms of BP reduction, renal function outcomes, or prevention of CVD events [1423, 1424, 1444, 1445] , supporting monotherapy with medication. However, renovascular hypertension typically develops in cases of severe renal artery stenosis (70-80% or more), yet these RCTs included a high proportion of cases with mild or moderate renal artery stenosis, raising concerns [1406, 1414, [1446] [1447] [1448] . Metaanalysis results showed that PTRA combination therapy did not demonstrate clear superiority over drug therapy, but it was somewhat effective in reducing the dose of antihypertensive medications, while the risk of CVD and renal events was equivalent (CQ19) [1449] .

While several studies have examined the predictive factors for the therapeutic efficacy of PTRA [1450] [1451] [1452] , no established factors have been identified. In patients with severe renal artery stenosis (≥70%) and treatment-resistant hypertension diagnosed by ABPM, PTRA resulted in a reduction in BP and the number of medications, with decreased urinary albumin [1453] . Additionally, a subgroup analysis of an RCT suggested that PTRA may improve outcomes in patients without albuminuria [1454] . When considering PTRA, it is advisable to make a comprehensive judgment based on the degree of renal artery stenosis, the morphology of the affected kidney, office BP, changes in eGFR, and urinary findings [1406, 1414, 1448] .

Currently, PTRA for renovascular hypertension is considered appropriate in cases with hemodynamically significant renal artery stenosis and any of the following conditions: ① fibromuscular dysplasia, ② treatment-resistant hypertension, ③ worsening hypertension or malignant hypertension, ④ unexplained or recurrent pulmonary edema or heart failure, ⑤ bilateral or unilateral renal artery stenosis, or ⑥ ischemic nephropathy with preserved renal morphology [626, 1406, 1414, 1448, 1455] . Note that in cases of atherosclerotic PTRA, the initial success rate without stents is somewhat lower, and the restenosis rate is higher [1456] , but the use of stents is expected to reduce the restenosis rate [1457] .

Though surgical treatments such as nephrectomy or surgical bypass surgery have decreased worldwide, surgical bypass surgery remains an option in cases where PTRAbased revascularization is difficult or in cases of recurrent restenosis after PTRA. The patency rates and outcomes of surgical bypass surgery are comparable to, or slightly better than those of PTRA [1458, 1459] , however a high mortality rate associated with surgery has also been noted [1460] .

【POINT 15d】 【Drug-induced hypertension】 1. NSAIDs increase BP and reduce the effects of diuretics, β-blockers, ACE inhibitors, and ARBs. This effect is more pronounced in older adults or in those with renal dysfunction. 2. Using Kampo formulas that contain glycyrrhizin (the main component of licorice), liver disease treatment drugs, and health supplements may cause hypertension with hypokalemia (pseudoaldosteronism). In such cases, discontinue the drugs or replace them with an MR antagonist. The use of glucocorticoids in large volume may cause an elevation in BP. 3. The use of cyclosporine and tacrolimus may cause an elevation in BP. Also, medications with sympathomimetic effects, such as erythropoietin, estrogen, and antidepressants, may potentially cause an elevation in BP.

The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and. . .

References

Abstract

4. Hypertension may be induced by molecular targeted anticancer drugs, particularly angiogenesis inhibitors (anti-VEGF antibody preparations and inhibitors against several types of kinase).

4. Drug-induced hypertension

4. Drug-induced hypertension

Among medical drugs, NSAIDs, licorice (glycyrrhizin) preparations, glucocorticoids, cyclosporine, erythropoietin, and hypoxia-inducible factor prolyl hydroxylase (HIF-PH) inhibitors, oral contraceptives, and sympathomimetic agents have been reported to induce hypertension and may reduce the efficacy of antihypertensive medications when used concomitantly. Additionally, recent reports have indicated that hypertension may be induced by molecularly targeted drugs . Hypertensive patients frequently present with comorbidities and may be followed by multiple healthcare providers. When patients whose BP had been well controlled develop difficulties in management, or in cases of refractory hypertension, drug-induced hypertension should be considered.

1) NSAIDs

1) NSAIDs

NSAIDs inhibit cyclooxygenase (COX), which is involved in the production of prostaglandins from arachidonic acid, thereby suppressing renal prostaglandin production. This leads to water and sodium retention and the inhibition of vasodilation [1461] . In older adults and in patients with renal impairment, renal prostaglandins play a compensatory role in maintaining renal function and suppressing BP elevation. Therefore, NSAID use, which inhibits prostaglandin production, can lead to BP elevation via impaired renal function. COX has two isoforms: COX-1, which is constantly expressed, and COX-2, which is induced during inflammation. Classical NSAIDs non-selectively inhibit both, while COX-2 selective inhibitors primarily inhibit the latter. The cardiovascular adverse effects of nonselective NSAIDs and COX-2 selective inhibitors are related not to the presence or absence of selectivity, but rather to the ratio of COX-1 to COX-2 inhibition and tissue-specific COX distribution. Therefore, the same precautions should be taken when using non-selective NSAIDs and COX-2 selective inhibitors [1462] [1463] [1464] .

In older adults, NSAIDs are more likely to cause acute kidney injury and promote BP elevation. Additionally, the combination of diuretics and NSAIDs increases the risk of

References

renal failure compared to diuretics alone. Therefore, when NSAIDs are used chronically in older hypertensive patients, they should be administered at low doses for a limited period with careful monitoring and renal function checks. If renal dysfunction is detected, discontinuation of the drug should be considered, or switching to acetaminophen if discontinuation is not possible.

Diuretics inhibit sodium reabsorption in the renal tubules while stimulating prostacyclin production. Therefore, the combination of NSAIDs and diuretics may reduce the BPlowering effect of diuretics. Additionally, the antihypertensive effects of ACE inhibitors and β-blockers may be reduced when used in combination with NSAIDs. The effects of combination use with ARBs have not been sufficiently studied, but they are believed to have effects similar to those of ACE inhibitors [1465] . The effects on BP are considered minimal when used in combination with CCBs.

2) Licorice (Glycyrrhiza), glycyrrhizin Licorice (Glycyrrhiza) is used in the treatment of liver diseases, digestive disorders, and various other traditional Chinese medicines, health supplements, and cosmetics. Glycyrrhizin inhibits the 11β-hydroxysteroid dehydrogenase enzyme, which metabolizes cortisol into inactive cortisone, thereby prolonging the half-life of cortisol and enhancing endogenous steroid effects [1466], leading to sodium and water retention, potassium depletion, and the onset of pseudohyper aldosteronism. The dosage and duration of administration of glycyrrhizin, and patient age (60 years or older) are considered risk factors for this condition [1467] . Diagnosis is suspected when hypertension is accompanied by hypokalemia, low renin activity, and low PAC. Since the use of traditional Chinese medicine or health supplements by patients is rarely reported, caution is warranted regarding their use. Clinically, improvement may occur with discontinuation of licorice (Glycyrrhiza) for several weeks (up to 4 months) or concomitant use of MR antagonists.

3) Glucocorticoids Glucocorticoids rarely cause hypertension when used at low doses for the long-term treatment of conditions such as asthma and rheumatoid arthritis. However, moderate-dose glucocorticoid therapy over an extended period is associated with a high incidence of hypertension [1468] . In particular, in older adults, BP increases significantly with increasing prednisolone dosage, and the increase becomes pronounced at doses of 20 mg/day or more [1469] . In this report, hypertension ( > 160/95 mmHg) was observed in 37.1% of older patients, and a high prevalence of a family history of hypertension was noted [1469] . The mechanisms underlying glucocorticoid-induced BP elevation include increased production of renin substrate leading to elevated angiotensin II [1398] , increased erythropoietin production leading to vasoconstriction [1470] , inhibition of nitric oxide (NO) production [1471] , or impaired NO utilization due to excessive superoxide production resulting in vascular endothelial dysfunction [1472] , and MR stimulation, among others. To date, the exact mechanisms remain poorly understood.

Treatment primarily involves reducing or discontinuing glucocorticoids; however, if this is difficult, CCBs, ACE inhibitors, ARBs, β-blockers, diuretics, or MR antagonists may be used.

4) Cyclosporine, tacrolimus Cyclosporine and tacrolimus are used to suppress rejection reactions in organ transplantation and bone marrow transplantation. Both drugs cause high rates of hypertension, although the incidence varies depending on dosage, treatment duration, and disease state. The mechanisms underlying the development of hypertension are not fully understood, but possible mechanisms include nephrotoxicity [1473], sympathetic nervous system activation [1474] , calcineurin inhibition [1475] , and vascular endothelial cell dysfunction [1476] . CCBs are effective for treating hypertension caused by immunosuppressive drugs, but combination with ACE inhibitors is reported to be more effective [1477] . Diuretics are also effective, but caution is needed regarding uric acid metabolism in kidney transplantation. CCBs may increase the blood levels of cyclosporine and tacrolimus, thus consideration should be given to measuring the blood levels of immunosuppressive drugs.

5) Erythropoiesis-stimulating agents (ESAs) ESAs improve renal anemia but cause an increase in BP. In post-marketing surveys in Japan, BP increases were reported in 29% of patients [1478] . The mechanism is thought to involve an increase in hematocrit levels due to anemia improvement by erythropoietin, leading to increased peripheral vascular resistance caused by increased blood viscosity; however, some reports suggest no association [1479] . Other possible factors include increased intracellular sodium concentration [1480], vascular endothelial dysfunction [1481] , and genetic predisposition [1482] . Reports indicate that erythropoietin-induced BP elevation is not observed prior to dialysis initiation [1483] . If BP increases, consider reducing or discontinuing erythropoietin. The usefulness of antihypertensive agents has also been reported in cases of mild increases [1484] . Additionally, while HIF-PH inhibitors are considered less likely to cause clinically significant BP increases compared to ESAs, caution is still necessary regarding the occurrence of hypertension-related events with HIF-PH inhibitors [1485] .

6) Estrogen

6) Estrogen

Estrogen is used as an oral contraceptive and for the treatment of menopausal symptoms. However, high-dose estrogen use has been associated with side effects such as BP elevation and thromboembolic events. The mechanism

The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and. . .

References

by which estrogen increases BP is thought to involve increased production of renin precursors in the liver, although the details remain unclear. In a study investigating oral contraceptives and health status, users had slightly higher BP and lipid levels compared to non-users matched for age; however, they reported higher satisfaction with health and QOL, leading to the conclusion that oral contraceptives can be used safely [1486] . The extent of BP elevation is dose-dependent, but caution is necessary even at low doses. To date, sufficient analysis of oral contraceptives and hypertension has not been conducted in Japan. Regular BP measurements should be performed during oral contraceptive use, and if BP increases, use should be discontinued and alternative contraceptive methods considered. If discontinuation is not possible, consideration should be given to the administration of ACE inhibitors or ARBs. For hormone replacement therapy, refer to "Chapter 10, Section 9. 3) After menopause". 7) Molecular targeted drugs Molecular targeted drugs, particularly anti-angiogenic agents (such as anti-VEGF antibodies and multiple kinase inhibitors), are used for the treatment of malignant tumors and age-related macular degeneration. However, they are recognized as having serious side effects, including hypertension induction and the onset of myocardial infarction and ischemic stroke [1487, 1488] . The incidence of hypertension varies depending on the drug, tumor type, and ethnicity, ranging from several percent to approximately 80%. The mechanism of onset is not fully understood, but it is thought to be associated with a reduced microvascular bed, increased peripheral vascular resistance due to decreased nitric oxide (NO) production caused by VEGF inhibition, and renal dysfunction [1489] [1490] [1491] . Recent studies have suggested that vascular endothelial cell damage and increased oxidative stress may also be involved. Strict BP control is necessary before initiating treatment if hypertension is present. At the onset of hypertension, consider reducing or discontinuing causative medications and initiate treatment with conventional antihypertensive agents. RAS inhibitors and CCBs are recommended [1489, 1491] . Recently, the concept of "onco-hypertension" has been proposed [997] , and collaboration between oncologists and hypertension specialists is important.

8) Other Drugs with sympathomimetic effects may cause an increase in BP. Excessive intake of phenylpropanolamine, which is contained in cold remedies, may cause an increase in BP. When used in combination with β-blockers, there is a risk of significant BP elevation due to α-receptor stimulation predominance, thus caution is necessary. Tricyclic and tetracyclic antidepressants inhibit the reuptake of catecholamines at sympathetic nerve endings, thereby suppressing the BP-lowering effects of peripheral sympathetic nerve inhibitors and may present with hypertensive emergency [1492] or hypertensive emergency [1493] . Serotoninnorepinephrine reuptake inhibitors (SNRIs), which are used as antidepressants, have pain-relieving effects due to the inhibition of catecholamine reuptake and are used as treatments for neuropathic pain. However, they may cause BP increases due to their sympathetic nervous system stimulation effects.

Monoamine oxidase (MAO) inhibitors used for the treatment of Parkinson's disease may also cause BP elevation or orthostatic dysregulation. The combination use of MAO inhibitors and tricyclic antidepressants is contraindicated. Concomitant use with ephedrine or methylephedrine may also cause BP elevation and tachycardia. If hypertension develops with these medications, dose reduction or discontinuation is necessary. If discontinuation is not possible, α-blockers or central sympathetic nerve inhibitors may be administered. Dopamine (D2) receptor antagonists such as metoclopramide, β-blockers, and tricyclic antidepressants used for gastrointestinal disorders may induce pheochromocytoma or hypertensive emergency, thus caution is required [1494] .

【POINT 15e】 【Hereditary hypertension】 1. Mutations in genes regulating renal salt reabsorption and adrenal steroid biosynthesis cause monogenic hypertension. 2. Essential hypertension is a complex disease involving genetic and environmental factors, with 30-70% of cases influenced by genetic factors. Numerous single nucleotide variants (SNVs) have been identified as being associated with alteration in BP. 3. The individual effect of these variants on BP is modest and is < 1 mmHg in the general population. It has been reported that the Japanese population may have a higher prevalence of SNVs associated with sodium sensitivity.

5. Hereditary hypertension

5. Hereditary hypertension

Causative genes of monogenic hypertension are listed in Table 15 -7. The majority of these genes are involved in adrenal steroid biosynthesis or renal sodium reabsorption [1495, 1496] . Although rare, monogenic hypertension may need to be considered if the hypertension occurs at a younger age and is accompanied by acid-base disturbances, altered serum potassium (K) levels, or abnormalities in RAA system; in these cases, consultation with a specialist is advisable. Plasma renin activity is often suppressed, reflecting increased circulating plasma volume. Among the diseases shown in Fig. 15 -3, PACs are elevated in familial hyperaldosteronism and PASNA syndrome, whereas they Y. Ohya

References

are either decreased or unaltered in other diseases. While pseudohypoaldosteronism type II (PHAII; also known as Gordon syndrome or familial hyperkalemic hypertension)presents with hyperkalemia, a majority of monogenic forms of hypertension (such as Liddle syndrome and familial hyperaldosteronism) result in decreased serum K levels.

When monogenic hypertension is suspected and a detailed genetic analysis is required, it is necessary to adhere to available guidelines such as the Japanese Medical Association's "Guidelines for Genetic Testing and Diagnosis in Medicine" [1497].

In essential hypertension, the contribution of genetic factors is estimated to be 30–70% [1498]. Genome-wide association studies (GWAS) have identified numerous genetic loci associated with BP. In general, the individual effects on BP are modest, with each accounting for less than 1 mmHg [1499]. Differences among populations and the involvement of epigenetic regulation such as DNA methylation have also been reported [1500, 1501]. Additionally,several GWAS investigated genetic loci that interact with sodium intake to influence BP [1502]. It has been reported that the prevalence of candidate SNVs associated with

Table 15-7 Causative genes involved in hereditary hypertension and their clinical features Monogenic hypertension

Causative genes Clinical features other than hypertension

Liddle syndrome

SCNN1A, SCNN1B,SCNN1G

Low K, low PRA, low PAC, metabolic alkalosis

Pseudo hypoaldosteronism type II (PHA II)

WNK4, WNK1,KLHL3, CUL3

High K, low PRA, metabolic acidosis, normal PAC, thiazideresponsive

Apparent mineralocorticoid excess (AME)

HSD11B2

Low PRA, low PAC, low K, growth delay, metabolic alkalosis, spironolactone responsiveness

Familial hyperaldosteronism type 1 (FH I) (Glucocorticoidresponsive aldosteronism [GRA])

Chimeric CYP11B1/CYP11B2

Low PRA, high PAC, glucocorticoid responsiveness

Familial hyperaldosteronism type 2 (FH II)

CLCN2

Low PRA, high PAC

Familial hyperaldosteronism type 3 (FH III)

KCNJ5

Familial hyperaldosteronism type 4 (FH IV)

CACNA1H

PASNA syndrome

CACNA1D

Low PRA, high PAC, seizures, neurological abnormalities

11β-hydroxylase (11β-OH) deficiency

CYP11B1

Congenital adrenal hyperplasia, low PRA, high DOC, high ACTH, low cortisol, virilization

17α-hydroxylase (17α-OH) deficiency

CYP17

Congenital adrenal hyperplasia, low PRA, high DOC, high ACTH, low cortisol, feminization

Early-onset type hypertension with severe exacerbation in pregnancy

NR3C2

Pregnancy-induced hypertension

Hereditary hypertension with brachydactyly

PDE3A

Brachydactyly, severe age-dependent, non-salt-sensitive hypertension

Hypomagnesemia, hypertension, and hypercholesterolemia,mitochondrial

MT-TI

Hypercholesterolemia, low Mg

Fig. 15-3 Causes of Monogenic Hypertension. (Source: Prepared based on refs. [1495, 1496])

The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and. . .

Abstract

increased salt sensitivity is higher in Japanese individuals [1503]. Several studies suggest that the calculating a genetic risk score may be useful in guiding hypertension management [1504].

Abstract

【POINT 15f】 【Vascular】 1. Diseases presenting with vascular (pulmonary) hypertension include Takayasu's arteritis (aortitis syndrome), other vascular inflammatory syndromes (nodular polyarteritis, systemic sclerosis), and aortic coarctation. Antihypertensive medications should be selected based on the pathophysiology of each disease.

Abstract

【Cerebral/Central Nervous System】

1. In cases of hypertension caused by increased intracranial pressure (Cushing's reaction) due to cerebrovascular disorders, brain tumors, encephalitis (myelitis), or head trauma, prioritize treatment for the underlying condition. 2. Compression of arteries around the lateral ventral region of the brainstem can cause BP elevation through increased sympathetic nerve activity (neurovascular compression syndrome). In cases accompanied by neurological symptoms such as hemifacial spasm, surgical decompression may be considered.

6. Other types of secondary hypertension

6. Other types of secondary hypertension

1) Vascular hypertension (1) Takayasu's arteritis (aortitis syndrome) Takayasu arteritis (aortitis syndrome) is a large vessel vasculitis affecting the aorta and its major branches, coronary arteries, and pulmonary arteries. Compared to Western countries, the incidence rate in Japan is higher, with a higher prevalence in women [1505] . The peak age of onset for women is around 20 years old, but onset in middle-aged and older adults is not uncommon. At onset, common symptoms include unexplained fever, generalized fatigue, neck pain, pain in various parts of the body, and dizziness, often resembling upper respiratory tract infection symptoms. Physical examination findings include significant BP differences between the upper limbs, absent peripheral pulses, and vascular murmurs in the neck or abdomen. Although hypertension is rarely diagnosed as the sole symptom, the prevalence of hypertension is approximately 40%, making it an important underlying condition for secondary hypertension [1506] . The mechanisms underlying the onset of hypertension include: ① narrowing of the aorta, ② decreased sensitivity of carotid baroreceptors, ③ narrowing of the renal arteries, ④ aortic valve regurgitation, and ⑤ aortic wall stiffening [1507] . Diagnosis is based on elevated C-reactive protein (CRP) levels and erythrocyte sedimentation rate (ESR) in blood tests, positive B52 in leukocyte antigen (HLA) testing, and vascular narrowing, dilation, and thickening of the vascular wall detected by ultrasound, contrast-enhanced CT, MRI, (18) F-FDG PET/ PET-CT, and angiography.

Early and appropriate diagnosis and treatment are crucial for preventing disease progression, and the time from symptom onset to diagnosis is associated with the severity of the disease [1506] . Treatment options include corticosteroids, immunosuppressive agents, biological agents, and antiplatelet drugs. Early treatment intervention is effective, and the incidence of hypertension and aortic regurgitation has decreased in cases diagnosed after 2000 [1508] . Once disease activity is controlled, invasive treatment of vascular lesions (surgical revascularization or endovascular therapy) may be considered to improve organ blood flow and prevent aneurysm rupture.

Uncontrolled hypertension is associated with a poor prognosis [1509], however since effective antihypertensive drug therapy has not been established, drugs should be selected based on renovascular hypertension or essential hypertension. Additionally, BP targets should be set with consideration for the severity of organ blood flow impairment and symptoms. The prevalence of concomitant aortic and renal artery stenosis is high [1506, 1510] , and if BP cannot be controlled with oral medications, revascularization surgery should also be considered. The indications for revascularization surgery are the same as those for aortic stenosis in the "Guidelines for the Management of Vascular Inflammatory Syndrome (2017 Revised Edition)" [1505] ; for renal artery stenosis, it is considered in accordance with chapter "3. Renovascular Hypertension." However, the restenosis rate after revascularization is higher with endovascular therapy than with surgical revascularization [1511] .

(2) Other vasculitic hypertension Hypertension caused by vascular inflammatory syndromes other than aortic inflammation syndrome (Takayasu's arteritis) includes nodular polyarteritis, systemic sclerosis, and others.

Polyarteritis nodosa is characterized by systemic symptoms such as fever and weight loss, fibrinoid necrosis, and inflammatory cell infiltration in small and medium-sized arteries. It is associated with multiple small aneurysms, stenosis, and occlusion of renal arterioles, and approximately 30% of cases present with hypertension (160/95 mmHg or higher) [1512] . Due to the high incidence of complications, such as renal failure, heart failure, and gastrointestinal bleeding, BP management is important. Treatment is determined based on the type and severity of organ lesions. Steroids are the mainstay of treatment, but Y. Ohya

References

symptomatic therapy such as antihypertensive drugs, vasodilators for ischemia, and treatment for peripheral neuropathy may be used in combination. Although effective antihypertensive therapy has not been established, reports indicate that intravenous administration of labetalol (β-blocker) or nitroprusside during the acute phase, followed by switching to lisinopril, hydrochlorothiazide, or labetalol (tablet) is effective [1513, 1514] .

Systemic sclerosis is characterized by an increase in collagen-rich connective tissue (fibrosis) in the dermis of the skin, skin hardening including the fingers, Raynaud's symptoms, and positive antinuclear antibodies (such as anti-Scl-70 antibodies or anti-centromere antibodies).

Approximately 10-15% of cases are associated with scleroderma nephropathy, but in typical cases, renal blood flow decreases due to narrowing or constriction of renal blood vessels, leading to activation of the RAS and rapid deterioration of renal function or malignant hypertension (scleroderma renal crisis: SRC). The efficacy of ACE inhibitors for SRC is well established [1515] , and treatment should be initiated early after onset [1516] . If BP control is inadequate with ACE inhibitors alone, combination therapy with CCBs or α-blockers should be considered [1516, 1517] .

(3) Aortic coarctation The characteristics of aortic coarctation are congenital or acquired narrowing of the aortic lumen leading to hypertension in the upper limbs and weakened pulses in the lower limbs. The extent of narrowing varies from localized to extensive aortic arch hypoplasia, and it often occurs in conjunction with aortic bicuspid valve disease. Due to the increased risk of cerebral aneurysms, heart failure, coronary artery disease, and aortic dissection, BP management is crucial. In this condition, increased arterial reflex waves from the narrowed aortic segment [1518] , increased peripheral vascular resistance in the upper body, reduced Windkessel effect in the aorta, and enhanced systemic vascular remodeling [1519] , as well as activation of the RAS and sympathetic nervous system [1520], are observed. Treatment involves surgical or catheter-based relief of the aortic coarctation. However, hypertension often persists postoperatively [1521] . Additionally, even if BP normalizes postoperatively, an increase in BP during exercise is associated with hypertension recurrence [1522] , thus BP should be evaluated using 24-h ABPM or exercise stress testing in addition to resting BP measurements [1523] [1524] [1525] [1526] . Regarding the selection of pharmacological therapy, thiazide diuretics, CCBs, ACE inhibitors, and ARBs have been mentioned [1527, 1528] , but their efficacy has not been verified in RCTs.

2) Cerebral and central nervous system hypertension For hypertension caused by cerebrovascular disorders, refer to Chapter 9. In central nervous system disorders, such as brain tumors (especially tumors in the posterior fossa), encephalitis (or meningitis), and brain trauma, increased intracranial pressure or ischemia in the brainstem can lead to increased sympathetic nerve activity and hypertension (Cushing's response).

Neurovascular compression syndrome is characterized by hypertension due to increased sympathetic nerve activity caused by compression of peripheral arteries around the ventrolateral area of the medulla oblongata [1529, 1530] . BP fluctuations are significant in cases of acute ischemic stroke, and poor functional outcomes have been reported [1531] . Surgical decompression reduces BP [1532] . In a prospective study of 48 cases of hypertension with unilateral facial nerve spasm and neurovascular compression, 14 cases (29%) no longer required antihypertensive medication after decompression, and BP decreased in many cases [1533] . Therefore, surgical decompression should be actively considered in cases with neurological symptoms such as hemifacial spasm or trigeminal neuralgia. However, since the efficacy and safety of decompression surgery have not been established, its application in cases without accompanying neurological symptoms should be carefully considered [1534] . Although effective antihypertensive drug therapy has not been established, BP-lowering effects have been reported with central sympathetic nerve inhibitors [1535] and CCBs with sympathetic nerve inhibitory effects [1536] .

CQ 18 Primary aldosteronism (PA): Are there prognostic differences between adrenalectomy and treatment with MR antagonists? ►In cases of unilateral lesions, since complete remission of aldosteronism is expected after adrenalectomy of the affected side, we weakly recommend adrenalectomy when the physician deems surgery appropriate, and the patient agrees.

【Recommendation strength 2, Evidence strength B, Consensus rate 100%】 ►In cases of bilateral PA or when the patient does not wish to undergo surgery, we strongly recommend continuing drug treatment using MR antagonists. 【Recommendation strength 1, Evidence strength B, Consensus rate 100%】

Summary of evidence

Summary of evidence

In global guidelines, the recommended standard treatment for unilateral primary aldosteronism (PA) is adrenalectomy of the affected side. However, evidence to demonstrate its superiority in long-term outcomes compared to drug treatment using MR antagonists has been limited. In this CQ, we conducted a meta-analysis of eight studies comparing the

The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and. . .

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Abstract

treatment effects of adrenalectomy and MR antagonists in unilateral PA. The results demonstrated that adrenalectomy significantly reduced the incidence of CVD events, SBP, and the number of medications compared to drug treatment with MR antagonists.

Explanation

Explanation

PA is diagnosed by adrenal vein sampling, and the treatment is determined based on the results. In the guidelines from various countries, adrenalectomy (Adx) of the affected side is recommended for unilateral lesions, and drug treatment with MR antagonists is recommended for bilateral lesions [274, 1377, 1378, 1537] . These have become established as standard treatments. In this CQ, we will examine the differences in clinical outcome between Adx and drug treatment using MR antagonists for the treatment of unilateral PA and recommend treatment methods based on evidence for unilateral and bilateral lesions. Many clinical trials comparing surgery and medication for PA treatment have a study population with unilateral lesions in the surgery group and predominantly bilateral lesions in the medication group, thus it is important to note that the pathophysiology and clinical background of the two groups differ. Even in clinical studies where drug treatment was chosen over surgery in unilateral lesions, these cases are likely to include patients with poor prognosis due to organ dysfunction or advanced age, suggesting the selection bias between the study populations of the two groups. To avoid this bias, recent reports have compared the surgical group and the drug treatment group after adjustment for both groups using methods such as propensity score matching [1391] .

An SR was conducted according to the above premises to evaluate the prognosis of Adx and MR antagonists [1538] . Among 526 studies identified through searches in PubMed, the Cochrane Library, and Ichushi-Web, eight reports that compared the effects of surgery and drug treatment in patients with unilateral PA were included in the metaanalysis [1539] [1540] [1541] [1542] [1543] [1544] [1545] [1546] . The outcomes included total mortality, incidence of CVD events, renal dysfunction, BP, hyperkalemia, left ventricular hypertrophy, number of oral medications, and complications associated with Adx. For total mortality, renal function decline, left ventricular hypertrophy, and complications associated with Adx, fewer than three studies were available, thus the meta-analysis was not conducted. For the remaining outcomes, we report the results of the meta-analysis comparing the differences between Adx and the treatment with MR antagonists.

In unilateral PA, the incidence rate of CVD events was significantly reduced in the Adx group by 0.63 in mean difference (95% CI 0.46 to 0.85). SBP was significantly reduced in the Adx group by 8.78 (95% CI 5.95 to 11.61), while DBP was reduced by 4.61 (95% CI 0.04 to 9.27) with no significant difference. Serum K concentration increased with Adx by 0.43 (95% CI 0.35 to 0.51]), and the number of oral medications decreased with Adx by 1.49 (95% CI 0.99 to 2.00). In summary, in unilateral PA, Adx significantly reduced the incidence of CVD events, SBP, and the number of oral medications compared to drug therapy with MR antagonists, while increasing serum K levels. Limitations of the study include the absence of RCTs in the included clinical trials, the lack of clear rationale for selecting MR antagonists over Adx, and the fact that all eight reports were from Asia, resulting in regional and racial biases.

Even in cases of unilateral PA that are relatively severe, surgical intervention may lead to biochemical cure, improvement in hypertension, and a reduction in CVD events [1385] . In contrast, with drug treatment, even with continuous administration of high-dose MR antagonists, in some case there may be insufficient suppression of excessive aldosterone action, resulting in poorer long-term outcomes, such as a higher incidence of CVD events, compared to essential hypertension [1375, 1540] . Based on this CQ's meta-analysis, in cases of PA diagnosed with unilateral lesions when physicians determine surgical intervention appropriate and patients agree surgery, Adx on the affected side is recommended over drug therapy with evidence strength B. However, in older adults, the efficacy of surgical therapy may be reduced in unilateral lesions, and postoperative renal function deterioration may be significant [1541] , thus surgical indications should be carefully assessed.

Bilateral PA has been reported to potentially improve long-term prognosis when MR antagonists are administered at adequate doses, as indicated by normalization of BP and serum K levels, and increased plasma renin activity [1392, 1540] . These reports of improved prognosis with MR antagonists provide evidence supporting the use in bilateral lesions. Considering the significance of specifically inhibiting aldosterone's effects, in bilateral PA, we strongly recommend continuing drug treatment with MR antagonists based on evidence strength B. However, treatment goals to improve the long-term prognosis of PA comparable to that of essential hypertension, differences in efficacy among multiple MR antagonists, and differences in the prognosis between MR antagonists and other antihypertensive drugs, all require further investigation.

Literature search

Literature search

Using PubMed, the Cochrane Library, and Medline Web, we extracted 526 studies that evaluated the prognosis of Adx or drug therapy as a treatment for PA. We performed a meta-analysis using eight studies that compared the Y. Ohya

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outcome of the surgery and drugs in patients with unilateral PA.

CQ 19 Is combined percutaneous transluminal renal angioplasty (PTRA) therapy recommended as a treatment for atherosclerotic renal artery stenosis with hypertension, compared to pharmacological therapy alone, with the aim of reducing mortality and incidence of CVD, as well as BP-lowering and renal protective effects?

►The superiority of PTRA combined therapy has not been established. However, renal angioplasty should be considered as appropriate.

【Recommendation withheld; Evidence strength C; Consensus rate 100%】

Summary of evidence

Summary of evidence

An SR was conducted to evaluate the efficacy of PTRA in combination with medical therapy, compared to medical therapy alone, for patients with atherosclerotic renal artery stenosis and hypertension. Percutaneous renal artery angioplasty in combination with medical therapy did not reduce the mortality or incidence of CVD compared to medical therapy alone. Additionally, no superiority was observed when outcomes were assessed as BP-lowering effects or changes in renal function. However, no increased risk of adverse events (acute kidney injury, dialysis initiation, vascular injury, etc.) was observed. Furthermore, the combination therapy significantly reduced the number of antihypertensive medications compared to monotherapy, suggesting its BP-lowering efficacy. Limitations of this SR include: ① The primary endpoints varied among RCTs, ② The number of cases with severe renal artery stenosis was limited, ③ Bilateral and unilateral renal artery stenosis were not clearly distinguished, ④ Some cases assigned to the PTRA combination therapy group did not undergo PTRA, ⑤ There were cases in the pharmacological therapy-alone group where PTRA was performed during the trial period, ⑥ Definitions varied between trials, for example, the definition of CVD and renal dysfunction. Based on the above results, PTRA in combination with pharmacological therapy for atherosclerotic renal artery stenosis with hypertension may be considered when patients desire surgery and physicians deem that appropriate (given the expected BPlowering effects).

Explanation 1) Basis for the CQ A SR (SR) was conducted on the treatment effects of PTRA, one of the revascularization procedures for hypertension complicated by atherosclerotic renal artery stenosis [1547] . The benefits identified in this CQ include:

(1) reduction in mortality from CVD, (2) reduction in the incidence of CVD, (3) reduction in SBP, (4) reduction in DBP, (5) inhibition of progression of renal dysfunction, (6) reduction in the number and the adverse effect of antihypertensive medications, (7) fewer adverse events.

2) SR target studies We extracted RCTs evaluating the efficacy of PTRA in hypertensive patients aged 18 years or older with atherosclerotic renal artery stenosis from MEDLINE (PubMed, Ovid SP), the Cochrane Library, and Medline Web.

3) Results [1423, 1424, 1438-1440, 1444, 1445, 1548, 1549] (1) Reduction in mortality from CVD (Fig. CQ19-1A )

(2) Reduction in the incidence rate of CVD (Fig. CQ19-1B )

(1) In the SR 4 RCTs, and (2) 5 RCTs were used. There was no significant difference in mortality from CVD or the incidence of CVD between PTRA combined therapy and pharmacological therapy alone.

(3) Reduction in SBP (Fig. CQ19-2A ) Eight RCTs were included in the SR. No significant difference was observed between PTRA combined therapy and pharmacological therapy alone. No significant difference was observed in two RCTs limited to unilateral renal artery stenosis, nor in two RCTs that evaluated BP using 24-h ABPM.

(4) Reduction in DBP (Fig. CQ19-2B ) Seven RCTs were included in the SR. There was no significant difference in DBP reduction between PTRA combined therapy and pharmacological therapy alone. In two RCTs, limited to unilateral renal artery stenosis, no significant difference was observed, and in two RCTs evaluating BP values using 24-h ABPM, no significant difference was observed.

(5) Prevention of progression in renal dysfunction (Fig. CQ19-3 ) Five RCTs were included in the SR. No significant difference was observed between PTRA combined therapy and pharmacological therapy alone in terms of inhibiting the progression of renal dysfunction. No significant difference was observed in either of the two RCTs that evaluated renal function using serum creatinine concentration or in the three RCTs that evaluated renal function using eGFR.

(6) Reduction in the number of antihypertensive medications taken (Fig. CQ19-4 ) Six RCTs were included in the SR. Combined PTRA therapy significantly reduced the number of antihypertensive medications compared to drug treatment alone.

(7) Adverse events (Fig. CQ19-5 ) Six RCTs were included in the SR. Percutaneous renal artery formation therapy combined with medical therapy did

The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and. . .

References

not show a significant difference in the occurrence of adverse events, including acute kidney injury, dialysis initiation, kidney transplantation, nephrectomy, renal artery injury, puncture site hematoma, arterial dissection, and death, compared to medical therapy alone.

4) Differences from previous SRs

In previous SRs evaluating the efficacy of PTRA as an adjunct therapy, no consistent superiority was observed compared to pharmacological therapy alone in terms of reducing mortality or the incidence of CVD events assoFig. CQ19-1 A CVD mortality, B CVD events (Combined PTRA therapy vs. pharmacological therapy alone). (Adapted from ref. [1547])

Fig. CQ19-2 BP reduction (PTRA combined therapy vs. pharmacological therapy alone). A SBP, B DBP. (Adapted from ref. [1547])

Y. Ohya

ciated with renal artery stenosis [1449, 1550, 1551]. Similarly, no superiority was observed in terms of slowing the progression of renal dysfunction with PRA as an adjunct therapy [253, 1449, 1550]. Additionally, the incidence of adverse events was not increased [253, 1449].

In previous SRs, while there was no superiority in reducing SBP, DBP was significantly reduced [253, 1449].

In the current SR, no significant difference in BP-lowering effects was observed; however, this may be due to differences in the included trials and the fact that the analysis was limited to RCTs, unlike previous SRs. Additionally, similar to previous SRs, PTRA combined with medical therapy reduced the number of antihypertensive medications compared to medical therapy alone [253, 1449].

Summary

In non-randomized trials, the therapeutic effects of PTRA,such as BP-lowering effects and inhibition of the progression of renal dysfunction, have been reported to be expected in cases with a high baseline BP or progressive renal dysfunction. However, patients with treatmentresistant hypertension or ischemic nephropathy were not included in the previous RCTs. RVHT develops in cases of severe renal artery stenosis, but previous RCTs have

included many cases with mild to moderate renal artery stenosis. Additionally, the relatively high number of cases where PTRA was performed during the study period suggests that conducting RCTs in cases of renal artery stenosis with typical symptoms such as treatment-resistant hypertension or fulminant pulmonary edema may be challenging.

Despite the limited inclusion of cases where PTRA is expected to be effective, the current SR and previous reports indicate a reduction in antihypertensive medication treatment, suggesting that percutaneous transluminal renal artery angioplasty may have BP-lowering effects and thus reduces the need for antihypertensive medication in appropriate cases. Further accumulation of evidence is required to define specific patient profiles where treatment effects are expected.

Literature search

Five SR committee members independently conducted literature searches in PubMed, the Cochrane Library, and Medline Web, extracted 1,123 documents as the first screening (titles and abstracts), excluded 1097 documents based on exclusion criteria, and performed a second screening (full text) of 26 documents. As a result, nine

Fig. CQ19-4 Reduction in the number of antihypertensive medications (combined PTRA therapy vs. pharmacological therapy alone). (Adapted from ref. [1547])

Fig. CQ19-3 Prevention of impairment in kidney function (combined PTRA therapy vs. pharmacological therapy alone). (Adapted from ref.

[1547])

The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and. . .

documents relevant to this CQ were used for metaanalysis.

Chapter 16. Special pathological conditions of hypertension

【POINT 16a】

【Hypertensive emergencies and urgencies】

1. In cases where a hypertensive emergency is suspected,

prompt examination and testing should be conducted

to diagnose the pathological condition and assess the

severity, with treatment initiated without delay.

2. Organ dysfunction progresses rapidly in cases such as

hypertensive encephalopathy, cerebral hemorrhage,

subarachnoid hemorrhage, acute aortic dissection,

acute heart failure with pulmonary edema due to

severe hypertension, acute coronary syndrome with

severe hypertension, pheochromocytoma crisis,

eclampsia, or pregnancy with severe hypertension.

Therefore, hospitalization is required, and intravenous antihypertensive treatment should be initiated

immediately. In principle, treatment should be

conducted in a facility with specialists in the relevant

organ systems or hypertension specialists. Accelerated malignant hypertension should be managed as an

emergency.

3. Persistent severe hypertension (typically ≥180/120

mmHg) without progression of acute organ dysfunction, or with a low likelihood of progression is

managed as a hypertensive emergency with oral

antihypertensive drugs.

1. Hypertensive emergencies and urgencies

1) Definition and classification

Hypertensive emergencies are not simply states of abnormally high BP, but rather conditions in which a severe

rise in BP (typically ≥180/120 mmHg) leads to acute damage and progression in target organs such as the brain,heart, kidneys, and large blood vessels. Even if BP is not abnormally high, conditions such as hypertensive encephalopathy, eclampsia, and aortic dissection, which involve a rapid rise in BP, are considered emergencies and require urgent BP reduction. In cases of severe hypertension without rapid progression of organ damage, the condition is classified as a hypertensive urgency. There is no evidence that emergent BP reduction improves outcomes in hypertensive urgency.

Hypertensive emergencies include accelerated malignant hypertension, hypertensive encephalopathy, hypertension complicated by acute aortic dissection, acute heart failure with pulmonary edema due to severe hypertension, acute coronary syndrome with severe hypertension, pheochromocytoma crisis, and pregnancy complicated by eclampsia or severe hypertension (Table 16-1) [183, 1552]. In a metaanalysis of international studies, the prevalence of hypertensive emergencies among patients presenting to the emergency department was 0.3–0.5% [1553, 1554], and

35.9% among patients with severe hypertension [1554],with a high in-hospital mortality of 9.9% [1554]. When a hypertensive emergency is suspected, rapid assessment is essential (Table 16-2) to promptly differentiate emergency from urgency, and to determine the appropriate antihypertensive drugs to use, the administration method, the target BP, and the timeframe required to achieve it. In cases of emergency, treatment should not be delayed by prolonged evaluation.

2) Principles of treatment

In hypertensive emergencies, hospitalization is the principle. Direct monitoring of BP in an intensive care unit is preferable. Intravenous antihypertensive drugs with rapid onset and titratability are typically used. However, overly rapid BP reduction may exacerbate ischemic organ damage due to decreased organ perfusion pressure, potentially leading to complications such as ischemic stroke, myocardial infarction, or progression of renal dysfunction.

Therefore, BP should be lowered cautiously.

Fig. CQ19-5 Incidence of adverse events (PTRA combined therapy vs. pharmacological therapy alone). (Adapted from ref. [1547])

Y. Ohya

Abstract

To achieve the target BP, BP should be lowered by no more than 25% of the baseline level within the first hour, then to approximately 160/100 mmHg over the next 2-6 h, and gradually to < 140/90 mmHg within the following 24-48 h [626]. In the acute phase of aortic dissection, SBP should be immediately reduced to < 120 mmHg, while in acute intracerebral hemorrhage, SBP should be rapidly lowered to < 140 mmHg. The rate and target of BP reduction may vary depending on the underlying condition (see details below). In pregnant women with severe hypertension, if SBP is ≥160 mmHg and/or DBP is ≥110 mmHg on multiple occasions, this should be considered a hypertensive emergency, and rapid BP reduction must be initiated promptly, with hospitalization required in principle [1229]. In cases of eclampsia, severe preeclampsia, or HELLP

syndrome, BP should be immediately lowered to < 160/105 mmHg [183, 447, 1555] .

Once the initial target BP is achieved, patients should be transitioned to oral medications, and intravenous treatment should be tapered and discontinued. Table 163 summarizes the dosage, onset of action, duration of effect, adverse effects, and precautions for parenteral drugs currently available in Japan, along with their main indications. In Japan, nicardipine, a CCB, is frequently used when no other compelling drugs are available. CCBs take time to start acting and have a relatively long duration of action, necessitating careful dose adjustment. In acute heart failure or acute coronary syndrome with severe hypertension, continuous intravenous nitroglycerin infusion is appropriate. In hypertensive emergencies, fluid volume depletion due to pressure diuresis is common, and loop diuretics are not recommended unless fluid volume overload is present.

In a meta-analysis, the prevalence of hypertensive urgency among patients visiting the emergency department was reported to be 0.9% [1553] . In a hypertensive urgency, a long history of hypertension and chronic organ damage are often observed. Therefore, it is assumed that the lower limit of the body's automatic blood flow regulation capacity is high. Consequently, antihypertensive treatment should be initiated within a few hours of diagnosis, followed by a The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and. . .

References

gradual reduction in BP to approximately 160/100 mmHg over 24 to 48 h [183] . In hypertensive urgency, BP is often controlled with oral medications. Previous oral medications may be resumed or intensified, or new oral medications may be initiated. Administration of the contents of nifedipine capsules or a single intravenous injection of nicardipine may cause excessive BP reduction or reflex tachycardia and should be avoided. Administer oral drugs with a relatively fast onset of action, such as intermediate-acting CCBs, ACE inhibitors, ARBs, α-β blockers (labetalol), or β-blockers, or consider concomitant use of loop diuretics, depending on the condition. Captopril has a relatively short onset and short duration of action, making dose adjustment easier. However, in cases of malignant hypertension with enhanced RAS activity or dehydration, captopril may cause excessive hypotension, thus administration should be initiated from a low dose (6.25-12.5 mg). In cases of renal dysfunction, ACE inhibitors or ARBs may cause hyperkalemia 1-2 days after administration, therefore caution is required. In cases of bilateral or solitary renal vascular hypertension, there is a risk of renal failure, thus ACE inhibitors or ARBs should not be used in suspicious cases, or if used, serum creatinine and serum potassium levels should be monitored. Initial treatment for hypertensive emergencies can be performed on an outpatient basis. However, after administration, the patient should be monitored in a medical facility for 5-6 h, followed by careful observation and adjustment of medication on an outpatient basis for 2-3 days. However, hospitalization is recommended for patients with strong risk factors such as a history of CVD. Given that many cases involve organ dysfunction or treatment resistance, referral to or consultation with a hypertension specialist is advisable.

3) Hypertensive encephalopathy Hypertensive encephalopathy is a condition in which a sudden or marked increase in BP exceeds the upper limit of cerebral autoregulation, resulting in hyperperfusion, disruption of the blood-brain barrier, and the development of vascular brain edema. It is more likely to occur in patients with long-standing hypertension with BP at ≥220/110 mmHg, and in normotensive individuals at ≥160/100 mmHg [1556] . Increased intracranial pressure can cause headache, nausea, vomiting, visual disturbances, altered consciousness, and seizures. Focal neurological deficits are In the package inserts, it is described that nicardipine and diltiazem may be indicated for "hypertensive emergencies" in Japan Y. Ohya

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uncommon, but neuroimaging is essential to exclude ischemic stroke, intracerebral hemorrhage, or neoplasm. MRI often reveals reversible posterior leukoencephalopathy syndrome (PRES), a form of vascular edema in the white matter, extending from the parietal to the occipital lobes. Without appropriate treatment, it can lead to cerebral hemorrhage, coma, or death, thus immediate diagnosis and reduction of mean BP by 20-25% are required [183, 447, 1555] . However, due to impaired cerebral vascular autoregulation, rapid and excessive BP reduction may cause cerebral ischemia, thus treatment should be initiated with intravenous drugs with titratable dosing (continuous infusion). Intravenous nicardipine is preferred as it does not reduce cerebral tissue oxygen supply [1557] . Diltiazem or nitroprusside may also be used. In cases with volume overload, furosemide may be administered concomitantly. Hydralazine should be avoided because it can increase intracranial pressure. Once BP is controlled, clinical symptoms and imaging findings gradually resolve.

4) Acute cerebrovascular diseases (see "Chapter 9, 1. Cerebrovascular diseases")

(1) Ischemic stroke Antihypertensive treatment is recommended when BP is ≥185/110 mmHg prior to thrombolytic therapy, or > 180/105 mmHg within 24 h after thrombolytic therapy [235, 650] . Following mechanical thrombectomy, rapid BP reduction should be undertaken only if SBP is ≧180 mmHg [235, 650, 651, 1558] . On the other hand, excessive BP reduction during and after thrombectomy should be avoided [235, 651, [1558] [1559] [1560] [1561] [1562] . In the acute phase (within 2 weeks of onset), in patients not eligible for thrombolytic therapy or mechanical thrombectomy, BP should generally not be lowered except under special circumstances [235, 650, 651] . Severe hypotension (shock) should be promptly corrected with intravenous fluids, vasopressors, and other appropriate measures [235, 650] .

(2) Intracerebral hemorrhage SBP should be reduced to < 140 mmHg as early as possible after onset and maintained > 110 mmHg [235] . A reduction in SBP of more than 90 mmHg is not recommended [235, 649] .

(3) Subarachnoid hemorrhage In patients with mild to moderate subarachnoid hemorrhage due to a ruptured cerebral aneurysm, SBP should be reduced to < 160 mmHg from onset until aneurysm treatment [235] .

5) Acute heart failure with increased BP (refer to Chapter 9, Section 2, 3) Heart failure)

In acute heart failure or acute decompensation of chronic heart failure with increased BP, the following conditions may be involved: excessive increase in peripheral vascular resistance (afterload mismatch), onset from HFpEF due to inadequate BP control, or acute coronary syndrome with hypertension. Initial management includes oxygen therapy, CPAP [1563, 1564] , and sublingual or spray administration of nitrates (nitroglycerin or isosorbide dinitrate) for pulmonary congestion [1565] . If fluid overload is present, diuretics are used concomitantly; early resolution of congestion with furosemide has been suggested to reduce inhospital mortality [1566] . These treatments aim to reduce BP, but rapid, condition-specific management is essential, therefore, prompt transfer to a specialized cardiovascular facility should be considered. Once adequate BP control is achieved, transition to appropriate antihypertensive treatment based on the patient's condition is required, and seamless continuation of treatment from the acute to chronic phase is crucial.

6) Severe hypertension in acute coronary syndrome (acute myocardial infarction, unstable angina)

For angina attacks with increased BP, sublingual or oral spray administration of nitroglycerin should be given as the initial treatment. In acute coronary syndrome complicated with hypertension, SBP should be promptly reduced to < 140 mmHg [183, 447, 1555] . Nitroglycerin is administered by continuous intravenous infusion to reduce myocardial oxygen demand and increase coronary blood flow. However, if right ventricular infarction is suspected, nitroglycerin should be avoided because of the risk of excessive BP reduction due to preload reduction. β-blockers may be used concomitantly if there are no contraindications such as significant bradycardia.

7) Aortic dissection (acute phase) In Stanford Type A aortic dissection, emergency surgery is indicated. In Type B, invasive intervention is recommended in cases of rupture, impending rupture, or branch vessel perfusion impairment. In Type B without these complications, drug treatment is recommended [833] . Rapid diagnosis and treatment by a specialized team are essential in all cases.

SBP should be targeted at 100-120 mmHg, with a heart rate < 60 beats per minute. Rapid control using intravenous medications is recommended during the hyperacute phase [183, 833, [1567] [1568] [1569] . Unless contraindicated, early intravenous administration of β-blockers is recommended for heart rate control [1570] [1571] [1572] [1573] [1574] . If β-blockers are contraindicated, non-dihydropyridine CCBs should be used. If target BP is not achieved after heart rate control, other antihypertensive drugs such as nicardipine, nitroglycerin, or nitroprusside may be used in combination, but agents should be selected with caution to avoid reflex tachycardia. When combining diltiazem with β-blockers, caution is required for bradycardia. 8) Pheochromocytoma, paraganglioma Pheochromocytoma crisis is characterized by a sudden rise in BP due to excessive catecholamine secretion. It can cause myocardial ischemia, life-threatening arrhythmias,

The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and. . .

References

and sudden death; therefore, urgent BP reduction is critical. SBP should be reduced to < 140 mmHg within 1 hour of treatment initiation [626] . Phentolamine 2-5 mg may be administered intravenously at a rate of 1 mg/min until BP stabilizes, and may be repeated every 3-5 min as needed. Following the initial bolus, continuous intravenous infusion of phentolamine may be used. Oral administration of selective α-blockers such as doxazosin should be initiated concurrently. If tachycardia develops, adequate α-blockade should be established before the addition of β-blockers. β-blocker monotherapy is contraindicated because it may precipitate BP elevation through unopposed α-adrenergic stimulation [1575] . In pheochromocytoma, intravascular volume depletion due to pressor effects is common, thus after α-blocker administration, adequate volume expansion with normal saline or other fluids is recommended to prevent hypotension. During surgical BP control, continuous intravenous infusion of phentolamine may be used depending on the patient's BP. However, nicardipine or nitroglycerin may be selected, as they offer easier dose titration and fewer adverse effects. 9) Accelerated malignant hypertension Accelerated malignant hypertension is characterized by a significant increase in BP, typically with a DBP of ≥120-130 mmHg, rapid progression of bilateral retinopathy and renal dysfunction, and a poor prognosis if left untreated, with potential complications, such as hypertensive encephalopathy, cerebral hemorrhage, and heart failure. Previously, malignant hypertension with papilledema (Keith-Wagener classification stage IV) was distinguished from accelerated hypertension presenting only exudative lesions, such as hemorrhage or cotton-wool spots (Keith-Wagener classification stage III). However, since there is no difference in the progression of organ damage or prognosis between the two, they are now collectively referred to as accelerated malignant hypertension.

Malignant hypertension often develops in patients with uncontrolled essential hypertension, either untreated or following discontinuation of antihypertensive therapy, but it can also develop from secondary hypertension such as renal parenchymal or renovascular hypertension [1576, 1577] . The incidence of malignant hypertension is reported to be 1-2 cases per 100,000 population per year [1578, 1579] , with no decline observed in Western countries [1577, 1580] . In the United Kingdom, the 5-year survival rate was poor at 24% in cases prior to 1967, but with the widespread use of antihypertensive drugs, it improved significantly to 93% in cases between 1997 and 2006 [1581] . However, renal outcomes remain poor, with reports indicating that 18% of patients developed end-stage kidney disease within 4 years of onset [1577], and 24% required renal replacement therapy within 5.6 years [1582] . The severity of renal dysfunction at onset and BP levels during follow-up are predictive factors for long-term renal prognosis [1582] , underscoring the importance of long-term BP management beyond the acute phase.

Accelerated malignant hypertension is characterized by progressive arteriolar injury with deposition of plasma components into the walls of small arteries throughout the body, resulting in proliferative endarteritis and fibrinoid necrosis, and should be regarded as a medical emergency [183] . Thrombotic microangiopathy (TMA) may also occur, characterized by platelet thrombosis in microvessels due to vascular endothelial dysfunction caused by increased shear stress, leading to thrombocytopenia, hemolytic anemia, and ischemic organ damage secondary to microcirculatory dysfunction [1555] . Many patients have a long history of hypertension, and rapid BP reduction carries the risk of ischemia in vital organs. Therefore, BP should be lowered gradually over several hours, with the goal of reducing mean BP by approximately 20-25% [183, 447, 1555] .

In accelerated malignant hypertension, progressive renal dysfunction and a vicious cycle of BP elevation occur as a result of volume depletion induced by diuretics and the activation of the RAS associated with necrotizing arteriolar thickening. Therefore, agents that inhibit the RAS, such as ACE inhibitors, ARBs, or β-blockers, are considered effective [183] . However, because fluid volume reduction caused by diuretics is common, administration of ACE inhibitors or ARBs may precipitate worsening renal function due to excessive BP reduction. When used, treatment should be initiated at low doses, with close monitoring of BP, renal function, and serum potassium. In cases of severe diuretic-induced volume depletion, intravenous fluid replacement with normal saline may be necessary. However, if sodium and water retention are present, loop diuretics should be used concomitantly.

【POINT 16b】 【Perioperative BP management】 1. To prevent perioperative complications in hypertensive patients, it is important to identify secondary hypertension, such as pheochromocytoma, and to assess target organ damage and comorbidities 2. If BP is ≥180/110 mmHg in elective surgery, prioritize BP control. 3. In principle, maintain stable BP control throughout the perioperative period by continuing oral or intravenous antihypertensive drugs, including oral administration of drugs on the morning of surgery. 4. New initiation of β-blockers on the day of surgery should be avoided in principle, however, chronic medication is recommended to continue. In high-risk patients with coronary artery disease (excluding those with coronary vasospastic angina or bronchial asthma), consider initiating β-blockers early in the Y. Ohya

References

preoperative period. 5. In patients taking ARBs or ACE inhibitors, monitor for hypotension, volume depletion, and renal dysfunction during and after surgery. In high-risk cases such as older adults, withholdings may be considered depending on the patient's condition and the invasiveness of the surgery to minimize BP fluctuations. 6. Alleviating pain, anxiety, or agitation is also essential to suppress an increase in BP.

2. Perioperative BP management

2. Perioperative BP management

1) Preoperative evaluation Hypertension is highly prevalent and is associated with an increased incidence of perioperative complications. High BP increases the risk of surgical complications such as bleeding; therefore, it is required to manage BP in appropriate levels before surgery [1583] . In patients with untreated hypertension, a differential diagnosis of secondary hypertension, evaluations of target organ damage and complications should be conducted, consequently recognize perioperative risks precisely. Particular attention should be given to conditions in which perioperative BP reductions may cause ischemic complications, with the goal of achieving stable BP control prior to surgery.

If pheochromocytoma is suspected, surgery should be postponed until further evaluation is completed, and tumor resection should be performed once the diagnosis is confirmed. In patients with renovascular hypertension, primary aldosteronism, or Cushing's syndrome, if preoperative BP is controlled below 160/100 mmHg, generally acceptable; however, in cases of elective surgery, treatment for curable secondary hypertension should be prioritized.

There are no reports or guideline-defined BP thresholds for safe surgical procedures. However, preoperative BP could be ≤130/80 mmHg or reduced to target BP values [626] . Preoperative BP control < 160/100 mmHg alone is not a reason to postpone surgery [1584] , but in the presence of hypertensive target organ damage or complications, it can affect the prognosis [1585, 1586] . If BP is ≥180/110 mmHg in elective surgery, postponing surgery may be considered [626] . White coat phenomenon is also common in patients undergoing elective surgery, so evaluation using home BP or 24-h ABPM is recommended [1587] .

2) Antihypertensive treatment in the perioperative period In patients receiving antihypertensive therapy, medications should be continued until the day of surgery and resumed as soon as possible postoperatively. Initiating β-blockers prior to non-cardiac surgery reduces the incidence of non-fatal myocardial infarction, but increases the risk of stroke, mortality, hypotension, and bradycardia [1588] . For patients on chronic β-blockers, treatment should be continued. However, initiation of β-blockers on the day of surgery should generally be avoided [1585] . In patients with high risk of coronary artery disease, a reduction in the incidence of non-fatal myocardial infarction may be expected by treatment with β-blockers. For details, refer to CQ16 in JSH2019.

If intraoperative hypotension, postoperative dehydration, or hypokalemia are concerns, preoperative withholdings of loop diuretics may be considered on an individual basis. However, there is no favorable evidence to support preoperative withholdings of thiazide diuretics [1589] . In patients receiving ACE inhibitors or ARBs, a decrease in fluid volume during the perioperative period may lead to reduction of BP or renal dysfunction, and continued administration increases the risk of intraoperative hypotension [1585, 1590] . However, reports regarding the adverse effect on major CVD events (death, stroke, myocardial injury) are inconsistent [1590, 1591] . In high-risk patients, such as older adults, the decision to withhold administration is considered depending on the patient's condition and the invasiveness of the surgery. If medication is withheld preoperatively, BP and fluid status should be monitored, and postoperative medication is recommended to be resumed promptly [1585] . Perioperative hypotension increases mortality, but postoperative SBP elevation ( > 130 mmHg) is associated with an increased risk of intracranial hemorrhage [1592] . Minimizing perioperative BP fluctuations may reduce complications [1593] .

For emergency surgery and intraoperative BP elevation, BP is managed with intravenous antihypertensive drugs. Postoperatively, due to unstable hemodynamics, antihypertensive treatment is recommended to be resumed early, administered intravenously if oral administration is not possible, and perioperative factors that may increase BP, including pain, anxiety, and agitation, is needed to be appropriately managed.

3) Dental surgery Since there is a risk of CVD during dental treatment, evaluation for the presence of hypertension and pretreatment BP management should be conducted in advance. If BP is ≥180/110 mmHg, prioritize management of hypertension except for emergency procedures [1594] . Patients taking antihypertensive drugs should be instructed to take them on the day of treatment and to control their BP prior to the procedure. BP rises significantly during procedures that cause pain or anxiety, or during prolonged dental procedures [1595] . Local anesthetics containing vasoconstrictive agents can be used safely in hypertensive patients [1596] . The use of local anesthetics containing epinephrine may increase plasma epinephrine levels, but the effect on BP is minimal if the dosage is not high [1597] . Consider the dosage and ensure adequate anesthesia for pain management [1595, 1597] .

The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and. . .

References

List of abbreviations

ABI ankle-brachial index

ABPM ambulatory blood pressure monitoring ACE angiotensin converting enzyme

ACTH adrenocorticotropic hormone

ADL activities of daily living

AHI apnea hypopnea index

AI artificial intelligence

AME apparent mineralocorticoid excess

ARB angiotensin Ⅱ receptor blocker

ARC active renin concentration

ARNI angiotensin receptor-neprilysin inhibitor ARR aldosterone-to-renin ratio

AVS adrenal venous sampling

AYA adolescent and young adult

baPWV brachial-ankle pulse wave velocity

BAT baroreflex activation therapy

BMI body mass index

BNP brain (or B-type) natriuretic peptide BP blood pressure

BRAF B-Raf proto-oncogene

BTK Bruton's tyrosine kinase

CAVI cardio-ankle vascular index

CCB calcium channel blocker

cfPWV carotid-femoral pulse wave velocity cGMP cyclic guanosine monophosphate

CI confidence interval

CK creatine kinase

CKD chronic kidney disease

CLEIA chemiluminescent enzyme immunoassay COPD chronic obstructive pulmonary disease COX cyclooxygenase

CPAP continuous positive pressure breathing CTA CT angiography

CVD cerebro- and cardiovascular disease

CYP cytochrome P450

DAPT dual antiplatelet therapy

DBP diastolic blood pressure

DKD diabetic kidney disease

DOC deoxycorticosterone

eGFR estimated glomerular filtration rate

ESA erythropoiesis stimulating agent

ESKD end-stage kidney disease

FDG fluorodeoxyglucose

FH familial hypercholesterolemia

FMD flow-mediated vasodilatation

GFR glomerular filtration rate

GWAS genome-wide association study

HBP home blood pressure

HBPM home blood pressure monitoring

HDL high density lipoprotein

HDP hypertensive disorders of pregnancy

HELLP hemolysis, elevated liver enzymes, and low platelets

HFmrEF heart failure with mid-range ejection fraction HFpEF heart failure with preserved ejection fraction HFrEF heart failure with reduced ejection fraction HIF-PH hypoxia-inducible factor prolyl hydroxylase High-NBP high normal BP

HQ Healthcare Question

HR hazard ratio

HSD2 hydroxysteroid dehydrogenase 2

ICER incremental cost-effectiveness ratio

IDH isolated diastolic hypertension

IGF-1 insulin-like growth factor-1

IMT intima-media thickness

IV inverse variance

KLHL3-

CUL3

Kelch-like 3 and Cullin 3

LDH lactate dehydrogenase

LDL low density lipoprotein

MAO monoamine oxidase

MCI mild cognitive impairment

MDCT multi-detector (row) CT

MEK mitogen-activated extracellular signal-regulated kinase

MIBG metaiodobenzylguanidine

MR mineralocorticoid receptor

MRA magnetic resonance angiography

MRI magnetic resonance imaging

mTOR mammalian target of rapamycin

N/A not applicable

NBP normal BP

NE not estimate

Y. Ohya

NSAIDs non-steroidal anti-inflammatory drugs NT-proBNP N-terminal prohormone of brain natriuretic peptide

NSAIDs non-steroidal anti-inflammatory drugs NT-proBNP N-terminal prohormone of brain natriuretic peptide

.

The Japanese Society of Hypertension Guidelines for the management of elevated blood pressure and. . .

References

References

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