2024 JCS_JHRS指南：心律失常的管理（更新版）

JCS/JHRS 2024 Guideline Focused Update on Management of Cardiac Arrhythmias

Yu-ki Iwasaki\*; Takashi Noda\*; Masaharu Akao; Tadashi Fujino; Teruyuki Hirano; Koichi Inoue; Kengo Kusano; Toshiyuki Nagai; Kazuhiro Satomi; Tetsuji Shinohara; Kyoko Soejima; Yohei Sotomi; Shinya Suzuki; Teiichi Yamane; Tsukasa Kamakura; Hiroyuki Kato; Arimi Katsume; Yusuke Kondo; Kenji Kuroki; Hisaki Makimoto; Hiroshige Murata; Takafumi Oka; Nobuaki Tanaka; Nobuhiko Ueda; Hiro Yamasaki; Seigo Yamashita; Ryobun Yasuoka; Kenji Yodogawa; Kazutaka Aonuma; Takanori Ikeda; Toru Minamino; Hideo Mitamura; Akihiko Nogami; Ken Okumura; Hiroshi Tada; Takashi Kurita; Wataru Shimizu; on behalf of the Japanese Circulation Society and Japanese Heart Rhythm Society Joint Working Group

Table of Contents

Foreword ∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙3 I. Implantable Cardiac Electrical Devices ∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙4 1. Indications for Primary Prevention of Implantable Cardioverter Defibrillators (ICDs)∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙4 2. ICD indications for Cardiac Sarcoidosis∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙6 3. Leadless Pacemaker∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙8 PQ1. How to Choose Between a Leadless Pacemaker and a Transvenous Pacemaker∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙10 4. Pacemaker Therapy for Reflex Syncope∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙11 5. Future Advances in Implantable Cardiac Electrical Devices∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙11 6. Conduction System Pacing (CSP)∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙12 7. CRT for Mid-Range QRS∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙16 II. Catheter Ablation ∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙18 1. Catheter Ablation Procedures for Atrial Fibrillation in Addition to Pulmonary Vein Isolation∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙18 2. Expanded Indication for Atrial Fibrillation Catheter Ablation∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙20 CQ1. Should Atrial Fibrillation Catheter Ablation Be Performed in Older Patients (>80 Years Old)?∙∙∙∙∙∙∙∙∙∙∙24 3. New Ablation Therapy for Atrial Fibrillation: Pulsed Field Ablation∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙26 4. Advances in Ventricular Premature Contraction (PVC)/Ventricular Tachycardia (VT) Ablation∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙27 CQ2. What Is the Optimal Treatment for Asymptomatic Idiopathic PVC Without Evidence of Left Ventricular Dysfunction?∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙28 III. Atrial Fibrillation Pharmacotherapy and Comprehensive Management ∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙30 1. Japanese Original Stroke Risk Assessment Tool: HELT-E 2 S 2 Score∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙30 PQ2. Which Patients Are Excluded From Anticoagulation Therapy?∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙32 2. Anticoagulation for High-Risk Older Patients∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙33 3. Specific Neutralizers for Factor Xa Inhibitors∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙37 4. Digitalis and Atrial Fibrillation∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙40 5. Atrial Fibrillation and Lifestyle Management/ Comprehensive Management∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙40

References ∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙45 Appendix1 Details of Members ∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙58 Appendix2 Disclosure of Potential Conflicts of Interest ∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙∙59

J-STAGE Advance Publication released online February 14, 2025 This document is an English version of JCS/JHRS 2024 Guideline Focused Update on Management of Cardiac Arrhythmias reported at the $88^{\mathrm{th}}$ Annual Scientific Meeting of the Japanese Circulation Society in 2024. (Website: https://www.j-circ.or.jp/cms/ wp-content/uploads/2024/03/JCS2024_Iwasaki.pdf) Refer to Appendix1 for the details of members. JCS Joint Working Groups: The Japanese Circulation Society; Japanese Heart Rhythm Society; Japanese Society for Cardiovascular Intervention and Therapy; Japan Heart Failure Society; Japan Stroke Association \*Drs. Iwasaki and Noda contributed equally to this work. Mailing address: Guideline Committee of the Japanese Circulation Society, 6th Floor, Uchikanda Central Building, 1-18-13 Uchikanda, Chiyoda-ku, Tokyo 101-0047, Japan. email: jcsGL@j-circ.or.jp All rights are reserved to the Japanese Circulation Society. For permissions, please email: cj@j-circ.or.jp ISSN-1346-9843

|List of Abbreviations| |---|

|ACC| American College of Cardiology| |---|---| |ACT| activated clotting time| |ADL|activities of daily living| |AF|atrial fibrillation| |AHA| American Heart Association| |BMI|body mass index| |BMS|bare metal stent| |CCI| Charlson comorbidity index| |ccr|creatinine clearance| |CFAE| complex fractionated atrial electrogram| |CKD|chronic kidney disease| |CLBBB|complete left bundle branch block | |CLS|closed loop stimulation| |CMR| cardiac magnetic resonance| ||cardiac output| |COPD|chronic obstructive pulmonary disease| |CRT|cardiac resynchronization therapy| |CRT-D|cardiac resynchronization therapy defibrillator| |CRT-P| cardiac resynchronization therapy pacemaker| |CSP|conduction system pacing| |OT|computed tomography| |DBP|diastolic blood pressure| |DDD/DDDR| dual chamber pacing, dual chamber sensing, and pacemaker activation or inhibition on a sensed event / rate-modulated pacing | |DOAC|direct oral anticoagulant | |ECG|electrocardiogram| |eGFR|estimated glomerular filtration rate| |EPS|electrophysiological study| |EV-ICD| extra vascular-implantable cardioverter defibrillator | |FAAM| fractionated signal areas in the atrial muscle| |FDA|US Food and Drug Administration| |FIRM|focal impulse and rotor modulation| |FNNC|filaminC| |Fxa|factorxa| |HBP|His bundle pacing| |HFpEF| heart failure with preserved ejection fraction| |HFrEF|heart failure with reduced ejection fraction| |HHRS|Heart Rhythm Society| |ICD|implantable cardioverter defibrillator| |ILAM|isochronal late activation map| |INR| international normalized ratio| |LBBA|left bundle branch area|

|LBBAP|left bundle branch area pacing| |---|---| |LBBB|left bundle branch block| |LGE|late gadolinium enhancement| |LMNA|laminAC| |LVA|low-voltage areas| |LVAD|left ventricular assist device| |LVEF|left ventricular ejection fraction| |MMSE|mini-mental state examination| |NRI| magnetic resonance imaging| |MRSA| methicillin-resistant Staphylococcus aureus| |NCDR| National Cardiovascular Data Registry| |NSAIDS|non-steroidal anti-inflammatory drugs| |NSVT|non-sustained ventricular tachycardia| |NYHA|New York Heart Association| |PCI|percutaneous coronary intervention| |PCWP|pulmonary capillary wedge pressure| |PFA|pulsed field ablation | |PLN|phospholamban| |PVC|premature ventricular contraction| |PvI|pulmonary vein isolation| |PVS|pulmonary vein stenosis| |0OL|quality of life| |RBM20| RNA binding motif protein 20| |RCT|randomized controlled trial| |RVP|right ventricular pacing| |SBP|systolic blood pressure| |SCD|sudden cardiac death| |S-ICD| subcutaneous implantable cardioverter defibrillator | |SPRM| Seattle proportional risk model| |SUV|standard uptake value| |VRWPT|R wave peak time in lead V6| |VDD| atrial-synchronized ventricular pacing (ventricle pacing, dual chamber sensing, and pacemaker activation or inhibition on a sensed event) | |VOM|vein of Marshall| |VOM-EI|ethanol injection into the vein of Marshall| |VF|ventricular fibrillation| ||ventricular tachycardia| |VVI/VVIR| ventricular demand pacing (ventricle pacing, ventricle sensing, and pacemaker inhibition on a sensed event) / rate-modulated pacing | |6MWD| 6-minute walking distance| | 18F-FDG- PET | 18F-fluorodeoxyglucose-positron emission tomography |

Advance Publication

JCS/JHRS 2024 Guideline Focused Update on Management of Cardiac Arrhythmias

Foreword

On the Focus Update

The Guidelines for the Pharmacological Treatment of Arrhythmias were first published in 2004, followed by the 2009 revision, 1 the 2013 revision of the Guidelines for the Pharmacological Treatment of Atrial Fibrillation (Drugs), 2 and a complete revision in 2020 as the Revision of the Guidelines for the Pharmacological Treatment of Arrhythmias. 3

During the several years since the last revision, drugs related to arrhythmia therapy have become available for clinical use, and evidence has been reported to revise the efficacy of conventional drugs. In particular, anticoagulation therapy for the prevention of cerebral infarction and systemic embolism has become widely used in the treatment of atrial fibrillation (AF), and a variety of evidence including neutralizing agents has been accumulated from Japan and overseas.

In Japan, the aging population is not only prescribed drugs for a single arrhythmic disease, but also for a variety of clinical backgrounds, such as frailty and cognitive function, which must be taken into consideration. The importance of comprehensive management, which includes not only drug therapy but also the identification and intervention of various modifiable risk factors, is now recognized worldwide.

Since the publication of the Guidelines for the Nonpharmacologic Treatment of Arrhythmias in 2000, guidelines for catheter ablation, pacemaker and implantable cardioverterdefibrillator (ICD) therapy, and arrhythmia surgery have been revised in 2006 and 2011. 4 In addition, the atrial fibrillation catheter ablation technique has become common practice due to remarkable progress in medical engineering technology and the establishment of treatment techniques and surgical procedures, diversifying the nonpharmacological treatment of arrhythmia. The 2019 revision 5 was further revised as the 2021 JCS/JHRS Guideline Focus Update for Nonpharmacologic Treatment of Arrhythmias. 6

As noted above, nonpharmacological treatment of arrhythmias has developed at an astonishing pace and is now being utilized for many patients. In Japan, where sudden cardiac deaths are estimated to be as many as 80,000 per year, 7 and a heart failure pandemic is expected to hit in 2025, the role of nonpharmacological therapies such as catheter ablation and ICDs is extremely important, and the demand for these therapies is expected to increase in the future.

Arrhythmia treatment has traditionally been divided into pharmacological and nonpharmacological, with respective guidelines being developed. However, they are not mutually exclusive treatments and in practice, hybrid therapies are often used, with many clinical trials now being conducted to establish evidence for this. In order to emphasize consistency and uniformity in the treatment of arrhythmias and to enhance convenience for practicing physicians involved in arrhythmia treatment, the 2024 JCS/ JHRS Guideline Focus Update for Arrhythmia Treatment (hereinafter referred to as the Focus Update) was developed to unify “arrhythmia pharmacotherapy” and “arrhythmia nonpharmacological treatment”.

Recommended Class and Level of Evidence

In this Focus Update, the recommended classes and levels

of evidence are categorized as shown in Table1 and Table2 . Considering consistency with arrhythmia guidelines in the USA and Europe, the wording of the recommended classes is consistent. Arrhythmia treatment includes many treatments that have been used for a long time, and there is insufficient evidence from randomized controlled trials and other sources, making it difficult to conduct a systematic review using a uniform literature search formula. For this reason, we omitted the Minds recommended grades and Minds evidence level classification based on the Minds Clinical Practice Guideline Development Guide.

Clinical Questions

The Japanese Circulation Society guidelines have introduced a format in which clinical questions (CQs) are set, a systematic review is conducted using the GRADE system, and recommendations are clearly indicated. Because this is a focused update, we did not establish a systematic review group independent of the guideline writing committee members, and instead, we developed 2 CQs that occur in daily practice. In addition, 2 themes that may be helpful in deciding on a treatment plan are also included as Practical Questions (PQs) to answer clinical questions.

Providing Information to the Public and Patients

Currently, the readers of the Japanese Circulation Society guidelines include not only specialists of the disease in question who are engaged in actual medical treatment, but also the general public and patients, in addition to nonspecialists and primary care physicians. This diversification of guideline users is due to the growing importance of the process of sharing information about diseases and treatment between patients and their families and healthcare professionals, and forming a consensus through thorough consultation. Moreover, in promoting shared decisionmaking, providing information to citizens and patients is

||Table 1. Recommended Class Classification|| |---|---|---| | Class I| There is evidence or widespread agreement that the|| | Class I|procedure/treatment is effective and useful|| |Classlla| Likely to be effective/useful based on evidence/ opinions || |Class lib| Evidence/opinion indicates that efficacy and usefulness are not so well established || |Class Ill|There is evidence that the procedure/treatment is not|| |(No benefit)| effective or useful. Or there is a broad consensus of|| |Class ll||| |(Harm)| There is evidence or widespread agreement that the procedure/treatment is harmful ||

|Table 2. Levels of Evidence|| |---|---| |LevelA|Demonstrated in multiple randomized interventional| |LevelB| Demonstrated in a single randomized intervention clinical trial or a large non-randomized intervention clinical trial | |LevelC| Consensus among experts and/or small clinical trials (including backward-looking studies and registries) |

crucial, and this focus update guideline includes six topics related to arrhythmia treatment.

Publication of the Guidelines and Conflicts of Interest

This Focus Update was jointly prepared by the Japanese Circulation Society and the Japanese Heart Rhythm Society, with the participation of the Japanese Association of Cardiovascular Intervention and Therapeutics, the Japanese Heart Failure Society, and the Japanese Stroke Society. Six external reviewers were asked to review the manuscript, and revisions were made as necessary based on the opinions obtained.

Finally, the role of this 2024 Guideline Focused Update on Management of Cardiac Arrhythmias, is to provide information that will enable safe and effective implementation of the latest treatments in daily practice. However, in actual clinical practice, it is difficult to provide uniform treatment because of the variety of patients, their clinical backgrounds, and responses to treatment. The final decision regarding specific patient care and management should be made by the physician and medical staff in charge of the patient, who set individual goals with the patient and family, and share information and intentions as appropriate. We hope that this Focus Update will help in this regard.

I. Implantable Cardiac Electrical Devices

1. Indications for Primary Prevention of Implantable Cardioverter Defibrillators (ICDs)

Several randomized controlled trials (RCTs) have investigated the role of ICDs for primary prevention in patients with reduced left ventricular ejection fraction (LVEF), and have shown efficacy in preventing sudden cardiac death (SCD) in heart failure patients with LVEF ${\le}35\%$ . 8 , 9 On the other hand, the DANISH trial, a prospective comparative study of ICDs in 1,116 patients with nonischemic cardiomyopathy, showed no clear mortality benefit of ICDs for primary prevention in patients with nonischemic cardiomyopathy. 10 A meta-analysis of 6 trials for nonischemic

|Table 3. Recommendations and Levels of Evidence for||| |---|---|---| |Primary Prevention Indications for ICDs||| ||COR|LOE| |Assessment of comorbidities, including frailty||| ||ma|| |patients at high risk of arrhythmic death and|ma|| |iow risk of non-arrhythmic death when|ma|| | considering the ICD indications in elderly patients Use of the MADIT-ICD Benefit Score*1 or the |ma|| |SPRM*2 scoring should be considered to|iia|| |assess the risk of arrhythmic and non-|iia|E| ||iia|E| | arrhythmic death in HF patients when determining the ICD indication |iia|E| |ICD implantation should be considered in|iia|| |non-ischemic cardiomyopathy patients with||| |an LVEF|||

\* 1 https://redcap.urmc.rochester.edu/redcap/surveys/index.php?s =3H888TJ8N7 (accessed November 2023) \* 2 https://depts.washington.edu/sprm/about.php (accessed November 2023) CMR, cardiac magnetic resonsnce; COR, Class of Recommendation; EPS, electrophysiological study; FLNC, filamin C; HF, heart failure; ICD, implantable cardioverter defibrillator; LGE, late gadolinium enhancement; LMNA, lamin A/C; LOE, Level of Evidence; LVEF, left ventricular ejection fraction; PLN, phospholamban; RBM20, RNA binding motif protein 20; SPRM, Seattle Proportional Risk Model; VT, ventricular tachycardia.

cardiomyopathy, including DANISH, 11 showed that ICDs significantly reduced relative mortality; however; it was unclear whether the ICD was more useful in selected patients. It is necessary to identify the patient population in which ICDs are most useful.

In the subanalysis of the Nippon Storm study, Sasaki et al. reported that the incidence of appropriate ICD therapy in nonischemic cardiomyopathy patients for primary prevention was $21\%$ , during a mean follow-up of 775 days. 12 The HINODE study 13 showed that the mortality and appropriate ICD therapy rates were similar to those in MADIT-RIT for Japanese heart failure patients. In that study, 171 propensity-matched patients for primary prevention from among 354 enrolled patients were compared to 985 patients in the MADIT-RITstudy, 14 which revealed no significant differences in annual survival rates $(96.3\%$ in the HINODE group vs. $96.9\%$ in the MADITRIT group, $\mathrm{{P}{=}0.29}$ ) or annual appropriate ICD therapyfree rates $(94.7\%$ vs. $96.8\%$ , $\mathrm{{P}{=}0.61}$ ) between the 2 groups. The incidence of fatal arrhythmias in patients with heart failure in Japan in recent years is comparable to that in Europe and the USA, but higher than previously thought.

▋ ▋ 1.1 Elderly Patients ( Table3 )

Use of an ICD as primary prevention in elderly patients is effective in preventing SCD from fatal arrhythmias; however; it is essential to carefully consider the indication for ICD because of the higher risk of non-arrhythmic death from concomitant comorbidities compared with younger patients. Zakine et al. 15 compared the clinical outcomes of 150 patients with ICDs aged ${>}80$ years and 150 patients with ICDs aged ${<}80$ years from among 8,333 screened patients from 15 centers. During a mean follow-up of 3.0 years, there were no significant differences in appropriate ICD therapy ( $19.4\%$ vs. $21.6\%,$ , $\mathrm{{P{=}0.48)}}$ or complications related to the ICD $(21.2\%$ vs. $14.0\%$ , $\mathrm{{P}{=}0.10}$ ), but the all-cause mortality rate was significantly higher in the elderly patients $36.3\%$ vs. $12.9\%$ , $\mathbf{P}{=}0.0{\dot{0}}5,$ ). In the MADIT-ICD benefit score constructed from 4 MADIT studies, age $({\geq}75$ years) was associated with increased risk of non-arrhythmic death. 16

The EU-CERT- $\mathrm{ICD^{17}}$ is a prospective cohort study of 2,247 patients with ischemic and non-ischemic cardiomyopathy (1,516 in the ICD implantation group and 731 in the non-ICD implantation group, New York Heart

Association [NYHA] functional class II/III: LVEF ${\le}35\%$ ; NYHA functional class I: LVEF ${\le}30\%$ ) enrolled from 44 centers in 15 European countries. Multivariable models and propensity score matching revealed that the overall mortality rate was significantly lower in the ICD implantation group than in the control group $(5.6\%/$ year vs. $9.2\%/$ /year, hazard ratio [HR] 0.73, $\mathrm{{P}{=}0.014}$ ), but there was no significant mortality reduction by ICD in patients aged ${\geq}75$ years (HR 1.06, $\mathrm{P{=}}0.821$ ). A subanalysis of DANISH, a randomized controlled trial of ICDs in 1,116 patients with nonischemic cardiomyopathy, also found a mortality reduction with ICDs in patients aged ${\le}70$ years (HR 0.70, $\mathrm{{P}{=}0.03}$ ), but not in patients ${>}70$ years (HR 1.05, $\mathrm{{P}{=}0.84)}$ ). The non-sudden death rate was 2.7 per 100 person-years in patients ${\le}70$ years, and 5.4 per 100 person-years in patients ${>}70$ years, indicating a difference in modes of death. 18

Thus, the risk of non-arrhythmic death is higher in the older patient than in the young, and an ICD has a limited effect on mortality reduction. Therefore, when determining the indication for primary prevention ICD in older patients, it is important to select patients in whom ICDs will be highly effective in preventing arrhythmic death and in whom the risk of non-arrhythmic death is low.

It is important to assess frailty, dementia, and comorbidities when considering the risk of non-arrhythmic death. 19 In the National Cardiovascular Data Registry (NCDR), a cardiovascular disease database in the USA, 83,792 patients with primary prevention ICDs enrolled from 2006 to 2009 were reported to have frailty in $10\%$ and dementia in $1\%$ . The 1-year mortality rate was $22\%$ in patients with frailty and $2{\dot{7}}\%$ in those with dementia, compared with $12\%$ overall. 20 A meta-analysis of frailty and ICDs found a correlation between frailty and death, but the report pointed out that the definition of frailty was not consistent across studies and included the cumulative deficit model, low physical component summary score, low body weight, and 6-minute walking distance (6MWD). 21

In a report on 121 elderly patients after ICD implantation, 22 higher Charlson Comorbidity Index (CCI), 23 a score used to assess comorbidities for the prediction of death, significantly decreased survival rates, and the 5-year survival rates for patients with a CCI of 0 to 1, 2–3, and ${\ge}4$ were $78\%$ , $57\%$ , and $29\%$ , respectively. When considering the indication for an ICD in the older patient, it is necessary to consider frailty, cognitive function, and comorbidities for each individual case.

▋ ▋ 1.2 Risk Factors for Fatal Arrhythmias and ICD Indications ( Table3 )

Personalized assessment of the risk of SCD from fatal arrhythmias and the risk of non-arrhythmic death should be considered when determining the indication for primary-prevention ICD. Recently, a score that predicts fatal arrhythmias and non-arrhythmic deaths was reported. The MADIT-ICD benefit score is based on 8 predictors of life-threatening arrhythmias (LVEF ${\le}25\%$ , atrial arrhythmia, heart rate ${>}75$ beats/min, systolic blood pressure ${<}140\,\mathrm{mmHg}$ , myocardial infarction, age ${<}75$ years, male sex, and prior non-sustained ventricular tachycardia [NSVT]), and 7 predictors of non-arrhythmic death (ICD or implantable cardioverter-defibrillator with biventricular pacing [CRT-D], NYHA class ${>}\mathrm{II}$ , diabetes mellitus, body mass index [BMI] ${<}23\,\mathrm{kg}/\mathrm{m}^{2}$ , atrial arrhythmia, LVEF ${<}25\%$ , age ${>}75$ years) (https://is.gd/madit). 16 In the same

score, the risk of fatal arrhythmia is approximately 3-fold higher than the risk of non-arrhythmic death in the group with the highest score (76–100) ( $20\%$ vs. $7\%$ , $\mathrm{P}{<}0.001$ ). Dauw et al. also examined the usefulness of the MADITICD benefit score in 475 cardiac resynchronization therapy (CRT) patients and found that the rates of fatal arrhythmia were $1.8\%$ in the lowest benefit score group, $4.1\%$ in the intermediate benefit score group, and $14.4\%$ in the highest benefit score groups while arrhythmic deaths were $19.4\%$ , $14.6\%$ , and $3.3\%$ , respectively. 24 Thus, the MADIT-ICD benefit score may be useful for identifying the need for defibrillation function in CRT patients. However, Fukuoka et al. pointed out that this scoring system has the limitations that few Asian patients were included in the RCTs, and they are considered to be at low risk of SCD, 25 – 28 and that patients with multiple comorbidities and relatively preserved cardiac function were not included. 29

An ICD indication using the Seattle Proportional Risk Model (SPRM, http://depts.washington.edu/sprm/about. php) to predict risk of arrhythmic death and all-cause death has also been proposed. The SPRM is a predictive model of sudden and non-sudden death based on the clinical backgrounds of 9,885 heart failure patients without ICD implantation, and it uses NYHA functional class, diabetes mellitus, digoxin use, age, BMI, LVEF, systolic blood pressure, serum sodium level, and serum creatinine level as assessment factors. 30 Bilchick et al. 31 examined the validity of the SPRM using the NCDR registry, which is the American College of Cardiology’s suite of cardiovascular data registries. They performed overall survival analysis in quintiles of 98,846 patients with heart failure with reduced ejection fraction (HFrEF, LVEF ${\le}35\%$ ; 87,914 with ICD implantation and 10,932 without ICD implantation) using the SPRM. Fukuoka et al. validated the SPRM in a Japanese registry of heart failure patients, and reported that a $30\%$ reduction in mortality could be expected with an ICD in 667 Japanese patients with LVEF $\Bar{\le}35\%$ and at high risk of SCD as assessed by the SPRM. 32

The usefulness of scoring systems regarding ICD indication that includes both the risk of fatal arrhythmias and the risk of non-arrhythmic death has been reported, however; these risk stratification scores need to be validated in Japanese cohorts. In determining the indication for ICD, the benefit of an ICD should be assessed comprehensively, taking into account not only scores, but also the benefits of the ICD, including the patient’s life expectancy, and comorbidities. It is also important to provide sufficient information to the patient to enable comprehensive patient-centered decision-making.

▋ ▋ 1.3 Ischemic Cardiomyopathy

It was believed that patients with ischemic cardiomyopathy in Japan had a low risk of SCD after myocardial infarction, 33 , 34 and the use of ICD in patients with an ICD indication was reportedly low in real-world clinical practice. 35

It is well-known that primary-prevention patients have a lower rate of ICD therapy than secondary-prevention patients. 36 However, in a subanalysis of the Nippon Storm study of 493 patients with ischemic cardiomyopathy and an ICD, in which propensity score matching was used for selecting 133 patients for primary prevention and 133 patients for secondary prevention, there was no significant difference regarding the 2-year appropriate ICD therapy

rates ( $15.3\%$ in the primary-prevention group and $23.9\%$ in the secondary-prevention group, $\mathrm{{P}{=}0.114)}$ ). 37 In the JID-CAD registry of 392 patients with ischemic cardiomyopathy (165 for primary prevention and 227 for secondary prevention), the rate of appropriate ICD therapy in the primary- and secondary-prevention groups was similar $(\mathrm{P{=}0.576})$ . 38 An et al. also reported that the rate of appropriate ICD therapy was $37\%$ at 3 years in patients with ischemic cardiomyopathy (LVEF ${\le}30\%$ ) who met the MADIT-II inclusion criteria. 39 Thus, in Japanese patients with ischemic cardiomyopathy, the rate of appropriate ICD therapy currently does not differ between primary and secondary prevention patients, and it is suggested that the use of ICDs for primary prevention in patients with ischemic cardiomyopathy may not be sufficient.

In the 2022 European Society of Cardiology (ESC) guidelines for the management of patients with ventricular arrhythmias and the prevention of SCD, primary-prevention ICD therapy for heart failure patients with NYHA functional class II and LVEF ${\le}35\%$ is recommended Class I, and the presence of NSVT is not included. 40 On the other hand, NSVT has been reported as a predictor of SCD and a risk factor for appropriate ICD therapy. A previous meta-analysis reported that the specificity of NSVT for predicting SCD in patients with heart failure with reduced ejection fraction (HFrEF) was as high as $89–97\%$ . 41 Makimoto et al. indicated that NSVT after ICD implantation was documented in $32\%$ of patients with a primaryprevention ICD, and those with documented NSVT had a higher risk of subsequent appropriate ICD therapy. 42 In a Japanese multicenter observational prospective study (JANIES-SHD, $66\%$ ischemic heart disease), it was shown that low LVEF and documented NSVT on Holter ECG were independent predictors of fatal arrhythmic events. 43

Although the risk of fatal arrhythmias is clearly higher in patients with NSVT, the use of an ICD should be proactively considered, even in the absence of NSVT, in patients with ischemic cardiomyopathy and severely impaired left ventricular function.

recommend an ICD in patients with non-ischemic cardiomyopathy and left ventricular dysfunction (LVEF ${<}50\%$ ) who have ${\geq}2$ of the following 4 risks: (1) syncope, (2) LGE on CMR, (3) monomorphic VT induced during electrophysiological study (EPS), and (4) pathogenic mutations of the LMNA /phospholamban [ PLN ]/filamin C $[F L N C]/$ RNA binding motif protein 2 $)~[R B M2O]$ genes. 40 It is important to consider LGE on CMR and genetic testing in assessing the risk of lethal arrhythmias when considering the indication for primary prevention ICD.

2. ICD Indications for Cardiac Sarcoidosis

Sarcoidosis is a systemic inflammatory disease characterized by non-caseating granulomas of unknown cause. 47 Among the affected organs, pulmonary involvement is the most common, but cardiac involvement (cardiac sarcoidosis) is observed in ${\approx}5\%$ of patients, and cardiac involvement is responsible for about half of all deaths due to sarcoidosis. 48 , 49 In recent years, isolated cardiac sarcoidosis with lesions only in the heart 50 and a poor prognosis 51 as been reported, which has increased the importance of differential diagnosis.

▋ ▋ 2.1 Clinical Features of Cardiac Sarcoidosis

The clinical presentation of cardiac sarcoidosis is characterized by heart failure due to left ventricular dysfunction and SCD due to advanced atrioventricular block or fatal ventricular arrhythmias (VT/ventricular fibrillation [VF]). 52 Complete atrioventricular block is often attributed to granulomatous inflammation, 53 and VT/VF to scar formation due to tissue fibrosis, but it has been suggested that inflammation may directly cause VT/VF. 54 Because inflammation is the main pathophysiology in cardiac sarcoidosis, the mainstay of treatment is immunosuppressive therapy, including steroids. 55 , 56 Therefore, even in cases in which an ICD is indicated, adequate immunosuppressive therapy should be administered.

▋ ▋ 1.4 Non-Ischemic Cardiomyopathy ( Table3 )

Late gadolinium enhancement (LGE) on cardiac magnetic resonance (CMR) and genetic testing have been reported as useful in risk stratification of fatal arrhythmias in non-ischemic cardiomyopathy. In a meta-analysis of 2,948 patients with non-ischemic considering cardiomyopathy, LGE was present in $42\%$ of patients with a primaryprevention ICD, and the annual incidence of fatal arrhythmias was significantly higher in patients with LGE compared with those without LGE ( $17.2\%$ vs. $2.1\%$ , HR 7.8, $\mathrm{{P}{=}0.007]}$ ), but LGE did not correlate with LVEF $(\mathrm{P=}0.22)$ . 44 Furthermore, in a study of 1,020 patients with non-ischemic cardiomyopathy, the occurrence of fatal arrhythmias was significantly associated with LGE on CMR, but there was no significant association between LVEF ${\le}35\%$ and SCD. 45 These results may indicate the limitations of using LVEF alone to predict the risk of fatal arrhythmias in non-ischemic cardiomyopathy.

Regarding genetic testing, in a study of 487 individuals with non-ischemic cardiomyopathy, pathogenic gene variants were identified in $37\%$ of patients, and the patients with LMNA , a nuclear membrane lining protein, had a significantly higher risk of SCD and fatal arrhythmias. 46

In light of these findings, the 2022 ESC guidelines

Recent, relatively large-scale epidemiological studies showed a high incidence of VT/VF and SCD in patients with cardiac sarcoidosis. 57 , 58 In a study of patients who received an ICD for primary prevention, VT/VF more frequently occurred early after ICD implantation in those with cardiac sarcoidosis compared with those having dilated cardiomyopathy 59 In a multicenter retrospective study of 351 patients in Finland, SCD occurred in ${\approx}14\%.$ , accounting for $\stackrel{\sim}{\approx}80\%$ of deaths. 57 A multicenter retrospective study of 512 patients in Japan also reported an incidence of VT/VF or SCD of ${\approx}20\%$ in the first 5 years after diagnosis. 58 , 60

▋ ▋ 2.2 Factors Associated With the Development of VT/VF

Typical factors associated with the development of VT/VF are (1) LVEF ≤ 35%, 60 , 61 (2) advanced atrioventricular block, 62 , 63 (3) delayed enhancement on the right or left ventricle in CMR, 64 – 67 and (4) residual myocardial inflammation. VT/VF and SCD may occur in patients with preserved LVEF, and in those patients, the usefulness of risk stratification by cardiac EPS, 68 , 69 delayed enhancement on CMR, 67 cardiac $^{18}\mathrm{F}.$ -fluorodeoxyglucose-positron emission tomography ( 18 F-FDG-PET) and 67 gallium (Ga) scintigraphy has been reported. 67 , 70 , 71

JCS/JHRS 2024 Guideline Focused Update on Management of Cardiac Arrhythmias

|Table 4. Recommendations and Levels of Evidence for ICD Treatment in Cardiac Sarcoidosis||| |---|---|---| ||COR|LOE| |ICD implantation is recommended in patients with history of cardiac arrest or sustained VT||E| |ICD implantation is recommended in patients with LVEF≤35%||E| | ICD implantation (CRT-D) should be considered in patients with 35% |||

AV, atrioventricular; CMR, cardiac magnetic resonsnce; COR, Class of Recommendation; CRT-D, cardiac resynchronization therapy defibrillator; EPS, electrophysiological study; ICD, implantable cardioverter defibrillator; LGE, late gadolinium enhancement; LOE, Level of Evidence; LVEF, left ventricular ejection fraction; PET, positron emission tomography; VT/VF, ventricular tachycardia/ventricular fibrillation.

Mehta et al. investigated the prognostic value of EPS in 76 asymptomatic patients with histologically diagnosed extracardiac sarcoidosis and abnormal findings on cardiac 18 F-FDG-PET and CMR. In 8 of the 76 $(11\%)$ patients, VT/VF was induced, and during follow-up (median 5 years), 6 of 8 had VT/VF or SCD. In contrast, only 1 death occurred among the 68 patients in whom VT/VF was not induced. 72 Therefore, it is reasonable to use an EPS for risk stratification.

▋ ▋ 2.3 Usefulness of ICD for Cardiac Sarcoidosis

There are many reports on the usefulness of ICDs for cardiac sarcoidosis, both for primary and secondary prevention. 73 – 75 ICD implantation for primary prevention is particularly useful in patients with LVEF ${\le}35\%$ , 61 , 73 and is strongly recommended in the guidelines (Class I Recommendation). 40 , 76 In addition, as noted earlier, the risk of VT/VF or SCD is significantly increased in cardiac sarcoidosis patients with advanced atrioventricular block, indicating the need for a permanent pacemaker (especially when NSVT is present 77 ) or when CMR shows a large extent of delayed enhancement 67 , 74 , 78 and an ICD should be considered for these patients. 40 , 76

Recently, quantitative evaluation of delayed enhancement in CMR has become possible, and its usefulness in predicting VT/VF and SCD has been reported. 65 , 79 , 80 However, no standard quantitative methods with adequate consensus have been established. Among the studies of risk stratification using CMR, most studies defined a large extent of delayed enhancement for high risk of adverse events as ${>}20\%$ of myocardial weight, even after inflammation was controlled by immunosuppressive therapies. 58 , 65 , 79 , 80

Regarding 18 F-FDG-PET and 67Ga scintigraphy, not only are there reports suggesting their usefulness in risk stratification, 70 , 71 , 81 but also negative reports, 82 making it difficult to assess the risk using these modalities alone. In

particular, 18 F-FDG-PET imaging is difficult to use for judging the indication for ICD implantation as primary prevention, because the standardized uptake value (SUV) varies widely among centers and is difficult to quantify.

However, patients with right ventricular FDG accumulation or residual inflammation in abnormal areas on perfusion scintigraphy are at particularly high risk, 81 and in patients with residual inflammation that has been determined to be refractory to immunosuppressive drugs, risk assessment for SCD should be performed by cardiac function, delayed enhancement on CMR, and EPS. Kazmirczak et al. 83 validated these risk factors in a retrospective cohort of 290 patients using the American College of Cardiology (ACC)/American Heart Association (AHA)/ Heart Rhythm Society (HRS) guidelines. The guidelines were validated with an annual incidence of SCD or VT/VF ranging from $19.4\%$ to $81.7\%$ and from $2.1\%$ to $19.6\%.$ , respectively, in patients with Class I or IIa ICD indication. In a Japanese retrospective cohort of 188 patients, $3.9–6.8\%$ and $2.4–2.5\%$ per year of SCD or VT/VF, respectively, occurred in patients assigned a Class I or IIa Recommendation for ICD indication in the ACC/AHA/HRS guidelines, generally supporting the validity of the guidelines. 84

Therefore, the evidence-based decision on the indication for ICD treatment in Japanese patients with cardiac sarcoidosis is basically consistent with the European and American guidelines. Table4 shows the recommendations and level of evidence for ICD for cardiac sarcoidosis, and Figure1 shows the algorithm for determining the indication for ICD based on the recommendations.

Some patients with cardiac sarcoidosis cannot be evaluated by CMR because of permanent pacemaker implantation, intrabody metallic devices, or renal impairment. Although the evidence is not sufficient for recommendation, fragmented QRS on 12-lead ECG, 85 , 86 the T-peak to T-end interval to QT interval ratio, 87 and thinning of the ventricular septal base on echocardiography have been reported as

 Figure1. Algorithm for ICD implantation. CMR, cardiac magnetic resonance imaging; EPS, electrophysiological study; ICD, implantable cardioverter defibrillator; LVEF, left ventricular ejection fraction; VF, ventricular fibrillation; VT, ventricular tachycardia.

significantly associated with the risk of VT/VF. 88 Notably, Nordenswan et al. showed that the 5-year incidence of SCD in patients with cardiac sarcoidosis who do not meet the US guideline recommendations for a Class I or IIa indication is relatively high at $4.8\%$ ( $95\%$ confidence interval [CI] 1.2-19.1), 89 and more precise risk stratification is warranted.

3. Leadless Pacemaker

The indications for leadless pacemakers ( Figures2 , 3 ) were discussed in the 2021 JCS/JHRS Guideline Focus Update for Non-pharmacologic Treatment of Arrhythmias 6 regarding venous obstruction and stenosis, and the need for preservation of venous access. Since then, the indications for leadless pacemakers have continued to expand, and various evidences have emerged. This Focus Update describes the new models and modes that have become available, as well as new findings on efficacy and safety. Recommendations for leadless pacemaker implantation are listed in Table5 .

▋ ▋ 3.1 Applicable Age

Leadless pacemakers have tended to be used primarily in patients with bradycardic atrial fibrillation and older patients due to the difficulty in achieving atrioventricular synchronization such as VVIR or VDDR modes (Micra TM AV). However, concerns that transvenous pacemaker implantation in younger patients may result in prolonged exposure to infection risk and that high activity may increase the risk of lead damage have led to a reconsideration of the usefulness of leadless pacemakers in these populations.

Although no conclusions have been reached regarding the management of leadless pacemaker at the end of life (i.e., whether the pacemaker should be removed at the time of new implantation), $78\%$ of experts in the UK Expert Consensus 90 said that leadless pacemaker implantation in patients aged ${<}40$ years is reasonable. Patients recommended for leadless pacemaker implantation include those at high risk of infection, endstage renal failure, with a history of device infection, anatomic constraints that prevent transvenous lead implantation, on medications such as steroids or immunosuppressive drugs, under radiation therapy, congenital heart disease, ${<}40$ years of age, and with or in need of an intravascular catheter.

In a multicenter, retrospective, observational study of 35 patients aged 18–40 years, the safety endpoint (no major complications attributable to the system or procedure) was achieved $100\%$ of the time with an average of 26 months of observation and was stable at a pacing threshold of ${<}2\,\mathrm{V}$ at 0.24ms pulse width. The efficacy endpoint (threshold increase ${\leq}1.5\,\mathrm{V}$ from the time of implantation) was $94\%$ . 91

Although implantation of a leadless pacemaker in younger patients is expected to expand in the future, the 2021 ESC guideline comments that careful decisions should be made for patients whose life expectancy is expected to exceed 20 years. 92 The possibility of multiple implantations and the decision at the time of battery depletion (i.e., choice between removal and turning it off, etc.) should be considered.

▋ ▋ 3.2 Safety

The Micra CED study used U.S. Medicare data to evaluate the mid-term outcomes at 3 years after implantation of the Micra TM VR (6,219 patients) and transvenous VVI leadless pacemaker (10,212 patients). Compared with transvenous VVI pacemakers, the Micra TM VR had a similar all-cause mortality rate (HR 0.97, $95\%$ CI 0.92–1.03), but lower rates of remote complications (HR 0.68, $95\%$ CI 0.59– 0.78), device re-intervention (HR 0.59, $95\%$ CI 0.44-0.78), infection $(<\!0.2\%$ vs. $0.7\%$ , $\mathrm{P}{<}0.0001$ ), and heart failure

 Figure2. Leadless pacemakers available in Japan (as of November 2023). ( Left ) VVI type, ( Right ) VVI or VDD type.

 Figure3. Schematic diagram of leadless pacemaker implantation in the heart.

hospitalization. A significant reduction in the heart failure hospitalization rate was found (HR 0.90, $95\%$ CI 0.84– 0.97). 93 These results indicate that the benefits of leadless pacemakers are maintained in the medium term perspective.

▋ ▋ 3.3 New Leadless Pacemaker

The Aveir TM VR (Abbott) was approved in Japan in December 2022 and implantation has begun. This leadless pacemaker, an improvement on its predecessor Nanostim TM , is characterized by the ability to measure electrical information before fixation and the possibility of upgrading to DDD in the future (DDD is not approved in Japan as of January 2024). In a prospective DDD leadless study of 300 patients published in June 2023, the implantation success rate was $98.3\%$ , device- and procedure-related complications (e.g., intraoperative and postoperative dislodgement in $1.7\%$ and $0.7\%$ of patients, respectively) were ${\approx}9.7\%$ , and ${>}70\%$ atrioventricular synchronization at 3 months after implantation was observed in $90.2\%$ of patients. 94 The Aveir TM VR was implanted in 200 patients in LEADLESS-II Phase 2, and a mean follow-up of 3.9 months showed that both safety $(96.0\%$ , $95\%$ CI 92.2– $98.2\%$ ) and efficacy endpoints $(95.9\%,95\%\,\mathrm{CI}\,92.1\mathrm{-}98.2\%)$ were favorable. The most common complications were tamponade (3 patients, $1.5\%$ ; open chest in 2 cases) and incomplete implantation $(1.5\%)$ , which were considered generally similar to those for Micra TM . 95 For Nanostim TM , the predecessor of Aveir TM , an extraction system was available and it has been reported that extraction is possible up to 9 years after implantation. 96 However, the degree of difficulty of removal after long-term implantation has not been fully investigated, leaving many aspects still unknown.

▋ ▋ 3.4 VDD Mode

The Micra TM AV uses an accelerometer to sense atrial contraction and enables atrial-synchronized ventricular (VDD) pacing. The MARVEL2 study of patients with normal sinus node function and complete atrioventricular block showed a higher rate of synchronized atrioventricular pacing in the VDD mode compared with VVI mode, but the evaluation was limited to relatively short periods of time at rest. 97

| Table 5. Recommendations and Levels of Evidence for Leadless Pacemaker Implantation ||| |---|---|---| |||| ||COR|LOE| |||| | Implantation of a leadlesspacemaker is recommended for patients with the followingrecommended for patients with the following conditions: ||| |(1) high risk of infection, (2) endstage renal||| |failure, (3) history of device infection, (4)||| | anatomic cause of difficulty in transvenous lead implantation such as congenital heart ||| |||E| |disease, (5) on drug therapy such as steroids||| | or immunosuppressive drugs, (6) under radiation therapy, (7) under long-term ||| |intravascular catheter placement or a past||| |||| | history of long-term intravascular catheter placement ||| |Evaluation of the following risk factors for||| |||| | cardiac perforation and effusion is recommended: ||| | recommended: (1) age ≥85 years, (2) BMI |||

BMI, body mass index; COPD, chronic obstructive pulmonary disease; COR, Class of Recommendation; HF, heart failure; LOE, Level of Evidence.

In the Accel AV study, 152 patients with atrioventricular block were implanted with the Micra TM AV, and their atrioventricular synchrony in daily life was evaluated at 1 month. The VDD mode of the Micra TM AV demonstrated an average of $85.4\%$ atrioventricular synchrony at rest and improved quality of life. 98 On the other hand, atrioventricular synchrony during activity was low at $74.8\%$ , but careful reconfiguration resulted in an additional improvement of ${>}10\%$ . The fusion of A3 (the period between ventricular diastole and A4 (atrial contraction) due to increased heart rate, and decreased sensing of atrial contraction due to body movement were considered to be responsible for loss of atrioventricular synchrony. In highly active patients, patients with atrioventricular block and preserved sinus function, and in patients with atrial dysfunction, Micra TM AV may decrease the rate of atrioventricular synchrony. Optimization of the outpatient program setting is considered important once patients return to daily activities. 99

▋ ▋ 3.5 Risk Assessment of Complications

Leadless pacemakers have no lead or pocket-related complications than transvenous pacemakers, but myocardial perforation and pericardial effusion occur in $1–2\%$ of cases. 100 , 101 Preoperative risk assessment is important because some patients require open chest surgery for myocardial perforation.

Piccini et al. 102 collected data on 2,817 patients from 3 international clinical trials of Micra TM , and validated a risk score for pericardial effusion on implantation in 32 patients with pericardial effusion. Among many clinical characteristics, the investigators ultimately determined that age ${>}85$ years, BMI ${<}20\,\mathrm{kg}/\mathrm{m}^{2}$ , female sex, heart failure, old myocardial infarction, pulmonary hypertension, chronic obstructive pulmonary disease (COPD), and dialysis were risk enhancing factors, and age ${<}85$ years, atrial fibrillation, post open heart surgery, and coronary artery disease were risk-reducing factors. They developed a risk score with 1 point for enhancing factors (2 points for COPD) and minus 1 point for reducing factors, and found that intermediaterisk (1 point) and high-risk (2 or more points) patients had significantly more pericardial effusions $(0.4\%$ , $1.5\%$ , and $4.8\%$ predictive value for each) than low-risk (0 point) patients. This high-risk group of patients should be especially cautioned because repeated Micra TM deployments increase the risk of pericardial effusions.

In the Micra VR Acute Performance registry in Japan that includes 300 patients, major complications at 1 and 6 months postoperatively were similar to those in the international registry, but Japanese patients were older, had lower BMI, were more likely to be female, and had more risk factors for pericardial effusion. 103

▋ ▋ 3.6 Leadless Pacemaker as a Replacement After Device Removal

There have been several reports on leadless pacemaker implantation as an alternative to temporary pacing in pacing-dependent patients after device removal due to infection. Beccarino et al. 104 reported the results of 86 patients, including 65 patients with bacteremia, who underwent device removal and simultaneous leadless pacemaker implantation. The patients were followed for 163 postoperative days, and there was no recurrence of infection. They reported that 25 deaths $(29\%)$ , $88\%$ of which were not causally related to infection; however, 9 patients had methicillin-resistant Staphylococcus aureus (MRSA) or Candida infection, and 3 patients had persistent infection despite lead removal.

Breeman et al. performed leadless pacemaker implantation before (4 patients), simultaneously (5 patients) or after (20 patients) device removal. During the 32 months of follow-up, no cases of re-infection were observed, but bleeding from the femoral artery occurred in 2 patients. 105 Bicong et al. also analyzed 39 patients who underwent leadless pacemaker implantation after device removal due to infection, and reported no cases of re-infection but 3 of complications (puncture site hematoma, femoral arteriovenous fistula, and pacemaker syndrome) after a mean follow-up of 2 years. 106

A multicenter study comparing leadless pacemaker implantation after device removal (184 patients) with initial leadless pacemaker implantation (995 patients) found no significant differences in implantation-related complications

( $1.6\%$ in the lead removal group vs. $2.2\%$ in the initial implantation group) or all-cause death $(5.4\%$ vs. $7.8\%$ , respectively) during a 33-month follow-up period. 107

Implantation of a leadless pacemaker after device removal may be useful, but further studies are needed to determine long-term outcomes.

PQ 1. How to Choose Between a Leadless Pacemaker and a Transvenous Pacemaker

As of October 2023, there are 2 types of leadless pacemakers approved in Japan: the VVI type (Micra TM VR: tine type; Aveir TM VR: screw type) and the VDD type (Micra TM AV). The VVI and VDD types have been implanted mainly in patients with bradycardia and atrial fibrillation, and in older patients. However, leadless pacemakers are now being reconsidered for use in younger patients to reduce or avoid the risk of device infection, lead damage, and venous obstruction. The decision for indication is often based on (1) venous access and infection risk, (2) the need for atrial pacing, and (3) the need for high atrioventricular synchrony. 90

Leadless pacemakers are implanted in the right ventricle, eliminating the need for intravenous leads or anterior thoracic subcutaneous pockets, which eliminate the most common causes of pacemaker complications. The Micra Coverage with Evidence Development (CED) Study using U.S. Medicare data showed a $30\%$ reduction in complications over 3 years for leadless pacemakers. 93 The risk of infection is thought to be reduced because the leadless pacemaker itself is implanted in the right ventricle, where blood flow is rapid, and is endothelialized relatively early, plus the surface area of the leadless pacemaker is much smaller than that of a venous lead implanted in a slowflowing vein. Therefore, the risk of infection is considered to be reduced in patients treated with steroids or immunosuppressive drugs, on hemodialysis, with a history of device infection, with congenital heart disease or with a narrowed or obstructed subclavian vein for any reason, those undergoing radiation therapy, and patients with an implanted or planned endovascular catheter or subcutaneous port. Note that Micra is considered difficult to remove due to endothelialization.

VVIR and VDD are the currently available modes for leadless pacemakers in Japan, neither of which can provide atrial stimulation. Transvenous pacemakers are recommended for patients who require atrial stimulation or atrioventricular synchronization, the benefits of which outweigh the risks of atrial lead insertion, or for those who require conduction system pacing. The limitation of current systems is the loss of atrioventricular synchrony during exercise in highly active patients with tachycardia ${>}115$ beats/min. In particular, a transvenous pacemaker is recommended for the treatment of atrioventricular block during exercise, because, at present, leadless pacemakers do not maintain atrioventricular synchronization, and the possibility of pacemaker syndrome cannot be ruled out. The battery life of current pacemakers is approximately 12 years, but next-generation pacemakers are expected to have a longer life. There are overseas reports of leadless implantation in children as a bridge to future transvenous pacemakers without the risk of lead breakage or venous obstruction, and future changes in indications are anticipated.

JCS/JHRS 2024 Guideline Focused Update on Management of Cardiac Arrhythmias

|Table 6. Recommendations and Levels of Evidence for Pacemaker Therapy for Reflex Syncope||| |---|---|---| ||COR|LOE| | DDD-CLS pacemaker should be considered for patients aged ≥40 years with recurrent cardioinhibitory reflex syncope who demonstrate cardioinhibitoryresponse in thehead-up tilt test |ma|| | DDDpacemaker therapymaybe consideredforpatients aged≥40yearswithrecurrent reflex syncope, with ECG evidence of cardioinhibitory spontaneous syncope (>3s of cardiac arrest with symptoms,>6s of cardiac arrest without symptoms),and inwhom other treatment options havefailed ||| |||| |Pacemaker therapy is not recommended for reflex syncope patients aged |||

COR, Class of Recommendation; DDD-CLS, dual-chamber pacemaker with a closed loop stimulation sensor; ECG, electrocardiogram; LOE, Level of Evidence.

4. Pacemaker Therapy for Reflex Syncope

Pacemaker therapy for reflex syncope is recommended in Japan for patients aged ${\geq}40$ years with documented long cardiac arrest ${\mathrm{>}}3\,\mathrm{s}$ symptomatic, ${>}6\,\mathrm{s}$ asymptomatic) and when other therapies such as counterpressure maneuver and orthostatic training are ineffective. 5

Recently, the efficacy of a dual-chamber pacemaker with a closed loop stimulation sensor (DDD-CLS) in preventing recurrent syncope in patients with recurrent cardioinhibitory reflex syncope has been reported. The DDD-CLS works with an algorithm that estimates myocardial contractility from changes in intracardiac impedance caused by right ventricular leads and adjusts the pacing rate.

A small, randomized open trial confirmed the efficacy of DDD-CLS in reducing recurrent syncope, 108 , 109 and a double-blind study reported that DDD-CLS reduced recurrent syncope and prolonged the time to first syncope 110 , 111 and improved quality of life (QOL). 112 In a retrospective study with 5-year follow-up, DDD-CLS significantly reduced the risk of syncope compared with physiotherapy. 113 A multicenter study of the head-up tilt test after DDD pacemaker implantation showed that DDD-CLS reduced syncope and hypotension caused by the head-up tilt test compared with DDD. 114 It is thought that the CLS sensor increases heart rate and maintains cardiac output from the early phase of reflex syncope, preventing syncope.

Based on the current evidence, this Focus Update recommends DDD-CLS pacemaker therapy as recommended Class IIa in patients aged ${\geq}40$ years with recurrent cardioinhibitory syncope who have undergone a head-up tilt test and demonstrated cardiac cardioinhibitory syncope. The long-term results are unknown, and a large-scale study is desirable in the future. Because the Head Up Tilt Study did not demonstrate the efficacy of conventional pacemakers in preventing reflex syncope with hypotensive reactions, 115 we continue to recommend Class III as before ( Table6 ).

5. Future Advances in Implantable Cardiac Electrical Devices

Although a secondary analysis of PRAETORIAN showed that subcutaneous ICDs (S-ICDs) reduce lead-related

complications by $30\%$ compared with transvenous ICDs, 116 the inability of S-ICDs to provide pacing for bradycardia and antitachycardia pacing for VT has led some patients to abandon S-ICD implantation. Recently, a solution was developed by combining an S-ICD with a dedicated leadless pacemaker. With this system, when antitachycardia pacing is ineffective, defibrillation is performed by the S-ICD. Animal studies have reported good communication between the S-ICD and the leadless pacemaker, as well as the success rates of antitachycardia pacing. 117 – 119

A multicenter, prospective, single-arm study in humans is ongoing as of February 2024, and results on the safety and efficacy of treatment with a combined S-ICD and leadless pacemaker are expected to be evaluated.

The S-ICD is recommended Class I in Japan for patients who are eligible for transvenous ICD implantation, have difficult venous access or are at high risk for infection and do not require bradycardia pacing, antitachycardia pacing for VT or CRT. 5 In addition to the S-ICD, an extravascular ICD (EV-ICD) with a substernal lead has been developed and is undergoing clinical trials in Japan as of May 2023. However, it is not suitable for patients who require continuous pacing because the pacing threshold is higher than that of transvenous ICDs. When placing a lead under the sternum, its position should be confirmed by multidirectional fluoroscopic imaging to avoid myocardial injury and pneumothorax. Because the lead has 2 coils and 2 ring electrodes, multiple sensing and pacing vectors can be selected.

In a multicenter prospective single-arm study (316 patients), 120 the success rate of defibrillation during EV-ICD implantation was $98.7\%$ (median energy 15J) with no intraoperative complications. The success rate of antitachycardia pacing was $50.8\%$ . Complications at 6 months after implantation were hematoma, infection, pain, wound dehiscence, lead migration, and inappropriate therapy in $7.3\%$ of patients. Inappropriate therapy occurred in 29 patients, with P-wave oversensing being the most common. 121 In unsuccessful defibrillation cases, studies analyzing CT images have suggested anatomic factors such as a large rib cage width, myocardium extending very posteriorly, and a caudal heart position in the chest, but multivariate analysis showed no significant differences. 122 Further studies on EV-ICDs are needed to accumulate evidence.

6. Conduction System Pacing (CSP)

When bradycardia is the primary pathology, hemodynamic improvement is delivered predominantly by heart rate maintenance; thus, dyssynchronous contraction (the “harmful effect”) by right ventricular apical pacing (RVP) is unlikely to be a major concern. In contrast, when left ventricular systolic dysfunction coexists, dyssynchronous contractions induced by RVP greatly outweigh the benefit of heart rate maintenance, resulting in a worsening of the condition ( Figure4 ). Substantial RVP (pacing burden ${>}20{-}40\%$ ) has been reported to increase cardiovascular events such as deterioration of LVEF and heart failure hospitalization. 122 – 124 Right ventricular high septal pacing, which captures the myocardium closer to the conduction system, has been attempted as an alternative to RVP, but did not protect left ventricular function. 125

Pacing-induced cardiomyopathy, a condition in which LVEF decreases over time under RVP, occurs in $12–20\%$ of patients after pacemaker implantation. 126 Previous studies demonstrated that a higher pacing burden, paced QRS duration ${>}160\,\mathrm{ms}$ , and low preoperative LVEF were risk factors for pacing-induced cardiomyopathy, especially in patients with mild-to-moderate LV dysfunction. 127 , 128

His bundle pacing (HBP), which directly captures the conduction system rather than the local myocardium, was expected to retain the physiological activation pattern in animal models 129 and clinical cases. 130 However, the low procedural success rate of HBP remains a major issue. 131 In recent years, a delivery catheter system for implantation

of a lead has become available, resulting in an increase in the procedural success rate. The clinical efficacy of CSP has gradually become evident, and not only HBP but also left bundle branch area pacing (LBBAP) is again attracting attention 97 , 100 , 128 , 131 – 140 ( Figures4 , 5 and Table7 ).

▋ ▋ 6.1 Definition of CSP

CSP is a pacing technique that captures the conduction system (His bundle, right bundle branch, left bundle branch, and left bundle branch fascicles), and is characterized by output-dependent changes in QRS morphology due to the different pacing thresholds between the conduction system and local myocardium.

HBP captures the His bundle directly by implanting a lead on the atrial or ventricular side of the tricuspid annulus, providing the most physiological activation. Selective HBP, or non-selective HBP, which captures the His bundle and local myocardium simultaneously, occurs when varying the pacing output.

LBBAP is a novel pacing technique achieved by deployment of a lead deep into the right ventricular septum that intends to capture the left bundle branch or fascicles beneath the left ventricular septal endocardium. Unlike HBP, the left bundle branch potential is not always evident. LBBAP is characterized by the presence of R waves in the terminal portion of lead $\mathrm{V_{l}}$ , indicating delayed activation of the right ventricle.

The currently recognized criteria for direct left bundle branch capture are: output-dependent changes in QRS morphology, the interval from LBB potential to V 6 RWPT

 Figure4. Benefits and disadvantages of right ventricular (RV) pacing. When bradycardia is the primary pathology, the induction of dyssynchronous contractions by RV pacing does not provide a major problem because the rate-maintaining effect of pacing is large. On the other hand, when left ventricular systolic dysfunction is the main pathology, dyssynchronous contractions (the “harmful effect”) induced by RV pacing greatly outweigh the heart rate maintenance effect and worsen the heart failure. ( Vertical axis ) Improvement or worsening of the patient’s condition with RV pacing; ( Horizontal axis ) Ratio of bradycardia to left ventricular systolic dysfunction in the patient’s condition (bradycardia should predominantly be present on the left and systolic dysfunction on the right); ( Black horizontal line ) Net benefit or disadvantage of RV pacing.

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JCS/JHRS 2024 Guideline Focused Update on Management of Cardiac Arrhythmias

 Figure5. History of cardiac pacing development. The history of the development of cardiac pacing over the past 60 years is presented. Originally developed for patients with bradycardia, cardiac pacing has now expanded to include the treatment of heart failure in patients with systolic dysfunction. Although there are other clinical trials that have had a similar impact, this figure focuses on representative large clinical trials. Red circles: Articles referred to in preparing this Focus Update. AF, atrial fibrillation; CRT, cardiac resynchronization therapy; LBBA, left bundle branch area; PM, pacemaker; VF, ventricular fibrillation.

|Table 7. Recommendations and Levels of Evidence for CSP||| |---|---|---| ||COR|LOE| |Indicationfor CSPfor bradyarrhythmias||| | CSP should be considered for patients with an indication for permanent pacing and with mild to moderate left ventricular dysfunction(LVEF35-50%) in whom substantial ventricular pacing (>20%) is anticipated |ma|| | CSP may be considered to avoid pacing-induced cardiomyopathy for patients with an indication for permanent pacing and with normal left ventricular function in whom substantial ventricular pacing (>20%) is anticipated ||| |CSP may be considered for patients requiring AV junction ablation||| |Indications for CSP as an alternative therapy to CRT||| | CSP should be considered for patients with an indication of CRT due to LBBB or substantial ventricular pacing when CRT is ineffective or cannot be established for any reason |na||

AV, atrioventricular; COR, Class of Recommendation; CRT, cardiac resynchronization therapy; CSP, conduction system pacing; LBBB, left bundle branch block; LOE, Level of Evidence; LVEF, left ventricular ejection fraction.

(R-wave peak time in lead V 6 ) equals the interval from pacing stimulus to V RWPT $(\pm10\,\mathrm{ms})$ , 141 the interval from 6 pacing stimulus to V 6 RWPT is ${<}75\,\mathrm{ms}$ (in patients with narrow QRS or isolated right bundle branch block) or ${<}80\,\mathrm{ms}$ (in patients with more advanced ventricular conduction system disease), 142 and $\mathrm{V_{6-}V_{1}}$ interpeak interval is ${>}44\,\mathrm{ms}$ . 143 In addition, an abrupt decrease in the interval from pacing stimulus to V 6 RWPT ${\tt>}10\,\mathrm{ms}$ by varying pacing output is a helpful maneuver to distinguish between nonselective LBBAP (simultaneous capture of left bundle branch and left ventricular septum) and left ventricular

septal pacing. 144 However, it is still unclear whether the long-term prognosis differs between left bundle branch capture and left ventricular septal pacing.

Currently, left ventricular septal pacing without direct left bundle branch capture is also categorized as LBBAP. 142 , 145

▋ ▋ 6.2 Features and Differences Between HBP and LBBAP

Although HBP is the most physiologic pacing technique,

 Figure6. Schematic diagrams of pacing sites in conduction system pacing ( Left panel ) and 12-lead QRS morphologies of nonselective and selective pacing of the conduction system ( Right panel ). In non-selective pacing, the conduction system (His bundle or left bundle branch) and the local myocardium are captured simultaneously, whereas in selective pacing, the conduction system is captured directly.

the target area for HBP lead placement is narrow, and the lead should be located distal to the conduction block site ( Figure6 ). Therefore, implementing HBP is generally considered a difficult procedure, but it does preserve not only left ventricular but also right ventricular physiologic activation. 146 Previous study has shown that HBP shortens the QRS duration and improves LVEF even in patients with right bundle branch block. 147 The introduction of a delivery catheter system for HBP has improved the procedural success rate by almost $92\%$ . 131 However, sensing failure (oversensing of atrial potentials and undersensing of ventricular potentials) and increased capture thresholds in the early and remote postoperative periods, and the need for lead replacement $(7{-}11\%)$ are still major concerns with HBP. 148 – 150 Thus, additional leads for backup pacing may be indicated when HBP is attempted in pacing-dependent patients. 92 , 145 – 150

LBBAP is characterized by a wider target area for lead implantation, high ventricular R wave, and low capture threshold, superior to HBP. Left ventricular activation time by LBBAP is comparable to that by HBP, 146 and the procedural success rate of LBBAP is relatively high at almost $90–98\%$ . 151 – 154

In a Japanese initial multicenter observational study of LBBAP implantation for bradycardia, the success rate

was $86.7\%$ . The study reported that the presence of interventricular septal thickness ${\tt>}11\;\mathrm{mm}$ , intraventricular conduction disturbance, and severe tricuspid regurgitation were predictors of implantation failure. 155 Furthermore, the success rate of HBP and LBBAP in patients with an indication of heart failure was $10–20\%$ lower than that in patients with an indication of bradycardia. Therefore, evaluation of cardiac morphology and pacing indication is important for procedural success. 153 – 157

LBBAP has specific complications such as interventricular septal perforation, intraseptal hematoma, and coronary artery injury. In a European multicenter registry, LBBAPrelated complications occurred in $8.3\%$ of patients, although the number of patients who required invasive intervention was limited. 153 In a Japanese multicenter study, perioperative LBBAP-related complications were observed in $4.0\%$ of patients (all with interventricular septal perforation), but therapeutic intervention was not required and lead re-implantation was safely achieved in all patients. 155 When performing LBBAP, it is important to understand the specific behavior of the lead associated with deep deployment in the interventricular septum, 158 changes in the unipolar signal on the distal electrode, 159 , 160 lead parameters throughout the follow-up, and possible complications.

▋ ▋ 6.3 Systems Used for CSP

A thin (4.1Fr) lumenless lead (SelectSecure TM lead), with the unique structure of an exposed helix electrode, is most commonly used for CSP implantation. Meanwhile, several studies have shown that procedural outcomes of CSP using stylet-driven leads were equivalent or superior to lumenless leads. 153 , 161 On the other hand, a single-center observational study showed that using stylet-driven leads resulted in significantly higher postoperative loss of left bundle branch area capture ( $32\%$ vs. $12\%$ ) compared with lumenless leads. 162 Fractures of the helix electrode and distal conductor have also been reported for LBBAP using stylet-driven leads. 163 , 164

Regarding the extraction of CSP leads, it was reported that lumenless leads were extracted with a high success rate $(97\%)$ at mid-term follow-up (25 ± 18 months) after HBP implantation. 165 On the other hand, there are limited reports of LBBAP lead extraction, 166 so the safety of extraction of the LBBAP lead located deeply in the septum for a long time is unclear and needs further evaluation, regardless of the lead design. It should be noted that LBBAP using either lumenless or styled-driven leads is not covered by Japan’s National Health Insurance as of February 2024.

▋ ▋ 6.4 Indications for CSP in Patients With Bradycardia

▋ ▋ 6.4.1 Patients With Bradycardia and Normal Cardiac Function

Several observational studies have evaluated the benefit of CSP for patients with bradycardia and normal cardiac function in whom substantial ventricular pacing is anticipated. Early reports have shown that CSP reduced heart failure hospitalizations compared with conventional RVP in patients with ventricular pacing burden ${>}40\%$ . 139 , 148 More recently, CSP has been shown to reduce the composite outcomes (heart failure hospitalization, upgrade to CRT, and all-cause mortality) by $47\%$ in patients with ventricular pacing burden ${>}20\%$ . 167 In an observational study of LBBAP, LBBAP also reduced the same composite outcomes by $54\%$ compared with RVP. 168

Accordingly, CSP may be considered for patients with an indication for permanent pacing with normal left ventricular function in whom substantial ventricular pacing $(>\!20\%)$ is anticipated to avoid pacing-induced cardiomyopathy. However, it should be noted that there are complications in performing CSP, including conduction system injury, worsening of tricuspid regurgitation, delayed interventricular septal perforation, and thromboembolism. 152 , 153 , 169 Moreover, the clinical outcome in the long-term follow-up is not yet fully explored. Therefore, CSP is not recommended for patients in whom an increased ventricular pacing is not anticipated.

▋ ▋ 6.4.2 Patients With Bradycardia and Mild-to-Moderate Left Ventricular Dysfunction (LVEF $\mathbf{35-50\%}$ )

The Biventricular Versus Right Ventricular Pacing in Heart Failure Patients with Atrioventricular Block (BLOCK HF) trial 137 evaluated the efficacy of CRT in patients who had indications for pacing and heart failure with reduced LV function (LVEF ${\leq}50\%$ ). The results demonstrated that patients randomly assigned to CRT had a lower incidence of the primary endpoints (all-cause death, worsening heart

failure requiring intravenous therapy, or an increase in the left ventricular end-systolic volume index of ${\geq}15\%$ ) compared with RVP. On the other hand, observational studies and meta-analyses have shown that CSP has no adverse effect on LVEF and significantly improves LVEF. 131 , 170 In small randomized controlled trials (RCTs) and observational studies enrolling patients with atrioventricular block and mild-to-moderate left ventricular dysfunction, CSP significantly improved LVEF compared with RVP. 171 , 172 Moreover, a meta-analysis assessing patients who upgraded from RVP either to CRT or CSP revealed that CSP significantly increased LVEF compared with RVP, and the extent of LVEF improvement was comparable to that of CRT. 173 The advantages of selecting CSP over CRT are that CSP with only 2 transvenous leads may reduce the incidence of device infection and venous occlusion, and extend the longevity of the device. 174 , 175 Therefore, CSP should be considered for patients with an indication for permanent pacing and mild-to-moderate left ventricular dysfunction (LVEF $35–50\%$ ) in whom substantial ventricular pacing $(>\!20\%)$ is anticipated.

▋ ▋ 6.5 Patients With Conduction System Disturbance and Heart Failure (CRT Indication)

Both observational studies and randomized crossover trials have shown that HBP significantly improves intraventricular conduction and hemodynamic parameters, resulting in greater LVEF improvement and reverse remodeling of the left ventricle compared with CRT. 157 , 176 – 180 Regarding LBBAP, its procedural success rate in CRT-indicated patients has been relatively high $(82–97\%)$ ). 181 – 183 A previous study conducting a within-patient comparison of HBP, LBBAP and CRT demonstrated that greater improvements in left ventricular electrical dyssynchrony and acute hemodynamic response were seen with HBP and LBBAP compared with CRT, with no difference between HBP and LBBAP. 146 In addition, multiple observational studies, small randomized crossover trials and meta-analyses in CRT-indicated patients showed that LBBAP resulted in shorter paced QRS duration, more remarkable improvement in LVEF, and significant reduction in all-cause death and heart failure hospitalizations compared with CRT. 184 – 191

In an observational study comparing CSP as a first-line therapy with CRT in CRT-indicated patients, CSP significantly reduced heart failure hospitalizations compared with CRT, but the procedural success rate of CSP was significantly lower $(84.4\%$ vs. $94.7\%$ ). 192 The potential role of CSP for CRT-indicated patients had been reported, but there have been no large RCTs comparing CSP with CRT. Moreover, most of the clinical trials evaluating the efficacy of CSP for CRT have been conducted in patients with LBBB or those requiring substantial right ventricular pacing, and the efficacy of CSP for patients with non-LBBB has not been fully elucidated. 147 , 193

Importantly, CRT demonstrated prognostic improvement in heart failure patients with wide QRS in several RCTs. 136 , 194 , 195 Therefore, CRT is an established treatment and the current first-line therapy for CRT-indicated patients (especially for LBBB patients). 5 However, several factors limit the benefit of CRT: an absence of optimal coronary veins for implantation of a left ventricular lead, failure of left ventricular lead placement due to technical issues, difficulty in continuing CRT due to phrenic nerve stimulation or high pacing threshold, and an insufficient response

to CRT (CRT non-responders).

Sharma et al. evaluated the feasibility of HBP as an alternative therapy for CRT in patients with failed left ventricular lead placement or non-response to CRT. 170 Their study presented a high procedural success rate for HBP, shortened paced QRS duration, and improvements in LVEF and heart failure symptoms. LBBAP showed similar results in a multicenter observational study. 196 Therefore, in CRT-indicated patients with LBBB or substantial ventricular pacing, CSP should be considered when CRT is ineffective or cannot be established for any reason. CSP combined with left ventricular lead (His-optimized CRT: HOT-CRT, LBB-optimized CRT: LOT-CRT) has been attempted in patients in whom CRT or CSP alone failed to improve electrical dyssynchrony. 197 , 198 This technique has been shown to achieve better resynchronization and is expected to be a novel therapeutic option for CRT nonresponders, and a biventricular pacemaker (CRT-P) device should be selected for performing CSP. When a CRT-D device is considered, a specific configuration of leads and ports 142 is required (not covered by Japan’s National Health Insurance as of February 2024).

▋ ▋ 6.6 Patients Requiring Atrioventricular Junction Ablation

In several RCTs, CRT has preserved LVEF after atrioventricular junction ablation compared with RVP. 199 , 200 CSP also demonstrated similar effects in a RCT. 201 In addition, CSP significantly improved LVEF compared with CRT in heart failure patients with chronic atrial fibrillation and LVEF ${\leq}40\%$ . 202

Therefore, CSP may be considered in patients requiring atrioventricular junction ablation. When device implantation precedes atrioventricular junction ablation, an LBBAP lead may reduce lead-related adverse events in the acute and chronic phases and is associated with a higher success rate in creating atrioventricular block compared with HBP. 203

7. CRT for Mid-Range QRS

CRT has been shown in multiple RCTs to be effective in patients with moderate to severe heart failure with reduced LVEF despite optimal medical therapy and a QRS duration ${\geq}120\,\mathrm{ms}$ . 204 – 209 In these RCTs and meta-analyses, complete left bundle branch block (CLBBB) waveform, and wide QRS $(>\!150\,\mathrm{ms})$ ) predicted the benefit of CRT, 204 – 211 and mid-range QRS duration between 120 and 150ms (120ms ≤ QRS duration<150ms) showed insufficient benefit of CRT, so-called “nonresponders”. 210 , 211 On the other hand, clinical characteristics for higher CRT efficacy have been proposed, such as sex, body size (including racial differences), and heart size, and if these are taken into account, CRT may be effectively used for mid-range QRS cases. 133 , 194 , 212 – 216

However, there is no consensus on the interpretation of these clinical characteristics, and there are currently differences in the definitions of mid-range QRS and recommended classes of CRT in various societies’ guidelines. 92 , 145 , 217 , 218 ( Table8 ). In preparing this Focus Update, we reviewed the recommended classifications based on the results of studies reported since the JCS/JHRS 2019 Guidelines on the Nonpharmacotherapy of Cardiac Arrhythmias.

▋ ▋ 7.1 Lower Limit of QRS Duration for CRT Indication

The lower limit of mid-range QRS in heart failure patients for whom CRT should be recommended has been controversial. Yu et al. reported that among patients with LVEF ${\le}35\%$ and narrow QRS, there were cases of dyssynchrony on echocardiography (tissue Doppler), suggesting that these patients may be responders for CRT. 219 , 220 However, a subsequent multicenter prospective study (PROSPECT) reported that echocardiographic dyssynchrony is unlikely to predict CRT responders at high rates. 221

In 2013, the results of EchoCRT, an RCT of patients with LVEF ${\le}35\%$ , QRS duration ${\leq}130\mathrm{ms}$ , and dyssynchrony

| Table 8. Recommendations for CRT Implantation for Mid-Range QRS in Each Society's Guidelines (for Sinus Rhythm)|||||||| |---|---|---|---|---|---|---|---| |Guideline|COR|LOE| QRS morphology |LVEF (%)| QRsduration (ms) | NYHAfunctional class |Other| | 2023HRS/APHRS/ LAHRS145 |||LBBB|≤35|120-149|—IV|Female, etc.| | 2023HRS/APHRS/ LAHRS145 |a|B-R|LBBB|≤35|120-149|1-V|| | 2023HRS/APHRS/ LAHRS145 ||B-NR|Non-LBBB|≤35|120-149|-IV|| | 2023HRS/APHRS/ LAHRS145 ||B-R|Non-LBBB|≤35|120-149|一|| | 2022AHA/ACC/ HFSA217 |a|B-NR|LBBB|≤35|120-149|-IV|| | 2022AHA/ACC/ HFSA217 ||B-NR|Non-LBBB|≤35|120-149|-IV|| |2021ESC92|a||LBBB|≤35|130-149||| |2021ESC92|||Non-LBBB|≤35|130-149||| |2017 CCS218|||LBBB|||||

Level of Evidence A: substantiated by multiple RCTs or meta-analyses; B: substantiated by a single RCT or large clinical trial that is not a randomized intervention; B-R: moderate-quality evidence from $\geq1$ RCT; B-NR: moderate-quality evidence from ${\geq}1$ well-designed and conducted non-RCT, observational trial, or case–control study. ACC, American College of Cardiology; AHA, American Heart Association; APHRS, Asian Pacific Heart Rhythm Society; CCS, Canadian Cardiovascular Society; COR, Class of Recommendation; ESC, European Society of Cardiology; HFSA, Heart Failure Society of America; HRS, Heart Rhythm Society; LAHRS, Latin American Heart Rhythm Society; LBBB, left bundle branch block; LOE, Level of Evidence; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association; RCT, randomized controlled trial.

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JCS/JHRS 2024 Guideline Focused Update on Management of Cardiac Arrhythmias

on echocardiography, were presented. 222 In the study, a CRT device was implanted in all patients, and 2 groups, CRT-on and CRT-off, were compared. There was no significant difference in the incidence of the primary endpoint (heart failure hospitalization and death) between groups (HR 1.2, CI 0.92–1.57, $\mathrm{{P}{=}0.15}$ ), and the mortality rate was significantly higher in the CRT-on group (HR 1.81, CI 1.11, $\mathrm{{P}{=}0.02}$ ). Based on these results, the efficacy of CRT in patients with QRS duration ${<}130\,\mathrm{ms}$ was judged to be low, and the ESC and CCS guidelines recommend Class III. 92 , 218

On the other hand, after the publication of EchoCRT, some reports were published suggesting the efficacy of CRT even in patients with 120ms ≤ QRS duration ${\mathrm{}}{<}130\,\mathrm{ms}$ . De Pooter et al. examined the incidence of septal flush, which is considered the best echocardiographic predictor of CRT responsiveness in LBBB patients, and reported that more than $60\%$ of women with mid-range QRS had this finding. 223 Furthermore, a subanalysis of EchoCRT showed the usefulness of CRT for patients with small left ventricular end-diastolic volume, 213 suggesting that sex, body size, and left ventricular size are useful in the process of selecting CRT.

Several clinical trials have reported that the response to CRT may be different in Japan, where many heart failure patients are smaller in stature than those in Europe and the USA. Oka et al. retrospectively analyzed the event rate (composite of all-cause death or heart failure hospitalization) and responder rate by echocardiographic measures. 224 Patients with LBBB and QRS duration ${\geq}150\,\mathrm{ms}$ had the lowest event rate $(28.9\%)$ and highest responder rate $(74\%)$ . In comparison, they also reported that although responder rates were significantly lower in patients with $120\mathrm{ms}\{\mathrm{QRS}}$ duration ${<}1\bar{5}0\,\mathrm{ms}$ than those with QRS duration ${\geq}150\,\mathrm{ms}$ , good responses were observed in more than half $51\%$ of LBBB and $52\%$ of non-LBBB patients) of the cases.

Varma et al. analyzed CRT in CLBBB cases and showed that QRS duration modified by left ventricular volume defined by echocardiography correlated with the efficacy of CRT in women. 212 Other studies have reported that QRS duration modified by left ventricular end-diastolic volume was significantly associated with prognosis in CRT patients, especially in women with small body size. 215 A meta-analysis of 5 RCTs also suggested that sex, QRS duration, etiology of heart failure, left ventricular enddiastolic diameter and body height influenced all-cause mortality and first hospitalization rates for heart failure. 206

Varma et al. also analyzed data from Advanced CRT, a registry of 251 Asian CRT cases ( $27\%$ of the registry), including Japanese patients, and reported that the CRT

responder rate, as defined by symptom score, was significantly higher in Asians than in non-Asians in both the 120ms ≤ QRS duration ${\mathrm{<}}150\,\mathrm{ms}$ and QRS duration ${\geq}150\,\mathrm{ms}$ groups. 216 Furthermore, when cardiac death or heart failure events were used as the endpoints, the benefit of CRT was demonstrated in Asians with 120ms ≤ QRS duration ${<}150\,\mathrm{ms}$ , and QRS duration modified by height was strongly associated with CRT efficacy.

The lower limit of QRS duration for recommending CRT is still controversial. However, considering that many RCTs have demonstrated the efficacy of CRT by including patients with QRS duration ${\geq}120\,\mathrm{ms}$ , and that mid-range QRS patients can be expected to be responsive in Japan, where there are many patients with small body size, the lower limit of QRS duration in this Focus Update has been set at 120ms. However, it should be noted that there is strong evidence for the efficacy of CRT at QRS duration ${\geq}130\,\mathrm{ms}$ . 225

▋ ▋ 7.2 Recommendations

Recommendations for CRT indications in mid-range QRS in sinus rhythm are shown in Table9 and a list of conditions is shown in Table10 .

▋ ▋ 7.2.1 Mid-Range QRS and LBBB

As noted earlier, it has been suggested that sex differences affect the efficacy of CRT, and to analyze this effect, a

| Table 9. Recommendations and Levels of Evidence for CRT Implantation for Mid-Range QRS (for Sinus Rhythm) ||| |---|---|---| ||COR|LOE| | CRT is recommended in HF patients with LVEF ≤35%, NYHA functional class II-IV, 120ms≤QRSduration |||

COR, Class of Recommendation; CRT, cardiac resynchronization therapy; HF, heart failure; LBBB, left bundle branch block; LOE, Level of Evidence; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association.

|Table 10. Recommendations for CRT Implantation for Mid-Range QRS (in Sinus Rhythm)||||||| |---|---|---|---|---|---|---| |COR|LOE| QRS morphology |LVEF (%)| QRSduration ms) | NYHAfunctional class |Other| |||LBBB|≤35|120-149|-V|Female, etc.| |iia|B-R|LBBB|≤35|120-149|1-IV|| ||B-NR|Non-LBBB|≤35|120-149|1I-IV|| ||B-R|Non-LBBB|≤30|120-149|||

Level of Evidence A: substantiated by multiple RCTs or meta-analyses; B-R: moderate-quality evidence from ≥1 RCT; B-NR: moderate-quality evidence from ${\geq}1$ well-designed and conducted non-RCT, observational trial, or case– control study. COR, Class of Recommendation; CRT, cardiac resynchronization therapy; LBBB, left bundle branch block; LOE, Level of Evidence; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association.

meta-analysis using RAFT, MADIT-CRT, and REVERSE, which showed a benefit of CRT on heart failure hospitalization or death, stratified LBBB patients with a QRS duration of 120–180ms in 10ms increments. 224 The results showed no sex difference in the $120\,\mathrm{ms}{\le}\mathrm{QRS}$ duration ${<}130\,\mathrm{ms}$ group, but the benefit was significantly higher in both the $130\,\mathrm{ms}{\le}\mathrm{QRS}$ duration ${<}140\,\mathrm{ms}$ group and the 140ms ≤ QRS duration ${<}150\mathrm{ms}$ group only in women (relative risk reduction $85\%$ and $69\%$ , respectively). However, in the QRS duration ${\geq}150\,\mathrm{ms}$ group, CRT significantly reduced the incidence of both heart failure and death, as well as death alone, without a sex difference, suggesting that a potential mechanism for sex differences in response to CRT may be related to anatomic differences, particularly body height (with a greater effect seen with shorter height). 212 , 215 , 226 – 233

Based on these results, CRT implantation in heart failure patients with NYHA functional class II or higher, with mid-range QRS of $120\,\mathrm{ms}{\le}\mathrm{QRS}$ duration ${<}150\,\mathrm{ms}$ and LBBB, is recommended as Class I for women and Class IIa for men ( Table9 ).

▋ ▋ 7.2.2 Mid-Range QRS and Non-LBBB

Clinical studies demonstrating the efficacy of CRT with

mid-range QRS in non-LBBB patients are still limited. In an observational study of 99 heart failure patients (LVEF ${<}35\%$ and NYHA functional class II or higher) with non-LBBB (right bundle branch block in $22.2\%$ and intraventricular conduction disturbance in $77.8\%$ ) and QRS duration ${\geq}120\,\mathrm{ms}$ , CRT improved LVEF by $4\%$ over a 13-month observation period. 234 Subsequently, subanalyses of non-LBBB patients were conducted in 2 large RCTs (MADIT-CRT, RAFT) that enrolled a large number of patients with NYHA cardiac function class II, 135 , 136 and neither showed a benefit of CRT.

Based on these results, the recommended class of CRT for mid-range QRS (120ms ≤ QRS duration ${<}150\,\mathrm{ms}$ ) in non-LBBB is unchanged from the JCS/JHRS 2019 Guidelines on the Nonpharmacotherapy of Cardiac Arrhythmias, with LVEF ${\le}35\%$ in NYHA cardiac function class III or higher and LVEF ${\le}30\%$ as a condition for Recommendation Class IIb.

However, the efficacy of CRT for patients with QRS duration ${<}120\,\mathrm{ms}$ or ${<}130\,\mathrm{ms}$ varies among reports, 92 , 145 , 217 , 218 so the indication for CRT should be carefully considered in each case.

II. Catheter Ablation

1. Catheter Ablation Procedures for Atrial Fibrillation in Addition to Pulmonary Vein Isolation ( Table11 )

In catheter ablation of atrial fibrillation (AF), pulmonary vein isolation (PVI) alone is not effective in maintaining sinus rhythm in some cases, especially in patients with persistent AF. In addition to PVI, various techniques for ablation of non-pulmonary veins substrates (beyond PVI) have been proposed, and many randomized controlled trials (RCTs) have investigated the efficacy of beyond PVI in

| Table 11. Recommendations and Levels of Evidence for AF Ablation Procedures in Addition to PVI ||| |---|---|---| ||COR|LOE| | For initial ablation of persistent AF, left atrial posterior wall isolation may be considered in addition toPVI ||E| | In persistent AF with LVA in the left atrium, ablation of LVA may be considered in addition toPvI ||E| | VOM ethanol infusion may be considered for atrial tachycardia in which the VOM is part of a circuit that makes it difficult to ablate the arrhythmia by other methods of catheter ablation ||| | In catheter ablationforlong-standing persistent AF,the addition of VOMethanol injection to conventional PVl maybe considered ||E|

AF, atrial fibrillation; COR, Class of Recommendation; LOE, Level of Evidence; LVA, low-voltage areas; PVI, pulmonary vein isolation; VOM, vein of Marshall.

maintaining sinus rhythm. This Focus Update offers a comprehensive review of these updates.

▋ ▋ 1.1 Additional Ablation to PVI for Non-PV Substrates

The STAR-AF2 study, which focused on catheter ablation for persistent AF, evaluated the effectiveness of additional intervention to PVI such as left atrial linear ablation (including the left atrial roof line and mitral isthmus line) or ablation of complex fractionated atrial electrograms (CFAEs) during AF. 235 Contrary to widespread expectations, the study did not confirm the benefits of additional ablation. Similarly, the concurrent CHASEAF trial also yielded comparable results, 236 casting doubt on the value of incorporating extra ablation methods in addition to PVI in the treatment of persistent AF.

On the other hand, the EARNEST-PVI trial, which aimed to establish the non-inferiority of PVI alone vs. PVI plus additional ablation (including linear ablation or CFAE ablation) in cases of persistent AF, did not demonstrate non-inferiority of PVI alone, 237 which was evident in the higher tendency of recurrence in the group receiving PVI alone.

The main causes of recurrence following AF catheter ablation include reconnection of the isolated PVs and the persistence of non-PV arrhythmic substrates. During the time of the STAR-AF2 and CHASE-AF trials, reconnection of the PVs was frequently observed and was considered the primary cause of recurrence. However, by the time of the EARNEST-PVI trial, the quality of PVI had improved, which might have made the effects of additional ablation more apparent. In recent years, there has been widespread adoption of ablation techniques including contact force and stability at the tip of the ablation catheter, and

Advance Publication

JCS/JHRS 2024 Guideline Focused Update on Management of Cardiac Arrhythmias

cryoballoon ablation. Consequently, there has been an increase in cases of no reconduction of PV potentials upon recurrence. 238 The mechanism of recurrence in these cases is thought to involve non-PV arrhythmic substrates, which may indicate that the effects of additional ablation have become more pronounced. This shift highlights a crucial aspect in evaluating the efficacy of catheter ablation: the impact of technological advancements in ablation catheters and related equipment on the outcomes of additional ablation of non-PV substrates. The evolution of these technologies significantly influences the effectiveness of additional ablation strategies, underscoring the importance of considering technological progress in the assessment of treatment efficacy.

Furthermore, a post-hoc analysis of the EARNEST-PVI trial investigated the characteristics of the patient groups for whom additional ablation was effective vs. those for whom it was not. In that study, patients were stratified using the DR-FLASH score, a predictor of left atrial low-voltage areas (LVA) (diabetes, renal impairment, female sex, left atrial enlargement, age, hypertension, persistent AF). Additional ablation proved effective in patients with a higher likelihood of arrhythmic substrates. 239 That finding underscored the importance of careful consideration in clinical practice regarding how to approach patient selection, which types of additional ablation techniques to apply, and which ablation technologies to use.

▋ ▋ 1.2 Left Atrial Posterior Wall Isolation

Posterior wall isolation is a popular additional ablation in catheter ablation for AF and involves augmenting PVI with a left atrial roof line and a line along the bottom of the left posterior wall. However, recent RCTs examining the effects of left atrial posterior wall isolation have yielded inconsistent results.

The CAPLA trial, for instance, evaluated the efficacy of adding left atrial posterior wall isolation to PVI in the initial catheter ablation of persistent AF. 240 The study observed a tendency for increased recurrence of atrial tachycardia. In the group that underwent posterior wall isolation, reconnection of the conduction block created by additional linear ablation may have formed circuits for iatrogenic atrial tachycardia, causing recurrence and negating the therapeutic benefit. Similarly, the RILI trial explored the effectiveness of posterior wall isolation in conjunction with PV re-isolation in patients experiencing PV reconnection during repeat catheter ablation for AF. 241 That study also reported suboptimal results that raised the possibility that the impact of PV reconnection may have obscured any additional benefits derived from posterior wall isolation.

On the other hand, some trials have demonstrated the efficacy of left atrial posterior wall isolation. There are reports that the additional posterior wall isolation improved outcomes in patients with persistent AF who did not have low voltage area in the left atrium and in whom atrial arrhythmias were induced by continuous stimulation. 242 There are also reports that the addition of posterior wall isolation to PVI improved outcomes in cryoballoon ablation for persistent AF were enhanced by adding posterior wall isolation to PVI, 243 , 244 although we should note that in Japan, as of February 2024, insurance does not cover cryoballoon ablation for left atrial posterior wall isolation. A meta-analysis of the effects of additional left atrial

posterior wall isolation to PVI indicated that posterior wall isolation might not be effective for paroxysmal AF, but could be beneficial for persistent AF. 245

Thus, routine implementation of posterior wall isolation is not yet substantiated by sufficient evidence from RCTs, but selectively applying this technique to certain patients might prove effective. It is also important to consider potential complications associated with left atrial posterior wall isolation, such as esophageal-related complications, including left atrial–esophageal fistula, 246 highlighting the need for careful patient selection.

▋ ▋ 1.3 Low Voltage Area Ablation

Left atrial LVA have attracted attention as indicators of myocardial damage that can serve as a substrate for arrhythmias. Several recent RCTs have explored ablation of LVA, but the results have been inconsistent, with some studies reporting limited additional benefits and others showing effectiveness. 247 – 252

The ERASE-AF trial showed that adding LVA ablation to PVI reduced atrial arrhythmia recurrence from $50\%$ to $35\%$ at 12 months in persistent AF, improving outcomes beyond PVI alone $(\mathrm{P{=}0.006})$ . 251 In the STABLE-SR-III trial, an RCT conducted among patients aged ${>}65$ years with paroxysmal AF found that the addition of LVA ablation significantly reduced recurrence rates, particularly in patients with LVA ablation (hazard ratio [HR] 0.49, $95\%$ confidence interval [CI] 0.25–0.94, $\mathrm{{P}{=}0.03\}$ ). 252 Meta-analyses have indicated that although LVA ablation does not show significant benefits in paroxysmal AF, it is associated with a notably higher non-recurrence rate in persistent AF. 253

These trials examining the efficacy of LVA ablation showed variability in the definition of the LVA (lowpotential cutoff value or multipoint mapping electrode catheter used), ablation endpoint (homogenization of the LVA or completion of linear ablation such as posterior wall isolation or anterior wall line), and patient background (proportion of patients with LVA). Establishing a standardized method for ablation of LVA is an important issue. Furthermore, the presence of LVA may reflect overall atrial myocardial fibrosis, and in such cases further progression of the arrhythmic substrate post-ablation can be anticipated, 254 which raises concerns about the long-term preventive effects against recurrence, even if short-term efficacy is achieved. Given these considerations, despite recent meta-analyses and multiple RCTs gradually building evidence for the effectiveness of LVA ablation in persistent AF, it is not yet considered a fully established method. Considering the potential adverse effects on left atrial function due to extensive ablation and the possibility of creating substrates for atrial tachycardia, this Focus Update recommends LVA ablation as a Class IIb indication in cases of persistent AF with LVA.

▋ ▋ 1.4 Chemical Ablation of the Vein of Marshall

The vein of Marshall (VOM), a remnant of the embryonic left superior vena cava, is susceptible to sympathetic and parasympathetic influences and has been implicated in the initiation and maintenance of AF. 255 Additionally, the VOM itself forms part of the arrhythmic circuit, causing difficulty in block formation during linear ablation of the mitral annulus and atrial tachycardia that is difficult to ablate from the endocardial side (VOM-related atrial

tachycardia).

Retrograde balloon cannulation and ethanol injection into the VOM (VOM-EI) creates a chemical ablation lesion in the area vascularized by the VOM. VOM-EI ablates the myocardium of the VOM, eliminating AT circuits, AF triggers, and parasympathetic innervation in this region. Additionally, it induces endocardial injury to the myocardium surrounding the mitral annulus, which the VOM vascularizes. It has been proposed that the VOM-EI may contribute to the treatment of AF. 256

The VENUS trial, which focused on catheter ablation for long-standing persistent AF, found that adding VOMEI to PVI significantly improved recurrence-free rates compared with conventional treatment $(49\%$ vs. $38\%$ , $\mathrm{{P}{=}0.04}$ ). 257 In a meta-analysis that included this trial, the VOM-EI group had significantly better outcomes. 258 VOM-EI is effective in cases of atrial tachycardia in which the VOM is part of the circuit and in cases of refractory long-standing persistent AF, and VOM-EI for these patients is considered reasonable.

However, this approach requires unique technical skills and experience, and controlling the extent of tissue damage from ethanol injection is difficult, posing potential risks. Additionally, as of February 2024, there is a lack of specialized equipment for this purpose, and existing medical devices need to be used off-label, which is not yet approved for insurance coverage. Therefore, while promising, several issues still need to be addressed in the application of VOM-EI.

▋ ▋ 1.5 Other Additional Ablation Strategy

Various methods and devices for identifying additional non-PV ablation sites are being proposed, including focal impulse and rotor modulation (FIRM) mapping for rotor ablation, CardioInsight TM , and ExTRaMap TM . However, since the publication of the 2021 JCS/JHRS Guideline Focus Update Edition on Arrhythmia Nonpharmacological Treatment, there has been limited evidence for these techniques.

As new ablation methods, there are approaches such as targeting fractionated signal areas in the atrial muscle (FAAM) during sinus rhythm, which are considered the source of non-PV triggers, 259 and techniques focusing on spatiotemporal electrogram dispersion as drivers of AF. 260 However, there is currently insufficient evidence to validate the effectiveness of these methods. Additionally, the BELIEF trial reported the effectiveness of left atrial appendage isolation adding to PVI. 261 Furthermore, the isolation of the left atrium in cases of extensive LVA has

also been proposed. 262 However, these isolation techniques are challenging to perform, and there is an increased risk of thrombosis post-isolation. Given the limited evidence supporting these additional ablation techniques, the risk of adverse outcomes, and the level of expertise required, their implementation should be carefully considered.

2. Expanded Indication for Atrial Fibrillation Catheter Ablation

▋ ▋ 2.1 Atrial Fibrillation Catheter Ablation as First-Line Treatment

Catheter ablation as first-line treatment for paroxysmal atrial fibrillation is considered a recommended Class IIa in the Arrhythmia nonpharmacologic treatment guidelines (revised 2019). 5 Recently, 3 RCTs investigated the efficacy of cryoballoon ablation as first-line treatment for paroxysmal AF 263 – 265 ( Table12 ).

The STOP AF First trial 263 compared cryoballoon PVI with antiarrhythmic agents (groups I or III) in 203 patients with symptomatic paroxysmal AF at 24 centers in the USA. After 12 months of follow-up, treatment success rates (successful procedure, non-recurrence of atrial arrhythmia, etc.) were significantly higher in the ablation group $(74.6\%$ vs. $45.0\%$ , $\mathrm{P{<}0.001\,}$ ). Only 2 patients in the ablation group had procedure-related complications (pericardial effusion and myocardial infarction), but the authors concluded that serious complications were rare.

The Early-AF trial 264 compared cryoballoon PVI with antiarrhythmic drug rhythm control in 303 patients with untreated and symptomatic paroxysmal AF at 18 Canadian centers. All patients underwent arrhythmia detection with an implantable ECG and were followed for 12 months. Recurrence of atrial tachyarrhythmia (AF, atrial flutter, atrial tachycardia) was significantly lower in the ablation group (42.9 vs. $67.8\%$ , $\mathrm{P{<}0.001\,}$ ). Serious complications occurred in 5 patients in the ablation group $(3.2\%$ , 3 patients with transverse paralysis, 2 patients with symptomatic bradycardia) and 6 patients in the antiarrhythmic drug group $(4.0\%$ , 2 patients with wide-QRS tachycardia, 1 patient with syncope, 1 patient with worsening heart failure, 2 patients with symptomatic bradycardia), but there was no significant difference between the 2 groups.

The Cryo-FIRST trial 265 compared cryoballoon ablation with antiarrhythmic drug therapy in 218 patients with untreated or symptomatic paroxysmal AF. The 12-month follow-up showed a significantly lower rate of recurrent atrial tachyarrhythmias in the ablation group ( $17.8\%$ vs.

|Table 12. Results of RCTs Showing the Effectiveness of Cryoballoon Ablation as First-Line Treatment||||||| |---|---|---|---|---|---|---| | Trial name| Country in which the. lawisbeingenforced | No. of registered patients (persons) | TargetAF type(%) | Mean follow-up (months) | Arrhythmiadetection method | Recurrence rate (%)* | | STOP-AF First263 |USA|20:3| Paroxysmal 100 |12| ·12-lead ECG · ECG telemonitoring (weekly) ·HolterECG(after6 and 12 months) |25.4/55.0| |EARLY-AF264|Canada|303| Paroxysmal 96 |12| Implantable loop recorder |42.9/67.8| |Cryo-FIRST265| Australia, Europe, South America |218| Paroxysmal 100 || ·Ambulatory ECG ·7-day Holter ECG |17.8/32.4|

\*Ablation/medication. AF, atrial fibrillation; ECG, electrocardiogram; RCT, randomized controlled trial.

$32.4\%$ , $\mathrm{{P}{=}0.01}$ ), but no significant difference in the incidence of serious complications between the 2 groups.

A meta-analysis of these 3 RCTs has also been reported. 266 When initial treatment for AF was compared between cryoballoon ablation and medical therapy, ablation was associated with significantly fewer recurrent atrial tachyarrhythmias, better improvement in symptoms and quality of life (QOL), and reduced medical resource utilization (hospitalization) compared with medical therapy. Serious side effects were similar between groups.

These results indicate that cryoballoon ablation is superior to medical therapy as the first-line treatment for symptomatic and recurrent paroxysmal AF. In this Focus Update, cryoballoon ablation is recommended as the first-line treatment for symptomatic recurrent paroxysmal AF ( Table13 ). It should be noted that all 3 RCTs were conducted in experienced centers known as “high-volume centers,” and the long-term efficacy of cryoballoon ablation is unknown because of the short-term results (1 year).

▋ ▋ 2.2 Indications for Catheter Ablation of Asymptomatic Atrial Fibrillation

Because AF is not immediately life-threatening, catheter ablation has been performed to improve patients’ QOL by maintaining sinus rhythm. In other words, the indication for catheter ablation of AF is symptomatic AF, and European and American guidelines do not describe the indication for asymptomatic AF.

In the Guidelines for the Nonpharmacologic Treatment of Arrhythmias (2019 revision), only asymptomatic paroxysmal AF with recurrent episodes is considered a recommended Class IIb. 5 The indications for catheter ablation in clinical practice are expanding beyond symptomatic AF, and new evidence reported in recent years is presented.

▋ ▋ 2.2.1 Impact of Early Rhythm Control

The EAST-AFNET trial 267 is the first RCT to report the impact of early rhythm control treatment on outcomes in patients with AF. Patients with AF within 1 year of diagnosis were randomized to early rhythm control (antiarrhythmic drug therapy or catheter ablation) or conventional therapy (rate control). After a mean follow-up of 5.1 years, study was terminated early because the primary endpoint (cardiovascular death, stroke, heart failure, or hospitalization for worsening acute coronary syndrome) was significantly higher in the conventional therapy group (3.9/100 patient-years vs. 5.0/100 patient-years, $\mathrm{{P}{=}0.005}$ ).

Although the ablation rate in that study was relatively low ( $19.4\%$ in the early rhythm control group and $7.0\%$ in the conventional therapy group), it is meaningful that it was the first study to demonstrate that early rhythm control is associated with improved prognosis in patients with AF. Subsequent subanalysis additionally reported similar results in asymptomatic and symptomatic patients. 268 An additional analysis showed that the prognostic benefit of early rhythm control was only observed in the high-embolic risk group with a CHA 2 DS 2 -VASc score ${\ge}4$ points. 269

▋ ▋ 2.2.2 Comparison of Symptomatic and Asymptomatic Patients

The CODE-AF trial 270 is a prospective multicenter observational study in Korea in which 1,515 patients with AF ( $64\%$ paroxysmal) were divided into 2 groups (symptomatic and asymptomatic), and their prognoses (primary endpoint:

||Table 13. Recommendation and Level of Evidence for|| |---|---|---| ||Cryoballoon Ablation for Symptomatic Paroxysmal|| ||COR|LOE| | Catheter ablationwithcryoballoonis recommended as first-line treatment for ||| |||| | symptomatic recurrent paroxysmal AF (selected afterpatient requests ablation and ||| |decision should be made afterproviding a||| |thorough explanation of other options and the||| |risks associated with the treatment)|||

AF, atrial fibrillation; COR, Class of Recommendation; LOE, Level of Evidence.

heart failure hospitalization, stroke, and cardiac death) were compared. Results showed that the symptomatic AF group had a poorer prognosis than the asymptomatic AF group $\scriptstyle(\mathbf{P=}0.04)$ , and rhythm control had a significantly lower incidence of primary endpoints than rate control, regardless of the presence or absence of symptoms. In the asymptomatic group, paroxysmal AF, left atrial diameter ${<}50\,\mathrm{mm}$ , and CHA 2 DS 2 -VASc score ${\geq}3$ were associated with improved prognosis.

▋ ▋ 2.2.3 Catheter Ablation to Reduce Progression of Atrial Fibrillation

The ATTEST trial 271 investigated whether radiofrequency catheter ablation could prevent progression from paroxysmal to persistent AF compared with antiarrhythmic drug therapy. A total of 255 patients were randomized 1:1 and followed for 3 years. Results showed that progression to persistent AF (or atrial tachycardia) occurred in $2.4\%$ of the ablation group, compared with $17.5\%$ in the antiarrhythmic drug treatment group, which demonstrated a reduction in AF progression by catheter ablation.

A subanalysis of EARLY-AF 272 reported that progression to persistent AF was significantly reduced in patients treated with cryoballoon ablation as first-line therapy for paroxysmal AF compared with those treated with antiarrhythmic drugs ( $1.9\%$ in the ablation group vs. $7.4\%$ in antiarrhythmic drug group. HR 0.25, $95\%$ CI 0.09–0.70). In addition, the study showed a significant improvement in QOL in the ablation group and a $69\%$ lower rate of hospitalization compared with the antiarrhythmic drug group. 272

These 2 RCTs are significant because they demonstrate for the first time that catheter ablation inhibits the progression of AF and is not performed only for symptomatic improvement.

▋ ▋ 2.2.4 Improving Patient Outcomes With Catheter Ablation As described in the 2021 JCS/JHRS Guideline Focus Update for Nonpharmacologic Treatment of Arrhythmias, 6 CABANA, a large RCT comparing whether AF catheter ablation improves patient outcomes compared with medical therapy did not clearly demonstrate an advantage of catheter ablation. Intention-to-treat analysis of the primary endpoint showed no significant difference between the groups, but per-protocol analysis showed a significant improvement in the ablation group compared with medical therapy $\mathrm{(P{=}0.046)}$ ). 273

▋ ▋ 2.2.5 Summary

Although there are no published RCTs that clearly demonstrate that catheter ablation improves the prognosis

||Table 14. Recommendation and Level of Evidence for||| |---|---|---|---| ||Catheter Ablation for Patients With Asymptomatic||| |Paroxysmal Recurrent AF|||| |||COR|LOE| | Catheter ablation should be considered for patientswith asymptomaticrecurrent paroxysmal AF and CHA2DS2-VASc score ≥3 points |||E|

AF, atrial fibrillation; COR, Class of Recommendation; LOE, Level of Evidence.

of patients with asymptomatic AF, new evidence is accumulating that (1) early SR maintenance therapy is associated with prognosis in patients with AF, and (2) catheter ablation prevents the progression of AF.

Considering that the purpose of AF catheter ablation is not only to improve patient symptoms and QOL, but also to meet the reality and demand in the field, this Focus Update is based on the above evidence, and recommends to consider catheter ablation for asymptomatic paroxysmal recurrent AF with a CHA 2 DS 2 -VASc score 3 as Class of IIa ( Table14 ).

▋ ▋ 2.3 Catheter Ablation for Atrial Fibrillation in the Patients With Heart Failure

Recently, a meta-analysis of RCTs has shown the efficacy of catheter ablation in patients with heart failure (HF)

complicated by AF. 274 , 275 Most of the RCTs included patients with HF with low left ventricular ejection function (HFrEF), in which catheter ablation reduced the all-cause mortality rate and improved the LVEF, 6-minute walk, and QOL compared with medical therapy. However, the study designs, including patient population, ablation methods and follow-up duration, were not uniform among the RCTs, so the results should be interpreted with extra caution 276 – 283 ( Table15 ).

The RAFT-AF 276 trial is the largest RCT in recent years, and showed a trend towards reduced all-cause mortality and HF hospitalization rates in the ablation therapy group compared with the medical therapy (rate control) group $(\mathrm{P{=}0.066})$ . Although the difference was not statistically significant, most of the events were seen after 18 months of enrollment, suggesting that the observation period may have been inadequate. The relatively large trials of CASTLE-AF, 279 and AATAC, 281 and the CABANA subanalysis 278 demonstrated a significant reduction in deaths in the ablation therapy group compared with the medical therapy group, suggesting that prognostic efficacy of catheter ablation in patients with HFrEF is high.

In terms of sufficient observation period, the CABANA trial with 49 months of follow-up is noteworthy, and in a subanalysis focusing on patients with HF (35%), 278 ablation therapy significantly reduced the primary composite endpoint of death, severe stroke, major bleeding and cardiac arrest compared with medical therapy (HR 0.64, $95\%$ CI 0.41–0.99). In addition, catheter ablation therapy signifi

|Table 15. Recent RCTs on the Treatment of AF With HF (Ablation Therapy vs. Medical Therapy)|||||||||| |---|---|---|---|---|---|---|---|---|---| | Trialname (year) | Noof patients | Age (years) | AF phenotype |NYHA| LAD (mm) | LVEF (9%0) | Follow-up (months) | Primary endpoint (vs. medical therapy) | Other results (vs. medical therapy) | | RAFT-AF276 (2022) |411|62|PAF/PSAF||46|30|| Reduction of all-cause mortality/HF, HR 0.71 (P=0.066) | Improvement in LVEF and QOL, decrease of NT-proBNP | | AMICA277 (2019) |202|65|PSAF||50|26|1２| No significant improvement in LVEF (P=0.36) | Higher SR maintenance rate, reduction of AF/AT burden, no significant improvement in 6MWD, QOL or BNP | | CABANA278 (2019) |778|68|PAF/PsAF|v||55|49| Reduction of death/ stroke/hemorrhage/ cardiacarrest,HR0.64 (95% CI 0.41-0.99) | Reduction in mortality rate, improvement in QOL | | CASTLE- AF279 (2018) |363|64|PAF/PSAF||48|32|37.6| Reduction of all-cause mortality/HF, HR 0.62 (P=0.007) | Improvement in LVEF/no improvement in 6MWD | | CAMERA- MRI280 (2017) |68|61|PSAF|V|48|33|| Improvement in LVEF (P ||

6MWD, 6-minute walk distance; AF, atrial fibrillation; BNP, B-type natriuretic peptide; COR, Class of Recommendation; HF, heart failure; LAD, left atrial dimension; LOE, Level of Evidence; LVEF, left ventricular ejection fraction; LVESD, left ventricular end-systolic dimension; LVESV, left ventricular end-systolic volume; NT-proBNP, N-terminal pro-BNP; QOL, quality of life; RCT, randomized controlled trial; SR, sinus rhythm; V O 2max , maximum oxygen consumption.

cantly reduced both AF recurrence ( $56\%$ vs. $72\%$ , HR 0.56, $95\%$ CI 0.42–0.74) and AF burden, and also improved QOL. 278 It should be noted, however, that the study included patients with mild HF ( $76\%$ of patients were NYHA II and median LVEF was $55\%$ ). Long-term results (7.8 years of follow-up) of the combined population of the CAMTAF 282 and ARC-AF 283 trials were also recently reported. There was no significant difference in death or cardiovascular hospitalization between the ablation therapy group and the medical therapy group, but $54\%$ of the medical therapy group had undergone ablation at the end of the study. Treatment-based prognostic analysis showed that the ablation therapy group had significantly lower mortality (HR 0.43, $95\%$ CI 0.20–0.91, $\mathbf{P}{=}0.028)$ and mortality/cardiovascular hospitalization (HR 0.48, $95\%$ CI 0.24–0.94, $\mathrm{P{=}0.031}$ ) rates compared with the drug treatment group. 284

The AMICA trial assessed improvement in cardiac function (left ventricular ejection fraction: LVEF) as a primary endpoint in patients with persistent AF and LVEF $\Bar{<}35\%$ , and the trial found that the improvement in LVEF was similarly observed in both groups, although the rate of sinus rhythm (SR) maintenance at 1 year was significantly higher in the ablation therapy group $(73.5\%$ vs. $50\%$ , $\mathrm{{P\bar{=}}0.001}$ ). 277 These conflicting results may be due to shorter follow-up duration (1 year) and more severe population compared with other trials. In fact, the AMICA trial included patients with severe low LVEF $(26\%)$ and severe HF ( $60\%$ of patients with NYHA III, and $43\%$ of patients with CRT-D implantation). The ARC-HF trial also did not show a significant difference in LVEF improvement, but patients with a markedly low LVEF of $24\%$ were included. 283

The CAMERA-MRI trial, an evaluation of cardiac function by magnetic resonance imaging (MRI), showed significant improvement in LVEF in the ablation therapy group. In particular, the late gadolinium enhancement (LGE)-negative group had a significantly greater improvement in LVEF compared with the LGE-positive group $(22.3\%$ vs. $11.6\%$ , $\mathbf{P{=}0.0069}$ ) and LGE-negative patients were more likely to normalize LVEF $(\mathrm{EF}{\geq}50\%)$ ) ( $\bar{7}3\%$ vs. $29\%$ , $\mathrm{P{=}}0.0093$ ). 280 The results were similarly observed after 4 years’ follow-up. 285 A subanalysis of the same study investigated the effect of catheter ablation on cardiac function in patients with persistent AF and idiopathic low LVEF, and found that myocardial T1 time, a surrogate of diffuse fibrosis, was significantly decreased and LVEF had significantly improved in the ablation therapy group compared with the medical therapy group. 286 That result indicated that catheter ablation therapy is an effective treatment for AF-induced cardiomyopathy. Based on these results, catheter ablation is strongly recommended for patients with AF-induced cardiomyopathy caused by cardiac dysfunction secondary to tachycardia or irregular and asynchronous myocardial contractions, or cardiac dysfunction that recovers by SR restoration, because catheter ablation can be highly expected to restore cardiac dysfunction in such patients. 286 – 289

On the other hand, the CASTLE-AF trial could not show a significant benefit of catheter ablation therapy over medical therapy in patients with NYHA III or LVEF ${<}25\%$ . 279 In light of the results of the AMICA trial 277 and ARC-HF trials, 283 it should be noted that both the cause and severity of LV dysfunction, as well as the severity of HF, may affect the clinical outcome.

In August 2023, results from the CASTLE-HTx trial, which assessed the efficacy of catheter ablation therapy with medical therapy in patients with symptomatic AF and endstage HF who were referred for heart transplantation evaluation, were published. 290 The study showed a significant reduction in the composite primary endpoint (all-cause death, heart transplantation, left ventricular assist device implantation) in the combination of catheter ablation and medical therapy group compared with the medical therapy alone group during 18 months’ follow-up $8\%$ vs. $30\%$ , HR 0.24, $95\%$ CI 0.11–0.52, $\mathrm{P{<}0.001}$ ). This result was supported by a significant reduction in AF burden (reduction rate: $30.8\%$ /year vs. $8.3\%$ /year) and a significant improvement in cardiac function (LVEF improvement rate: $7.8\%$ /year vs. $1.4\%/$ /year) in the combination of catheter ablation and medical therapy group. These results suggest that catheter ablation in combination with medical therapy is worthwhile for patients with AF and endstage HF if their condition is stable. However, the study did not demonstrate the efficacy of catheter ablation in patients with LVEF ${<}25\%$ .

In conclusion, catheter ablation therapy in patients with AF with HFrEF should be considered after careful consideration of the patient’s background, and the etiology and severity of HF.

The efficacy of catheter ablation in patients with AF with HF with preserved EF (HFpEF) has been reported in many single-center studies, 291 and meta-analyses showed that the rate of SR maintenance after catheter ablation therapy in patients with HFpEF was comparable to those without and those with HFrEF, and also demonstrated that catheter ablation therapy was associated with higher rate of SR maintenance, lower incidence of HF hospitalization and improvement in QOL compared with medical therapy. 292 , 293 Although a large-scale RCT is still lacking, a post-hoc analysis of the CABANA trial limited to patients with LVEF ${>}50\%$ found that catheter ablation therapy was associated with a $60\%$ reduction in death compared with medical therapy $(3.3\%$ vs. $8.6\%$ , HR 0.40, $95\%$ CI 0.18–0.88). 278 Furthermore, a recent RCT comparing the efficacy of catheter ablation (16 patients) and medical therapy (15 patients) in AF patients with HFpEF demonstrated that catheter ablation significantly improved hemodynamic parameters (pulmonary capillary wedge pressure [PCWP], cardiac output [CO]), exercise tolerance (peak V O 2 ) and QOL at 6 months compared with medical therapy, although the study population was quite limited. In particular, HF was hemodynamically improved in $75\%$ of AF ablation patients who successfully maintained SR, indicating the importance of maintaining SR in patients with HFpEF. 294

As noted, catheter ablation is a highly effective therapy in AF patients with HF; however, the indication for catheter ablation should be carefully judged based on the patient’s background, including cardiac function, NYHA, underlying cardiac disease and AF duration. In particular, catheter ablation therapy may worsen the prognosis in patients with severe HF and advanced AF. In addition, complex procedures, older patients and multiple comorbidities (HF, renal dysfunction, hypertension, etc.) increase the risk of perioperative complications related to catheter ablation procedures, and therefore, careful handling of each case is recommended. 295 , 296

Based on this evidence, we have made some changes in this Focus Update from the previous update regarding the recommendation of catheter ablation in AF patients with HF as follows. “Catheter ablation is recommended to

| Table 16. Recommendations and Levels of Evidence for Catheter Ablation of AF With HF ||| |---|---|---| |||| ||COR|LOE| |Catheter ablation is recommended to reverse||| |LV dysfunction in AF patients when AF||C| |induced cardiomyopathy is highly probable||C| |||| | Catheter ablation should be considered in selected patients withAFand HFrEFwho are receiving guideline-directed medical therapy |ila|| ||ila|| | for HF, to reduce mortality and hospitalization rates |ila|| |Catheter ablation may be considered in||| |patients with AF who have HF with HFpEF||E| |and no comorbidities contributing to HF, to||E| |reduce mortality and hospitalization rates|||

AF, atrial fibrillation; COR, Class of Recommendation; HF, heart failure; HFpEF, HF with preserved left ventricular ejection fraction; HFrEF, HF with reduced left ventricular ejection fraction; LOE, Level of Evidence; LV, left ventricular.

reverse LV dysfunction in AF patients when AF induced cardiomyopathy is highly probable” (classified as Class I), and “Catheter ablation is considered in AF patients with HF with preserved LVEF (HFpEF) without comorbidities that contribute to HF to reduce mortality and HF hospitalization” (classified as Class IIb) ( Table16 ).

CQ 1. Should Atrial Fibrillation Catheter Ablation Be Performed in Older Patients (>80 Years Old)?

Recommendation

We recommend that the option of catheter ablation for symptomatic AF not be ruled out solely because of advanced age (defined in this Focus Update as 80 years).

Catheter ablation for asymptomatic AF in the very old, aimed at improving prognosis, is not recommended.

Supplementary Item

1) First, evaluate symptoms. Check for HF symptoms such as palpitations and shortness of breath, and whether there is a decrease in QOL or daily living activities due to the decline in cardiac function caused by AF.

2) There is considerable individual variation in the overall condition of the older patient (frailty, cognitive abilities, comorbidities). Evaluate the general condition in each case, considering the progression of AF (duration and left atrial remodeling), and decide on ablation treatment through shared decision-making with the patient, weighing the benefits (symptom improvement) and risks.

Background and Priority of This CQ

Aging is a major risk factor for the development of AF, and its prevalence is high in older patients. Although AF catheter ablation is an invasive procedure and should be performed cautiously in older patients with low physical reserve and high comorbidity, the proportion of older patients undergoing real-world AF catheter ablation is increasing significantly.

According to the registries conducted by the Japanese Heart Rhythm Society, the percentage of patients aged 75 years undergoing AF catheter ablation increased from $8.5\%$ in 2011 (J-CARAF Registry) to $28.3\%$ in 2021 (J-AB Registry). 297 It is considered an important clinical issue to verify whether such a rapid spread of AF ablation in older patients is appropriate. However, because there are no

RCTs specifically for this age group, evidence must be determined from registry studies and subanalyses of RCTs.

Evidence Summary

PICO

P : Older patients with AF

I : Catheter Ablation

C : Young patients with AF

Significant outcomes related to benefit: recurrence-free rate, QOL, prognosis

Significant outcomes related to harm: complications associated with the procedure

Safety of Ablation in Older Patients With Atrial Fibrillation

A meta-analysis comparing the safety of catheter ablation in older and younger patients in registered studies has been conducted. 298 – 300 In these studies, age was consistently an independent predictor of complications. A study using the Japanese DPC database also found that age was associated with complications, with even a significant difference in complication rates between those aged ${<\!60}$ years and those aged 60–64 years. 296 The complication rate in the ${\geq}85$ age group $(6.8\%)$ was approximately 2.8-fold higher than that in the ${<\!60}$ age group $(2.5\%)$ . Considering that the overall complication rate was $5.8\%$ in the 2011 J-CARAF survey, 301 the current rate in the group aged ${\geq}85$ years is not prohibitively high, but more cautious decision-making is required compared with younger patients.

Efficacy of Ablation in Older Patients With Atrial Fibrillation

A meta-analysis comparing recurrence rates after catheter ablation in older and younger patients in a registry study was inconsistent, with some studies reporting that age was associated with recurrence, 298 , 299 and others reporting no significant difference in recurrence rates between age groups. 300 This result indicates that reasonable outcomes can be expected with appropriate patient selection.

Quality of Life Improvement Effects of Ablation in Older Patients With Atrial Fibrillation

Catheter ablation has been shown to significantly improve QOL for patients with symptomatic AF. 302 , 303 In an agespecific subanalysis, the advantage of ablation over conservative treatment was consistent between older and younger patients, suggesting that catheter ablation may improve QOL in symptomatic AF regardless of age. 303

Prognosis Improvement Effects of Ablation in Older Patients With Atrial Fibrillation

Catheter ablation has not been conclusively proven to improve prognosis for the general patient population with AF. 273 The CABANA trial, a RCT comparing catheter ablation with drug therapy for the treatment of AF with risk factors, found no significant difference between treatments. However, in a subanalysis by age, the catheter ablation group showed better prognosis in younger patients, but not in older patients, indicating a significant interaction. 304

The CASTLE-AF trial, which showed that AF catheter ablation can significantly reduce all-cause death and HF hospitalization in patients with HF, did not show such an effect in the older subgroup ( ${\geq}65$ years old). 279 In older patients, factors other than AF may influence prognosis. Therefore, catheter ablation of asymptomatic AF for the primary purpose of improving prognosis is generally not recommended.

Conclusion

Although advanced age does present a significant risk for

complications in AF ablation, the reported incidence of these complications is not excessively high. Furthermore, efficacy does not show a significant difference compared with younger patients. Therefore, age alone should not be the sole criterion for deeming ablation unsuitable. Although ablation’s effect in maintaining SR can lead to improved QOL, its impact on overall prognosis remains unclear. Therefore, AF ablation in older patients should be considered for those who are presumed to be at low risk from the procedure based on their overall health status. The primary objective should be to improve QOL and daily living activities that have been diminished due to symptomatic AF.

▋ ▋ 2.4 Angioplasty for Pulmonary Vein Stenosis After Atrial Fibrillation Catheter Ablation

Pulmonary vein stenosis (PVS) is a well-known complication of AF catheter ablation, although its incidence of PVS is recognized as relatively rare $(3.4–42.4\%)$ , and $0.7–3.6\%$ of patients require interventional treatment due to some symptoms. 305 – 308 The incidence has reported to be relatively high when segmental PV ostial isolation was performed for AF, but the incidence decreased once the wide-area circumferential ablation technique became popular for PVI. However, with the spread of balloon technology, the incidence has increased again, and caution is needed. The wide variation in incidence is due to different methods for detecting PVS. Some reports assessed only symptomatic patients, while others prospectively evaluated all patients

by computed tomography (CT) scan after catheter ablation.

Symptoms were variable, including cough, shortness of breath, dyspnea, chest pain, bloody sputum (hemoptysis), and recurrent pneumonia, and these symptoms usually occurred about 100 days after the procedure. 307 In general, if stenosis is limited to a single PV, the patient is often asymptomatic, but if the stenosis involves multiple PVs or acutely progresses, some symptoms are more likely to occur. 308 In particular, stenosis of the ipsilateral upper and lower PVs is likely to cause severe symptoms, and stenosis of 3–4 PVs may be life-threatening.

There were no guidelines regarding treatment of PVS in the past. Percutaneous transluminal PV angioplasty has been reported as an effective treatment for PVS or PV occlusion in Japan 309 and other countries. 310 In Japan, percutaneous transluminal PV angioplasty has not been approved by insurance as of February 2024 ( Figure7 ).

Because there are no devices specifically designed for the PVs (balloon and stent), percutaneous transluminal PV angioplasty is performed mainly using devices for the lower limb vessels, and its efficacy and safety have been reported at the single-center level. 309 – 312 Complications associated with this procedure, including cardiac tamponade, stent loss, and cerebral infarction, are estimated to be $3–4\%$ , 313 but no complications have been reported in Japan. 309 In addition to complications, restenosis after stent dilation should be considered with this procedure. The restenosis rate after stenting has been reported to be significantly lower than that of balloon dilation alone, so it is important to obtain a large dilation diameter. 311 , 312 There are only scattered reports of surgical intervention for PVS, 314 and

 Figure7. Percutaneous transluminal pulmonary vein angioplasty for severe pulmonary vein stenosis after catheter ablation for atrial fibrillation. Balloon dilatation and stenting were performed for severe stenosis of the left upper pulmonary vein. ABL, ablation; AP, anteroposterior view; BA, balloon angioplasty; BMS, bare metal stent.

efficacy and safety are not clear.

The number of cases of PVS after AF ablation is small, and the efficacy and safety of this technique have not yet been established. In the clinical setting, it is currently performed out of necessity in cases of PVS or occlusion with symptoms or lung dysfunction. Therefore, we describe the current status of this treatment in this Focus Update. It is recommended that the indication of PV angioplasty must be thoroughly assessed, informed consent be given by the patient, and the procedure should be performed under the backup of cardiovascular surgery and the cooperation of an experienced arrhythmia specialist and a percutaneous coronary intervention specialist.

3. New Ablation Therapy for Atrial Fibrillation: Pulsed Field Ablation

▋ ▋ 3.1 Principles and Properties

When an electric field is externally applied to a cell by direct current with an extremely short pulse width (nanoseconds to microseconds), a force corresponding to the magnitude of the electric field intensity is applied to the cell membrane. When this force becomes larger than the level at which the cell membrane can maintain its structure, small pores are created in the lipid bilayer of the membrane. If the applied voltage is near a critical voltage (i.e., the voltage that provides an electric field strength just high enough to disrupt the cell membrane) for a very short time, the holes formed in the cell membrane are small and the membrane can be spontaneously repaired (reversible electroporation).

However, when an electric field far exceeding a critical voltage is applied, a large irreparable hole is created in the membrane, leading to cell death (irreversible electroporation). Pulsed field ablation (PFA) uses a catheter to induce irreversible electroporation in targeted myocardial cells, creating lesions. 315

The threshold of the electric field for irreversible electroporation of cardiomyocytes is much lower than that of vascular smooth muscle, endothelial cells, and nerves. Current thermal energy-mediated catheter ablation procedures cause damage to surrounding tissues (pulmonary vein stenosis, phrenic nerve palsy, left atrial esophageal fistula, gastric dysmotility, etc.), but PFA selectively injures target myocardial cells, so the risk of adjacent tissue damage is extremely low. 315

PFA does not need to generate contact force between the catheter and the target, as is the case with radiofrequency catheter ablation, and the effect of PFA is not weakened by insufficient contact force. The durability of PVI may be maintained if the catheter and target site are not too far apart. Thus, PFA is expected to greatly improve both the efficacy and safety of current catheter ablation techniques.

▋ ▋ 3.2 Clinical Data

The first in-human clinical trial of PFA (IMPULSE/ PEFCAT) was performed in 81 patients with paroxysmal AF. 316 The catheter was a 12Fr over-the-wire type (FARAWAVE TM ) with a basket- or petal-shaped tip that fitted the shape of the pulmonary vein entry. PFA delivery time for PVI was ${<}3\,\mathrm{min}$ , and total procedure time was $1.5\,\mathrm{h}$ , including 3-dimensional mapping of the left atrium (av. 18min).

The output waveform was modified from monophasic

to biphasic 1, 2, and 3 throughout the study period, and the maintenance of PVI at 3 months improved from $18\%$ in the monophasic setting to $100\%$ in the biphasic 3 setting. The safety profile of the study included only 1 patient with cardiac tamponade, and no other adverse events (e.g., stroke, phrenic nerve palsy, pulmonary vein stenosis, or esophageal injury). A total of 121 patients were followed up, and at 1 year showed a SR maintenance rate of $78.5\%$ for all patients and $84.5\%$ for patients with optimized waveforms. 317

Clinical trials of PFA catheters for PVI are ongoing, using several other manufacturers’ catheters besides FARAWAVE TM , and in 2023 the results of the PULSED AF trial using a loop-type PFA catheter (PulseSelect TM , Medtronic, Inc.) were published. 318 That study was a multicenter, prospective, observational study of 300 patients with AF (150 paroxysmal, 150 persistent) from 41 centers in 9 countries, including Japan. The 1-year follow-up showed that the primary efficacy endpoint (rate of acute procedural failure/recurrent arrhythmia/avoidance of antiarrhythmic drug escalation) was significantly higher for paroxysmal than for persistent AF ( $\bar{6}6.2\%$ and $55.1\%$ , respectively), and the primary safety endpoint (procedure-or device-related adverse events) was $0.7\%$ (1 cerebrovascular event/150 paroxysmal AF patients, 1 cardiac tamponade/150 persistent AF patients).

In 2023, the 1-year follow-up results of the VARIPULSE ® variable loop catheter (Biosense Webster, Inc.) for PVI (inspire study) were also reported. 319 The VARIPULSE ® catheter is integrated with the CARTO system, a 3-dimensional mapping system, enabling both mapping and PFA with the same catheter of 226 patients with drug-refractory symptomatic paroxysmal AF in the study, 83 patients reached 1-year follow-up. The non-recurrence rate of symptomatic AF, atrial flutter, and atrial tachycardia was $78.9\%$ , and no major adverse events were observed during the period.

All 3 trials were prospective studies of a PFA group alone, but in August 2023 the results of a prospective RCT (ADVENT) comparing a PFA group with a radiofrequency/ cryoablation group were reported, showing that PFA was noninferior in both efficacy and safety. 320

▋ ▋ 3.3 Safety

Left atrial esophageal fistula is a rare but fatal complication. The myocardial selectivity of PFA is a promising feature for avoiding this injury. In an experiment using swine esophagi ablated from the inferior vena cava, injury (including 1 left atrial esophageal fistula) occurred in all subjects in the radiofrequency ablation (RFA) group (4 cases), but not in the PFA group (6 cases). 321 Animal studies have also shown that PFA has minimal effect on the phrenic nerve. 322 A single 200-J PFA was delivered from the right atrium of swine to the phrenic nerve, which was captured in 17/19 cases immediately after ablation and in all 19 cases 30min later; 15 cases were followed up 3–13 weeks later and showed no problems with the phrenic nerve. Clinically, transient phrenic nerve palsy immediately after PFA has been reported, 323 but is not considered as a long-term problem.

The effect of PFA on pulmonary vein stenosis was also examined in an animal study. 324 Ten pigs underwent PFA in one pulmonary vein and RFA in another pulmonary vein, and the pulmonary vein diameters were evaluated

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angiographically before and after PFA and 3 months later. PFA showed a $11\%$ decrease just after ablation, but a $19\%$ increase at 3 months. In contrast, RFA showed a $23\%$ decrease immediately and a $7\%$ decrease at 3 months. Similar results were clinically demonstrated in a subanalysis of the IMPULSE and PEFCAT studies, 325 suggesting that PFA has no or very little effect on pulmonary vein stenosis.

Coronary artery spasm is currently considered the only concerning effect of PFA on the surrounding organs. A case of coronary spasm induced in the left circumflex artery after PFA to the mitral isthmus was reported, 326 and its effects on coronary spasm have since been comprehensively studied. 327 No coronary spasm was observed after PVI (25 patients) or posterior wall isolation (5 patients), but severe right coronary artery stenosis was induced in all 5 patients after ablation to the cavo-tricuspid isthmus (CTI) and they recovered on average 5.5min after nitroglycerin administration. Subsequently, PFA was performed to the CTI in 15 patients after coronary (5 patients) or intravenous (10 patients) nitroglycerin injection, and moderate and mild coronary stenosis was induced in 1 and 2 patients, respectively, but severe stenosis was not induced. Thus, coronary spasm should be kept in mind when PFA is performed in the immediate vicinity of a coronary artery.

▋ ▋ 3.4 Outlook

PFA injures the myocardium in a few seconds by direct current application, resulting in a shorter treatment time compared with conventional RFA and cryoenergy, and with less injury to surrounding organs due to its selective targeting of myocardial cells. Clinical studies to date suggest that efficacy is comparable, at least in the short term. Although PFA is expected to become the first choice for catheter ablation instead of thermal energy in the future, the evidence is still limited, and its efficacy and safety should continue to be carefully evaluated.

4. Advances in Ventricular Premature Contraction (PVC)/Ventricular Tachycardia (VT) Ablation

▋ ▋ 4.1 Evaluation of Arrhythmic Substrate in PVC/VT Patients

In the presence of ventricular arrhythmias, it is important to evaluate for structural heart disease, including coronary artery disease. The 2022 ESC guidelines 40 recommend 12-lead ECG, echocardiography, coronary evaluation with CT or coronary angiography, and cardiac magnetic resonance imaging (MRI) to investigate structural heart disease as a Class IIa indication. In cases of scar-related VT, contrast-enhanced MRI is useful for determining the ablation strategy, and in cases of suspected idiopathic VT, MRI is also recommended for identifying potential structural heart disease.

▋ ▋ 4.2 Indication and Timing

cardioverter defibrillator (ICD) implantation. These studies have shown that catheter ablation is effective in preventing recurrent VT, especially in patients with ischemic heart disease who are taking amiodarone. Many RCTs conducted after the publication of the 2019 JCS/JHRS guidelines on the non-pharmacotherapy of cardiac arrhythmias” support the strategy of performing catheter ablation as the first-line treatment for the prevention of recurrent VT. 5

Recent advances and widespread use of 3-dimensional mapping systems and high-density mapping using multipolar catheters have facilitated the identification of ablation target sites, 332 thereby increasing the procedural success rate. The SURVIVE-VT trial compared catheter ablation with antiarrhythmic drugs as a first-line treatment for the prevention of recurrent VT associated with myocardial infarction. After 2 years of follow-up, the ablation group had an improvement in the composite endpoint consisting of cardiovascular death, appropriate therapy by ICD, unscheduled hospitalization for heart failure, and treatment-related serious complications $(28.2\%$ in the ablation group vs. $46.6\%$ in the antiarrhythmic drug group, hazard ratio [HR] 0.52, $95\%$ confidence interval [CI] 0.30– 0.90, $\mathrm{P{=}0.021]}$ ). This difference was mainly driven by a significantly high incidence of drug side effects and serious drug treatment-related complications such as the occurrence of slow VT below the VT detection zone of the ICD in the antiarrhythmic drug group. There was no difference in the incidence of cardiovascular death between the 2 groups. As of February 2024, the VANISH2 (NCT02830360) is ongoing to evaluate the superiority of catheter ablation as a first-line treatment for sustained VT.

The PAUSE-SCD trial is a multicenter RCT including Asian countries that compared catheter ablation prior to ICD implantation with medical therapy in patients with structural heart disease and a history of monomorphic VT. 333 Patients with dilated cardiomyopathy and arrhythmogenic right ventricular cardiomyopathy as well as those with ischemic heart disease were included in the study, which is different from previous RCTs that mainly included patients with ischemic heart disease. During a mean follow-up of 31.3 months, the incidence of primary endpoints (recurrent VT, hospitalization for cardiovascular events, and death) was significantly lower in the ablation group $49.3\%$ in the ablation group vs. $65.5\%$ in the control group, HR 0.58, $95\%$ CI 0.35–0.96, $\mathrm{{P}{=}0.04)}$ ). This difference was mainly due to the reduction in VT recurrence in the ablation group, and there was no significant difference in the incidence of hospitalization for cardiovascular events or death between the 2 groups.

▋ ▋ 4.2.1 Catheter Ablation for VT Associated With Structural Heart Disease

PARTITA trial 334 is a European multicenter RCT published at the same time as the PAUSE-SCD trial. It compared catheter ablation with medical therapy in patients who experienced the first appropriate shock after ICD implantation. Catheter ablation reduced ICD therapies and improved the composite endpoint (death or hospitalization for worsening heart failure: $4\%$ in the ablation group vs. $42\%$ in the control group, HR 0.11, $95\%$ CI 0.01–0.85, $\mathbf{P{=}0.034}$ ).

RCTs such as the SMASH VT, 328 VTACH, 329 SMS, 330 and VANISH 331 trials were conducted to investigate the efficacy of catheter ablation for the prevention of VT recurrence in patients after myocardial infarction and implantable

The BERLIN VT trial 335 is another European multicenter RCT that aims to evaluate the optimal timing of VT ablation in patients with myocardial infarction and a history of sustained VT. It compared a prophylactic ablation before ICD/CRT-D implantation with an elective ablation after at least 3 appropriate ICD shocks following ICD/ CRT-D implantation. The incidence of sustained VT was

| Table 17. Recommendation and Level of Evidence for Catheter Ablation in Brugada Syndrome ||| |---|---|---| | Table 17. Recommendation and Level of Evidence for Catheter Ablation in Brugada Syndrome ||| ||COR|LOE| |Catheter ablation of triggering PVCs and/or||| |RVOT epicardial substrate should be||| |considered inpatients with Brugada||E| |syndrome with recurrent appropriate ICD|a|E| |shocks that are refractory to drug therapy or|a|| |when pharmacological treatment is||| |contraindicated due to adverse effects|||

COR, Class of Recommendation; ICD, implantable cardioverter defibrillator; LOE, Level of Evidence; PVC, premature ventricular contraction; RVOT, right ventricular outflow tract.

lower in the prophylactic ablation group; however, there was an increase in the incidence of hospitalizations for worsening heart failure and no improvement in the prognosis $(32.9\%$ in the prophylactic ablation group vs. $27.7\%$ in the standby ablation group, HR 1.09, $95\%$ CI 0.62–1.92, $\mathrm{{P}{=}0.77}$ ). The results of the study did not validate VT ablation prior to device implantation to prevent VT recurrence.

Taken together, these results suggest that an early catheter ablation strategy significantly reduces recurrent VT and ICD therapies, especially in patients with ischemic heart disease, compared with antiarrhythmic drug therapy. However, there are conflicting results regarding whether catheter ablation reduces mortality and hospitalization for cardiovascular events, and future studies will be needed. It should be mentioned that complication rates were relatively high, ranging from $2.8\%$ to $8.7\%$ , in these RCTs, which were mainly conducted at experienced centers. 5 , 328 – 335 With consideration of patient risk, ablation should be performed only at experienced centers.

▋ ▋ 4.2.2 Idiopathic PVC/VT

Catheter ablation for idiopathic PVC/VT originating from the right ventricular outflow tract or left bundle branch has a high success rate with a low complication rate, and RCTs have shown that catheter ablation is more effective than antiarrhythmic drug therapy for idiopathic PVC/VT of the right ventricular outflow tract origin. 336 , 337 The 2022 ESC guidelines recommend catheter ablation as the first-line treatment for symptomatic PVC/VT originating from the right ventricular outflow tract or left ventricular bundle branch as a Class I indication. 40 Catheter ablation or flecainide is recommended as a Class IIa treatment for symptomatic PVC/VT of other origin. The success rate of catheter ablation for PVC/VT from sites other than the ventricular outflow tract is slightly less than that of originating from the ventricular outflow tract. 336 In this Focus Update, we follow the 2019 JCS/JHRS guideline on non-pharmacotherapy of cardiac arrhythmias. 5 Catheter ablation is recommended as a Class I indication in patients with frequent PVC/non-sustained ventricular tachycardia (NSVT; ${\geq}10\%$ of the total number of beats) who have serious symptoms or severe ventricular dysfunction due to tachycardia and for whom antiarrhythmic drugs are ineffective, not tolerated or not the patient’s preference. In patients with symptomatic idiopathic PVCs originating from the right or left ventricular outflow tract and for whom antiarrhythmic drugs are ineffective, not tolerated or not the patient’s preference, catheter ablation should be considered (Class IIa Recommendation). In patients with

symptomatic idiopathic PVCs originating from sites other than the ventricular outflow tract and for whom antiarrhythmic drugs are ineffective, not tolerated or not the patient’s preference, catheter ablation may be considered (Class IIb Recommendation).

▋ ▋ 4.2.3 Epicardial Ablation for Brugada Syndrome

The effectiveness of endocardial or epicardial ablation of PVCs triggering VF, and epicardial ablation of an abnormal arrhythmogenic substrate in the right ventricular outflow tract have been reported in patients with Brugada syndrome with recurrent ICD shocks. 338 , 339 Successful epicardial ablation has already been reported, and the long-term results are excellent. 340

The BRAVO registry 341 reports the results of epicardial catheter ablation in 159 patients with Brugada syndrome. During a follow-up period of approximately 4 years, the VF-free survival rate after a single procedure was $81\%$ , and the final success rate after repeat procedures was $96\%$ . The 5-year VF-free survival rate was $98\%$ in patients who did not develop type 1 ECG after a drug provocation test. Therefore, in this Focus Update, catheter ablation of VFtriggering PVCs and epicardial ablation of the abnormal potential area in the right ventricular outflow tract are recommended as a Class IIa indication in patients with recurrent appropriate ICD shocks refractory to drug therapy ( Table17 ). Currently, 2 RCTs investigating the efficacy of epicardial ablation for Brugada syndrome are ongoing (NCT03294278, NCT02704416).

Recent studies have shown that there are some cases in which abnormal potential areas exist in the epicardial right inferior wall and left lateral wall as well as in the right ventricular outflow tract. 340 , 341 In particular, this is often observed in patients with an early repolarization pattern in the inferolateral leads on 12-lead ECG. 340 It has not been fully elucidated whether abnormal potentials found outside the right ventricular outflow tract are involved in the development of VF and should be ablated.

CQ 2. What Is the Optimal Treatment for Asymptomatic Idiopathic PVC Without Evidence of Left Ventricular Dysfunction?

Recommendation

In patients with idiopathic PVC who have no symptoms and no evidence of left ventricular dysfunction, it is recommended to follow-up first and consider treatment after the evaluation described below.

Supplementary Item

1) The incidence of PVCs (the PVC burden), the presence of NSVT, and the presence of structural heart disease (echocardiography, cardiac contrast-enhanced MRI) should be evaluated. 2) Regular follow-up of ECG and cardiac function is recommended. When symptoms (palpitations, loss of consciousness, etc.) appear or cardiac function deteriorates, catheter ablation should be considered after shared decision-making with the patient.

Background and Priority of This CQ

PVCs are often not accompanied by symptoms and prognosis is good in the absence of structural heart disease (i.e., idiopathic PVCs). 342 Catheter ablation of idiopathic PVCs is highly effective with a low complication rate. Although rare, there is a concern about PVC-induced

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cardiomyopathy and induction of lethal ventricular arrhythmias. The effectiveness of catheter ablation has been reported in such cases. 343 , 344 At present, there is no method to accurately predict the occurrence of PVC-induced cardiomyopathy or lethal ventricular arrhythmias. It is important to evaluate whether ablation is beneficial for patients with asymptomatic idiopathic PVCs.

Evidence Summary PICO P : idiopathic PVC I : Catheter Ablation C : Observation O : Outcome Significant outcomes related to benefit: reduction in sudden cardiac death, worsening of LVEF, and hospitalization for worsening heart failure Significant outcomes related to harm: procedure-related complications (cardiac tamponade)

Risk Factors for PVC-Induced Cardiomyopathy

It is known that patients with a high incidence of PVCs (high PVC burden) are at a high risk for developing PVCinduced cardiomyopathy. Baman et al. reported that the risk of developing PVC-induced cardiomyopathy increased when the PVC burden was ${\ge}24\%$ of the total daily heartbeats on 24-hour Holter ECG in 174 patients with idiopathic PVCs. On the other hand, they reported that there were no patients with LVEF worsening when the PVC burden was ${<}10\%$ . 345

There are intra-day and daily variations in the incidence of PVCs. Hsia et al. suggested that $_{24-48\,\mathrm{h}}$ of ECG monitoring is not sufficient for accurate assessment of PVC burden, and that prolonged ECG monitoring over ${\geq}1$ week is important. 346 It is desirable to establish a more accurate risk assessment based on the PVC burden using long-term ECG monitoring.

Catheter Ablation for PVC-Induced Cardiomyopathy

According to 1 meta-analysis including patients with a mean preoperative PVC burden of $24\%$ , success rates of catheter ablation ranged from $66\%$ to $90\%$ , and mean LVEF improvement was $7.7\%$ $95\%$ CI 6.1–9.4%). 347 In another report, the complication rate of catheter ablation was $2.4\%$ , and no procedure-related deaths occurred. 336

Prognosis of PVC-Induced Cardiomyopathy

Lee et al. prospectively investigated the prognosis of 100 untreated and asymptomatic patients with idiopathic PVCs. 348 Among patients with a mean PVC burden of $18.4\%$ at enrollment, PVCs spontaneously resolved in 44 patients $(44\%)$ during a mean follow-up of 15.4 months. The 4 patients $(4\%)$ without spontaneous resolution of PVCs had LVEF worsening (LVEF ${<}50\%$ ), and 1 $(1\%)$ had heart failure. Niwano et al. followed 239 Japanese patients with PVCs ≥ 1,000beats/day originating from the right or left ventricular outflow tract for an average of 5.6 years. They found that 13 patients $(5.4\%)$ had a decrease in LVEF of ${\ge}6\%$ ; however, none of them manifested heart failure symptoms. 349 In that study, deterioration of cardiac function was mainly observed in patients with PVCs of ${\geq}20{,}000$ beats/day. Based on the results of these studies, LVEF worsening is rare during the follow-up of a patient with idiopathic PVCs, and it is even more rare to have a manifestation of heart failure symptoms. Even in cases of PVC-induced cardiomyopathy, cardiac function restores within 4–6 months in many cases if PVCs are suppressed by catheter ablation, and the overall prognosis is considered favorable. 343 , 350

There is no clear consensus on the therapeutic intervention for asymptomatic idiopathic PVCs, and clinical evidence that supports catheter ablation as the first-line treatment is lacking. Regular follow-up of ECGs and cardiac function is recommended.

When there is a risk of developing PVC-induced cardiomyopathy, such as high PVC burden, catheter ablation may be considered after evaluation of the patient’s background, the estimated success rate of ablation, and the risks associated with the procedure. The 2022 ESC guidelines recommend regular follow-up of cardiac function in patients with asymptomatic idiopathic PVCs (Class I Recommendation). Catheter ablation is indicated only when the PVC burden exceeds $20\%$ . 40

▋ ▋ 4.3 New Ablation Techniques

▋ ▋ 4.3.1 New Mapping Methods of Detecting Arrhythmic Substrates

In scar-related VT, it is sometimes necessary to identify the ablation target sites during baseline rhythm when monomorphic VT cannot be induced or hemodynamically unstable VT is induced. Because areas with low voltage and delayed/isolated potentials are associated with critical isthmuses of the VT circuits, ablation targeting these areas has been performed. 351 , 352 However, this can damage areas unrelated to the VT circuit.

Recently, the usefulness of functional substrate identification has been reported to estimate the location of the VT isthmus from activation maps obtained by high-density mapping using catheters with multipolar electrodes during SR and pacing. 353 – 355 The VT isthmus is highly correlated with the area where electrical propagation is relatively slow compared with other areas in the ventricle. Aziz et al. reported that the area of dense isochronal crowding (area of conduction delay in the ventricle: deceleration zone) revealed by the isochronal late activation map (ILAM) method correlated with the VT circuit. Ablation at the deceleration zone was highly successful in eliminating VT. 354 Changing the direction of the wavefront in the ventricle by pacing may reveal areas of abnormal potentials that were not apparent during SR. Pacing from multiple directions is useful for identifying abnormal arrhythmic substrates. It has been reported that a pacing protocol using extrastimuli unmasked abnormal potentials that were not apparent during SR and that the areas with conduction delay during extrastimuli were associated with VT isthmuses. 356 – 358

▋ ▋ 4.3.2 Special Ablation Techniques

Recent studies using high-density mapping of the endocardium and epicardium during VT have shown that human VT is infrequently restricted to a single myocardial surface, but rather is characterized by complex 3-dimensional activation. 359 If the VT origin exists in the midmyocardium, endo- and epicardial ablations may be ineffective. Ethanol infusion into the coronary artery branch has been performed as an alternative approach to conventional RFA in such patients. Recently, the effectiveness of ethanol infusion into the coronary venous branch has been reported (not covered by insurance in Japan). Valderrábano et al. performed ethanol infusion into the coronary vein in patients with VT refractory to conventional catheter ablation and the 1-year VT-free survival rate was $84\%$ . 360 Stereotactic radiotherapy

is expected to be a noninvasive treatment for refractory VT and many clinical studies are ongoing. 361 , 362 However, there are reports of serious complications such as pericardioesophageal fistula in the late phase, and studies evaluating the safety of stereotactic radiotherapy will be needed. 363 As of February 2024, this treatment has not been approved in Japan.

Other approaches to treatment of VT with deep myocardial origin include ablation using low ionic irrigation

(half-normal saline), 364 and long-duration ablation (nonapproved therapy). The effectiveness of prolonged ablation with 20–35W for >2min ( ≤ 5min) with careful observation of impedance drop has been reported for ventricular arrhythmias originating from the left ventricular summit. 365 Because these approaches can increase the risk of steam pop and serious complications such as cardiac tamponade, the indications should be considered in light of efficacy and safety.

III. Atrial Fibrillation Pharmacotherapy and Comprehensive Management

1. Japanese Original Stroke Risk Assessment Tool: HELT-E 2 S 2 Score

▋ ▋ 1.1 HELT-E 2 S 2 Score Development Background

The CHADS 2 and CHA 2 DS 2 -VASc scores have been conventionally used for simple stroke risk assessment in patients with atrial fibrillation (AF). However, an integrated analysis of 3 Japanese registries (J-RHYTHM registry, Fushimi AF registry, and Shinken Database) raised questions about their applicability in Japan. 366 The analysis revealed that age ( ≥ 75 years), hypertension, and previous stroke were significant independent risk factors. 366

Further analysis in the J-RISK study, 367 , 368 which included 2 additional registries (Hokuriku-Plus AF registry and Keio Interhospital Cardiovascular Study), confirmed similar risk factors (age 75–84 years, hypertension, and previous stroke) and identified additional risks: age ${\geq}85$ years, body mass index (BMI) ${<}18.5\,\mathrm{kg}/\mathrm{m}^{2}$ , and persistent/ permanent AF. 367 Conversely, diabetes, heart failure and vascular disease, components of the CHADS 2 and CHA 2 DS 2 -VASc scores, were not identified as independent risk factors ( Table18 ). 368

▋ ▋ 1.2 HELT-E 2 S 2 Score

In the J-RISK study, 6 risk factors were weighted based on hazard ratios (HRs): 1 point for hypertension (H: Hypertension), age 75–84 years (E: Elderly), BMI ${<}18.5\mathrm{kg}/\mathrm{m}^{2}$ (L: Low BMI), persistent/permanent AF (T: Type of AF), and 2 points for age ${\geq}85$ years (E: Extreme elderly) and previous stroke (S: previous Stroke). Consequently, the HELT-E 2 S 2 score was developed, with a maximum of 7

|Table 18. HELT-E2S2 Score||| |---|---|---| |Acronym|Risk factor|Score| ||Hypertension|| ||Elderly, age 75-84 years|| ||Low BMI (||

AF, atrial fibrillation; BMI, body mass index. (Modified from Okumura K, et al., 2021. 368 )

points ( Table18 ). 368 The incidence of ischemic stroke, stratified by the HELT-E 2 S 2 score ranged from $0.57\%/$ year for 0 points to $5.82\%$ year for ${\ge}5$ points in patients without anticoagulation therapy ( Figure8 ). 368 A significant reduction in the hazard of ischemic stroke was observed in patients with HELT-E 2 S 2 score ${\geq}2$ when comparing those with and without anticoagulation ( Figure9 ). 368 However, it is important to note that this difference in incidence does not necessarily reflect the efficacy of anticoagulant therapy, as the results were not adjusted for patient background ( Figures8 , 9 ). 368

▋ ▋ 1.3 HELT-E 2 S 2 Score and Existing Risk Scores: Comparison and Consistency

In the J-RISK study, the C-statistic for the HELT-E 2 S 2 score in predicting incident stroke was 0.681, significantly higher than that of the CHADS 2 score (0.647) and the CHA 2 DS 2 -VASc score (0.641), with P values of 0.027 and 0.008, respectively. 368 The C-statistics in patients without/ with anticoagulation were as follows: HELT-E 2 S 2 score 0.703/0.685, CHADS 2 score 0.657/0.655 (comparison test for HELT-E 2 S 2 score, $\mathrm{P=}0.108/0.077$ ) and CHA 2 DS 2 -VASc score 0.655/0.646 (same comparison test, $\mathrm{P=}0.052/0.027)$ ). 368

An external validation using integrated data from the RAFFINE Study and SAKURA AF Registry in Japan

 Figure8. HELT-E 2 S 2 score and stroke incidence. (Adapted from Okumura K, et al., 2021. 368 )

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 Figure9. Stroke incidence by HELT-E 2 S 2 score in patients with and without anticoagulant (OAC). (Adapted from Okumura K, et al., 2021. 368 ) CI, confidence interval; HR, hazard ratio.

found the C-statistic for the HELT-E 2 S 2 score to be 0.661, slightly higher than the CHADS 2 score (0.644) and CHA 2 DS 2 -VASc score (0.650), though these differences were not statistically significant $\scriptstyle({\bar{\mathrm{P}}}=0.15$ and $\mathrm{{P}{=}0.37}$ , respectively). 369 In the integrated analysis of these registries, all HELT-E 2 S 2 score components, except hypertension, were identified as independent risk factors. 369

Challenges remain in using the HELT-E 2 S 2 score for initiating anticoagulation therapy, which requires an analysis of the net clinical benefit, considering the balance between the risk of stroke and major bleeding. Currently, the JCS/JHRS 2020 Guideline on Pharmacotherapy of Cardiac Arrhythmias 4 recommends starting anticoagulation therapy for patients with a CHADS 2 score ≥ 1. The appropriateness of replacing this criterion with the HELTE 2 S 2 score needs to be considered. The HELT-E 2 S 2 score includes 3 components of the CHADS 2 score: age ( ≥ 75 years), hypertension, and previous stroke, but not diabetes or heart failure. Although diabetes and heart failure are not identified as independent risk factors, they do encompass high-risk patients (see Section 1.3.3 ). Therefore, the current guideline recommendation to initiate anticoagulation in patients with a CHADS 2 score ≥ 1 remains valid. On the other hand, components of the HELT-E 2 S 2 score not included in the CHADS 2 score, such as $\mathrm{BMI}<\!18.5\,\mathrm{kg}/\mathrm{m}^{2}$ and persistent/permanent AF, are effectively considered under “other risks” in the JCS/JHRS 2020 Guideline on Pharmacotherapy of Cardiac Arrhythmias. 3 (now focusing on low body weight $[{\le}50\,\mathrm{kg}]$ instead of BMI). Therefore, the components of the HELT-E 2 S 2 score align with the risk factors presented in the JCS/JHRS 2020 Guideline on Pharmacotherapy of Cardiac Arrhythmias. 3 In this Focus Update, the flowchart for Recommendations for anticoagulation therapy in AF ( Figure12 in the 2020 Revision of

| Table 19. Recommendations and Levels of Evidence for Risk Assessment of Cardiogenic Embolism in Japanese Patients With AF ||| |---|---|---| ||COR|LOE| |Using the CHADS2 score is recommended||E| | Using the HELT-E2S2 score should be considered |iia|E| | Using the CHA2DS2-VASc score may be considered ||EB|

AF, atrial fibrillation; COR, Class of Recommendation; LOE, Level of Evidence.

the Guidelines for the pharmacological treatment of arrhythmias) has been left unchanged and further validation data should be accumulated in the future. The recommendations for each risk score in light of the HELT-E 2 S 2 score’s emergence are shown in Table19 .

▋ ▋ 1.3.1 Hypertension

Hypertension is included in both the CHADS 2 and CHA 2 DS 2 -VASc scores, and was recognized as an independent risk factor for stroke in an integrated analysis of 3 Japanese registries. 366

In the J-RISK study, patients with a baseline systolic blood pressure (SBP) ${\geq}150\,\mathrm{mmHg}$ did not show a significantly different stroke risk than those with $\mathrm{SBP\!<\!150\,mmHg}$ (HR 1.41, $\mathrm{{P}{=}0.097}$ ). 370 However, in the J-RHYTHM registry, patients with a baseline SBP ${\geq}136\,\mathrm{mmHg}$ (4th quartile) showed similar stroke risk to those with SBP ${<}116\mathrm{mmHg}$ (1st quartile) (HR 1.01, $\mathrm{{P{=}0.968}}$ ), but the risk was significantly increased when considering the SBP

closest to the stroke event (HR 2.80, $\mathrm{P}{<}0.001$ ). 371 For diastolic blood pressure (DBP), patients in the 4th quartile $(\geq\!80\,\mathrm{mmHg})$ ) were at increased risk compared with those in the 1st quartile $(<\!65\,\mathrm{mmHg})$ ) (HR 1.65, $\mathbf{P{=}0.046})$ ). 371

Therefore, the risk of stroke in patients with hypertension is strongly influenced by blood pressure control throughout the disease course. The data from J-RHYTHM registry suggests that maintaining SBP ${\leq}136\,\mathrm{mmHg}$ and DBP ${<}80\,\mathrm{mmHg}$ correlates with a lower risk of stroke. 371 Conversely, poor control of either SBP or DBP is associated with a substantially higher risk of stroke. Moreover, inadequate blood pressure control is associated with an increased risk of cerebral hemorrhage, underscoring the importance of proper blood pressure control before initiating anticoagulation therapy.

▋ ▋ 1.3.2 BMI ${\pmb<}18.5\,\mathfrak{k g}/\mathfrak{m}^{2}$ and Persistent/Permanent AF

The J-RHYTHM registry reported a HR for embolism of 1.22 $95\%$ CI 0.63–2.38) in patients with a BMI ${<}18.5\,\mathrm{kg}/\mathrm{m}^{2}$ compared with those with a BMI of $18.5{-}24.9\,\mathrm{kg}/\mathrm{m}^{2}$ , showing a trend towards increased risk, though not statistically significant. 372 Meanwhile, the Fushimi AF registry identified a higher HR of 2.19 $({\bf P}{<}0.01)$ for stroke or systemic embolism in patients weighing ${<}50\,\mathrm{kg}$ . 373 This suggests that low body weight or BMI may be a surrogate marker associated with conditions such as cancer and, or it could directly contribute to increased stroke risk through factors such enhanced neurohumoral activity and endothelial dysfunction. 373

It was traditionally believed that persistent/permanent AF posed a similar embolic risk as paroxysmal AF, based on subanalysis of large clinical trials. 374 However, recent data suggest a higher stroke risk in persistent/permanent AF. For example, the ANAFIE registry reported an increased stroke risk in persistent/permanent AF compared with paroxysmal AF (HR 1.64/1.68, respectively, both $\mathrm{P}{<}0.\bar{001}$ ). 375 Similarly, the Fushimi AF registry found the highest stroke risk when AF progressed from paroxysmal to persistent (HR 4.10, $\mathrm{P{<}0.001}$ vs. paroxysmal AF that did not progress), and an elevated risk in already persistent/ permanent AF (HR 2.20, $\mathbf{P}{=}0.025$ ). 376

Persistent/permanent AF contributes to stroke risk through mechanisms such as progressive left atrial remodeling and endothelial damage (one of Virchow’s triad). The duration of AF itself is associated with blood stagnation, another element of Virchow’s triad, emphasizing the significant role of persistent/permanent AF in thrombus formation.

Reflecting on these insights, low body weight and persistent/permanent AF have been included as risk factors for considering anticoagulation therapy in the JCS/ JHRS 2020 Guideline on Pharmacotherapy of Cardiac Arrhythmias. 3

ischemic stroke risk for those with diabetes duration of ${<}5$ years was comparable to that of patients with diabetes of 5–10 years’ (HR 1.20, $\mathrm{{P}}{=}0.12)$ , but was significantly higher in patients with diabetes for ${\geq}10$ years (HR 1.45, $\mathrm{P{=}0.001}$ ). 378 Additionally, stroke risk in patients with HbA1c levels between $7\%$ and $8\%$ was similar to those with HbA1c between $6\%$ and $7\%$ (HR 1.08, $\mathrm{{P}{=}0.47}$ ), increasing to HR 1.44 ( $\mathrm{{P}{=}0.004)}$ in patients with HbA1c ${>}8\%$ . 378

In the ANAFIE registry, ${>}90\%$ of elderly Japanese AF patients were on anticoagulant drugs regardless of HbA1c level. The stroke/systemic embolism risk was comparable in patients with HbA1c between $7\%$ and $8\%$ to those with HbA1c ${<}6\%$ (HR 1.10) and slightly increased in patients with HbA1c ${\geq}8\%$ (HR 1.48, not statistically significant). 379 The PREFER in AF study reported that diabetic patients on insulin therapy had a higher stroke risk (HR 2.19, $\mathbf{P{=}0.009)}$ ) than non-diabetic patients, while those not treated with insulin had a similar risk to non-diabetics (HR 0.93, $\mathrm{{P}{=}0.80)}$ ). 380 Anticoagulation therapy should be considered for diabetic patients at a substantially high risk of ischemic stroke.

Regarding heart failure, the original CHADS 2 score defines it as “recent heart failure”. 381 European and American cohort studies report a 5–17-fold increased stroke risk within 30 days following heart failure hospitalization. 382 – 384 The Danish National Database Study found persistently elevated risk up to 30 years post-hospitalization, remaining 1.5–2-fold higher. 382 Similarly, the Fushimi AF Registry observed the highest risk of stroke/systemic embolism within 30 days of heart failure hospitalization, with a sustained increase for up to 360 days posthospitalization (HR 3.94, $95\%$ CI 2.42–6.17). 385

The phase III trial of direct oral anticoagulants (DOAC) defined heart failure as LVEF ${\leq}40\%$ , NYHA class ≥ II, or recent heart failure symptoms within 3–6 months, a definition also used in the J-RISK study. 367 Although this definition is clear, patients with stable heart failure, adequately managed with modern heart failure medications, may not face a substantial stroke risk. However, a history of heart failure hospitalization is associated with a significant stroke risk. 385

In the Fushimi AF registry, elevated levels of B-type natriuretic peptide (BNP) or NT-proBNP (above median levels of ${\geq}169.4\,\mathrm{{ps}/\mathrm{{mL}}}$ or ${\geq}1{,}457\,\mathrm{{ps}/\mathrm{{mL}}}$ , respectively) were associated with an increased risk of stroke/systemic embolism (HR 1.97, $\mathrm{{P}{=}0.03}$ ). 385 Additionally, the HokurikuPlus AF registry reported a higher thromboembolism risk, including ischemic stroke, in patients with $\mathrm{BNP}\!\geq\!170\,\mathrm{ps}/\mathrm{mL}$ (vs. BNP ${<}170\,\mathrm{pg}/\mathrm{mL}$ ; HR 3.86, $\mathrm{P{=}}0.0003\$ ). 386

PQ 2. Which Patients Are Excluded From Anticoagulation Therapy?

▋ ▋ 1.3.3 Diabetes Mellitus and Heart Failure

Diabetes and heart failure, included in the CHADS 2 score, are not part of the HELT-E 2 S 2 score. However, it’s important to note that both conditions encompass high-risk patients for stroke, even if they are not identified as independent risk factors.

Studies examining stroke risk in AF patients with diabetes mellitus have shown varying results. In the ATRIA study, the stroke risk for AF patients with diabetes mellitus of $^{<3}$ years duration was similar to those without diabetes. 377 Another study found that in AF patients with diabetes, the

Although anticoagulation therapy has become widespread with the emergence of DOACs, certain patients are less likely to be eligible. For example, rivaroxaban, apixaban, and edoxaban are contraindicated in patients with a creatinine clearance (CCr) <15mL/min, and dabigatran is contraindicated in patients with a CCr ${<}30\,\mathrm{mL/min}$ . The Japanese Society for Dialysis Therapy (JSDT) generally advises against using warfarin in maintenance hemodialysis patients due to the increased risks of bleeding and embolism. 387 This Focus Update follows the JSDT guidelines in contraindicating warfarin in maintenance hemodialysis

patients. 387 However, warfarin is necessarily used in certain scenarios, such as the perioperative period of AF ablation and for conditions such mechanical valve replacements and secondary prevention of ischemic stroke. 3

Even if renal function is within the range of indications for anticoagulation, continuing anticoagulation can be challenging in patients with recurrent bleeding or a history of life-threatening bleeding. Resuming anticoagulation after a bleeding episode may be possible if the bleeding source is identified and controlled. However, in cases of unmanageable bleeding source, such as diverticular hemorrhage, continuing anticoagulation therapy becomes difficult. Cognitive, intellectual and psychiatric disabilities in patients, especially when lacking support for medication management, also pose a challenge.

The decision to discontinue anticoagulation based solely on advanced age is not universally agreed upon. A meta-analysis, primarily from the warfarin era, revealed that anticoagulation does not significantly affect efficacy or bleeding in patients in their 80s and 90s. 388 In contrast, recent data from the DOAC era suggest that anticoagulation offers a net clinical benefit for these age groups. 389

In Japan, a subanalysis of the ANAFIE registry, which enrolled nearly 30,000 older AF patients (including approximately 8,000 aged ${\geq}85$ years), reported varying anticoagulation rates by age. The study observed anticoagulation rates ${>}90\%$ up to age 90, $8\dot{0}\%$ for ages 95–99, and $50\%$ for age ≥ 100. 390 Although severe renal dysfunction $(\mathrm{CCr}\,{<}\,30\,\mathrm{mL/min})$ was common in these age groups $(>\!20\%$ for ages 85–89 and ${>}40\%$ for age ${\ge}90$ ), a significant proportion maintained $\mathrm{CCr}\!\geq\!30\,\mathrm{mL}/\mathrm{min}$ . The decision not to anticoagulate should be based on individual characteristics such as renal function and bleeding risk, rather than age alone. In principle, anticoagulation should be administered as described in the package insert, even for older patients.

In practice, anticoagulation may be withheld based on the physician’s judgment and patient preference. A cluster analysis of 2,445 ANAFIE registry patients not on anticoagulation identified 2 distinct groups. 391 One was a low-risk group (1,388 patients) with a mean age of 80.9 years, $100\%$ paroxysmal AF, $21.0\%$ previous catheter ablation, a $1.08\%$ annual rate of stroke/systemic embolism, $0.69\%$ major bleeding per year, and $2.72\%$ annual all-cause mortality rate. The other was a high-risk group (1,057 patients) with a mean age of 84.9 years, a history of bleeding in $10.8\%$ , a $3.30\%$ annual rate of stroke/systemic embolism, $1.19\%$ major bleeding per year, and $8.81\%$ annual all-cause mortality rate. 391 This analysis should be interpreted carefully, as it may suggest the need for careful monitoring or the need for a broader application of anticoagulation therapy in potentially beneficial patients. Low-risk patients should be monitored closely because stroke risk factors and AF burden may worsen with age. The high-risk group had a higher incidence of ischemic stroke and a lower than expected incidence of major bleeding, indicating that more patients could be considered for anticoagulation under careful management.

The decision not to administer anticoagulation therapy to older AF patients should be made carefully, considering contraindications, bleeding risks, and patient preference. Physicians should make informed decisions after thorough explanations and understanding from both the patient and their family.

2. Anticoagulation for High-Risk Older Patients

Anticoagulation therapy with DOAC for prevention of stroke in patients with AF has steadily become routine daily practice in Japan since the first DOAC, dabigatran, was introduced in 2011. 391a At the same time, data on older patients with various risks associated with anticoagulation therapy have accumulated, 375 , 391b and here we summarize the latest evidence on how to treat older patients at high risk for anticoagulation therapy.

▋ ▋ 2.1 Renal Dysfunction

AF and chronic kidney dysfunction (CKD) frequently coexist: AF exacerbates CKD, and conversely, the progression of CKD increases the incidence of AF. Given that CKD poses a dual risk for both ischemic stroke and major bleeding, appropriate anticoagulation therapy is essential, especially in patients with CKD. However, because all DOACs are excreted by the kidneys (renal excretion rates are $80\%$ for dabigatran, $50\%$ for edoxaban, $35\%$ for rivaroxaban, and $27\%$ for apixaban), patients with a CCr ${<}25$ or $30\,\mathrm{mL}/\mathrm{min}$ have been excluded from the large-scale RCTs of DOACs and real-world data of patients with severe CKD are also scarce.

In the J-ELD AF registry of 3,015 Japanese AF patients aged ${\geq}75$ years taking on-label doses of apixaban, 455 $(15.1\%)$ exhibited $15{\le}\mathrm{CCr}{<}30\,\mathrm{mL}/\mathrm{min}$ and most of these patients $(97.4\%)$ met the dose reduction criteria of apixaban. 392 The annual incidence of stroke or systemic embolism in this cohort was $1.67\%$ , which was comparable to the $1.76\%$ in patients with CCr ${\ge}50\,\mathrm{mL/min}$ (1,165 patients, $38.6\%$ ). The annual incidence of bleeding requiring hospitalization in patients with $15{\le}\mathrm{CCr}{<}30\,\mathrm{mL}/\mathrm{min}$ was $3.1\hat{3\%}$ , which was numerically but nonsignificantly higher than the $1.39\%$ in patients with $\mathrm{CCr}\!\geq\!50\,\mathrm{\bar{m}L/m i n}$ (HR 2.00, $\mathbf{P}{=}0.075$ ). Annual all-cause and cardiovascular mortality rates were $7.87\%$ and $2.62\%$ , respectively, in patients with $15{\le}\mathrm{CCr}{<}30\,\mathrm{mL}/\mathrm{min}$ . These rates were significantly higher than the $1.75\%$ in all-cause mortality and $0.46\%$ in cardiovascular mortality rates in those with $\mathrm{CCr}\!\geq\!50\,\mathrm{mL}/\mathrm{min}$ .

In a subanalysis of the ANAFIE registry, among 26,202 Japanese patients aged ${\geq}75$ years with nonvalvular AF, the percentages of patients with CC $\tt S r\ge50\,\mathrm{mL/min}$ , $30{\le}\mathrm{CCr}$ ${<}50\,\mathrm{mL/min}$ , $15{\le}\mathrm{CCr}{<}30\,\mathrm{mL}/\mathrm{min}$ , and $\mathrm{CCr}<\!15\,\mathrm{mL}/\mathrm{min}$ were $44.2\%$ , $41.1\%$ , $13.2\%$ , and $1.5\%$ , respectively. 393 The incidences of both stroke/systemic embolism and major bleeding increased with progression of CKD. The annual incidence of stroke or systemic embolism was $2.6\%$ for CCr ${\ge}50\,\mathrm{mL/min}$ and $4.0\%$ for $15{\le}\mathrm{CCr}{<}30\,\mathrm{mL}/\mathrm{min}$ (HR 1.31; $\mathbf{P{=}}0.032)$ ). Further, the annual incidence of major bleeding was $1.8\%$ for $\mathrm{CCr}\geq50\,\mathrm{mL}/\mathrm{min}$ and $2.8\%$ for $15{\le}\mathrm{CCr}{<}30$ (HR 1.12, $\mathrm{P{=}}0.439)$ . In a comparison of DOAC and warfarin groups, the annual incidence of stroke or systemic embolism in patients with $30{\le}\mathrm{CCr}{<}50\,\mathrm{mL}/\mathrm{min}$ was $2.7\%$ vs. $3.8\%$ (HR 0.75, $\mathrm{P{=}}0.024$ ), and that of major bleeding was $1.7\%$ vs. $2.8\%$ (HR 0.64, $\mathrm{P{=}}0.003$ ). The incidences of both stroke/systemic embolism and major bleeding in the DOAC group were significantly lower than those in the warfarin group. The annual incidence of stroke/systemic embolism in patients with $15{\le}\mathrm{CCr}{<}30\,\mathrm{mL}/\mathrm{min}$ was $3.6\%$ with DOAC vs. $4.0\%$ with warfarin (HR 0.89, $\mathrm{P{=}}0.541$ ), and the incidence of major bleeding was $2.4\%$ with DOAC

| Table 20. Recommendations and Levels of Evidence for Treating Older Patients With AF at High Risk for Anticoagulation Therapy (Renal Dysfunction) ||| |---|---|---| ||COR|LOE| | Anticoagulationformildtomoderaterenal dysfunction with 30≤CCr |||

\*Except for perioperative AF ablation, mechanical valve, previous stroke. AF, atrial fibrillation; CCr, creatinine clearance; COR, Class of Recommendation; DOAC, direct oral anticoagulant; LOE, Level of Evidence.

vs. $3.5\%$ with warfarin (HR 0.67, $\mathbf{P}{=}0.065$ ), and both stroke/systemic embolism and major bleeding were similar between the DOAC and warfarin groups. In a comparison of a non-anticoagulant group and warfarin group, the annual incidence of stroke/systemic embolism in patients with $15{\le}\mathrm{CCr}{<}30\,\mathrm{mL}/\mathrm{min}$ was $5.9\%$ vs. $4.0\%$ (HR 1.80, $\mathrm{{P}{=}0.047]}$ ), which was significantly higher in the nonanticoagulant group. On the other hand, the incidence of major bleeding was $2.3\%$ in the nontreated group and $3.5\%$ in the warfarin group (HR 0.65, $\mathbf{P{=}}0.306$ ), which was not significantly different.

Patients with CKD are often elderly and frail. They also have high rates of comorbidities such as hypertension, diabetes mellitus, ischemic heart disease, and heart failure. Not only do these comorbidities contribute to impaired drug metabolism, but polypharmacy also increases the risk of drug–drug interactions and elevated anticoagulant blood concentrations, making it difficult to maintain the international normalized ratio (INR) within the optimal range in patients treated with warfarin. In a meta-analysis of large-scale RCTs of DOACs, treatment with a DOAC was associated with a lower risk of stroke/systemic embolism and major bleeding than warfarin in the $30{\le}\mathrm{CCr}{<}50\,\mathrm{mL}/\mathrm{min}$ group, consistent with the ANAFIE registry results. 394 Although there are no RCTs comparing DOACs and warfarin in patients with $\mathrm{CCr}<\!30\,\mathrm{mL}/\mathrm{min}$ , the results of the ANAFIE registry showed that a DOAC was at least as effective and safe as warfarin in patients with CCr ${<}30\,\mathrm{mL/min}$ . Given that apixaban and edoxaban showed a lower risk of major bleeding at $30{\le}\mathrm{CCr}{<}50\,\mathrm{mL}/\mathrm{min}$ in a subanalysis of renal function in a large-scale RCT 395 , 396 it seems reasonable to select these drugs in patients with $15{\le}\mathrm{CCr}{<}30\,\mathrm{mL}/\mathrm{min}$ .

Thus, real-world data on DOACs in patients with moderate to severe renal dysfunction are accumulating. The JCS/JHRS 2020 Guideline on Pharmacotherapy of Cardiac Arrhythmias stated that DOACs are contraindicated in patients on dialysis, and so is warfarin except in some cases, such as the perioperative period of AF ablation, mechanical valves, and for secondary stroke prevention. Based on the evidence so far, this Focus Update has established anticoagulation recommendations for each stage of renal dysfunction ( Table20 ). Because $16.4\%$ of patients taking anticoagulants experience a decrease in

CCr of ${\geq}20\%$ within 1 year, 397 and the estimated glomerular filtration rate (eGFR) decreases over time by $1{-}2\,\mathrm{mL/min}/$ $1.73\,\mathrm{m}^{2}/$ /year in patients with renal dysfunction, 398 it is essential to perform regular blood tests once every “CCr value $"10"$ months (e.g., once every 3 months for CCr $30\,\mathrm{mL/min})$ , as well as careful checking of liver function and hemoglobin level.

▋ ▋ 2.2 Low Body Weight

Low body weight in patients with AF is a risk for developing stroke. In the HELT-E 2 S 2 score, BMI <18.5 (HR 1.55) was identified as 1 of 6 independent risk factors. 368 In addition, a higher incidence of all-cause and cardiovascular death has been reported in AF patients with low body weight. 372

Underweight is often associated with other risk factors and comorbidities such as advanced age, frailty, CKD, and cancer. 399 As a consequence, anticoagulation is often withheld in underweight patients. When warfarin is used, it is often difficult to maintain an optimal INR range, 373 , 400 and even when a DOAC is used, there is concern that blood levels may become elevated, making the patient more prone to major bleeding. 401

In a Korean observational study comparing outcomes in underweight $({\le}60\,\mathrm{kg})$ patients treated with a DOAC or warfarin, the DOAC (14,013 patients) was associated with a lower rate of ischemic stroke (HR 0.591, $\mathrm{P}{<}0.0001)$ ), major bleeding (HR 0.705, $\mathrm{P}{<}0.0001]$ ), intracranial bleeding (HR 0.554, $\mathrm{P}{<}0.0001\$ ), and all-cause death (HR 0.705, $\mathrm{P}{<}0.0001\$ ), compared with warfarin (7,576 patients) after propensity score matching to adjust for confounding factors. Moreover, the superiority of the DOAC over warfarin was consistent in patients ${\leq}50\,\mathrm{kg}$ . 402

In the J-ELD AF registry, 1,019 $(33.7\%)$ weighed ${\mathrm{>}}60\,\mathrm{kg},$ , 1,126 $(37.2\%)$ were $50{\mathrm{-}}60\,{\mathrm{kg}},$ , and 880 $(29.1\%)$ were ${<}50\,\mathrm{kg}$ . Although the annual incidences of stroke/systemic embolism for each body weight group were $1.69\%$ , $1.82\%$ , and $1.23\%$ (P=0.6), respectively, those of bleeding requiring hospitalization were $1.{37\%}$ , $1.73\%$ , and $2.73\%$ ( $\mathrm{{P=}}\bar{0}.154)$ ). After adjusting for patient background in a multivariate analysis, body weight ${<}50\,\mathrm{kg}$ was not a significant risk for either stroke/systemic embolism or bleeding requiring hospitalization. 403

The use of DOACs is preferable because of their superiority over warfarin regarding both efficacy and safety ( Table21 ). In such cases, the CCr, which tends to be lower than the eGFR value in patients with low body weight, should be accurately ascertained. In addition, because some DOACs include body weight as a criterion for dose reduction, care should be taken to avoid inappropriate overdoses.

▋ ▋ 2.3 Frailty

Frailty is defined as a state of general weakness caused by an age-related decline in physiological function. The prevalence of frailty increases with age, and it is reported to be $35.1\%$ in those aged ${\geq}85$ years. 404 Frail patients are more likely to have a variety of coexisting chronic diseases, including heart failure, dementia, COPD, diabetes, and CKD. They also have a high risk of falls, low nutritional intake, and polypharmacy. Therefore, it is generally believed that anticoagulation therapy is difficult for frail patients with such backgrounds, and as a result, anticoagulation therapy has tended to be avoided in this group of patients.

JCS/JHRS 2024 Guideline Focused Update on Management of Cardiac Arrhythmias

| Table 21. Recommendations and Levels of Evidence for Treating Older Patients With AF at High Risk for Anticoagulation Therapy (Low Body Weight, Frail Patients, Patients With Dementia, and Polypharmacy) ||| |---|---|---| ||COR|LOE| | Minimizing the number of drugs as much as possible in consideration of the need to prevent cardiovascular disease is recommended when anticoagulating patients with polypharmacy. Avoiding the use of drugs that may increase the risk of bleeding such as antiplatelet agents and NSAIDs is recommended when anticoagulating patients with polypharmacy ||E| |Anticoagulation should be considered regardless of the presence of low body weight||E| |Anticoagulation should be considered regardless of frailty status||E| | Anticoagulation should be considered regardless of the presence of cognitive decline (MMSE ≤23points) |na||

AF, atrial fibrillation; COR, Class of Recommendation; LOE, Level of Evidence; MMSE, Mini-Mental State Examination; NSAIDs, nonsteroidal anti-inflammatory drugs.

In the ANAFIE registry, 2,951 older AF patients who were assessed for frailty using the Kihon Checklist defined by the Ministry of Health, Labour and Welfare 405 were divided into a healthy group (959 patients who scored ≤ 8 on the Kihon Checklist), a pre-frail group (924 patients who scored 9–14), and a frail group (1,068 patients who scored ≥ 15). 406 Anticoagulant drugs were administered to $95.6\%$ , $94.7\%$ , and $94.{\bar{1}}\%$ of patients in each respective group. The annual all-cause mortality rates for these groups were $1.45\%$ , $2.56\%$ , and $7.15\%$ , respectively $(\mathrm{P}{<}0.001)$ , reflecting the patients’ backgrounds. The respective annual stroke/systemic embolism rates were $1.20\%$ , $1.67\%$ , and $2.37\%$ $(\mathrm{P{=}0.025})$ , and $0.76\%$ , $0.63\%$ , and $1.41\%$ per year $(\mathrm{P{=}0.029})$ for major bleeding. In the multivariate model, the adjusted HRs for stroke/systemic embolism and major bleeding were 1.05 $(\mathrm{P{=}0.857})$ ) and 1.69 $(\mathrm{P{=}0.155})$ ), respectively. This relationship between frailty and patient outcomes was generally similar to that observed in the ENGAGE-AF study. 407

In the ANAFIE registry, $95\%$ of patients with AF aged ${\geq}75$ years were on anticoagulant therapy ( $60\%$ with DOACs) regardless of their frailty status. Data on the effect of anticoagulation in frail patients are limited, but given that anticoagulation generally reduces ischemic stroke by about one-third, 408 the stroke/systemic embolism rate without anticoagulation can be estimated to be approximately 3-fold higher than the reported rates. Although frail patients are at a higher risk of bleeding due to their multiple comorbidities, it is important to reaffirm that the benefits of anticoagulation for the prevention of embolism are greater ( Table21 ). For frail patients, DOACs often meet the criteria for dose reduction 406 and may offer a safety advantage over warfarin. 407

▋ ▋ 2.4 Dementia

Dementia is a syndrome rather than a disease and cognitive decline in patients with AF can be problematic for anticoagulation therapy, because of the greater risk of intracranial hemorrhage due to falls and trauma, medication errors, and low adherence. 409 Especially in the era when warfarin was the sole oral anticoagulant, managing anticoagulation therapy in patients with cognitive impairment was challenging due to the complexity of dose adjustment and the high risk of intracranial hemorrhage. However, with the emergence of DOACs, anticoagulation in older

patients, including those with cognitive impairment, has become more manageable, prompting a reconsideration of the approach to therapy.

In the ANAFIE registry, the Mini-Mental State Examination (MMSE) was administered to 2,963 patients at enrollment to create 2 groups: a normal cognitive function group (MMSE ${\geq}24$ points) and a cognitive impairment group (MMSE ${\le}23$ points). 410 The cognitive impairment group was older than the normal cognitive function group (83.9 years vs. 80.7 years, $\mathrm{P}{<}0.001.$ ), and the prevalence of heart failure $(44.7\%$ vs. $29.4\%$ , $\mathrm{P{<}0.001}$ ) and cerebrovascular disease $35.5\%$ vs. $23.0\%$ , $\mathrm{P}{<}0.001$ ) was higher. The all-cause mortality rate was approximately 4-fold higher in the cognitive impairment group than in the normal cognitive function group $(9.49\%$ vs. $2.38\%$ per year, $\mathrm{P}{<}0.001\$ ). However, there were no significant differences in the rates of stroke/systemic embolism $(2.11\%$ vs. 1.65 per year, $\mathrm{{P}{=}0.307.}$ ) and major bleeding ( $1.30\%$ vs. $0.75\%$ per year, $\mathrm{P{=}0.090}$ ).

Similar to the data on frail patients, these results were obtained in patient populations where more than $90\%$ were taking anticoagulants, both in the normal cognitive function and cognitive impairment groups. Although clear data on the efficacy of anticoagulation in cognitively impaired patients are lacking, the estimated 3-fold increase in stroke rate 408 without anticoagulation therapy suggests that the benefit of stroke prevention outweighs the risk of major bleeding. Therefore, anticoagulation therapy should be considered for cognitively impaired older patients with AF, using DOACs in particular because of their greater ease in administration ( Table21 ). However, it is crucial to ensure a supportive environment for the patient around medication management, including assistance from family members, facilities and on-site medication counseling.

▋ ▋ 2.5 Polypharmacy

Polypharmacy is not merely defined by the high number of medications taken, but can lead to increased risks of adverse drug events, medication errors, and poor medication adherence. AF is common in older persons and is often associated with various cardiovascular and lifestyle-related diseases that increase the number of medications taken. There are no criteria for withholding anticoagulants or for reducing the dose of anticoagulants for AF patients with polypharmacy.

| Table 22. Recommendations and Levels of Evidence for Older Patients With AF at High Risk of Anticoagulation(WithConcomitant Antiplatelet Agents) ||| |---|---|---| ||COR|LOE| |Antiplatelet agents should not be used*|(Harm)|E|

\*Combination therapy with an anticoagulant plus an antiplatelet agent should be used within 1 year after percutaneous coronary intervention (PCI), but in other cases, the use of antiplatelet agents in older patients who are eligible for anticoagulant therapy is rather harmful. In a small number of cases with very high thrombotic risk (e.g., patients with previous stent thrombosis, PCI for complex lesions, and unstable warfarin control), concomitant use of antiplatelet agents may be necessary. If there is any doubt about the decision, consultation with a specialist is highly recommended. AF, atrial fibrillation; COR, Class of Recommendation; LOE, Level of Evidence.

Although minimizing the number of medications being taken by older AF patients is often argued, using multiple medications is not exclusively negative. Management of cardiovascular risk factors such as hypertension, diabetes mellitus, and CKD, along with preventive measures for myocardial infarction and heart failure, can improve prognosis and alleviate symptoms in many older patients.

Subanalyses of large RCTs of DOACs in AF patients 411 , 412 showed no increase in stroke/systemic embolism with an increasing number of drugs, but there was an increase in major bleeding and all-cause death, which reflected the high prevalence of both multimorbidities 413 and frail patients 414 among those with polypharmacy. On the other hand, the absence of an increase in thrombotic events suggests the effectiveness of the administered drugs in reducing such events.

In the ANAFIE registry, 415 the median number of medications was 6, and patients receiving ${\geq}5^{416}$ accounted for approximately $60\%$ of patients. The patients were divided into groups based on the number of medications: 0–4, 5–8, and ${\geq}9$ . 417 More than $90\%$ of patients in each group received anticoagulants and the incidence of stroke/ systemic embolism was $1.5\%$ , $1.7\%$ , and $1.8\%$ per year, respectively $(\mathrm{P{=}0.780})$ ), but the incidence of major bleeding increased significantly with ${\geq}9$ drugs $(0.8\%$ , $1.1\%$ , and $1.7\%$ per year, respectively, $\scriptstyle{\mathrm{~P<}0.001}$ ). Notably, in the ELDERCARE-AF subanalysis, 418 , 419 the efficacy of anticoagulation for stroke/systemic embolism prevention was larger in the high-risk group (older, renal dysfunction), though no significant interaction was observed, suggesting at least equal or greater preventive effects in high-risk patients. Considering that polypharmacy patients are often older with impaired renal function, it is estimated that anticoagulation therapy reduces stroke/systemic embolism by about one-third, 408 or even more, in polypharmacy patients. Therefore, polypharmacy patients should be treated with anticoagulation, although careful attention should be paid for increased bleeding risks under the treatment ( Table21 ).

Questions may arise regarding the need for special dose reduction when prescribing anticoagulants to patients on a large number of medications. Warfarin interacts with various drugs, 420 but its dose is adjusted at each clinic visit to account for these interactions. On the other hand, DOACs have fewer interactions with other drugs, with

exceptions such as P-glycoprotein inhibitors (verapamil and amiodarone), particularly for dabigatran and edoxaban. For these interactions, dose reduction recommendation/ criteria are already considered and for anticoagulation of AF patients, the response to fluctuations in blood levels due to the concomitant use of other drugs is already incorporated into the dosage regimens specified in the package inserts.

In the ANAFIE registry, the increased events in the group taking ${\geq}9$ drugs included gastrointestinal bleeding $(1.3\%$ , $2.0\%$ vs. $3.1\%$ per year, $\scriptstyle{\mathrm{~P<}0.001}$ ) and fall fracture events $(4.5\%$ , $6.6\%$ vs. $9.2\%$ per year, $\mathrm{P}{<}0.001$ ). Special attention should be paid to falls when using warfarin, which has a high incidence of intracranial hemorrhage. The concomitant use of drugs that may increase the risk of bleeding, such as antiplatelet agents and nonsteroidal anti-inflammatory drugs (NSAIDs), should be avoided as much as possible to prevent gastrointestinal bleeding 421 and intracranial bleeding due to falls. 422

In principle, anticoagulation therapy should be administered to older AF patients with polypharmacy as described in the package insert ( Table21 ). However, it is important to minimize the number of drugs (and doses) as much as possible, while considering the need to prevent cardiovascular disease. It is also important to avoid drugs that may increase bleeding risk.

▋ ▋ 2.6 Concomitant Antiplatelet Agents ( Table22 )

The combination of an anticoagulant and antiplatelet agent was a standard therapy for patients with AF and concomitant atherosclerotic disease. The AFIRE trial, a large-scale RCT conducted in Japan, compared anticoagulant monotherapy with a combination of anticoagulant and antiplatelet agent (in this trial, the anticoagulant was rivaroxaban) in patients with AF and stable coronary artery disease, and demonstrated the superiority of anticoagulant monotherapy. 423 Clinical guidelines in Japan as well as in Europe and the USA now recommend the use of anticoagulant monotherapy in these patients. 423

The AFIRE trial showed a higher risk of all-cause death in the combination group, possibly due in part to an increase in cardiovascular events after major bleeding, especially within 30 days after major bleeding. 424 Subgroup analyses further demonstrated the superiority of anticoagulant monotherapy also in high thrombotic risk populations such as those with previous myocardial infarction or peripheral artery disease, 425 those with previous heart failure, 426 those with severe coronary artery disease such as multivessel disease or left main trunk disease, 427 and for all stent types (bare metal/drug-eluting 1st/2nd generation). 423 , 428 The superiority of anticoagulant monotherapy was also more pronounced in patients with a longer time since stenting, 428 and de-escalation to anticoagulant monotherapy is recommended even in patients who have been on the combination therapy for many years.

Aspirin has been shown to be ineffective in preventing stroke in patients with AF, 429 and the ESC guidelines state that antiplatelet therapy alone is not recommended for stroke prevention in patients with AF (Class III). 430 Combination therapy with an anticoagulant plus an antiplatelet agent should be used within 1 year after percutaneous coronary intervention (PCI), but in other cases, the use of antiplatelet agents in older patients who are eligible for anticoagulant therapy is rather harmful. There

fore, this Focus Update provides a general recommendation that, in principle, antiplatelet agents should not be administered to patients with AF. However, in a small number of cases of very high thrombotic risk (e.g., patients with previous stent thrombosis, PCI for complex lesions, and unstable warfarin control), concomitant use of antiplatelet agents may be necessary. If there is any doubt about the decision, consultation with a specialist is highly recommended.

▋ ▋ 2.7 Edoxaban 15mg for the Very Old at High Bleeding Risk ( Table23 )

All 4 DOACs are available in standard and reduced doses, which are selected according to patient background. For edoxaban, in addition to $60\,\mathrm{mg}$ or $30\,\mathrm{mg}$ once daily, a very low dose of $15\,\mathrm{mg}$ once daily was added in August 2021 for very old patients at high risk of bleeding based on the results of the ELDERCARE-AF trial. 431

ELDERCARE-AF included very old Japanese patients $\{\geq\!80$ years old) with nonvalvular AF who had a CHADS 2 score ${\geq}2$ , who were at high risk of bleeding and were considered ineligible for oral anticoagulation at approved doses. “High bleeding risk” was defined as any of the following 5 conditions: (1) low CCr (15–30mL/min), (2) low body weight $({\leq}45\,\mathrm{kg})$ , (3) history of bleeding from a critical area or organ (including cerebral hemorrhage), (4) current use of an antiplatelet agent, and (5) continuous use of NSAIDs. These patients were randomized 1:1 to edoxaban $15\,\mathrm{mg}$ or placebo to evaluate efficacy and safety. In the edoxaban $15\mathrm{mg}$ group, the primary efficacy endpoint (stroke or systemic embolism) was significantly lower (HR 0.34, $\mathbf{P}{<}0.{\overset{.}{0}}01)$ ), but the primary safety endpoint (ISTH criteria major bleeding) was numerically higher but not significantly different (HR 1.87, $\mathrm{{P}{=}0.09}$ ), indicating a benefit of the use of edoxaban 15mg.

Following the main analysis described above, the results of the subanalyses were also presented. The age subanalysis 418 divided patients into 3 age groups (80–84, 85–89, and ${\geq}90$ years), and the results were generally consistent across all age groups. However, there was a trend toward more major bleeding in the edoxaban group among patients aged ${\ge}90$ years, although the difference was not significant. In a subanalysis of renal function, 419 patients were divided into 3 groups according to CCr (15–29mL/min, 30–49mL/min, and ${>}50\,\mathrm{mL}/\mathrm{min}$ ). The results were consistent across all groups in terms of efficacy, but most major bleeding events were concentrated in the $15{-}29\,\mathrm{mL}/\mathrm{min}$ group. A subanalysis of frailty 432 found no difference in the efficacy or safety of edoxaban $15\,\mathrm{mg}$ in patients with or without frailty. Another subanalysis 433 subdivided patients according to B-type natriuretic peptide (BNP) level at enrollment ( ${<}200$ , 200–400, and ${\mathrm{>}400}\,{\mathrm{pg/mL}}$ ), and again no difference in efficacy or safety was apparent among the 3 groups. Finally, a subanalysis 434 of risk factors for major bleeding with edoxaban $15\,\mathrm{mg}$ found $\mathrm{CCr\15{-}29\,m L/m i n}$ , anemia, and prolonged prothrombin time as significant factors.

These results indicate that edoxaban $15\,\mathrm{mg}$ is beneficial in very old patients with AF at high risk of bleeding who meet the ELDERCARE-AF enrollment criteria, regardless of their clinical background. However, caution should be exercised, especially in patients aged ${>}90$ years or with CCr <30mL/min. Insurance coverage of edoxaban $15\mathrm{mg}$ follows the ELDERCARE-AF enrollment criteria, and there is no

| Table 23. Recommendations and Levels of Evidence for OlderPatients With AF at High Risk of Anticoagulation(WithVery Old Patients With High Bleeding Risk) |||| |---|---|---|---| | Table 23. Recommendations and Levels of Evidence for OlderPatients With AF at High Risk of Anticoagulation(WithVery Old Patients With High Bleeding Risk) |||| | Table 23. Recommendations and Levels of Evidence for OlderPatients With AF at High Risk of Anticoagulation(WithVery Old Patients With High Bleeding Risk) |||| |||COR|LOE| |Edoxaban 15 mg is recommended for very|||| |elderly patients with high risk of bleeding*|||| |who are unable toreceive anticoagulants at|||| |approved doses||||

$^{\star}{\geq}80$ years of age and having any of the following 5 conditions: (1) low CCr (15 to 30mL/min), (2) low body weight $({\leq}45\,\mathsf{k g})$ , (3) history of bleeding from a critical area or organ (including cerebral hemorrhage), (4) current use of an antiplatelet agent, and (5) continuous use of NSAIDs. However, the necessity of (4) and (5) should be examined first. AF, atrial fibrillation; CCr, creatinine clearance; COR, Class of Recommendation; LOE, Level of Evidence; NSAIDs, nonsteroidal anti-inflammatory drugs.

evidence in patients who do not meet these criteria. Patient selection should be made in accordance with the package insert. Furthermore, ELDERCARE-AF only included patients who had not been anticoagulated within 8 weeks prior to randomization. It should be noted that there is no evidence that it is appropriate to reduce the dose of DOACs from the on-label dose to $15\,\mathrm{mg}$ because the patient meets the criteria for enrollment in ELDERCARE-AF.

A subanalysis of the Fushimi AF registry, which examined how many AF patients in daily clinical practice met the ELDERCARE-AF criteria, 435 revealed that $12.8\%$ of all AF patients, and $52.9\%$ of AF patients aged ${\geq}80$ years with a CHADS 2 score ${\geq}2$ matched the criteria. Those matched patients were older, had more comorbidities, and a significantly higher incidence of all events compared with the non-matched patients. Among matched patients, $48.8\%$ were prescribed anticoagulants at enrollment, but anticoagulants were discontinued at an annual rate of $15.5\%$ over time. Similarly, in the ANAFIE registry, 436 matched patients $(22.0\%$ of all patients) experienced more adverse events than non-matched patients, including stroke/ systemic embolism (2-year cumulative $3.8\%$ vs. $2.8\%$ ), major bleeding $(2.8\%$ vs. $1.8\%$ ), all-cause death ( $12.5\%$ vs. $5.4\%$ ), and cardiovascular death $4.3\%$ vs. $1.4\%$ ). Anticoagulants were prescribed in $89.0\%$ of the matched patients, and there was a trend toward fewer events in the DOAC group than in the warfarin group.

3. Specific Neutralizers for Factor Xa Inhibitors

All physicians, regardless of specialty, should be aware that andexanet alfa, a neutralizing agent for factor Xa (FXa) inhibitors (i.e., apixaban, edoxaban, and rivaroxaban), is now available ( Figure10 ). 3 Although the use of neutralizers for non-major bleeding should be discouraged, all patients on oral anticoagulants should be appropriately given a neutralizing agent when life-threatening bleeding or bleeding that is difficult to control occurs.

Andexanet alfa is a genetically engineered FXa decoy protein that has been modified to inactivate the prothrombinto-thrombin catalytic activity of FXa. When andexanet alfa is administered, the FXa inhibitor binds to andexanet alfa rather than to its original target, FXa, which preserves FXa function and neutralizes the FXa inhibitory effect.

 Figure10. Response to active bleeding during anticoagulation therapy in patients with atrial fibrillation. DOAC, direct oral anticoagulant. (Adapted from Japanese Circulation Society. 2020. 3 )

Andexanet alfa can act as a neutralizer of the 3 FXa inhibitors in a single drug when administered at high or low doses ( Figure11 ). According to a final report 438 of the international phase III ANNEXA- $\mathbf{.}4^{437}$ trial in patients with acute major bleeding within $18\,\mathrm{h}$ of taking an FXa inhibitor (479 patients including 19 Japanese), $93\%$ of the apixaban group $\mathrm{(n{=}172)}$ ), $71\%$ of the edoxaban group $\mathrm{(n{=}28)}$ , and $94\%$ of the rivaroxaban group $\mathrm{(n{=}132)}$ ) showed anti-Xa inhibitory activity after rapid intravenous injection of andexanet alfa. The neutralizing effect was maintained until the end of 2-h continuous intravenous infusion. Because the half-life of andexanet alfa in blood is approximately 4h, the neutralizing effect gradually diminished after the end of intravenous infusion, and $80\%$ of patients achieved good hemostasis. Although $10\%$ of patients had a post-dose embolic event, all events occurred before the resumption of oral anticoagulant. This Focus Update recommends the use of andexanet alfa in patients with AF in the setting of life-threatening or difficult-to-control bleeding that requires

Figure11 shows the administration method of andexanet alfa, as well as that of idarucizumab, a neutralizing agent for dabigatran that became available earlier for clinical use. In contrast to idarucizumab, which maintains its neutralizing effect for $24\,\mathrm{h}$ after rapid intravenous infusion, the neutralizing effect of andexanet alfa is achieved by rapid intravenous infusion followed by a 2-h continuous infusion ( Figure11 ). Specifically, when it is ${<}8\,\mathrm{h}$ after the last dose, a higher dose is given to neutralize rivaroxaban or edoxaban, but a lower dose for apixaban. A lower dose is given for all FXa inhibitors if ${\mathrm{>}}8\,\mathrm{h}$ have elapsed since the last dose. Because andexanet alfa dose-dependently inactivates the anti-IIa and anti-Xa activities of heparin, monitoring such as activated clotting time (ACT) is required when using andexanet alfa under heparin administration.

Considering the circumstances in which andexanet alfa is used, any delay in administering it should be avoided. Start with a loading dose of 2V $(400\,\mathrm{mg})$ with $30\,\mathrm{mg/min}$ ,

Advance Publication

JCS/JHRS 2024 Guideline Focused Update on Management of Cardiac Arrhythmias

A Dabigatran neutralizer (idarucizumab) administration

5 g rapid intravenous infusion


B Factor Xa inhibitor neutralizer (andexanet alfa) administration

Rapid +

Dose of andexanet alfa according to type of factor Xa inhibitor and time of last dose

 Figure11. Application and effect of neutralizers for direct oral anticoagulants.

and check the appropriate dose (high or low) by the end of the loading dose administration. If the dose is high, repeat the same loading dose after completion of the initial loading dose. If the dose is low, continuous infusion is started just after completion of the initial loading dose.

A meta-analysis of studies using idarucizumab, andexanet alfa, or a prothrombin complex concentrate at the onset of life-threatening or difficult-to-control bleeding under DOAC treatment 439 showed that $76.7\%$ of patients in the idarucizumab group and $80.7\%$ of patients in the andexanet alfa group achieved good hemostasis. The mortality rate was $17.4\%$ in the idarucizumab group and $18.9\%$ in the andexanet alfa group. The embolization rate was significantly lower in the idarucizumab group $(3.8\%)$ than in the andexanet alfa group $(10.7\%)$ . In addition to neutralizers, the patient’s individual risk of embolism, bleeding-induced hypercoagulability, and withdrawal of anticoagulants can affect the incidence of embolism after major bleeding. For example, the rate of intracranial bleeding with a high risk of subsequent embolism was $69\%$ in ANNEXA-4 437 with andexanet alfa, but $33\%$ in RE-VERSE AD, 440 which tested the neutralizing effect of idarucizumab on dabigatran.

It is unclear whether andexanet alfa itself carries a risk of hypercoagulation and embolism in patients on FXa inhibitors who have a major bleeding event. 441 The final results of the RCT comparing andexanet alfa to conventional therapy for intracranial bleeding in patients on Xa inhibitors (ANNEXA-1 trial) will answer this question.

Physicians who may be involved in emergency treatment for major bleeding should confirm in advance the storage location of neutralizers for each anticoagulant and the shortest delivery route to the administration site. They should also simulate the administration method and be

|Table 24. Recommendation and Level of Evidence for||| |---|---|---| |Neutralizers to FXa Inhibitors||| ||COR|LOE| |Administration of andexanet alfa is||| |recommended in situations involving||| |life-threatening or uncontrollable bleeding,||| | where urgent reversal of FXa inhibitor effects is required |||

COR, Class of Recommendation; FXa, factor Xa; LOE, Level of Evidence.

prepared to respond quickly and accurately when a neutralizing agent is needed. In the event of major bleeding under FXa inhibitor therapy, some institutions may not have ready access to andexanet alfa. In such cases, the use of a prothrombin complex concentrate may be considered, although it is not covered by insurance as of February 2024. In a meta-analysis of patients with major bleeding under DOAC treatment, the prothrombin complex concentrate achieved hemostasis in $80.1\%$ , death in $17.4\%$ , and embolization in $4.3\%$ , which were acceptable results compared with specific neutralizers. The study showed a 3.63-fold increased risk of death in patients who did not achieve good hemostasis. 439

In Japan, where the use of DOACs is more prevalent than of warfarin, major bleeding is expected to increase in patients taking DOACs. When patients on anticoagulants develop life-threatening bleeding or bleeding that is difficult to stop, we collect as much accurate information as possible about which anticoagulant was last taken, and use an appropriate neutralizing agent. It is important to keep in

| Table 25. Recommendations and Levels of Evidence for Pharmacological Treatment of Heart Rate Regulation Therapy for AF ||| |---|---|---| |||| ||COR|LOE| |Digitalis||| | If digoxin blood levels are checked regularly, oral digoxinmay beconsidered tocontrol ||| |||| |heartrateorimproveQOL|||

AF, atrial fibrillation; QOL, quality of life.

mind that anticoagulation therapy should be resumed to prevent subsequent embolisms when the patient enters a stable phase.

4. Digitalis and Atrial Fibrillation

Digitalis has long been widely used as a heart rate regulator in AF patients. A meta-analysis of 19 trials published between 1993 and 2014 reported that digitalis use was associated with increased mortality rates, 442 especially in AF without heart failure (HF). Therefore, recent guidelines do not recommend the use of digitalis in patients with AF and preserved cardiac function.

Digitalis is often used clinically to control the heart rate in AF patients with reduced cardiac function, because its inotropic effects can be expected to improve cardiac function. However, previous clinical studies have reported that long-term use of digitalis increases the mortality rate, 443 – 445 and an additional analysis of the AF-CHF trial also showed that digitalis use was related to all-cause death, cardiac death, and arrhythmia-related death. 443 Based on these results, in the 2021 JCS/JHFS Guideline Focused Update on Diagnosis and Treatment of Acute and Chronic Heart Failure, 446 long-term use of digitalis is listed as Class III (harm). Additionally, because digitalis has an inferior effect on improving the prognosis as compared with $\beta$ -blockers, 445 the JCS/JHRS 2020 Guideline on Pharmacotherapy of Cardiac Arrhythmias states that $\beta$ -blockers are the first choice for controlling heart rate in AF with reduced cardiac function, and digitalis is positioned as the second choice. 3

However, the RATE-AF trial 447 published in 2020 reported different outcomes. 448 This randomized open-label trial included 160 patients with persistent AF (mean heart rate 100 ± 18beats/min) with HF symptoms (NYHA class II or higher). The patients were divided into a digoxin group (mean $161\,\mu\mathrm{g/day})$ ) and a bisoprolol group (mean 3.2mg/day). Doses were adjusted to achieve a heart rate of 100beats/min or less (concomitant use of other drugs was allowed if the effect was poor), and the effects on improving quality of life (QOL) were compared. There was no significant difference in the resting heart rate ( $76.9{\pm}12.1\$ beats/min in the digoxin group vs. $74.8{\pm}11.6\$ beats/min in the bisoprolol group, $\mathrm{{P}{=}0.40)}$ ) at 6 months, and QOL was similar in both groups. At 12 months, the median NT-proBNP was $960\,\mathrm{pg/mL}$ in the digoxin group and $1{,}250\,\mathrm{pg/mL}$ in the bisoprolol group $(\mathrm{P{=}\bar{0}.005})$ ), and the digoxin group exhibited better outcomes in various aspects, including NT-proBNP level and sub-items such as daily activity, treatment satisfaction, and NYHA class. Adverse events were also lower in the digoxin group ( $25\%$ vs. $64\%$ , $\mathrm{P{<}0.001\,}$ ). Until

now, there have been no reports showing the superiority of digitalis over $\beta$ -blockers in heart rate control in AF complicated with HF, but a meta-analysis has cast doubt on the effectiveness of $\beta$ -blockers in improving the prognosis for AF patients complicated with HF. 449 In view of this, they reported that the use of other drugs should be considered in a well-balanced manner, rather than preferentially using $\beta\cdot$ -blockers. 448 However, because this trial enrolled a small number of patients with only persistent AF, and evaluated the improvement of QOL and symptoms but not the long-term prognostic efficacy, digitalis should not be simply regarded as a superior drug.

On the other hand, many of the reports that digitalis is associated with a poor prognosis have been observational studies or post-hoc analysis of RCTs, and it has been pointed out that they may be looking at confounding between digitalis and the patients’ backgrounds. 449 Furthermore, meta-analyses in RCTs have shown that the digitalis has no effect on prognosis. 450

Considering all findings, despite the unexplored longterm prognostic efficacy of digitalis, its recommendation level has been upgraded from Class III (harm) to Class IIb (usable) when digoxin blood levels are regularly checked ( Table 25 3 ).

▋ ▋ 4.1 Precautions in the Use of Digitalis

Digitalis, characterized by a long half-life and renal excretion, demands therapeutic caution due to its narrow range of blood concentration. Older patients, who are often underweight and/or have poor renal function, are susceptible to increased drug effects. Therefore, the blood concentration of digitalis in those patients should be measured once or twice each year, and attending physicians should monitor for symptoms such as nausea and loss of appetite. A follow-up analysis of an RCT involving patients with HF under sinus rhythm revealed a higher mortality rate associated with digoxin blood levels ${\ge}1.2\,\mathrm{ng}/\mathrm{mL}$ at 1 month after initiation. 448 Maintaining the digoxin blood concentration within the range of $0.5{-}0.8\,\mathrm{ng}/\mathrm{mL}$ was suggested to decrease the mortality rate. 448 Therefore, for the prevention of adverse effects, measuring the blood concentration when using digoxin in AF patients is recommended. For long-term users, regular monitoring of the digoxin blood concentration is desirable.

Digitalis is contraindicated in patients with underlying diseases such as cardiac amyloidosis or obstructive hypertrophic cardiomyopathy. The JCS 2020 Guideline on Diagnosis and Treatment of Cardiac Amyloidosis classifies digitalis usage as Class III, 451 with the rationale being that digitalis binds to amyloid proteins, increasing the drug sensitivity and potentially leading to fatal arrhythmias. Additionally, because digitalis is a substrate of P-glycoproteins, the concomitant use with drugs such as amiodarone and verapamil, and diuretics (spironolactone, tolvaptan) should be carefully monitored due to an increased blood concentration of those drugs.

5. Atrial Fibrillation and Lifestyle Management/Comprehensive Management

▋ ▋ 5.1 Atrial Fibrillation and Lifestyle Management

AF is common not only among older adults but also among middle-aged adults with lifestyle-related diseases

such as hypertension, and it causes complications such as thromboembolism, stroke, and HF. 430 Therefore, it is important to manage and guide patients with AF not only to treat AF itself but also to reduce their risk of developing cardiovascular complications and diseases. The JCS/ JHRS 2020 Guideline on Pharmacotherapy of Cardiac Arrhythmias 3 notes the importance of management of comorbidities and lifestyle (HF, valvular heart disease, hypertension, diabetes mellitus, obstructive sleep disorder, CKD, obesity, and smoking) in patients with AF. This Focus Update adds recommendations regarding alcohol and caffeine, for which new evidence has been reported, and physical activity as lifestyle management strategies.

▋ ▋ 5.1.1 Alcohol and Caffeine

Excessive alcohol consumption is a known risk factor for developing AF, 452 – 455 and is also a risk factor for bleeding during anticoagulation therapy. 456 The JCS/JHRS 2020 Guideline on Pharmacotherapy of Cardiac Arrhythmias 3 recommends that the risk of bleeding complications in patients with AF should be assessed using the HAS-BLED score (Recommendation Class I), and heavy alcohol drinking is one of the components of the HAS-BLED score. In addition, excessive alcohol consumption by patients with AF increases the risk of thromboembolism and death. 457 A recent RCT reported that abstinence from alcohol reduces recurrent AF in patients with AF who are regular drinkers. 458

In this Focus Update, therefore, patients with AF who are being considered for prophylaxis and anticoagulation should be advised and managed to avoid excessive alcohol consumption ( Table26 , Recommendation Class IIa).

Caffeine intake is considered a risk factor for the development of supraventricular extrasystoles, which trigger the onset of AF. 459 The JCS/JHRS 2020 Guideline on Pharmacotherapy of Cardiac Arrhythmias 3 recommends limiting caffeine intake when supraventricular extrasystoles compromise QOL (Recommendation Class I). However, recent reports indicate that adequate caffeine intake does not increase the risk of AF, 460 , 461 and that habitual coffee consumption of 1–3 cups/day reduces the risk of developing AF. 462 On the other hand, it should be noted that caffeine intake may increase palpitation symptoms unrelated to AF. 463

▋ ▋ 5.1.2 Physical Activity

Many clinical studies have shown that moderate exercise and physical activity are beneficial to cardiovascular health. 464 However, a higher incidence of AF can be seen in athletes, and several small clinical studies have reported that intense physical activity (mainly endurance sports) increases the incidence of AF. 465 – 467 On the other hand, in a small number of studies (25 controls vs. 26 receiving exercise therapy), the cumulative duration of AF (AF burden) increased over time without exercise therapy in AF patients, whereas appropriate exercise therapy significantly suppressed the AF burden. 468 In light of these findings, active exercise should be encouraged to prevent the development and recurrence of AF. However, excessive endurance exercise (e.g., marathons and long-distance triathlons) with high cardiovascular load should be avoided, especially for those aged ${>}50$ years.

| Table 26. Recommendation and Level of Evidence for Alcohol Consumption by Patients With AF ||| |---|---|---| ||COR|LOE| | Advice and management to avoid excessive alcohol consumption should be considered |a||

AF, atrial fibrillation; COR, Class of Recommendation; LOE, Level of Evidence.

The benefits of cardiac rehabilitation for patients with chronic HF have been attracting attention. Interestingly, cardiac rehabilitation has been reported to improve exercise

|Table 27. Recommendation and Level of Evidence for||| |---|---|---| ||COR|LOE| |Educating moderate physical activity to||| |prevent onset or recurrence of AF (excluding||| |excessive endurance exercise, which may|a|| |induce AF)should be considered|||

AF, atrial fibrillation; COR, Class of Recommendation; LOE, Level of Evidence.

tolerance and QOL in patients with AF complicated with HF. 469 The JCS/JACR 2021 Guideline on Rehabilitation in Patients With Cardiovascular Disease 470 recommends that exercise therapy be considered to improve exercise tolerance and QOL in AF patients with reduced exercise tolerance or those with concomitant HF (Recommendation Class IIa). Note, however, that exercise therapy is relatively contraindicated in patients with AF tachycardia whose heart rate is not under control. 470

The degree to which exercise and physical activity are effective in patients with AF has not been fully elucidated. In general, it is recommended to maintain an appropriate intensity of exercise while monitoring the patient’s heart rate, blood pressure response, and symptom onset. This Focus Update recommends that patients with AF should be instructed to engage in moderate physical activity to prevent the onset or recurrence of AF ( Table27 , Recommendation Class IIa).

▋ ▋ 5.2 Comprehensive Management of Patients With Atrial Fibrillation

In 2050, the number of patients with AF in Japan is projected to be approximately 1.03 million, accounting for almost $1.1\%$ of the total population. 3 The increasing prevalence of AF is mainly due to the aging of society and the increase in risk factors and comorbidities. Complications caused by AF, such as cerebral infarction and HF, contribute to the strain on medical resources and rising medical costs. 430 , 471 , 472

To correct these problems, the following approaches are necessary: (1) early diagnosis of AF, (2) understanding the characteristics of individual patients with AF, and (3) comprehensive management. First, (1) the diagnosis of AF is based on ECG recordings, either 12-lead ECG recordings or unipolar ECG recordings of ${\tt\ge}30\,s$ . Next, (2) the risk of cerebral infarction, degree of symptoms, duration of AF including whether it is paroxysmal or persistent, cardiac status and cardiovascular risk factors that may cause the onset and progression of AF are evaluated in each patient. (3) The patient’s comorbidities and lifestyle should be

taken into account in the integrated therapeutic intervention. The JCS/JHRS 2020 Guideline on Pharmacotherapy of Cardiac Arrhythmias proposed 5 treatment steps for the acute and chronic management of patients with AF (Step 1: Acute rate and rhythm control, Step 2: Manage precipitating factors, Step 3: Assess stroke risk, Step 4: Assess heart rate, and Step 5: Assess symptoms). 3

Recently, the ESC proposed the ABC pathway (“A” Anticoagulation/Avoid stroke: anticoagulation and stroke prevention, “B” Better symptom management: symptom improvement, “C” Cardiovascular and Comorbidity optimization: detection and management of aggravating factors), which aims to provide integrated treatment for patients with AF. 430 The implementation of the ABC pathway has been reported to improve all-cause mortality rates and the composite of stroke/major bleeding/cardiovascular death, and first hospitalization, 473 reduce the incidence of cardiovascular events, $\mathbf{474},\mathbf{475}$ and lower healthcare-related costs. 476

Regarding rhythm vs. rate control, the AFFIRM study 477 compared a rhythm control group that actively maintained sinus rhythm with antiarrhythmic drugs with a rate control group that underwent heart rate control to reduce symptoms about 20 years ago, and found no significant difference in all-cause deaths (HR 1.15, $95\%$ confidence interval [CI] 0.99–1.34, $\mathrm{{P}{=}0.08)}$ ). Rate control was recognized as a safe treatment option that was comparable to rhythm control. However, catheter ablation for AF was not widely used at that time, and this finding needs to be reevaluated now that catheter ablation is widely used. To address this issue, the EAST-AFNET 4 trial 267 (1,395 patients in the early rhythm control group vs. 1,394 patients in the rate control [usual care] group) compared the efficacy and safety of early rhythm control (with antiarrhythmic drugs or catheter ablation) with rate control in patients with early onset AF ( ${\left<}1\right>}$ year after initial diagnosis), and revealed that the early rhythm control significantly reduced the incidence of cardiovascular event (composite of death from cardiovascular cause, stroke, or hospitalization with worsening of HF or acute coronary syndrome) (3.9/100 patient-years vs. 5.0/100 patient-years, HR 0.79, $96\%$ CI 0.66–0.94, $\mathrm{P{=}}0.005$ ). In addition, a Korean cohort study enrolling 22,635 patients with AF was followed for 2 years for a composite endpoint of cardiovascular death, stroke, heart failure hospitalization, and acute myocardial infarction. Patients with early onset AF within 1 year had fewer composite endpoints in the rhythm control group than in the rate control group (HR 0.81, $95\%$ CI 0.71–0.93, $\mathrm{P{=}}0.002$ ), but there was no difference between the two groups for patients with AF more than 1 year after onset (HR 0.97, $95\%$ CI 0.78–1.20, $\mathrm{{P}{=}0.76}$ ). 478 Such reports have recently pointed out the importance of early rhythm control before the development of adverse events such as atrial remodeling. 479 However, it should be noted that in this trial, 267 there were many first-episode AF patients, and many patients in both groups were not receiving rhythm control therapy at 2 years $(34.9\%$ in the early rhythm control therapy group vs. $85.4\%$ in the rate control [usual care] group).

In response to this recent reaffirmation of the importance of rhythm control, this Focus Update makes a minor revision to the 5-step treatment for patients with AF in the JCS/JHRS 2020 Guideline on Pharmacotherapy of Cardiac Arrhythmias, and describes rhythm control and rate control in parallel as “Step 4: Improvement of symptoms”. The

choice of treatment between rhythm control and rate control is determined on a case-by-case basis.

▋ ▋ 5.2.1 4-Step Management of Patients With Atrial Fibrillation (Step 1: Acute Management) ( Figure12 )

Appropriate heart rate control or maintenance of sinus rhythm should be performed during the acute phase to stabilize hemodynamics. If the patient is hemodynamically compromised, emergency electrical cardioversion should be performed to restore sinus rhythm.

▋ ▋ 5.2.2 4-Step Management of Patients With Atrial Fibrillation (Step 2: Risk Factors Management) ( Figure12 )

Appropriate treatment of comorbidities and improved dietary habits reduce the risk of cardiovascular events associated with the development and progression of AF. Comorbidities (hypertension, HF, coronary artery disease, diabetes, sleep apnea, etc.) and unfavorable lifestyle habits (obesity, smoking, excessive alcohol intake, lack of physical activity, etc.) play a major role in the development of complications in patients with AF. Step 2 includes identification and appropriate management of these comorbidities and lifestyle habits.

For example, improving modifiable risk factors such as reducing weight, smoking cessation, reduction of excessive alcohol intake, and regular physical activity can reduce atrial remodeling as well as recurrent AF. Targeted interventions (119 patients) for risk factors such as hypertension, dyslipidemia, HF, diet, and cardiac rehabilitation as compared with control group (126 patients) resulted in significantly higher maintenance of sinus rhythm ( $75\%$ vs. $6\Bar{3\%}$ , odds ratio 1.765, $95\%$ CI lower limit 1.021, $\mathrm{P}{<}0.042)$ ). 480 In contrast, a study of aggressive blood pressure lowering alone in patients with AF after catheter ablation showed no effect on AF recurrence (HR 0.94, $95\%$ CI 0.65–1.38, $\mathbf{P}{=}0.763)$ ), 481 which suggests that comprehensive improvement, rather than correction of single risk factors, is needed to prevent recurrence and improve prognosis in AF.

In this Focus Update, we recommend the importance of treating comorbidities such as hypertension, diabetes, and sleep apnea, as well as improving lifestyle habits such as obesity, smoking, and excessive alcohol consumption, to reduce the risk of developing and recurrent AF ( Table28 , Recommendation Class I).

▋ ▋ 5.2.3 4-Step Management of Patients With Atrial Fibrillation (Step 3: Stroke Prevention) ( Figure12 )

The risk of stroke is assessed, and patients at risk are given oral anticoagulants. AF increases the risk of stroke by approximately 5-fold, 482 but this risk is not uniform across patients with AF and is increased by the presence of stroke risk factors and their modifiers. 483 Previously, it was recognized that the risk of thromboembolism was similar whether the AF was paroxysmal or persistent. However, a recent meta-analysis found that persistent AF was associated with higher risk of thromboembolism (HR 1.38, $95\%$ CI 1.19–1.61, $\mathrm{P}{<}0.001$ ) compared with paroxysmal AF. 484 In the J-RISK study 368 conducted in Japan, persistent/ permanent AF was also considered an independent risk factor contributing to the development of stroke (for details, see Chapter III.1.1 ). Assessment of stroke risk in patients with AF must strike a balance between simplicity, practicality, and accuracy. 485 , 486

Advance Publication

JCS/JHRS 2024 Guideline Focused Update on Management of Cardiac Arrhythmias

 Figure12. Comprehensive management of atrial fibrillation.

In the JCS/JHRS 2020 Guideline on Pharmacotherapy of Cardiac Arrhythmias, 3 risk assessment for stroke was based on the CHADS 2 score (HF, hypertension, age ${>}75$ years, diabetes, history of stroke or transient ischemic attack), 487 but this Focus Update recommends the use of the CHADS 2 score and HELT-E 2 S 2 score ( Table19 ).

Oral anticoagulants reduce the risk of stroke and death in patients with AF. 488 They include vitamin K antagonists (warfarin) and DOACs, but DOACs are preferred because of their ease of administration, stable efficacy, fewer interactions with diet and other drugs, and less intracranial bleeding. 430 , 489 , 490 Warfarin should be used only when a DOAC is not available. On the other hand, the question of whether DOACs should be administered to patients at very high risk of bleeding has long been debated. To address this issue, the superiority of edoxaban $15\,\mathrm{mg}$ once daily over placebo in preventing stroke or systemic embolism in Japanese patients aged ${>}80$ years with nonvalvular AF who were unable to receive the approved doses of existing oral anticoagulants due to bleeding concerns was verified 431 (see Chapter III.2.7 for details). In patients who require long-term anticoagulation but for whom anticoagulation is not appropriate due to high bleeding risk, percutaneous left atrial appendage closure or thoracoscopic left atrial appendage closure may be considered on a case-by-case basis. 491

▋ ▋ 5.2.4 4-Step Management of Patients With Atrial Fibrillation (Step 4: Symptom Improvement) ( Figure12 )

Symptom improvement is achieved by maintaining sinus rhythm (Rhythm control) and/or appropriate heart rate

| Table 28. Recommendations and Levels of Evidence for Rhythm Control in Patients With AF ||| |---|---|---| |||| ||COR|LOE| |Treatment of comorbidities such as||| |hypertension, diabetes, and sleep apnea,||| | and modifications of lifestyle such as obesity, smoking,and excessive alcohol consumption ||| |||| | to enhance the effectiveness of rhythm control are recommended ||| | Rhythm control therapy in patients with early- stageAF should be considered |iia|| ||||

AF, atrial fibrillation; COR, Class of Recommendation; LOE, Level of Evidence.

control (Rate control). Rhythm control is a therapeutic strategy to return to and maintain sinus rhythm. Antiarrhythmic drugs, electrical cardioversion, and catheter ablation/Maze procedure are the primary means of rhythm control. Return to and maintenance of sinus rhythm is effective in improving symptoms of AF, exercise capacity, 282 QOL, 492 left ventricular ejection fraction (LVEF), 280 and left atrial diameter, 283 and reducing hospitalizations. 493

In recent years, the ablation technology for AF has evolved dramatically, and its efficacy and safety have improved markedly. In the CASTLE-AF trial, 279 catheter ablation in AF patients complicated by HF with reduced LVEF (HFrEF) significantly reduced rates of all-cause mortality (HR 0.53, $95\%$ CI 0.32–0.86, $\mathrm{{P}{=}0.01}$ ) and hospitalization for worsening HF (HR 0.62, $95\%$ CI 0.43–0.87, $\mathbf{P{=}}0.007]$ ) compared with medical treatment (Rate control).

| Table 29. Patient Profile for AF in Which Rhythm Control Is ConsideredPreferable | |---| || | (1) Severe symptoms (palpitations, syncope, chest discomfort, etc-) | |(2) Persistence of AF which can lead to the onset or worsening| |(3) Relatively few comorbidities related to the development of AF| |(4) No significant severe left atrial enlargement and minimal| | intra-atrial conduction delay (mild atrial remodeling)| |(5)Patient preference for rhythm control|

AF, atrial fibrillation.

On the other hand, in the aforementioned EAST-AFNET 4 trial, 267 the rate of catheter ablation at 2 years after allocation was not so high $(19.4\%)$ , and the proportion of patients receiving antiarrhythmic drugs was $45.7\%$ , indicating the usefulness of antiarrhythmic drugs for earlystage AF.

Table29 shows patient profile for atrial fibrillation in which rhythm control is considered preferable. Rhythm control with catheter ablation and/or antiarrhythmic drugs should be aggressively considered for these patients. With regard to age, we note that in a Korean cohort study 494 the benefit of early rhythm control waned with increasing age and was more beneficial in patients with AF who were younger than 75 years. Given the results of the EASTAFNET 4 trial, rhythm control should be a priority, at least in patients with early-stage AF, and this Focus Update recommends that rhythm control therapy be considered for patients with early-stage AF to improve symptoms and QOL ( Table28 , Recommendation Class IIa).

On the other hand, rate control is intended to prevent the onset or worsening of palpitations and HF by appropriately controlling heart rate during AF. Patients with persistent or permanent AF who are considered to have difficulty maintaining sinus rhythm are the main target. Drugs used include $\beta$ -blockers, digitalis, and nondihydropyridine calcium antagonists (contraindication for patients with low cardiac function).

References

1. Japanese Circulation Society. Guidelines for drug treatment of arrhythmias (JCS 2009). [in Japanese] 2. JCS Joint Working Group. Guidelines for pharmacotherapy of atrial fibrillation (JCS 2013). Circ J 2014; 78: 1997–2021. 3. Japanese Circulation Society and Japanese Heart Rhythm Society Joint Working Group. JCS/JHRS 2020 guideline on pharmacotherapy of cardiac arrhythmias. Circ J 2022; 86: 1790–1924. 4. JCS Joint Working Group. Guidelines for non-pharmacotherapy of cardiac arrhythmias (JCS 2011). Circ J 2013; 77: 249–274. 5. JCS/JHRS Joint Working Group. JCS/JHRS 2019 guideline on non-pharmacotherapy of cardiac arrhythmias. Circ J 2021; 85: 1104–1244. 6. Japanese Circulation Society / the Japanese Heart Rhythm Society Joint Working Group. JCS/JHRS 2021 guideline focused update on non-pharmacotherapy of cardiac arrhythmias. Circ J 2022; 86: 337–363. 7. Fire and Disaster Management Agency (FDMA). 2021 Edition: Current status of emergency rescue services. [in Japanese] Available at: https://www.fdma.go.jp/publication/rescue/post-3. html (accessed August 2, 2024) 8. Moss AJ, Zareba W, Hall WJ, Klein H, Wilber DJ, Cannom DS, et al.; Multicenter Automatic Defibrillator Implantation Trial II Investigators. Prophylactic implantation of a defibrillator in patients with myocardial infarction and reduced ejection fraction. N Engl J Med 2002; 346: 877–883. 9. Bardy GH, Lee KL, Mark DB, Poole JE, Packer DL, Boineau R, et al.; Sudden Cardiac Death in Heart Failure Trial (SCD-HeFT) Investigators. Amiodarone or an implantable cardioverterdefibrillator for congestive heart failure. N Engl J Med 2005; 352: 225–237. 10. Køber L, Thune JJ, Nielsen JC, Haarbo J, Videbæk L, Korup E, et al.; DANISH Investigators. Defibrillator implantation in patients with nonischemic systolic heart failure. N Engl J Med 2016; 375: 1221–1230. 11. Golwala H, Bajaj NS, Arora G, Arora P. Implantable cardioverter-defibrillator for nonischemic cardiomyopathy: An updated meta-analysis. Circulation 2017; 135: 201–203. 12. Sasaki S, Noda T, Okumura K, Nitta T, Aizawa Y, Ohe T, et al. Effectiveness of implantable cardioverter defibrillator in patients with non-ischemic heart failure with systolic dysfunction: Subanalysis of the Nippon storm study. Circ J 2022; 87: 92–100. 13. Aonuma K, Ando K, Kusano K, Asai T, Inoue K, Inamura Y, et al.; HINODE Investigators. Primary results from the Japanese Heart Failure and Sudden Cardiac Death Prevention Trial (HINODE). ESC Heart Fail 2022; 9: 1584–1596. 14. Moss AJ, Schuger C, Beck CA, Brown MW, Cannom DS, Daubert JP, et al.; MADIT-RIT Trial Investigators. Reduction in inappropriate therapy and mortality through ICD programming. N Engl J Med 2012; 367: 2275–2283. 15. Zakine C, Garcia R, Narayanan K, Gandjbakhch E, Algalarrondo V, Lellouche N, et al. Prophylactic implantable cardioverterdefibrillator in the very elderly. Europace 2019; 21: 1063–1069. 16. Younis A, Goldberger JJ, Kutyifa V, Zareba W, Polonsky B, Klein H, et al. Predicted benefit of an implantable cardioverterdefibrillator: The MADIT-ICD benefit score. Eur Heart J 2021; 42: 1676–1684. 17. Zabel M, Willems R, Lubinski A, Bauer A, Brugada J, Conen D, et al.; EU-CERT-ICD Study Investigators. Clinical effectiveness of primary prevention implantable cardioverter-defibrillators: Results of the EU-CERT-ICD controlled multicentre cohort study. Eur Heart J 2020; 41: 3437–3447. 18. Elming MB, Nielsen JC, Haarbo J, Videbæk L, Korup E, Signorovitch J, et al. Age and outcomes of primary prevention implantable cardioverter-defibrillators in patients with nonischemic systolic heart failure. Circulation 2017; 136: 1772–1780. 19. Savelieva I, Fumagalli S, Kenny RA, Anker S, Benetos A, Boriani G, et al. EHRA expert consensus document on the management of arrhythmias in frailty syndrome, endorsed by the Heart Rhythm Society (HRS), Asia Pacific Heart Rhythm Society (APHRS), Latin America Heart Rhythm Society (LAHRS), and Cardiac Arrhythmia Society of Southern Africa (CASSA). Europace 2023; 25: 1249–1276. 20. Green AR, Leff B, Wang Y, Spatz ES, Masoudi FA, Peterson PN, et al. Geriatric conditions in patients undergoing defibrillator implantation for prevention of sudden cardiac death: Prevalence and impact on mortality. Circ Cardiovasc Qual Outcomes 2016; 9: 23–30. 21. Chen MY, Orkaby AR, Rosenberg MA, Driver JA. Frailty, implantable cardioverter defibrillators, and mortality: A systematic review. J Gen Intern Med 2019; 34: 2224–2231. 22. Poupin P, Bouleti C, Degand B, Paccalin M, Le Gal F, Bureau ML, et al. Prognostic value of Charlson Comorbidity Index in the elderly with a cardioverter defibrillator implantation. Int J Cardiol 2020; 314: 64–69. 23. Charlson ME, Pompei P, Ales KL, MacKenzie CR. A new method of classifying prognostic comorbidity in longitudinal studies: Development and validation. J Chronic Dis 1987; 40: 373–383. 24. Dauw J, Martens P, Nijst P, Meekers E, Deferm S, Gruwez H, et al. The MADIT-ICD benefit score helps to select implantable cardioverter-defibrillator candidates in cardiac resynchronization therapy. Europace 2022; 24: 1276–1283. 25. Zheng ZJ, Croft JB, Giles WH, Mensah GA. Sudden cardiac death in the United States, 1989 to 1998. Circulation 2001; 104: 2158–2163. 26. Berdowski J, Berg RA, Tijssen JG, Koster RW. Global incidences of out-of-hospital cardiac arrest and survival rates: Systematic review of 67 prospective studies. Resuscitation 2010; 81: 1479– 1487. 27. Ueda N, Noda T, Kusano K, Yasuda S, Kurita T, Shimizu W. Use of implantable cardioverter-defibrillators for primary prevention of sudden cardiac death in Asia. JACC Asia 2023; 3: 335–345. 28. Fukuoka R, Kawamura A, Kohsaka S. Prediction of sudden arrhythmic death in patients with heart failure: Towards validation in a worldwide broader range of patients. Eur Heart J 2021; 42: 4772–4773. 29. Younis A, Goldenberg I. Extending the MADIT-ICD benefit score to heterogenous heart failure populations. Eur Heart J 2021; 42: 4774–4775. 30. Shadman R, Poole JE, Dardas TF, Mozaffarian D, Cleland JG, Swedberg K, et al. A novel method to predict the proportional risk of sudden cardiac death in heart failure: Derivation of the Seattle Proportional Risk Model. Heart Rhythm 2015; 12: 2069–2077. 31. Bilchick KC, Wang Y, Cheng A, Curtis JP, Dharmarajan K, Stukenborg GJ, et al. Seattle heart failure and proportional risk models predict benefit from implantable cardioverter-defibrillators. J Am Coll Cardiol 2017; 69: 2606–2618. 32. Fukuoka R, Kohno T, Kohsaka S, Shiraishi Y, Sawano M, Abe T, et al. Prediction of sudden cardiac death in Japanese heart failure patients: International validation of the Seattle Proportional Risk Model. Europace 2020; 22: 588–597. 33. Tanno K, Miyoshi F, Watanabe N, Minoura Y, Kawamura M, Ryu S, et al. Are the MADIT II criteria for ICD implantation appropriate for Japanese patients? Circ J 2005; 69: 19–22. 34. Shiga T, Hagiwara N, Ogawa H, Takagi A, Nagashima M, Yamauchi T, et al.; Heart Institute of Japan Acute Myocardial Infarction-II (HIJAMI-II) Investigators. Sudden cardiac death and left ventricular ejection fraction during long-term follow-up after acute myocardial infarction in the primary percutaneous coronary intervention era: Results from the HIJAMI-II registry. Heart 2009; 95: 216–220. 35. Satake H, Fukuda K, Sakata Y, Miyata S, Nakano M, Kondo M, et al.; CHART-2 Investigators. Current status of primary prevention of sudden cardiac death with implantable cardioverter defibrillator in patients with chronic heart failure: A report from the CHART-2 Study. Circ J 2015; 79: 381–390. 36. van Welsenes GH, van Rees JB, Borleffs CJ, Cannegieter SC, Bax JJ, van Erven L, et al. Long-term follow-up of primary and secondary prevention implantable cardioverter defibrillator patients. Europace 2011; 13: 389–394. 37. Kondo Y, Noda T, Sato Y, Ueda M, Nitta T, Aizawa Y, et al. Comparison of 2-year outcomes between primary and secondary prophylactic use of defibrillators in patients with coronary artery disease: A prospective propensity score-matched analysis from the Nippon Storm Study. Heart Rhythm O2 2021; 2: 5–11. 38. Kabutoya T, Mitsuhashi T, Shimizu A, Nitta T, Mitamura H, Kurita T, et al. Prognosis of Japanese patients with coronary artery disease who underwent implantable cardioverter defibrillator implantation: The JID-CAD Study. Circ Rep 2021; 3: 69–76. 39. An Y, Ando K, Soga Y, Nomura A, Nagashima M, Hayashi K, et al. Mortality and predictors of appropriate implantable cardioverter defibrillator therapy in Japanese patients with Multicenter Automatic Defibrillator Implantation Trial II criteria. J Arrhythm 2017; 33: 17–22. 40. Zeppenfeld K, Tfelt-Hansen J, de Riva M, Winkel BG, Behr ER, Blom NA, et al.; ESC Scientific Document Group. 2022 ESC Guidelines for the management of patients with ventricular arrhythmias and the prevention of sudden cardiac death. Eur Heart J 2022; 43: 3997–4126. 41. de Sousa MR, Morillo CA, Rabelo FT, Nogueira Filho AM, Ribeiro AL. Non-sustained ventricular tachycardia as a predictor of sudden cardiac death in patients with left ventricular dysfunction: A meta-analysis. Eur J Heart Fail 2008; 10: 1007–1014. 42. Makimoto H, Zielke S, Clasen L, Lin T, Gerguri S, Müller P, et al. Clinical significance of precedent asymptomatic non-sustained ventricular tachycardias on subsequent ICD interventions and heart failure hospitalization in primary prevention ICD patients. Eur J Med Res 2020; 25: 5. 43. Kinoshita T, Hashimoto K, Yoshioka K, Miwa Y, Yodogawa K, Watanabe E, et al. Risk stratification for cardiac mortality using electrocardiographic markers based on 24-hour Holter recordings: The JANIES-SHD study. J Cardiol 2020; 75: 155– 163. 44. Di Marco A, Anguera I, Schmitt M, Klem I, Neilan TG, White JA, et al. Late gadolinium enhancement and the risk for ventricular arrhythmias or sudden death in dilated cardiomyopathy: Systematic review and meta-analysis. JACC Heart Fail 2017; 5: 28–38. 45. Klem I, Klein M, Khan M, Yang EY, Nabi F, Ivanov A, et al. Relationship of LVEF and myocardial scar to long-term mortality risk and mode of death in patients with nonischemic cardiomyopathy. Circulation 2021; 143: 1343–1358. 46. Gigli M, Merlo M, Graw SL, Barbati G, Rowland TJ, Slavov DB, et al. Genetic risk of arrhythmic phenotypes in patients with dilated cardiomyopathy. J Am Coll Cardiol 2019; 74: 1480–1490. 47. Muchtar E, Blauwet LA, Gertz MA. Restrictive cardiomyopathy: Genetics, pathogenesis, clinical manifestations, diagnosis, and therapy. Circ Res 2017; 121: 819–837. 48. Terasaki F, Azuma A, Anzai T, Ishizaka N, Ishida Y, Isobe M, et al.; Japanese Circulation Society Joint Working Group. JCS 2016 Guideline on diagnosis and treatment of cardiac sarcoidosis: Digest version. Circ J 2019; 83: 2329–2388. 49. De Bortoli A, Birnie DH. Diagnosis and treatment of cardiac sarcoidosis. Circ J 2023; 87: 471–480. 50. Terasaki F, Kusano K, Nakajima T, Yazaki Y, Morimoto SI, Culver DA, et al. The characteristics of Japanese guidelines on diagnosis and treatment of cardiac sarcoidosis compared with the previous guidelines. Sarcoidosis Vasc Diffuse Lung Dis 2022; 39: e2022028. 51. Takaya Y, Nakamura K, Nishii N, Ito H. Clinical outcomes of patients with isolated cardiac sarcoidosis confirmed by clinical diagnostic criteria. Int J Cardiol 2021; 345: 49–53. 52. Birnie DH, Nery PB, Ha AC, Beanlands RS. Cardiac Sarcoidosis. J Am Coll Cardiol 2016; 68: 411–421. 53. Banba K, Kusano KF, Nakamura K, Morita H, Ogawa A, Ohtsuka F, et al. Relationship between arrhythmogenesis and disease activity in cardiac sarcoidosis. Heart Rhythm 2007; 4: 1292–1299. 54. Kusano KF, Satomi K. Diagnosis and treatment of cardiac sarcoidosis. Heart 2016; 102: 184–190. 55. Nagai T, Nagano N, Sugano Y, Asaumi Y, Aiba T, Kanzaki H, et al. Effect of corticosteroid therapy on long-term clinical outcome and left ventricular function in patients with cardiac sarcoidosis. Circ J 2015; 79: 1593–1600. 56. Nagai T, Nagano N, Sugano Y, Asaumi Y, Aiba T, Kanzaki H, et al. Effect of discontinuation of prednisolone therapy on risk of cardiac mortality associated with worsening left ventricular dysfunction in cardiac sarcoidosis. Am J Cardiol 2016; 117: 966–971. 57. Ekström K, Lehtonen J, Nordenswan HK, Mäyränpää MI, Räisänen-Sokolowski A, Kandolin R, et al. Sudden death in cardiac sarcoidosis: An analysis of nationwide clinical and cause-of-death registries. Eur Heart J 2019; 40: 3121–3128. 58. Nabeta T, Kitai T, Naruse Y, Taniguchi T, Yoshioka K, Tanaka H, et al. Risk stratification of patients with cardiac sarcoidosis: The ILLUMINATE-CS registry. Eur Heart J 2022; 43: 3450–3459. 59. Takaya Y, Kusano K, Nishii N, Nakamura K, Ito H. Early and frequent defibrillator discharge in patients with cardiac sarcoidosis compared with patients with idiopathic dilated cardiomyopathy. Int J Cardiol 2017; 240: 302–306. 60. Kusano K, Ishibashi K, Noda T, Nakajima K, Nakasuka K, Terasaki S, et al. Prognosis and outcomes of clinically diagnosed cardiac sarcoidosis without positive endomyocardial biopsy findings. JACC Asia 2021; 1: 385–395. 61. Kandolin R, Lehtonen J, Airaksinen J, Vihinen T, Miettinen H, Ylitalo K, et al. Cardiac sarcoidosis: Epidemiology, characteristics, and outcome over 25 years in a nationwide study. Circulation 2015; 131: 624–632. 62. Nordenswan HK, Lehtonen J, Ekström K, Kandolin R, Simonen P, Mäyränpää M, et al. Outcome of cardiac sarcoidosis presenting with high-grade atrioventricular block. Circ Arrhythm Electrophysiol 2018; 11: e006145. 63. Takaya Y, Kusano KF, Nakamura K, Ito H. Outcomes in patients with high-degree atrioventricular block as the initial manifestation of cardiac sarcoidosis. Am J Cardiol 2015; 115: 505–509. 64. Nadel J, Lancefield T, Voskoboinik A, Taylor AJ. Late gadolinium enhancement identified with cardiac magnetic resonance imaging in sarcoidosis patients is associated with long-term ventricular arrhythmia and sudden cardiac death. Eur Heart J Cardiovasc Imaging 2015; 16: 634–641. 65. Ekström K, Lehtonen J, Hänninen H, Kandolin R, Kivistö S, Kupari M. Magnetic resonance imaging as a predictor of survival free of life-threatening arrhythmias and transplantation in cardiac sarcoidosis. J Am Heart Assoc 2016; 5: e003040. 66. Murtagh G, Laffin LJ, Beshai JF, Maffessanti F, Bonham CA, Patel AV, et al. Prognosis of myocardial damage in sarcoidosis patients with preserved left ventricular ejection fraction: Risk stratification using cardiovascular magnetic resonance. Circ Cardiovasc Imaging 2016; 9: e003738. 67. Coleman GC, Shaw PW, Balfour PC Jr, Gonzalez JA, Kramer CM, Patel AR, et al. Prognostic value of myocardial scarring on CMR in patients with cardiac sarcoidosis. JACC Cardiovasc Imaging 2017; 10: 411–420. 68. Okada DR, Smith J, Derakhshan A, Gowani Z, Zimmerman SL, Misra S, et al. Electrophysiology study for risk stratification in patients with cardiac sarcoidosis and abnormal cardiac imaging. Int J Cardiol Heart Vasc 2019; 23: 100342. 69. Zipse MM, Tzou WS, Schuller JL, Aleong RG, Varosy PD, Tompkins C, et al. Electrophysiologic testing for diagnostic evaluation and risk stratification in patients with suspected cardiac sarcoidosis with preserved left and right ventricular systolic function. J Cardiovasc Electrophysiol 2019; 30: 1939–1948. 70. Segawa M, Fukuda K, Nakano M, Kondo M, Satake H, Hirano M, et al. Time course and factors correlating with ventricular tachyarrhythmias after introduction of steroid therapy in cardiac sarcoidosis. Circ Arrhythm Electrophysiol 2016; 9: e003353. 71. Blankstein R, Osborne M, Naya M, Waller A, Kim CK, Murthy VL, et al. Cardiac positron emission tomography enhances prognostic assessments of patients with suspected cardiac sarcoidosis. J Am Coll Cardiol 2014; 63: 329–336. 72. Mehta D, Mori N, Goldbarg SH, Lubitz S, Wisnivesky JP, Teirstein A. Primary prevention of sudden cardiac death in silent cardiac sarcoidosis: Role of programmed ventricular stimulation. Circ Arrhythm Electrophysiol 2011; 4: 43–48. 73. Kron J, Sauer W, Schuller J, Bogun F, Crawford T, Sarsam S, et al. Efficacy and safety of implantable cardiac defibrillators for treatment of ventricular arrhythmias in patients with cardiac sarcoidosis. Europace 2013; 15: 347–354. 74. Azoulay LD, Waintraub X, Haroche J, Amoura Z, Cohen Aubart F. Factors associated with implantable cardioverter defibrillators appropriate therapy in cardiac sarcoidosis: A meta-analysis. Sarcoidosis Vasc Diffuse Lung Dis 2020; 37: 17–23. 75. Mohsen A, Jimenez A, Hood RE, Dickfeld T, Saliaris A, Shorofsky S, et al. Cardiac sarcoidosis: Electrophysiological outcomes on long-term follow-up and the role of the implantable cardioverter-defibrillator. J Cardiovasc Electrophysiol 2014; 25: 171–176. 76. Al-Khatib SM, Stevenson WG, Ackerman MJ, Bryant WJ, Callans DJ, Curtis AB, et al. 2017 AHA/ACC/HRS Guideline for management of patients with ventricular arrhythmias and the prevention of sudden cardiac death: Executive summary: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Circulation 2018; 138: e210–e271. 77. Kamada H, Ishibashi K, Miyazaki Y, Wakamiya A, Ueda N, Nakajima K, et al. Fatal arrhythmic risks in cardiac sarcoidosis with mildly impaired cardiac function. JACC Asia 2023; 3: 755–763. 78. Stevenson A, Bray JJH, Tregidgo L, Ahmad M, Sharma A, Ng A, et al. Prognostic value of late gadolinium enhancement detected on cardiac magnetic resonance in cardiac sarcoidosis. JACC Cardiovasc Imaging 2023; 16: 345–357. 79. Crawford T, Mueller G, Sarsam S, Prasitdumrong H, Chaiyen N, Gu X, et al. Magnetic resonance imaging for identifying patients with cardiac sarcoidosis and preserved or mildly reduced left ventricular function at risk of ventricular arrhythmias. Circ Arrhythm Electrophysiol 2014; 7: 1109–1115. 80. Ise T, Hasegawa T, Morita Y, Yamada N, Funada A, Takahama H, et al. Extensive late gadolinium enhancement on cardiovascular magnetic resonance predicts adverse outcomes and lack of improvement in LV function after steroid therapy in cardiac sarcoidosis. Heart 2014; 100: 1165–1172. 81. Bekki M, Tahara N, Tahara A, Sugiyama Y, Maeda-Ogata S, Honda A, et al. Localization of myocardial FDG uptake for prognostic risk stratification in corticosteroid-naïve cardiac sarcoidosis. J Nucl Cardiol 2022; 29: 2132–2144. 82. Gowani Z, Habibi M, Okada DR, Smith J, Derakhshan A, Zimmerman SL, et al. Utility of cardiac magnetic resonance imaging versus cardiac positron emission tomography for risk stratification for ventricular arrhythmias in patients with cardiac sarcoidosis. Am J Cardiol 2020; 134: 123–129. 83. Kazmirczak F, Chen KA, Adabag S, von Wald L, Roukoz H, Benditt DG, et al. Assessment of the 2017 AHA/ACC/HRS Guideline recommendations for implantable cardioverterdefibrillator implantation in cardiac sarcoidosis. Circ Arrhythm Electrophysiol 2019; 12: e007488. 84. Takenaka S, Kobayashi Y, Nagai T, Kato Y, Komoriyama H, Nagano N, et al. Applicability of the AHA/ACC/HRS Guideline for implantable cardioverter defibrillator implantation in Japanese patients with cardiac sarcoidosis. JACC Clin Electrophysiol 2021; 7: 1410–1418. 85. Ogura S, Nakamura K, Morita H, Nakagawa K, Nishii N, Akagi S, et al. Fragmented QRS as a predictor of cardiac events in patients with cardiac sarcoidosis. J Cardiol 2022; 79: 446–452. 86. Hagiwara H, Watanabe M, Kadosaka T, Koizumi T, Kobayashi Y, Koya T, et al. Fragmented QRS on 12-lead electrocardiogram predicts long-term prognosis in patients with cardiac sarcoidosis. Heart Vessels 2023; 38: 803–816. 87. Kobayashi Y, Nagai T, Takenaka S, Kato Y, Komoriyama H, Nagano N, et al. Long-term prognostic significance of ventricular repolarization dispersion in patients with cardiac sarcoidosis. Am J Cardiol 2021; 152: 125–131. 88. Nagano N, Nagai T, Sugano Y, Morita Y, Asaumi Y, Aiba T, et al. Association between basal thinning of interventricular septum and adverse long-term clinical outcomes in patients with cardiac sarcoidosis. Circ J 2015; 79: 1601–1608. 89. Nordenswan HK, Pöyhönen P, Lehtonen J, Ekström K, Uusitalo V, Niemelä M, et al. Incidence of sudden cardiac death and life-threatening arrhythmias in clinically manifest cardiac sarcoidosis with and without current indications for an implantable cardioverter defibrillator. Circulation 2022; 146: 964–975. 90. Roberts PR, ElRefai M, Foley P, Rao A, Sharman D, Somani R, et al. UK expert consensus statement for the optimal use and clinical utility of leadless pacing systems on behalf of the British Heart Rhythm Society. Arrhythm Electrophysiol Rev 2022; 11: e19. 91. Strik M, Clementy N, Mondoly P, Eschalier R, Ramirez FD, Racine HP, et al. Implantation of a leadless pacemaker in young adults. J Cardiovasc Electrophysiol 2023; 34: 412–417. 92. Glikson M, Nielsen JC, Kronborg MB, Michowitz Y, Auricchio A, Barbash IM, et al. 2021 ESC Guidelines on cardiac pacing and cardiac resynchronization therapy. Eur Heart J 2021; 42: 3427–3520. 93. Crossley GH, Piccini JP, Longacre C, Higuera L, Stromberg K, El-Chami MF. Leadless versus transvenous single-chamber ventricular pacemakers: 3 year follow-up of the Micra CED study. J Cardiovasc Electrophysiol 2023; 34: 1015–1023. 94. Knops RE, Reddy VY, Ip JE, Doshi R, Exner DV, Defaye P, et al.; Aveir DR i2i Study Investigators. A dual-chamber leadless pacemaker. N Engl J Med 2023; 388: 2360–2370. 95. Reddy VY, Exner DV, Doshi R, Tomassoni G, Bunch TJ, Estes NAM, et al.; LEADLESS II Investigators. Primary results on safety and efficacy from the LEADLESS II-Phase 2 Worldwide Clinical Trial. JACC Clin Electrophysiol 2022; 8: 115–117. 96. Neuzil P, Petru J, Chovanec M, Hubbard C, Simon J, Ryu P, et al. PO-693-05 Removal of a chronically-implanted leadless ventricular pacemaker after 9-years using a highly torque retrieval catheter a case report. Heart Rhythm 2022; 19 Suppl: S407–S408. 97. Steinwender C, Khelae SK, Garweg C, Chan JYS, Ritter P, Johansen JB, et al. Atrioventricular synchronous pacing using a leadless ventricular pacemaker: Results from the MARVEL 2 Study. JACC Clin Electrophysiol 2020; 6: 94–106. 98. Chinitz LA, El-Chami MF, Sagi V, Garcia H, Hackett FK, Leal M, et al. Ambulatory atrioventricular synchronous pacing over time using a leadless ventricular pacemaker: Primary results from the AccelAV study. Heart Rhythm 2023; 20: 46–54. 99. Neugebauer F, Noti F, van Gool S, Roten L, Baldinger SH, Seiler J, et al. Leadless atrioventricular synchronous pacing in an outpatient setting: Early lessons learned on factors affecting atrioventricular synchrony. Heart Rhythm 2022; 19: 748–756. 100. Reynolds D, Duray GZ, Omar R, Soejima K, Neuzil P, Zhang S, et al.; Micra Transcatheter Pacing Study Group. A leadless intracardiac transcatheter pacing system. N Engl J Med 2016; 374: 533–541. 101. Garg A, Koneru JN, Fagan DH, Stromberg K, Padala SK, ElChami MF, et al. Morbidity and mortality in patients precluded for transvenous pacemaker implantation: Experience with a leadless pacemaker. Heart Rhythm 2020; 17: 2056–2063. 102. Piccini JP, Cunnane R, Steffel J, El-Chami MF, Reynolds D, Roberts PR, et al. Development and validation of a risk score for predicting pericardial effusion in patients undergoing leadless pacemaker implantation: Experience with the Micra transcatheter pacemaker. Europace 2022; 24: 1119–1126. 103. Ando K, Inoue K, Harada T, Shizuta S, Yoshida Y, Kusano K, et al. Safety and performance of the Micra VR leadless pacemaker in a Japanese cohort: Comparison with global studies. Circ J 2023; 87: 1809–1816. 104. Beccarino NJ, Choi EY, Liu B, Kim BS, Pagan E, Saleh M, et al. Concomitant leadless pacing in pacemaker-dependent patients undergoing transvenous lead extraction for active infection: Mid-term follow-up. Heart Rhythm 2023; 20: 853–860. 105. Breeman KTN, Beurskens NEG, Driessen AHG, Wilde AAM, Tjong FVY, Knops RE. Timing and mid-term outcomes of using leadless pacemakers as replacement for infected cardiac implantable electronic devices. J Interv Card Electrophysiol 2023; 66: 1477–1485. 106. Bicong L, Allen JC, Arps K, Al-Khatib SM, Bahnson TD, Daubert JP, et al. Leadless pacemaker implantation after lead extraction for cardiac implanted electronic device infection. J Cardiovasc Electrophysiol 2022; 33: 464–470. 107. Mitacchione G, Schiavone M, Gasperetti A, Arabia G, Breitenstein A, Cerini M, et al. Outcomes of leadless pacemaker implantation following transvenous lead extraction in high-volume referral centers: Real-world data from a large international registry. Heart Rhythm 2023; 20: 395–404. 108. Occhetta E, Bortnik M, Audoglio R, Vassanelli C; INVASY Study Investigators. Closed loop stimulation in prevention of vasovagal syncope. Inotropy Controlled Pacing in Vasovagal Syncope (INVASY): A multicentre randomized, single blind, controlled study. Europace 2004; 6: 538–547. 109. Russo V, Rago A, Papa AA, Golino P, Calabrò R, Russo MG, et al. The effect of dual-chamber closed-loop stimulation on syncope recurrence in healthy patients with tilt-induced vasovagal cardioinhibitory syncope: A prospective, randomised, single-blind, crossover study. Heart 2013; 99: 1609–1613. 110. Baron-Esquivias G, Morillo CA, Moya-Mitjans A, MartinezAlday J, Ruiz-Granell R, Lacunza-Ruiz J, et al. Dual-chamber pacing with closed loop stimulation in recurrent reflex vasovagal syncope: The SPAIN study. J Am Coll Cardiol 2017; 70: 1720–1728. 111. Brignole M, Russo V, Arabia F, Oliveira M, Pedrote A, Aerts A, et al.; BioSync CLS trial Investigators. Cardiac pacing in severe recurrent reflex syncope and tilt-induced asystole. Eur Heart J 2021; 42: 508–516. 112. Barón-Esquivias G, Moya-Mitjans A, Martinez-Alday J, RuizGranell R, Lacunza-Ruiz J, Garcia-Civera R, et al. Impact of dual-chamber pacing with closed loop stimulation on quality of life in patients with recurrent reflex vasovagal syncope: Results of the SPAIN study. Europace 2020; 22: 314–319. 113. Russo V, Rago A, De Rosa M, Papa AA, Simova I, Petrov I, et al. Does cardiac pacing reduce syncopal recurrences in cardioinhibitory vasovagal syncope patients selected with head-up tilt test?: Analysis of a 5-year follow-up database. Int J Cardiol 2018; 270: 149–153. 114. Palmisano P, Dell’Era G, Russo V, Zaccaria M, Mangia R, Bortnik M, et al. Effects of closed-loop stimulation vs. DDD pacing on haemodynamic variations and occurrence of syncope induced by head-up tilt test in older patients with refractory cardioinhibitory vasovagal syncope: The Tilt test-Induced REsponse in Closed-loop Stimulation multicentre, prospective, single blind, randomized study. Europace 2018; 20: 859–866. 115. Fananapazir L, Epstein ND, Curiel RV, Panza JA, Tripodi D, McAreavey D. Long-term results of dual-chamber (DDD) pacing in obstructive hypertrophic cardiomyopathy. Evidence for progressive symptomatic and hemodynamic improvement and reduction of left ventricular hypertrophy. Circulation 1994; 90: 2731–2742. 116. Knops RE, Pepplinkhuizen S, Delnoy PPHM, Boersma LVA, Kuschyk J, El-Chami MF, et al. Device-related complications in subcutaneous versus transvenous ICD: A secondary analysis of the PRAETORIAN trial. Eur Heart J 2022; 43: 4872–4883. 117. Breeman KTN, Swackhamer B, Brisben AJ, Quast ABE, Carter N, Shuros A, et al. Long-term performance of a novel communicating antitachycardia pacing-enabled leadless pacemaker and subcutaneous implantable cardioverter-defibrillator system: A comprehensive preclinical study. Heart Rhythm 2022; 19: 837–846. 118. Quast ABE, Tjong FVY, Koop BE, Wilde AAM, Knops RE, Burke MC. Device orientation of a leadless pacemaker and subcutaneous implantable cardioverter-defibrillator in canine and human subjects and the effect on intrabody communication. Europace 2018; 20: 1866–1871. 119. Tjong FVY, Brouwer TF, Koop B, Soltis B, Shuros A, Schmidt B, et al. Acute and 3-month performance of a communicating leadless antitachycardia pacemaker and subcutaneous implantable defibrillator. JACC Clin Electrophysiol 2017; 3: 1487–1498. 120. Friedman P, Murgatroyd F, Boersma LVA, Manlucu J, O’Donnell D, Knight BP, et al.; Extravascular ICD Pivotal Study Investigators. Efficacy and safety of an extravascular implantable cardioverter-defibrillator. N Engl J Med 2022; 387: 1292–1302. 121. Molnár L, Crozier I, Haqqani H, O’Donnell D, Kotschet E, Alison J, et al. The extravascular implantable cardioverterdefibrillator: Characterization of anatomical parameters impacting substernal implantation and defibrillation efficacy. Europace 2022; 24: 762–773. 122. Tops LF, Schalij MJ, Bax JJ. The effects of right ventricular apical pacing on ventricular function and dyssynchrony implications for therapy. J Am Coll Cardiol 2009; 54: 764–776. 123. Sweeney MO, Hellkamp AS, Ellenbogen KA, Greenspon AJ, Freedman RA, Lee KL, et al.; MOde Selection Trial Investigators. Adverse effect of ventricular pacing on heart failure and atrial fibrillation among patients with normal baseline QRS duration in a clinical trial of pacemaker therapy for sinus node dysfunction. Circulation 2003; 107: 2932–2937. 124. Kiehl EL, Makki T, Kumar R, Gumber D, Kwon DH, Rickard JW, et al. Incidence and predictors of right ventricular pacing-induced cardiomyopathy in patients with complete atrioventricular block and preserved left ventricular systolic function. Heart Rhythm 2016; 13: 2272–2278. 125. Kaye GC, Linker NJ, Marwick TH, Pollock L, Graham L, Pouliot E, et al.; Protect-Pace trial investigators. Effect of right ventricular pacing lead site on left ventricular function in patients with high-grade atrioventricular block: Results of the Protect-Pace study. Eur Heart J 2015; 36: 856–862. 126. Huizar JF, Kaszala K, Tan A, Koneru J, Mankad P, Kron J, et al. Abnormal conduction-induced cardiomyopathy: JACC review topic of the week. J Am Coll Cardiol 2023; 81: 1192–1200. 127. Lamas GA, Lee KL, Sweeney MO, Silverman R, Leon A, Yee R, et al. Mode Selection Trial in Sinus-Node Dysfunction: Ventricular pacing or dual-chamber pacing for sinus-node dysfunction. N Engl J Med 2002; 346: 1854–1862. 128. Wilkoff BL, Cook JR, Epstein AE, Greene HL, Hallstrom AP, Hsia H, et al.; Dual Chamber and VVI Implantable Defibrillator Trial Investigators. Dual-chamber pacing or ventricular backup pacing in patients with an implantable defibrillator: The Dual Chamber and VVI Implantable Defibrillator (DAVID) Trial. JAMA 2002; 288: 3115–3123. 129. Mabo P, Scherlag BJ, Munsif A, Otomo K, Lazzara R. A technique for stable His-bundle recording and pacing: Electrophysiological and hemodynamic correlates. Pacing Clin Electrophysiol 1995; 18: 1894–1901. 130. Deshmukh P, Casavant DA, Romanyshyn M, Anderson K. Permanent, direct His-bundle pacing: A novel approach to cardiac pacing in patients with normal His-Purkinje activation. Circulation 2000; 101: 869–877. 131. Zanon F, Ellenbogen KA, Dandamudi G, Sharma PS, Huang W, Lustgarten DL, et al. Permanent His-bundle pacing: A systematic literature review and meta-analysis. Europace 2018; 20: 1819– 1826. 132. Connolly SJ, Kerr CR, Gent M, Roberts RS, Yusuf S, Gillis AM, et al. Effects of physiologic pacing versus ventricular pacing on the risk of stroke and death due to cardiovascular causes. N Engl J Med 2000; 342: 1385–1391. 133. Cleland JG, Daubert JC, Erdmann E, Freemantle N, Gras D, Kappenberger L, et al.; Cardiac Resynchronization-Heart Failure (CARE-HF) Study Investigators. The effect of cardiac resynchronization on morbidity and mortality in heart failure. N Engl J Med 2005; 352: 1539–1549. 134. Sweeney MO, Bank AJ, Nsah E, Koullick M, Zeng QC, Hettrick D, et al. Search AV Extension and Managed Ventricular Pacing for Promoting Atrioventricular Conduction (SAVE PACe) Trial. Minimizing ventricular pacing to reduce atrial fibrillation in sinus-node disease. N Engl J Med 2007; 357: 1000–1008. 135. Moss AJ, Hall WJ, Cannom DS, Klein H, Brown MW, Daubert JP, et al.; MADIT-CRT Trial Investigators. Cardiacresynchronization therapy for the prevention of heart-failure events. N Engl J Med 2009; 361: 1329–1338. 136. Tang AS, Wells GA, Talajic M, Arnold MO, Sheldon R, Connolly S, et al.; Resynchronization-Defibrillation for Ambulatory Heart Failure Trial Investigators. Cardiac-resynchronization therapy for mild-to-moderate heart failure. N Engl J Med 2010; 363: 2385–2395. 137. Curtis AB, Worley SJ, Adamson PB, Chung ES, Niazi I, Sherfesee L, et al.; Biventricular versus Right Ventricular Pacing in Heart Failure Patients with Atrioventricular Block (BLOCK HF) Trial Investigators. Biventricular pacing for atrioventricular block and systolic dysfunction. N Engl J Med 2013; 368: 1585– 1593. 138. Reddy VY, Exner DV, Cantillon DJ, Doshi R, Bunch TJ, Tomassoni GF, et al.; LEADLESS II Study Investigators. Percutaneous implantation of an entirely intracardiac leadless pacemaker. N Engl J Med 2015; 373: 1125–1135. 139. Sharma PS, Dandamudi G, Naperkowski A, Oren JW, Storm RH, Ellenbogen KA, et al. Permanent His-bundle pacing is feasible, safe, and superior to right ventricular pacing in routine clinical practice. Heart Rhythm 2015; 12: 305–312. 140. Vijayaraman P. Left bundle branch pacing optimized cardiac resynchronization therapy: A novel approach. JACC Clin Electrophysiol 2021; 7: 1076–1078. 141. Jastrzębski M, Kiełbasa G, Curila K, Moskal P, Bednarek A, Rajzer M, et al. Physiology-based electrocardiographic criteria for left bundle branch capture. Heart Rhythm 2021; 18: 935–943. 142. Burri H, Jastrzebski M, Cano Ó, Čurila K, de Pooter J, Huang W, et al. EHRA clinical consensus statement on conduction system pacing implantation: Endorsed by the Asia Pacific Heart Rhythm Society (APHRS), Canadian Heart Rhythm Society (CHRS), and Latin American Heart Rhythm Society (LAHRS). Europace 2023; 25: 1208–1236. 143. Jastrzębski M, Burri H, Kiełbasa G, Curila K, Moskal P, Bednarek A, et al. The V6-V1 interpeak interval: A novel criterion for the diagnosis of left bundle branch capture. Europace 2022; 24: 40–47. 144. Wu S, Chen X, Wang S, Xu L, Xiao F, Huang Z, et al. Evaluation of the criteria to distinguish left bundle branch pacing from left ventricular septal pacing. JACC Clin Electrophysiol 2021; 7: 1166–1177. 145. Chung MK, Patton KK, Lau CP, Dal Forno ARJ, Al-Khatib SM, Arora V, et al. 2023 HRS/APHRS/LAHRS guideline on cardiac physiologic pacing for the avoidance and mitigation of heart failure. Heart Rhythm 2023; 20: e17–e91. 146. Ali N, Arnold AD, Miyazawa AA, Keene D, Chow JJ, Little I, et al. Comparison of methods for delivering cardiac resynchronization therapy: An acute electrical and haemodynamic within-patient comparison of left bundle branch area, His bundle, and biventricular pacing. Europace 2023; 25: 1060–1067. 147. Sharma PS, Naperkowski A, Bauch TD, Chan JYS, Arnold AD, Whinnett ZI, et al. Permanent His bundle pacing for cardiac resynchronization therapy in patients with heart failure and right bundle branch block. Circ Arrhythm Electrophysiol 2018; 11: e006613. 148. Vijayaraman P, Naperkowski A, Subzposh FA, Abdelrahman M, Sharma PS, Oren JW, et al. Permanent His-bundle pacing: Long-term lead performance and clinical outcomes. Heart Rhythm 2018; 15: 696–702. 149. Teigeler T, Kolominsky J, Vo C, Shepard RK, Kalahasty G, Kron J, et al. Intermediate-term performance and safety of His-bundle pacing leads: A single-center experience. Heart Rhythm 2021; 18: 743–749. 150. Palmisano P, Ziacchi M, Dell’Era G, Donateo P, Ammendola E, Coluccia G, et al. Rate and nature of complications of conduction system pacing compared with right ventricular pacing: Results of a propensity score-matched analysis from a multicenter registry. Heart Rhythm 2023; 20: 984–991. 151. Padala SK, Master VM, Terricabras M, Chiocchini A, Garg A, Kron J, et al. Initial experience, safety, and feasibility of left bundle branch area pacing: A Multicenter Prospective Study. JACC Clin Electrophysiol 2020; 6: 1773–1782. 152. Su L, Wang S, Wu S, Xu L, Huang Z, Chen X, et al. Long-term safety and feasibility of left bundle branch pacing in a large single-center study. Circ Arrhythm Electrophysiol 2021; 14: e009261. 153. Jastrzębski M, Kiełbasa G, Cano O, Curila K, Heckman L, De Pooter J, et al. Left bundle branch area pacing outcomes: The multicentre European MELOS study. Eur Heart J 2022; 43: 4161–4173. 154. Raymond-Paquin A, Verma A, Kolominsky J, Sanchez-Somonte P, Gul EE, Pillai A, et al. Left bundle branch area pacing in patients with atrioventricular conduction disease: A prospective multicenter study. Heart Rhythm 2022; 19: 1484–1490. 155. Kato H, Sato T, Shimeno K, Mito S, Nishida T, Soejima K. Predictors of implantation failure in left bundle branch area pacing using a lumenless lead in patients with bradycardia. J Arrhythm 2023; 39: 766–775. 156. Upadhyay GA, Vijayaraman P, Nayak HM, Verma N, Dandamudi G, Sharma PS, et al.; His-SYNC Investigators. His corrective pacing or biventricular pacing for cardiac resynchronization in heart failure. J Am Coll Cardiol 2019; 74: 157–159. 157. Vinther M, Risum N, Svendsen JH, Møgelvang R, Philbert BT. A Randomized Trial of His pacing versus biventricular pacing in symptomatic HF patients with left bundle branch block (His-Alternative). JACC Clin Electrophysiol 2021; 7: 1422–1432. 158. Jastrzębski M, Moskal P, Hołda MK, Strona M, Bednarek A, Kiełbasa G, et al. Deep septal deployment of a thin, lumenless pacing lead: A translational cadaver simulation study. Europace 2020; 22: 156–161. 159. Ponnusamy SS, Basil W, Vijayaraman P. Electrophysiological characteristics of septal perforation during left bundle branch pacing. Heart Rhythm 2022; 19: 728–734. 160. Shali S, Wu W, Bai J, Wang W, Qin S, Wang J, et al. Current of injury is an indicator of lead depth and performance during left bundle branch pacing lead implantation. Heart Rhythm 2022; 19: 1281–1288. 161. De Pooter J, Calle S, Timmermans F, Van Heuverswyn F. Left bundle branch area pacing using stylet-driven pacing leads with a new delivery sheath: A comparison with lumen-less leads. J Cardiovasc Electrophysiol 2021; 32: 439–448. 162. Tan ESJ, Lee JY, Boey E, Soh R, Seow SC, Teo LJT, et al. Predictors of loss of capture in left bundle branch pacing: A multicenter experience. Heart Rhythm 2022; 19: 1757–1758. 163. le Polain de Waroux JB, Wielandts JY, Gillis K, Hilfiker G, Sorgente A, Capulzini L, et al. Repositioning and extraction of stylet-driven pacing leads with extendable helix used for left bundle branch area pacing. J Cardiovasc Electrophysiol 2021; 32: 1464–1466. 164. Thaler R, Sinner MF, Joghetaei N, Fichtner S. Early sudden distal conductor fracture of a stylet-driven lead implanted for left bundle branch area pacing. HeartRhythm Case Rep 2023; 9: 28–30. 165. Vijayaraman P, Subzposh FA, Naperkowski A. Extraction of the permanent His bundle pacing lead: Safety outcomes and feasibility of reimplantation. Heart Rhythm 2019; 16: 1196–1203. 166. Vijayaraman P. Extraction of left bundle branch pacing lead. JACC Clin Electrophysiol 2020; 6: 903–904. 167. Tan ESJ, Soh R, Lee JY, Boey E, Ho KH, Aguirre S, et al. Clinical outcomes in conduction system pacing compared to right ventricular pacing in bradycardia. JACC Clin Electrophysiol 2023; 9: 992–1001. 168. Sharma PS, Patel NR, Ravi V, Zalavadia DV, Dommaraju S, Garg V, et al. Clinical outcomes of left bundle branch area pacing compared to right ventricular pacing: Results from the Geisinger-Rush Conduction System Pacing Registry. Heart Rhythm 2022; 19: 3–11. 169. Ayala Valani L, Dion D, Daneault B, Ayala-Paredes F. Deep septal perforation during left bundle branch area pacing resulting in left ventricular capture and delayed systemic embolism. Can J Cardiol 2023; 39: 1432–1435. 170. Sharma PS, Dandamudi G, Herweg B, Wilson D, Singh R, Naperkowski A, et al. Permanent His-bundle pacing as an alternative to biventricular pacing for cardiac resynchronization therapy: A multicenter experience. Heart Rhythm 2018; 15: 413–420. 171. Kronborg MB, Mortensen PT, Poulsen SH, Gerdes JC, Jensen HK, Nielsen JC. His or para-His pacing preserves left ventricular function in atrioventricular block: A double-blind, randomized, crossover study. Europace 2014; 16: 1189–1196. 172. Slotwiner DJ, Raitt MH, Del-Carpio Munoz F, Mulpuru SK, Nasser N, Peterson PN. Impact of physiologic pacing versus right ventricular pacing among patients with left ventricular ejection fraction greater than $\bar{3}\bar{5}\%$ : A systematic review for the 2018 ACC/AHA/HRS Guideline on the evaluation and management of patients with bradycardia and cardiac conduction delay: A report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines and the Heart Rhythm Society. Circulation 2019; 140: e483–e503. 173. Kaza N, Htun V, Miyazawa A, Simader F, Porter B, Howard JP, et al. Upgrading right ventricular pacemakers to biventricular pacing or conduction system pacing: A systematic review and meta-analysis. Europace 2023; 25: 1077–1086. 174. Krahn AD, Longtin Y, Philippon F, Birnie DH, Manlucu J, Angaran P, et al. Prevention of arrhythmia device infection trial: The PADIT Trial. J Am Coll Cardiol 2018; 72: 3098–3109. 175. Kolek MJ, Dresen WF, Wells QS, Ellis CR. Use of an antibacterial envelope is associated with reduced cardiac implantable electronic device infections in high-risk patients. Pacing Clin Electrophysiol 2013; 36: 354–361. 176. Arnold AD, Shun-Shin MJ, Keene D, Howard JP, Sohaib SMA, Wright IJ, et al. His resynchronization versus biventricular pacing in patients with heart failure and left bundle branch block. J Am Coll Cardiol 2018; 72: 3112–3122. 177. Moriña-Vázquez P, Moraleda-Salas MT, Manovel-Sánchez AJ, Fernández-Gómez JM, Arce-Léon Á, Venegas-Gamero J, et al. Early improvement of left ventricular ejection fraction by cardiac resynchronization through His bundle pacing in patients with heart failure. Europace 2020; 22: 125–132. 178. Kato H, Yanagisawa S, Sakurai T, Mizuno C, Ota R, Watanabe R, et al. Efficacy of His bundle pacing on LV relaxation and clinical improvement in HF and LBBB. JACC Clin Electrophysiol 2022; 8: 59–69. 179. Lustgarten DL, Crespo EM, Arkhipova-Jenkins I, Lobel R, Winget J, Koehler J, et al. His-bundle pacing versus biventricular pacing in cardiac resynchronization therapy patients: A crossover design comparison. Heart Rhythm 2015; 12: 1548–1557. 180. Upadhyay GA, Vijayaraman P, Nayak HM, Verma N, Dandamudi G, Sharma PS, et al.; His-SYNC Investigators. On-treatment comparison between corrective His bundle pacing and biventricular pacing for cardiac resynchronization: A secondary analysis of the His-SYNC Pilot Trial. Heart Rhythm 2019; 16: 1797–1807. 181. Huang W, Wu S, Vijayaraman P, Su L, Chen X, Cai B, et al. Cardiac resynchronization therapy in patients with nonischemic cardiomyopathy using left bundle branch pacing. JACC Clin Electrophysiol 2020; 6: 849–858. 182. Zhang W, Huang J, Qi Y, Wang F, Guo L, Shi X, et al. Cardiac resynchronization therapy by left bundle branch area pacing in patients with heart failure and left bundle branch block. Heart Rhythm 2019; 16: 1783–1790. 183. Vijayaraman P, Ponnusamy S, Cano Ó, Sharma PS, Naperkowski A, Subsposh FA, et al. Left bundle branch area pacing for cardiac resynchronization therapy: Results from the International LBBAP Collaborative Study Group. JACC Clin Electrophysiol 2021; 7: 135–147. 184. Chen X, Ye Y, Wang Z, Jin Q, Qiu Z, Wang J, et al. Cardiac resynchronization therapy via left bundle branch pacing vs. optimized biventricular pacing with adaptive algorithm in heart failure with left bundle branch block: A prospective, multi-centre, observational study. Europace 2022; 24: 807–816. 185. Wang Y, Zhu H, Hou X, Wang Z, Zou F, Qian Z, et al.; LBBP-RESYNC Investigators. Randomized trial of left bundle branch vs biventricular pacing for cardiac resynchronization therapy. J Am Coll Cardiol 2022; 80: 1205–1216. 186. Wu S, Su L, Vijayaraman P, Zheng R, Cai M, Xu L, et al. Left bundle branch pacing for cardiac resynchronization therapy: Nonrandomized on-treatment comparison with His bundle pacing and biventricular pacing. Can J Cardiol 2021; 37: 319–328. 187. Pujol-Lopez M, Jiménez-Arjona R, Garre P, Guasch E, Borràs R, Doltra A, et al. Conduction system pacing vs biventricular pacing in heart failure and wide QRS patients: LEVEL-AT Trial. JACC Clin Electrophysiol 2022; 8: 1431–1445. 188. Vijayaraman P, Sharma PS, Cano Ó, Ponnusamy SS, Herweg B, Zanon F, et al. Comparison of left bundle branch area pacing and biventricular pacing in candidates for resynchronization therapy. J Am Coll Cardiol 2023; 82: 228–241. 189. Vijayaraman P, Zalavadia D, Haseeb A, Dye C, Madan N, Skeete JR, et al. Clinical outcomes of conduction system pacing compared to biventricular pacing in patients requiring cardiac resynchronization therapy. Heart Rhythm 2022; 19: 1263–1271. 190. Ezzeddine FM, Pistiolis SM, Pujol-Lopez M, Lavelle M, Wan EY, Patton KK, et al. Outcomes of conduction system pacing for cardiac resynchronization therapy in patients with heart failure: A multicenter experience. Heart Rhythm 2023; 20: 863–871. 191. Parlavecchio A, Vetta G, Caminiti R, Coluccia G, Magnocavallo M, Ajello M, et al. Left bundle branch pacing versus biventricular pacing for cardiac resynchronization therapy: A systematic review and meta-analysis. Pacing Clin Electrophysiol 2023; 46: 432–439. 192. Diaz JC, Sauer WH, Duque M, Koplan BA, Braunstein ED, Marín JE, et al. Left bundle branch area pacing versus biventricular pacing as initial strategy for cardiac resynchronization. JACC Clin Electrophysiol 2023; 9: 1568–1581. 193. Tan ESJ, Soh R, Lee JY, Boey E, de Leon J, Chan SP, et al. Conduction system versus biventricular pacing in heart failure with non-left bundle branch block. J Cardiovasc Electrophysiol 2023; 34: 976–983. 194. Bristow MR, Saxon LA, Boehmer J, Krueger S, Kass DA, De Marco T, et al.; Comparison of Medical Therapy, Pacing, and Defibrillation in Heart Failure (COMPANION) Investigators. Cardiac-resynchronization therapy with or without an implantable defibrillator in advanced chronic heart failure. N Engl J Med 2004; 350: 2140–2150. 195. Goldenberg I, Kutyifa V, Klein HU, Cannom DS, Brown MW, Dan A, et al. Survival with cardiac-resynchronization therapy in mild heart failure. N Engl J Med 2014; 370: 1694–1701. 196. Vijayaraman P, Herweg B, Verma A, Sharma PS, Batul SA, Ponnusamy SS, et al. Rescue left bundle branch area pacing in coronary venous lead failure or nonresponse to biventricular pacing: Results from International LBBAP Collaborative Study Group. Heart Rhythm 2022; 19: 1272–1280. 197. Vijayaraman P, Herweg B, Ellenbogen KA, Gajek J. Hisoptimized cardiac resynchronization therapy to maximize electrical resynchronization: A feasibility study. Circ Arrhythm Electrophysiol 2019; 12: e006934. 198. Jastrzębski M, Moskal P, Huybrechts W, Curila K, Sreekumar P, Rademakers LM, et al. Left bundle branch-optimized cardiac resynchronization therapy (LOT-CRT): Results from an international LBBAP collaborative study group. Heart Rhythm 2022; 19: 13–21. 199. Doshi RN, Daoud EG, Fellows C, Turk K, Duran A, Hamdan MH, et al.; PAVE Study Group. Left ventricular-based cardiac stimulation post AV nodal ablation evaluation (the PAVE study). J Cardiovasc Electrophysiol 2005; 16: 1160–1165. 200. Orlov MV, Gardin JM, Slawsky M, Bess RL, Cohen G, Bailey W, et al. Biventricular pacing improves cardiac function and prevents further left atrial remodeling in patients with symptomatic atrial fibrillation after atrioventricular node ablation. Am Heart J 2010; 159: 264–270. 201. Huang W, Wang S, Su L, Fu G, Su Y, Chen K, et al. His-bundle pacing vs biventricular pacing following atrioventricular nodal ablation in patients with atrial fibrillation and reduced ejection fraction: A multicenter, randomized, crossover study-The ALTERNATIVE-AF trial. Heart Rhythm 2022; 19: 1948–1955. 202. Occhetta E, Bortnik M, Magnani A, Francalacci G, Piccinino C, Plebani L, et al. Prevention of ventricular desynchronization by permanent para-Hisian pacing after atrioventricular node ablation in chronic atrial fibrillation: A crossover, blinded, randomized study versus apical right ventricular pacing. J Am Coll Cardiol 2006; 47: 1938–1945. 203. Pillai A, Kolominsky J, Koneru JN, Kron J, Shepard RK, Kalahasty G, et al. Atrioventricular junction ablation in patients with conduction system pacing leads: A comparison of Hisbundle vs left bundle branch area pacing leads. Heart Rhythm 2022; 19: 1116–1123. 204. Cazeau S, Ritter P, Bakdach S, Lazarus A, Limousin M, Henao L, et al. Four chamber pacing in dilated cardiomyopathy. Pacing Clin Electrophysiol 1994; 17: 1974–1979. 205. Bakker PF, Meijburg HW, de Vries JW, Mower MM, Thomas AC, Hull ML, et al. Biventricular pacing in end-stage heart failure improves functional capacity and left ventricular function. J Interv Card Electrophysiol 2000; 4: 395–404. 206. Cazeau S, Leclercq C, Lavergne T, Walker S, Varma C, Linde C, et al.; Multisite Stimulation in Cardiomyopathies (MUSTIC) Study Investigators. Effects of multisite biventricular pacing in patients with heart failure and intraventricular conduction delay. N Engl J Med 2001; 344: 873–880. 207. Abraham WT, Fisher WG, Smith AL, Delurgio DB, Leon AR, Loh E, et al.; MIRACLE Study Group. Cardiac resynchronization in chronic heart failure. N Engl J Med 2002; 346: 1845–1853. 208. Leclercq C, Walker S, Linde C, Clementy J, Marshall AJ, Ritter P, et al. Comparative effects of permanent biventricular and right-univentricular pacing in heart failure patients with chronic atrial fibrillation. Eur Heart J 2002; 23: 1780–1787. 209. Auricchio A, Stellbrink C, Sack S, Block M, Vogt J, Bakker P, et al.; Pacing Therapies in Congestive Heart Failure (PATH-CHF) Study Group. Long-term clinical effect of hemodynamically optimized cardiac resynchronization therapy in patients with heart failure and ventricular conduction delay. J Am Coll Cardiol 2002; 39: 2026–2033. 210. Daubert JC, Saxon L, Adamson PB, Auricchio A, Berger RD, Beshai JF, et al.; European Heart Rhythm Association (EHRA). 2012 EHRA/HRS expert consensus statement on cardiac resynchronization therapy in heart failure: Implant and follow-up recommendations and management. Europace 2012; 14: 1236–1286. 211. Sipahi I, Chou JC, Hyden M, Rowland DY, Simon DI, Fang JC. Effect of QRS morphology on clinical event reduction with cardiac resynchronization therapy: Meta-analysis of randomized controlled trials. Am Heart J 2012; 163: 260–267. 212. Varma N, Lappe J, He J, Niebauer M, Manne M, Tchou P. Sex-specific response to cardiac resynchronization therapy: Effect of left ventricular size and QRS duration in left bundle branch block. JACC Clin Electrophysiol 2017; 3: 844–853. 213. Varma N, Sogaard P, Bax JJ, Abraham WT, Borer JS, Dickstein K, et al. Interaction of left ventricular size and sex on outcome of cardiac resynchronization therapy among patients with a narrow QRS duration in the EchoCRT Trial. J Am Heart Assoc 2018; 7: e009592. 214. Linde C, Cleland JGF, Gold MR, Claude Daubert J, Tang ASL, Young JB, et al. The interaction of sex, height, and QRS duration on the effects of cardiac resynchronization therapy on morbidity and mortality: An individual-patient data meta-analysis. Eur J Heart Fail 2018; 20: 780–791. 215. Zweerink A, Friedman DJ, Klem I, van de Ven PM, Vink C, Biesbroek PS, et al. Size matters: Normalization of QRS duration to left ventricular dimension improves prediction of long-term cardiac resynchronization therapy outcome. Circ Arrhythm Electrophysiol 2018; 11: e006767. 216. Varma N, Wang JA, Jaswal A, Sethi KK, Kondo Y, Joung B, et al. CRT efficacy in “Mid-Range” QRS duration among Asians contrasted to non-Asians, and influence of height. JACC Clin Electrophysiol 2022; 8: 211–221. 217. Heidenreich PA, Bozkurt B, Aguilar D, Allen LA, Byun JJ, Colvin MM, et al. 2022 AHA/ACC/HFSA Guideline for the management of heart failure: A report of the American College of Cardiology/American Heart Association Joint Committee on Clinical Practice Guidelines. Circulation 2022; 145: e895–e1032. 218. Ezekowitz JA, O’Meara E, McDonald MA, Abrams H, Chan M, Ducharme A, et al. 2017 Comprehensive update of the Canadian cardiovascular society guidelines for the management of heart failure. Can J Cardiol 2017; 33: 1342–1433. 219. Yu CM, Lin H, Zhang Q, Sanderson JE. High prevalence of left ventricular systolic and diastolic asynchrony in patients with congestive heart failure and normal QRS duration. Heart 2003; 89: 54–60. 220. Yu CM, Chan YS, Zhang Q, Yip GW, Chan CK, Kum LC, et al. Benefits of cardiac resynchronization therapy for heart failure patients with narrow QRS complexes and coexisting systolic asynchrony by echocardiography. J Am Coll Cardiol 2006; 48: 2251–2257. 221. Chung ES, Leon AR, Tavazzi L, Sun JP, Nihoyannopoulos P, Merlino J, et al. Results of the Predictors of Response to CRT (PROSPECT) trial. Circulation 2008; 117: 2608–2616. 222. Ruschitzka F, Abraham WT, Singh JP, Bax JJ, Borer JS, Brugada J, et al.; EchoCRT Study Group. Cardiac-resynchronization therapy in heart failure with a narrow QRS complex. N Engl J Med 2013; 369: 1395–1405. 223. De Pooter J, Kamoen V, El Haddad M, Stroobandt R, De Buyzere M, Jordaens L, et al. Gender differences in electro-mechanical characteristics of left bundle branch block: Potential implications for selection and response of cardiac resynchronization therapy. Int J Cardiol 2018; 257: 84–91. 224. Oka T, Inoue K, Tanaka K, Hirao Y, Isshiki T, Kimura T, et al. Effect of QRS morphology and duration on clinical outcomes after cardiac resynchronization therapy: Analysis of Japanese multicenter registry. Circ J 2018; 82: 1813–1821. 225. Nakai T, Mano H, Ikeya Y, Aizawa Y, Kurokawa S, Ohkubo K, et al. Narrower QRS may be enough to respond to cardiac resynchronization therapy in lightweight patients. Heart Vessels 2020; 35: 835–841. 226. Zusterzeel R, Selzman KA, Sanders WE, Caños DA, O’Callaghan KM, Carpenter JL, et al. Cardiac resynchronization therapy in women: US Food and Drug Administration metaanalysis of patient-level data. JAMA Intern Med 2014; 174: 1340–1348. 227. Cheng YJ, Zhang J, Li WJ, Lin XX, Zeng WT, Tang K, et al. More favorable response to cardiac resynchronization therapy in women than in men. Circ Arrhythm Electrophysiol 2014; 7: 807–815. 228. Salden OAE, van Stipdonk AMW, den Ruijter HM, Cramer MJ, Kloosterman M, Rienstra M, et al. Heart size corrected electrical dyssynchrony and its impact on sex-specific response to cardiac resynchronization therapy. Circ Arrhythm Electrophysiol 2021; 14: e008452. 229. Steffel J, Varma N, Robertson M, Singh JP, Bax JJ, Borer JS, et al. Effect of gender on outcomes after cardiac resynchronization therapy in patients with a narrow QRS complex: A subgroup analysis of the EchoCRT Trial. Circ Arrhythm Electrophysiol 2016; 9: e003924. 230. Varma N, Manne M, Nguyen D, He J, Niebauer M, Tchou P. Probability and magnitude of response to cardiac resynchronization therapy according to QRS duration and gender in nonischemic cardiomyopathy and LBBB. Heart Rhythm 2014; 11: 1139–1147. 231. Varma N, Mittal S, Prillinger JB, Snell J, Dalal N, Piccini JP. Survival in women versus men following implantation of pacemakers, defibrillators, and cardiac resynchronization therapy devices in a large, nationwide cohort. J Am Heart Assoc 2017; 6: e005031. 232. Poole JE, Singh JP, Birgersdotter-Green U. QRS duration or QRS morphology: What really matters in cardiac resynchronization Therapy? J Am Coll Cardiol 2016; 67: 1104–1117. 233. Stewart RA, Young AA, Anderson C, Teo KK, Jennings G, Cowan BR. Relationship between QRS duration and left ventricular mass and volume in patients at high cardiovascular risk. Heart 2011; 97: 1766–1770. 234. Rickard J, Bassiouny M, Cronin EM, Martin DO, Varma N, Niebauer MJ, et al. Predictors of response to cardiac resynchronization therapy in patients with a non-left bundle branch block morphology. Am J Cardiol 2011; 108: 1576–1580. 235. Verma A, Jiang CY, Betts TR, Chen J, Deisenhofer I, Mantovan R, et al.; STAR AF II Investigators. Approaches to catheter ablation for persistent atrial fibrillation. N Engl J Med 2015; 372: 1812–1822. 236. Vogler J, Willems S, Sultan A, Schreiber D, Lüker J, Servatius H, et al. Pulmonary vein isolation versus defragmentation: The CHASE-AF Clinical Trial. J Am Coll Cardiol 2015; 66: 2743– 2752. 237. Inoue K, Hikoso S, Masuda M, Furukawa Y, Hirata A, Egami Y, et al.; OCVC Arrhythmia Investigators. Pulmonary vein isolation alone vs. more extensive ablation with defragmentation and linear ablation of persistent atrial fibrillation: The EARNEST-PVI trial. Europace 2021; 23: 565–574. 238. De Pooter J, Strisciuglio T, El Haddad M, Wolf M, Phlips T, Vandekerckhove Y, et al. Pulmonary vein reconnection no longer occurs in the majority of patients after a single pulmonary vein isolation procedure. JACC Clin Electrophysiol 2019; 5: 295–305. 239. Sato T, Sotomi Y, Hikoso S, Nakatani D, Mizuno H, Okada K, et al.; Osaka Cardio Vascular Conference (OCVC)-Arrhythmia Investigators. DR-FLASH score is useful for identifying patients with persistent atrial fibrillation who require extensive catheter ablation procedures. J Am Heart Assoc 2022; 11: e024916. 240. Kistler PM, Chieng D, Sugumar H, Ling LH, Segan L, Azzopardi S, et al. Effect of catheter ablation using pulmonary vein isolation with vs without posterior left atrial wall isolation on atrial arrhythmia recurrence in patients with persistent atrial fibrillation: The CAPLA Randomized Clinical Trial. JAMA 2023; 329: 127–135. 241. Kim D, Yu HT, Kim TH, Uhm JS, Joung B, Lee MH, et al. Electrical posterior box isolation in repeat ablation for atrial fibrillation: A prospective randomized clinical study. JACC Clin Electrophysiol 2022; 8: 582–592. 242. Yamaji H, Higashiya S, Murakami T, Hina K, Kawamura H, Murakami M, et al. Efficacy of an adjunctive electrophysiological test-guided left atrial posterior wall isolation in persistent atrial fibrillation without a left atrial low-voltage area. Circ Arrhythm Electrophysiol 2020; 13: e008191. 243. Ahn J, Shin DG, Han SJ, Lim HE. Does isolation of the left atrial posterior wall using cryoballoon ablation improve clinical outcomes in patients with persistent atrial fibrillation?: A prospective randomized controlled trial. Europace 2022; 24: 1093–1101. 244. Aryana A, Allen SL, Pujara DK, Bowers MR, O’Neill PG, Yamauchi Y, et al. Concomitant pulmonary vein and posterior wall isolation using cryoballoon with adjunct radiofrequency in persistent atrial fibrillation. JACC Clin Electrophysiol 2021; 7: 187–196. 245. Jiang X, Liao J, Ling Z, Meyer C, Sommer P, Futyma P, et al. Adjunctive left atrial posterior wall isolation in treating atrial fibrillation: Insight from a large secondary analysis. JACC Clin Electrophysiol 2022; 8: 605–618. 246. Thiyagarajah A, Kadhim K, Lau DH, Emami M, Linz D, Khokhar K, et al. Feasibility, safety, and efficacy of posterior wall isolation during atrial fibrillation ablation: A systematic review and meta-analysis. Circ Arrhythm Electrophysiol 2019; 12: e007005. 247. Rolf S, Kircher S, Arya A, Eitel C, Sommer P, Richter S, et al. Tailored atrial substrate modification based on low-voltage areas in catheter ablation of atrial fibrillation. Circ Arrhythm Electrophysiol 2014; 7: 825–833. 248. Kircher S, Arya A, Altmann D, Rolf S, Bollmann A, Sommer P, et al. Individually tailored vs. standardized substrate modification during radiofrequency catheter ablation for atrial fibrillation: A randomized study. Europace 2018; 20: 1766–1775. 249. Yang G, Zheng L, Jiang C, Fan J, Liu X, Zhan X, et al.; STABLE-SR-II Investigators. Circumferential pulmonary vein isolation plus low-voltage area modification in persistent atrial fibrillation: The STABLE-SR-II Trial. JACC Clin Electrophysiol 2022; 8: 882–891. 250. Masuda M, Asai M, Iida O, Okamoto S, Ishihara T, Nanto K, et al. Additional low-voltage-area ablation in patients with paroxysmal atrial fibrillation: Results of the randomized controlled VOLCANO Trial. J Am Heart Assoc 2020; 9: e015927. 251. Huo Y, Gaspar T, Schönbauer R, Wójcik M, Fiedler L, Roithinger FX, et al. Low-voltage myocardium-guided ablation trial of persistent atrial fibrillation. NEJM Evid 2022; 1: EVIDoa2200141. 252. Chen H, Li C, Han B, Xiao F, Yi F, Wei Y, et al.; STABLE-SR-III Investigators. Circumferential pulmonary vein isolation with vs without additional low-voltage-area ablation in older patients with paroxysmal atrial fibrillation: A randomized clinical trial. JAMA Cardiol 2023; 8: 765–772. 253. Junarta J, Siddiqui MU, Riley JM, Dikdan SJ, Patel A, Frisch DR. Low-voltage area substrate modification for atrial fibrillation ablation: A systematic review and meta-analysis of clinical trials. Europace 2022; 24: 1585–1598. 254. Yamaguchi T, Otsubo T, Takahashi Y, Nakashima K, Fukui A, Hirota K, et al. Atrial structural remodeling in patients with atrial fibrillation is a diffuse fibrotic process: Evidence from high-density voltage mapping and atrial biopsy. J Am Heart Assoc 2022; 11: e024521. 255. Hwang C, Chen PS. Ligament of Marshall: Why it is important for atrial fibrillation ablation. Heart Rhythm 2009; 6 Suppl: S35–S40. 256. Valderrábano M, Chen HR, Sidhu J, Rao L, Ling Y, Khoury DS. Retrograde ethanol infusion in the vein of Marshall: Regional left atrial ablation, vagal denervation and feasibility in humans. Circ Arrhythm Electrophysiol 2009; 2: 50–56. 257. Valderrábano M, Peterson LE, Swarup V, Schurmann PA, Makkar A, Doshi RN, et al. Effect of catheter ablation with vein of Marshall ethanol infusion vs catheter ablation alone on persistent atrial fibrillation: The VENUS Randomized Clinical Trial. JAMA 2020; 324: 1620–1628. 258. Mhanna M, Beran A, Al-Abdouh A, Sajdeya O, Altujjar M, Alom M, et al. Adjunctive vein of Marshall ethanol infusion during atrial fibrillation ablation: A Systematic review and meta-analysis. J Atr Fibrillation 2021; 14: 20200492. 259. Hirokami J, Hiroshima K, Yamaji K, Korai K, Nagashima M, Fukunaga M, et al. Relationship between fractionated signal areas in the atrial muscle during sinus rhythm and atrial pacing and non-pulmonary vein foci: Novel mapping strategy. Circ Arrhythm Electrophysiol 2020; 13: e008667. 260. Chen J, Arentz T, Cochet H, Müller-Edenborn B, Kim S, Moreno-Weidmann Z, et al. Extent and spatial distribution of left atrial arrhythmogenic sites, late gadolinium enhancement at magnetic resonance imaging, and low-voltage areas in patients with persistent atrial fibrillation: Comparison of imaging vs. electrical parameters of fibrosis and arrhythmogenesis. Europace 2019; 21: 1484–1493. 261. Di Biase L, Burkhardt JD, Mohanty P, Mohanty S, Sanchez JE, Trivedi C, et al. Left atrial appendage isolation in patients with longstanding persistent AF undergoing catheter ablation: BELIEF Trial. J Am Coll Cardiol 2016; 68: 1929–1940. 262. Zedda A, Huo Y, Kronborg M, Ulbrich S, Mayer J, Pu L, et al. Left atrial isolation and appendage occlusion in patients with atrial fibrillation at end-stage left atrial fibrotic disease. Circ Arrhythm Electrophysiol 2021; 14: e010011. 263. Wazni OM, Dandamudi G, Sood N, Hoyt R, Tyler J, Durrani S, et al.; STOP AF First Trial Investigators. Cryoballoon ablation as initial therapy for atrial fibrillation. N Engl J Med 2021; 384: 316–324. 264. Andrade JG, Wells GA, Deyell MW, Bennett M, Essebag V, Champagne J, et al.; EARLY-AF Investigators. Cryoablation or drug therapy for initial treatment of atrial fibrillation. N Engl J Med 2021; 384: 305–315. 265. Kuniss M, Pavlovic N, Velagic V, Hermida JS, Healey S, Arena G, et al.; Cryo-FIRST Investigators. Cryoballoon ablation vs. antiarrhythmic drugs: First-line therapy for patients with paroxysmal atrial fibrillation. Europace 2021; 23: 1033–1041. 266. Andrade JG, Wazni OM, Kuniss M, Hawkins NM, Deyell MW, Chierchia GB, et al. Cryoballoon ablation as initial treatment for atrial fibrillation: JACC state-of-the-art review. J Am Coll Cardiol 2021; 78: 914–930. 267. Kirchhof P, Camm AJ, Goette A, Brandes A, Eckardt L, Elvan A, et al.; EAST-AFNET 4 Trial Investigators. Early rhythm-control therapy in patients with atrial fibrillation. N Engl J Med 2020; 383: 1305–1316. 268. Willems S, Borof K, Brandes A, Breithardt G, Camm AJ, Crijns HJGM, et al. Systematic, early rhythm control strategy for atrial fibrillation in patients with or without symptoms: The EAST-AFNET 4 trial. Eur Heart J 2022; 43: 1219–1230. 269. Rillig A, Borof K, Breithardt G, Camm AJ, Crijns HJGM, Goette A, et al. Early rhythm control in patients with atrial fibrillation and high comorbidity burden. Circulation 2022; 146: 836–847. 270. Kim JY, Park HS, Park HW, Choi EK, Park JK, Kim JB, et al. Clinical outcomes of rhythm control strategies for asymptomatic atrial fibrillation according to the quality-of-life score: The CODE-AF (Comparison Study of Drugs for Symptom Control and Complication Prevention of Atrial Fibrillation) Registry. J Am Heart Assoc 2022; 11: e025956. 271. Kuck KH, Lebedev DS, Mikhaylov EN, Romanov A, Gellér L, Kalējs O, et al. Catheter ablation or medical therapy to delay progression of atrial fibrillation: The randomized controlled atrial fibrillation progression trial (ATTEST). Europace 2021; 23: 362–369. 272. Andrade JG, Deyell MW, Macle L, Wells GA, Bennett M, Essebag V, et al.; EARLY-AF Investigators. Progression of atrial fibrillation after cryoablation or drug therapy. N Engl J Med 2023; 388: 105–116. 273. Packer DL, Mark DB, Robb RA, Monahan KH, Bahnson TD, Poole JE, et al.; CABANA Investigators. Effect of catheter ablation vs antiarrhythmic drug therapy on mortality, stroke, bleeding, and cardiac arrest among patients with atrial fibrillation: The CABANA Randomized Clinical Trial. JAMA 2019; 321: 1261–1274. 274. Simader FA, Howard JP, Ahmad Y, Saleh K, Naraen A, Samways JW, et al. Catheter ablation improves cardiovascular outcomes in patients with atrial fibrillation and heart failure: A meta-analysis of randomized controlled trials. Europace 2023; 25: 341–350. 275. Şaylık F, Çınar T, Akbulut T, Hayıroğlu Mİ. Comparison of catheter ablation and medical therapy for atrial fibrillation in heart failure patients: A meta-analysis of randomized controlled trials. Heart Lung 2023; 57: 69–74. 276. Parkash R, Wells GA, Rouleau J, Talajic M, Essebag V, Skanes A, et al. Randomized ablation-based rhythm-control versus rate-control trial in patients with heart failure and atrial fibrillation: Results from the RAFT-AF trial. Circulation 2022; 145: 1693–1704. 277. Kuck KH, Merkely B, Zahn R, Arentz T, Seidl K, Schlüter M, et al. Catheter ablation versus best medical therapy in patients with persistent atrial fibrillation and congestive heart failure: The Randomized AMICA Trial. Circ Arrhythm Electrophysiol 2019; 12: e007731. 278. Packer DL, Piccini JP, Monahan KH, Al-Khalidi HR, Silverstein AP, Noseworthy PA, et al.; CABANA Investigators. Ablation versus drug therapy for atrial fibrillation in heart failure: Results from the CABANA Trial. Circulation 2021; 143: 1377–1390. 279. Marrouche NF, Brachmann J, Andresen D, Siebels J, Boersma L, Jordaens L, et al.; CASTLE-AF Investigators. Catheter ablation for atrial fibrillation with heart failure. N Engl J Med 2018; 378: 417–427. 280. Prabhu S, Taylor AJ, Costello BT, Kaye DM, McLellan AJA, Voskoboinik A, et al. Catheter ablation versus medical rate control in atrial fibrillation and systolic dysfunction: The CAMERA-MRI Study. J Am Coll Cardiol 2017; 70: 1949–1961. 281. Di Biase L, Mohanty P, Mohanty S, Santangeli P, Trivedi C, Lakkireddy D, et al. Ablation versus amiodarone for treatment of persistent atrial fibrillation in patients with congestive heart failure and an implanted device: Results from the AATAC Multicenter Randomized Trial. Circulation 2016; 133: 1637– 1644. 282. Hunter RJ, Berriman TJ, Diab I, Kamdar R, Richmond L, Baker V, et al. A randomized controlled trial of catheter ablation versus medical treatment of atrial fibrillation in heart failure (the CAMTAF trial). Circ Arrhythm Electrophysiol 2014; 7: 31–38. 283. Jones DG, Haldar SK, Hussain W, Sharma R, Francis DP, Rahman-Haley SL, et al. A randomized trial to assess catheter ablation versus rate control in the management of persistent atrial fibrillation in heart failure. J Am Coll Cardiol 2013; 61: 1894–1903. 284. Zakeri R, Ahluwalia N, Tindale A, Omar F, Packer M, Khan H, et al.; ARC-HF and CAMTAF Investigators. Long-term outcomes following catheter ablation versus medical therapy in patients with persistent atrial fibrillation and heart failure with reduced ejection fraction. Eur J Heart Fail 2023; 25: 77–86. 285. Sugumar H, Prabhu S, Costello B, Chieng D, Azzopardi S, Voskoboinik A, et al. Catheter ablation versus medication in atrial fibrillation and systolic dysfunction: Late outcomes of CAMERA-MRI Study. JACC Clin Electrophysiol 2020; 6: 1721–1731. 286. Prabhu S, Costello BT, Taylor AJ, Gutman SJ, Voskoboinik A, McLellan AJA, et al. Regression of diffuse ventricular fibrosis following restoration of sinus rhythm with catheter ablation in patients with atrial fibrillation and systolic dysfunction: A substudy of the CAMERA MRI Trial. JACC Clin Electrophysiol 2018; 4: 999–1007. 287. Martin CA, Lambiase PD. Pathophysiology, diagnosis and treatment of tachycardiomyopathy. Heart 2017; 103: 1543–1552. 288. Raymond-Paquin A, Nattel S, Wakili R, Tadros R. Mechanisms and clinical significance of arrhythmia-induced cardiomyopathy. Can J Cardiol 2018; 34: 1449–1460. 289. Brembilla-Perrot B, Ferreira JP, Manenti V, Sellal JM, Olivier A, Villemin T, et al. Predictors and prognostic significance of tachycardiomyopathy: Insights from a cohort of 1269 patients undergoing atrial flutter ablation. Eur J Heart Fail 2016; 18: 394–401. 290. Sohns C, Fox H, Marrouche NF, Crijns HJGM, CostardJaeckle A, Bergau L, et al.; CASTLE HTx Investigators. Catheter ablation in end-stage heart failure with atrial fibrillation. N Engl J Med 2023; 389: 1380–1389. 291. Johner N, Namdar M, Shah DC. Safety, efficacy and prognostic benefit of atrial fibrillation ablation in heart failure with preserved ejection fraction. Arrhythm Electrophysiol Rev 2022; 11: e18. 292. Aldaas OM, Lupercio F, Darden D, Mylavarapu PS, Malladi CL, Han FT, et al. Meta-analysis of the usefulness of catheter ablation of atrial fibrillation in patients with heart failure with preserved ejection fraction. Am J Cardiol 2021; 142: 66–73. 293. Gu G, Wu J, Gao X, Liu M, Jin C, Xu Y. Catheter ablation of atrial fibrillation in patients with heart failure and preserved ejection fraction: A meta-analysis. Clin Cardiol 2022; 45: 786–793. 294. Chieng D, Sugumar H, Segan L, Tan C, Vizi D, Nanayakkara S, et al. Atrial fibrillation ablation for heart failure with preserved ejection fraction: A Randomized Controlled Trial. JACC Heart Fail 2023; 11: 646–658. 295. Hosseini SM, Rozen G, Saleh A, Vaid J, Biton Y, Moazzami K, et al. Catheter ablation for cardiac arrhythmias: Utilization and in-hospital complications, 2000 to 2013. JACC Clin Electrophysiol 2017; 3: 1240–1248. 296. Yokoyama Y, Miyamoto K, Nakai M, Sumita Y, Ueda N, Nakajima K, et al. Complications associated with catheter ablation in patients with atrial fibrillation: A report from the JROAD-DPC Study. J Am Heart Assoc 2021; 10: e019701. 297. Japanese Heart Rhythm Society. Summary report on the results of all eight surveys from the catheter ablation registry for atrial fibrillation (J-CARAF). [in Japanese] Available at: https://new. jhrs.or.jp/pdf/case-registy/j-caraf202002_01.pdf (accessed August 2, 2024) 298. Lee WC, Wu PJ, Chen HC, Fang HY, Liu PY, Chen MC. Efficacy and safety of ablation for symptomatic atrial fibrillation in elderly patients: A meta-analysis. Front Cardiovasc Med 2021; 8: 734204. 299. Li F, Zhang L, Wu LD, Zhang ZY, Liu HH, Zhang ZY, et al. Do elderly patients with atrial fibrillation have comparable ablation outcomes compared to younger ones?: Evidence from Pooled Clinical Studies. J Clin Med 2022; 11: 4468. 300. Prasitlumkum N, Tokavanich N, Trongtorsak A, Cheungpasitporn W, Kewcharoen J, Chokesuwattanaskul R, et al. Catheter ablation for atrial fibrillation in the elderly ${>}75$ years old: Systematic review and meta-analysis. J Cardiovasc Electrophysiol 2022; 33: 1435–1449. 301. Inoue K, Murakawa Y, Nogami A, Shoda M, Naito S, Kumagai K, et al. Current status of catheter ablation for atrial fibrillation: Updated summary of the Japanese Catheter Ablation Registry of Atrial Fibrillation (J-CARAF). Circ J 2014; 78: 1112–1120. 302. Raine D, Langley P, Shepherd E, Lord S, Murray S, Murray A, et al. Effect of catheter ablation on quality of life in patients with atrial fibrillation and its correlation with arrhythmia outcome. Open Heart 2015; 2: e000302. 303. Mark DB, Anstrom KJ, Sheng S, Piccini JP, Baloch KN, Monahan KH, et al.; CABANA Investigators. Effect of catheter ablation vs medical therapy on quality of life among patients with atrial fibrillation: The CABANA Randomized Clinical Trial. JAMA 2019; 321: 1275–1285. 304. Bahnson TD, Giczewska A, Mark DB, Russo AM, Monahan KH, Al-Khalidi HR, et al.; CABANA Investigators. Association between age and outcomes of catheter ablation versus medical therapy for atrial fibrillation: Results from the CABANA Trial. Circulation 2022; 145: 796–804. 305. Raeisi-Giglou P, Wazni OM, Saliba WI, Barakat A, Tarakji KG, Rickard J, et al. Outcomes and management of patients with severe pulmonary vein stenosis from prior atrial fibrillation ablation. Circ Arrhythm Electrophysiol 2018; 11: e006001. 306. Cappato R, Calkins H, Chen SA, Davies W, Iesaka Y, Kalman J, et al. Updated worldwide survey on the methods, efficacy, and safety of catheter ablation for human atrial fibrillation. Circ Arrhythm Electrophysiol 2010; 3: 32–38. 307. Packer DL, Keelan P, Munger TM, Breen JF, Asirvatham S, Peterson LA, et al. Clinical presentation, investigation, and management of pulmonary vein stenosis complicating ablation for atrial fibrillation. Circulation 2005; 111: 546–554. 308. Holmes DR Jr, Monahan KH, Packer D. Pulmonary vein stenosis complicating ablation for atrial fibrillation: Clinical spectrum and interventional considerations. JACC Cardiovasc Interv 2009; 2: 267–276. 309. Ogawa T, Yamashita S, Oseto H, Yokoyama M, Itakura R, Kang R, et al. Pulmonary vein angioplasty for pulmonary vein stenosis after ablation therapy for atrial fibrillation: A report of 7 cases. Circ J 2022; 86: 1229–1236. 310. Almakadma AH, Sarma D, Hassett L, Miranda W, Alkhouli M, Reeder GS, et al. Pulmonary vein stenosis-balloon angioplasty versus stenting: A systematic review and meta-analysis. JACC Clin Electrophysiol 2022; 8: 1323–1333. 311. Prieto LR, Schoenhagen P, Arruda MJ, Natale A, Worley SE. Comparison of stent versus balloon angioplasty for pulmonary vein stenosis complicating pulmonary vein isolation. J Cardiovasc Electrophysiol 2008; 19: 673–678. 312. Li YJ, Pan X, Wang C, He B. Stent implantation for severe pulmonary vein stenosis or occlusion secondary to atrial fibrillation ablation. Int J Cardiol 2020; 301: 85–89. 313. Fender EA, Widmer RJ, Hodge DO, Cooper GM, Monahan KH, Peterson LA, et al. Severe pulmonary vein stenosis resulting from ablation for atrial fibrillation: Presentation, management, and clinical outcomes. Circulation 2016; 134: 1812–1821. 314. Schoene K, Sommer P, Arya A, Kostelka M, Mohr FW, Misfeld M, et al. Complex cases of acquired pulmonary vein stenosis after radiofrequency ablation: Is surgical repair an option? Europace 2019; 21: 73–79. 315. Ramirez FD, Reddy VY, Viswanathan R, Hocini M, Jaïs P. Emerging technologies for pulmonary vein isolation. Circ Res 2020; 127: 170–183. 316. Reddy VY, Neuzil P, Koruth JS, Petru J, Funosako M, Cochet H, et al. Pulsed field ablation for pulmonary vein isolation in atrial fibrillation. J Am Coll Cardiol 2019; 74: 315–326. 317. Reddy VY, Dukkipati SR, Neuzil P, Anic A, Petru J, Funasako M, et al. Pulsed field ablation of paroxysmal atrial fibrillation: 1-Year outcomes of IMPULSE, PEFCAT, and PEFCAT II. JACC Clin Electrophysiol 2021; 7: 614–627. 318. Verma A, Haines DE, Boersma LV, Sood N, Natale A, Marchlinski FE, et al.; PULSED AF Investigators. Pulsed field ablation for the treatment of atrial fibrillation: PULSED AF Pivotal Trial. Circulation 2023; 147: 1422–1432. 319. Duytschaever M, De Potter T, Grimaldi M, Anic A, Vijgen J, Neuzil P, et al.; inspIRE Trial Investigators. Paroxysmal atrial fibrillation ablation using a novel variable-loop biphasic pulsed field ablation catheter integrated with a 3-dimensional mapping system: 1-Year outcomes of the Multicenter inspIRE Study. Circ Arrhythm Electrophysiol 2023; 16: e011780. 320. Reddy VY, Gerstenfeld EP, Natale A, Whang W, Cuoco FA, Patel C, et al.; ADVENT Investigators. Pulsed field or conventional thermal ablation for paroxysmal atrial fibrillation. N Engl J Med 2023; 389: 1660–1671. 321. Koruth JS, Kuroki K, Kawamura I, Brose R, Viswanathan R, Buck ED, et al. Pulsed field ablation versus radiofrequency ablation: Esophageal injury in a novel porcine model. Circ Arrhythm Electrophysiol 2020; 13: e008303. 322. van Driel VJ, Neven K, van Wessel H, Vink A, Doevendans PA, Wittkampf FH. Low vulnerability of the right phrenic nerve to electroporation ablation. Heart Rhythm 2015; 12: 1838–1844. 323. Pansera F, Bordignon S, Bologna F, Tohoku S, Chen S, Urbanek L, et al. Catheter ablation induced phrenic nerve palsy by pulsed field ablation-completely impossible?: A case series. Eur Heart J Case Rep 2022; 6: ytac361. 324. van Driel VJ, Neven KG, van Wessel H, du Pré BC, Vink A, Doevendans PA, et al. Pulmonary vein stenosis after catheter ablation: Electroporation versus radiofrequency. Circ Arrhythm Electrophysiol 2014; 7: 734–738. 325. Kuroki K, Whang W, Eggert C, Lam J, Leavitt J, Kawamura I, et al. Ostial dimensional changes after pulmonary vein isolation: Pulsed field ablation vs radiofrequency ablation. Heart Rhythm 2020; 17: 1528–1535. 326. Gunawardene MA, Schaeffer BN, Jularic M, Eickholt C, Maurer T, Akbulak RÖ, et al. Coronary spasm during pulsed field ablation of the mitral isthmus line. JACC Clin Electrophysiol 2021; 7: 1618–1620. 327. Reddy VY, Petru J, Funasako M, Kopriva K, Hala P, Chovanec M, et al. Coronary arterial spasm during pulsed field ablation to treat atrial fibrillation. Circulation 2022; 146: 1808–1819. 328. Reddy VY, Reynolds MR, Neuzil P, Richardson AW, Taborsky M, Jongnarangsin K, et al. Prophylactic catheter ablation for the prevention of defibrillator therapy. N Engl J Med 2007; 357: 2657–2665. 329. Kuck KH, Schaumann A, Eckardt L, Willems S, Ventura R, Delacrétaz E, et al.; VTACH study group. Catheter ablation of stable ventricular tachycardia before defibrillator implantation in patients with coronary heart disease (VTACH): A multicentre randomised controlled trial. Lancet 2010; 375: 31–40. 330. Kuck KH, Tilz RR, Deneke T, Hoffmann BA, Ventura R, Hansen PS, et al.; SMS Investigators. Impact of substrate modification by catheter ablation on implantable cardioverterdefibrillator interventions in patients with unstable ventricular arrhythmias and coronary artery disease: Results from the multicenter randomized controlled SMS (Substrate Modification Study). Circ Arrhythm Electrophysiol 2017; 10: e004422. 331. Sapp JL, Wells GA, Parkash R, Stevenson WG, Blier L, Sarrazin JF, et al. Ventricular tachycardia ablation versus escalation of antiarrhythmic drugs. N Engl J Med 2016; 375: 111–121. 332. Arenal Á, Ávila P, Jiménez-Candil J, Tercedor L, Calvo D, Arribas F, et al. Substrate ablation vs antiarrhythmic drug therapy for symptomatic ventricular tachycardia. J Am Coll Cardiol 2022; 79: 1441–1453. 333. Tung R, Xue Y, Chen M, Jiang C, Shatz DY, Besser SA, et al.; PAUSE-SCD Investigators. First-line catheter ablation of monomorphic ventricular tachycardia in cardiomyopathy concurrent with defibrillator implantation: The PAUSE-SCD Randomized Trial. Circulation 2022; 145: 1839–1849. 334. Della Bella P, Baratto F, Vergara P, Bertocchi P, Santamaria M, Notarstefano P, et al. Does timing of ventricular tachycardia ablation affect prognosis in patients with an implantable cardioverter defibrillator?: Results from the Multicenter Randomized PARTITA Trial. Circulation 2022; 145: 1829–1838. 335. Willems S, Tilz RR, Steven D, Kääb S, Wegscheider K, Gellér L, et al.; BERLIN VT Investigators. Preventive or deferred ablation of ventricular tachycardia in patients with ischemic cardiomyopathy and implantable defibrillator (BERLIN VT): A Multicenter Randomized Trial. Circulation 2020; 141: 1057–1067. 336. Latchamsetty R, Yokokawa M, Morady F, Kim HM, Mathew S, Tilz R, et al. Multicenter outcomes for catheter ablation of idiopathic premature ventricular complexes. JACC Clin Electrophysiol 2015; 1: 116–123. 337. Ling Z, Liu Z, Su L, Zipunnikov V, Wu J, Du H, et al. Radiofrequency ablation versus antiarrhythmic medication for treatment of ventricular premature beats from the right ventricular outflow tract: Prospective randomized study. Circ Arrhythm Electrophysiol 2014; 7: 237–243. 338. Nademanee K, Veerakul G, Chandanamattha P, Chaothawee L, Ariyachaipanich A, Jirasirirojanakorn K, et al. Prevention of ventricular fibrillation episodes in Brugada syndrome by catheter ablation over the anterior right ventricular outflow tract epicardium. Circulation 2011; 123: 1270–1279. 339. Talib AK, Takagi M, Shimane A, Nakano M, Hayashi T, Okajima K, et al. Efficacy of endocardial ablation of drug-resistant ventricular fibrillation in Brugada syndrome: Long-term outcome. Circ Arrhythm Electrophysiol 2018; 11: e005631. 340. Nademanee K, Haissaguerre M, Hocini M, Nogami A, Cheniti G, Duchateau J, et al. Mapping and ablation of ventricular fibrillation associated with early repolarization syndrome. Circulation 2019; 140: 1477–1490. 341. Nademanee K, Chung FP, Sacher F, Nogami A, Nakagawa H, Jiang C, et al. Long-term outcomes of Brugada substrate ablation: A report from BRAVO (Brugada Ablation of VF Substrate Ongoing Multicenter Registry). Circulation 2023; 147: 1568– 1578. 342. Kennedy HL, Whitlock JA, Sprague MK, Kennedy LJ, Buckingham TA, Goldberg RJ. Long-term follow-up of asymptomatic healthy subjects with frequent and complex ventricular ectopy. N Engl J Med 1985; 312: 193–197. 343. Yokokawa M, Kim HM, Good E, Chugh A, Pelosi F Jr, Alguire C, et al. Relation of symptoms and symptom duration to premature ventricular complex-induced cardiomyopathy. Heart Rhythm 2012; 9: 92–95. 344. Bogun F, Crawford T, Reich S, Koelling TM, Armstrong W, Good E, et al. Radiofrequency ablation of frequent, idiopathic premature ventricular complexes: Comparison with a control group without intervention. Heart Rhythm 2007; 4: 863–867. 345. Baman TS, Lange DC, Ilg KJ, Gupta SK, Liu TY, Alguire C, et al. Relationship between burden of premature ventricular complexes and left ventricular function. Heart Rhythm 2010; 7: 865–869. 346. Hsia BC, Greige N, Patel SK, Clark RM, Ferrick KJ, Fisher JD, et al. Determining the optimal duration for premature ventricular contraction monitoring. Heart Rhythm 2020; 17: 2119–2125. 347. Zang M, Zhang T, Mao J, Zhou S, He B. Beneficial effects of catheter ablation of frequent premature ventricular complexes on left ventricular function. Heart 2014; 100: 787–793. 348. Lee AKY, Andrade J, Hawkins NM, Alexander G, Bennett MT, Chakrabarti S, et al. Outcomes of untreated frequent premature ventricular complexes with normal left ventricular function. Heart 2019; 105: 1408–1413. 349. Niwano S, Wakisaka Y, Niwano H, Fukaya H, Kurokawa S, Kiryu M, et al. Prognostic significance of frequent premature ventricular contractions originating from the ventricular outflow tract in patients with normal left ventricular function. Heart 2009; 95: 1230–1237. 350. Gopinathannair R, Etheridge SP, Marchlinski FE, Spinale FG, Lakkireddy D, Olshansky B. Arrhythmia-induced cardiomyopathies: Mechanisms, recognition, and management. J Am Coll Cardiol 2015; 66: 1714–1728. 351. Di Biase L, Santangeli P, Burkhardt DJ, Bai R, Mohanty P, Carbucicchio C, et al. Endo-epicardial homogenization of the scar versus limited substrate ablation for the treatment of electrical storms in patients with ischemic cardiomyopathy. J Am Coll Cardiol 2012; 60: 132–141. 352. Jaïs P, Maury P, Khairy P, Sacher F, Nault I, Komatsu Y, et al. Elimination of local abnormal ventricular activities: A new end point for substrate modification in patients with scar-related ventricular tachycardia. Circulation 2012; 125: 2184–2196. 353. Anter E, Kleber AG, Rottmann M, Leshem E, Barkagan M, Tschabrunn CM, et al. Infarct-related ventricular tachycardia: Redefining the electrophysiological substrate of the isthmus during sinus rhythm. JACC Clin Electrophysiol 2018; 4: 1033– 1048. 354. Aziz Z, Shatz D, Raiman M, Upadhyay GA, Beaser AD, Besser SA, et al. Targeted ablation of ventricular tachycardia guided by wavefront discontinuities during sinus rhythm: A new functional substrate mapping strategy. Circulation 2019; 140: 1383–1397. 355. Hattori M, Komatsu Y, Naeemah QJ, Hanaki Y, Ichihara N, Ota C, et al. Rotational activation pattern during functional substrate mapping: Novel target for catheter ablation of scarrelated ventricular tachycardia. Circ Arrhythm Electrophysiol 2022; 15: e010308. 356. Jackson N, Gizurarson S, Viswanathan K, King B, Massé S, Kusha M, et al. Decrement evoked potential mapping: Basis of a mechanistic strategy for ventricular tachycardia ablation. Circ Arrhythm Electrophysiol 2015; 8: 1433–1442. 357. de Riva M, Naruse Y, Ebert M, Androulakis AFA, Tao Q, Watanabe M, et al. Targeting the hidden substrate unmasked by right ventricular extrastimulation improves ventricular tachycardia ablation outcome after myocardial infarction. JACC Clin Electrophysiol 2018; 4: 316–327. 358. Srinivasan NT, Garcia J, Schilling RJ, Ahsan S, Babu GG, Ang R, et al. Multicenter study of dynamic high-density functional substrate mapping improves identification of substrate targets for ischemic ventricular tachycardia ablation. JACC Clin Electrophysiol 2020; 6: 1783–1793. 359. Tung R, Raiman M, Liao H, Zhan X, Chung FP, Nagel R, et al. Simultaneous endocardial and epicardial delineation of 3D reentrant ventricular tachycardia. J Am Coll Cardiol 2020; 75: 884–897. 360. Valderrábano M, Fuentes Rojas SC, Lador A, Patel A, Schurmann PA, Tapias C, et al. Substrate ablation by multivein, multiballoon coronary venous ethanol for refractory ventricular tachycardia in structural heart disease. Circulation 2022; 146: 1644–1656. 361. Cuculich PS, Schill MR, Kashani R, Mutic S, Lang A, Cooper D, et al. Noninvasive cardiac radiation for ablation of ventricular tachycardia. N Engl J Med 2017; 377: 2325–2336. 362. Robinson CG, Samson PP, Moore KMS, Hugo GD, Knutson N, Mutic S, et al. Phase I/II trial of electrophysiology-guided noninvasive cardiac radioablation for ventricular tachycardia. Circulation 2019; 139: 313–321. 363. Haskova J, Jedlickova K, Cvek J, Knybel L, Neuwirth R, Kautzner J. Oesophagopericardial fistula as a late complication of stereotactic radiotherapy for recurrent ventricular tachycardia. Europace 2022; 24: 969. 364. Nguyen DT, Tzou WS, Sandhu A, Gianni C, Anter E, Tung R, et al. Prospective multicenter experience with cooled radiofrequency ablation using high impedance irrigant to target deep myocardial substrate refractory to standard ablation. JACC Clin Electrophysiol 2018; 4: 1176–1185. 365. Garg L, Daubert T, Lin A, Dhakal B, Santangeli P, Schaller R, et al. Utility of prolonged duration endocardial ablation for ventricular arrhythmias originating from the left ventricular summit. JACC Clin Electrophysiol 2022; 8: 465–476. 366. Suzuki S, Yamashita T, Okumura K, Atarashi H, Akao M, Ogawa H, et al. Incidence of ischemic stroke in Japanese patients with atrial fibrillation not receiving anticoagulation therapy: Pooled analysis of the Shinken Database, J-RHYTHM Registry, and Fushimi AF Registry. Circ J 2015; 79: 432–438. 367. Okumura K, Tomita H, Nakai M, Kodani E, Akao M, Suzuki S, et al.; J-RISK AF Research Group. Risk factors associated with ischemic stroke in Japanese patients with nonvalvular atrial fibrillation. JAMA Netw Open 2020; 3: e202881. 368. Okumura K, Tomita H, Nakai M, Kodani E, Akao M, Suzuki S, et al.; J-RISK AF Research Group. A novel risk stratification system for ischemic stroke in Japanese patients with non-valvular atrial fibrillation. Circ J 2021; 85: 1254–1262. 369. Yamauchi T, Okumura Y, Nagashima K, Watanabe R, Saito Y, Yokoyama K, et al. External validation of the HELT-E 2 S 2 score in Japanese patients with nonvalvular atrial fibrillation: A pooled analysis of the RAFFINE and SAKURA Registries. Circ J 2023; 87: 1777–1787. 370. Kodani E, Tomita H, Nakai M, Akao M, Suzuki S, Hayashi K, et al.; J-RISK AF Research Group. Impact of baseline blood pressure on adverse outcomes in Japanese patients with nonvalvular atrial fibrillation: The J-RISK AF. Eur Heart J Open 2022; 2: oeac081. 371. Kodani E, Atarashi H, Inoue H, Okumura K, Yamashita T, Otsuka T, et al.; J-RHYTHM Registry Investigators. Impact of blood pressure control on thromboembolism and major hemorrhage in patients with nonvalvular atrial fibrillation: A subanalysis of the J-RHYTHM Registry. J Am Heart Assoc 2016; 5: e004075. 372. Inoue H, Kodani E, Atarashi H, Okumura K, Yamashita T, Origasa H; J-RHYTHM Registry Investigators. Impact of body mass index on the prognosis of Japanese patients with non-valvular atrial fibrillation. Am J Cardiol 2016; 118: 215–221. 373. Hamatani Y, Ogawa H, Uozumi R, Iguchi M, Yamashita Y, Esato M, et al. Low body weight is associated with the incidence of stroke in atrial fibrillation patients: Insight from the Fushimi AF Registry. Circ J 2015; 79: 1009–1017. 374. Hohnloser SH, Pajitnev D, Pogue J, Healey JS, Pfeffer MA, Yusuf S, et al.; ACTIVE W Investigators. Incidence of stroke in paroxysmal versus sustained atrial fibrillation in patients taking oral anticoagulation or combined antiplatelet therapy: An ACTIVE W Substudy. J Am Coll Cardiol 2007; 50: 2156– 2161. 375. Yamashita T, Suzuki S, Inoue H, Akao M, Atarashi H, Ikeda T, et al. Two-year outcomes of more than 30 000 elderly patients with atrial fibrillation: Results from the All Nippon AF In the Elderly (ANAFIE) Registry. Eur Heart J Qual Care Clin Outcomes 2022; 8: 202–213. 376. Ogawa H, An Y, Ikeda S, Aono Y, Doi K, Ishii M, et al.; Fushimi AF Registry Investigators. Progression from paroxysmal to sustained atrial fibrillation is associated with increased adverse events. Stroke 2018; 49: 2301–2308. 377. Ashburner JM, Go AS, Chang Y, Fang MC, Fredman L, Applebaum KM, et al. Effect of diabetes and glycemic control on ischemic stroke risk in AF patients: ATRIA Study. J Am Coll Cardiol 2016; 67: 239–247. 378. Abdel-Qadir H, Gunn M, Lega IC, Pang A, Austin PC, Singh SM, et al. Association of diabetes duration and glycemic control with stroke rate in patients with atrial fibrillation and diabetes: A Population-Based Cohort Study. J Am Heart Assoc 2022; 11: e023643. 379. Terauchi Y, Inoue H, Yamashita T, Akao M, Atarashi H, Ikeda T, et al. Impact of glycated hemoglobin on 2-year clinical outcomes in elderly patients with atrial fibrillation: Sub-analysis of ANAFIE Registry, a large observational study. Cardiovasc Diabetol 2023; 22: 175. 380. Patti G, Lucerna M, Cavallari I, Ricottini E, Renda G, Pecen L, et al. Insulin-requiring versus noninsulin-requiring diabetes and thromboembolic risk in patients with atrial fibrillation: PREFER in AF. J Am Coll Cardiol 2017; 69: 409–419. 381. Gage BF, Waterman AD, Shannon W, Boechler M, Rich MW, Radford MJ. Validation of clinical classification schemes for predicting stroke: Results from the National Registry of Atrial Fibrillation. JAMA 2001; 285: 2864–2870. 382. Adelborg K, Szépligeti S, Sundbøll J, Horváth-Puhó E, Henderson VW, Ording A, et al. Risk of stroke in patients with heart failure: A population-based 30-year cohort study. Stroke 2017; 48: 1161–1168. 383. Witt BJ, Brown RD Jr, Jacobsen SJ, Weston SA, Ballman KV, Meverden RA, et al. Ischemic stroke after heart failure: A community-based study. Am Heart J 2006; 152: 102–109. 384. Alberts VP, Bos MJ, Koudstaal P, Hofman A, Witteman JC, Stricker B, et al. Heart failure and the risk of stroke: The Rotterdam Study. Eur J Epidemiol 2010; 25: 807–812. 385. Iguchi M, Tezuka Y, Ogawa H, Hamatani Y, Takagi D, An Y, et al. Incidence and risk factors of stroke or systemic embolism in patients with atrial fibrillation and heart failure: The Fushimi AF Registry. Circ J 2018; 82: 1327–1335. 386. Hayashi K, Tsuda T, Nomura A, Fujino N, Nohara A, Sakata K, et al.; Hokuriku-Plus AF Registry Investigators. Impact of B-type natriuretic peptide level on risk stratification of thromboembolism and death in patients with nonvalvular atrial fibrillation: The Hokuriku-Plus AF Registry. Circ J 2018; 82: 1271–1278. 387. Hirakata H, Nitta K, Inaba M, Shoji T, Fujii H, Kobayashi S, et al; Japanese Society for Dialysis Therapy. Japanese Society for Dialysis Therapy guidelines for management of cardiovascular diseases in patients on chronic hemodialysis. Ther Apher Dial 2012; 16: 387–435. 388. Barssoum K, Kumar A, Thakkar S, Sheth AR, Kharsa A, Ibrahim M, et al. Meta-analysis of safety and efficacy of anticoagulation versus no anticoagulation in octogenarians and nonagenarians with atrial fibrillation. High Blood Press Cardiovasc Prev 2021; 28: 271–282. 389. Raposeiras-Roubín S, Alonso Rodríguez D, Camacho Freire SJ, Abu-Assi E, Cobas-Paz R, Rodríguez Pascual C, et al. Vitamin K antagonists and direct oral anticoagulants in nonagenarian patients with atrial fibrillation. J Am Med Dir Assoc 2020; 21: 367–373. 390. Hiasa KI, Kaku H, Inoue H, Yamashita T, Akao M, Atarashi H, et al. Age-related differences in the clinical characteristics and treatment of elderly patients with atrial fibrillation in Japan: Insight from the ANAFIE (All Nippon AF In Elderly) Registry. Circ J 2020; 84: 388–396. 391. Suzuki S, Yamashita T, Akao M, Atarashi H, Ikeda T, Okumura K, et al. Clinical phenotypes of older adults with non-valvular atrial fibrillation not treated with oral anticoagulants by hierarchical cluster analysis in the ANAFIE Registry. PLoS One 2023; 18: e0280753. 391a. Akao M, Ogawa H, Masunaga N, Minami K, Ishigami K, Ikeda S, et al. 10-year trends of antithrombotic therapy status and outcomes in Japanese atrial fibrillation patients: The Fushimi AF registry. Circ J 2022; 86: 726–736. 391b. Okumura K, Yamashita T, Suzuki S, Akao M; J-ELD AF Investigators. A multicenter prospective cohort study to investigate the effectiveness and safety of apixaban in Japanese elderly atrial fibrillation patients (J-ELD AF Registry). Clin Cardiol 2020; 43: 251–259. 392. Akao M, Yamashita T, Suzuki S, Okumura K; J-ELD AF investigators. Impact of creatinine clearance on clinical outcomes in elderly atrial fibrillation patients receiving apixaban: J-ELD AF Registry subanalysis. Am Heart J 2020; 223: 23–33. 393. Shimizu W, Yamashita T, Akao M, Atarashi H, Ikeda T, Koretsune Y, et al. Renal function and clinical outcomes among elderly patients with nonvalvular atrial fibrillation from ANAFIE. JACC Asia 2023; 3: 475–487. 394. Del-Carpio Munoz F, Gharacholou SM, Munger TM, Friedman PA, Asirvatham SJ, Packer DL, et al. Meta-analysis of renal function on the safety and efficacy of novel oral anticoagulants for atrial fibrillation. Am J Cardiol 2016; 117: 69–75. 395. Hohnloser SH, Hijazi Z, Thomas L, Alexander JH, Amerena J, Hanna M, et al. Efficacy of apixaban when compared with warfarin in relation to renal function in patients with atrial fibrillation: Insights from the ARISTOTLE trial. Eur Heart J 2012; 33: 2821–2830. 396. Bohula EA, Giugliano RP, Ruff CT, Kuder JF, Murphy SA, Antman EM, et al. Impact of renal function on outcomes with edoxaban in the ENGAGE AF-TIMI 48 Trial. Circulation 2016; 134: 24–36. 397. Nakagawara J, Ikeda T, Ogawa S, Kitazono T, Minematsu K, Miyamoto S, et al. Real-world outcomes of rivaroxaban treatment in patients with nonvalvular atrial fibrillation and worsening renal function. J Cardiol 2019; 74: 501–506. 398. Böhm M, Ezekowitz MD, Connolly SJ, Eikelboom JW, Hohnloser SH, Reilly PA, et al. Changes in renal function in patients with atrial fibrillation: An analysis from the RE-LY Trial. J Am Coll Cardiol 2015; 65: 2481–2493. 399. Murakawa Y, Ikeda T, Ogawa S, Kitazono T, Nakagawara J, Minematsu K, et al. Impact of body mass index on real-world outcomes of rivaroxaban treatment in Japanese patients with non-valvular atrial fibrillation. Heart Vessels 2020; 35: 1125– 1134. 400. Boriani G, Ruff CT, Kuder JF, Shi M, Lanz HJ, Rutman H, et al. Relationship between body mass index and outcomes in patients with atrial fibrillation treated with edoxaban or warfarin in the ENGAGE AF-TIMI 48 trial. Eur Heart J 2019; 40: 1541–1550. 401. Park CS, Choi EK, Kim HM, Lee SR, Cha MJ, Oh S. Increased risk of major bleeding in underweight patients with atrial fibrillation who were prescribed non-vitamin K antagonist oral anticoagulants. Heart Rhythm 2017; 14: 501–507. 402. Lee SR, Choi EK, Park CS, Han KD, Jung JH, Oh S, et al. Direct oral anticoagulants in patients with nonvalvular atrial fibrillation and low body weight. J Am Coll Cardiol 2019; 73: 919–931. 403. Kadosaka T, Nagai T, Suzuki S, Sakuma I, Akao M, Yamashita T, et al.; J-ELD AF investigators. Association of low body weight with clinical outcomes in elderly atrial fibrillation patients receiving Apixaban-J-ELD AF registry subanalysis. Cardiovasc Drugs Ther 2022; 36: 691–703. 404. Kojima G. Frailty as a predictor of disabilities among community-dwelling older people: A systematic review and meta-analysis. Disabil Rehabil 2017; 39: 1897–1908. 405. Ministry of Health, Labour and Welfare. 基本チェックリスト . [in Japanese] Available at: https://www.mhlw.go.jp/topics/2009/05/ dl/tp0501-1f_0005.pdf (accessed August 2, 2024) 406. Akishita M, Suzuki S, Inoue H, Akao M, Atarashi H, Ikeda T, et al. Frailty and outcomes in older adults with non-valvular atrial fibrillation from the ANAFIE registry. Arch Gerontol Geriatr 2022; 101: 104661. 407. Wilkinson C, Wu J, Searle SD, Todd O, Hall M, Kunadian V, et al. Clinical outcomes in patients with atrial fibrillation and frailty: Insights from the ENGAGE AF-TIMI 48 trial. BMC Med 2020; 18: 401. 408. Segal JB, McNamara RL, Miller MR, Kim N, Goodman SN, Powe NR, et al. Prevention of thromboembolism in atrial fibrillation: A meta-analysis of trials of anticoagulants and antiplatelet drugs. J Gen Intern Med 2000; 15: 56–67. 409. Gumbinger C, Holstein T, Stock C, Rizos T, Horstmann S, Veltkamp R. Reasons underlying non-adherence to and discontinuation of anticoagulation in secondary stroke prevention among patients with atrial fibrillation. Eur Neurol 2015; 73: 184–191. 410. Nagata K, Inoue H, Yamashita T, Akao M, Atarashi H, Ikeda T, et al. Impact of cognitive impairment on clinical outcomes in elderly patients with atrial fibrillation: ANAFIE Registry. BMJ Neurol Open 2023; 5: e000370. 411. Piccini JP, Hellkamp AS, Washam JB, Becker RC, Breithardt G, Berkowitz SD, et al. Polypharmacy and the efficacy and safety of rivaroxaban versus warfarin in the prevention of stroke in patients with nonvalvular atrial fibrillation. Circulation 2016; 133: 352–360. 412. Jaspers Focks J, Brouwer MA, Wojdyla DM, Thomas L, Lopes RD, Washam JB, et al. Polypharmacy and effects of apixaban versus warfarin in patients with atrial fibrillation: Post hoc analysis of the ARISTOTLE trial. BMJ 2016; 353: i2868. 413. Alexander KP, Brouwer MA, Mulder H, Vinereanu D, Lopes RD, Proietti M, et al.; ARISTOTLE Investigators. Outcomes of apixaban versus warfarin in patients with atrial fibrillation and multi-morbidity: Insights from the ARISTOTLE trial. Am Heart J 2019; 208: 123–131. 414. Gutiérrez-Valencia M, Izquierdo M, Cesari M, Casas-Herrero Á, Inzitari M, Martínez-Velilla N. The relationship between frailty and polypharmacy in older people: A systematic review. Br J Clin Pharmacol 2018; 84: 1432–1444. 415. Koretsune Y, Yamashita T, Akao M, Atarashi H, Ikeda T, Okumura K, et al. Baseline demographics and clinical characteristics in the All Nippon AF in the Elderly (ANAFIE) Registry. Circ J 2019; 83: 1538–1545. 416. Mannucci PM, Nobili A, Pasina L. REPOSI Collaborators (REPOSI is the acronym of REgistro POliterapie SIMI, Società Italiana di Medicina Interna). Polypharmacy in older people: Lessons from 10 years of experience with the REPOSI register. Intern Emerg Med 2018; 13: 1191–1200. 417. Yamashita T, Akao M, Atarashi H, Ikeda T, Koretsune Y, Okumura K, et al. Effect of polypharmacy on clinical outcomes in elderly patients with non-valvular atrial fibrillation: A sub-analysis of the ANAFIE Registry. Circ J 2022; 87: 6–16. 418. Kuroda M, Tamiya E, Nose T, Ogimoto A, Taura J, Imamura Y, et al. Effect of 15-mg edoxaban on clinical outcomes in 3 age strata in older patients with atrial fibrillation: A prespecified subanalysis of the ELDERCARE-AF Randomized Clinical Trial. JAMA Cardiol 2022; 7: 583–590. 419. Yoshida T, Nakamura A, Funada J, Amino M, Shimizu W, Fukuzawa M, et al. Efficacy and safety of edoxaban $15\,\mathrm{mg}$ according to renal function in very elderly patients with atrial fibrillation: A subanalysis of the ELDERCARE-AF Trial. Circulation 2022; 145: 718–720. 420. Wang M, Zeraatkar D, Obeda M, Lee M, Garcia C, Nguyen L, et al. Drug-drug interactions with warfarin: A systematic review and meta-analysis. Br J Clin Pharmacol 2021; 87: 4051–4100. 421. Chen A, Stecker E, A Warden B. Direct oral anticoagulant use: A practical guide to common clinical challenges. J Am Heart Assoc 2020; 9: e017559. 422. Scotti P, Séguin C, Lo BWY, de Guise E, Troquet JM, Marcoux J. Antithrombotic agents and traumatic brain injury in the elderly population: Hemorrhage patterns and outcomes. J Neurosurg 2019; 133: 486–495. 423. Yasuda S, Kaikita K, Akao M, Ako J, Matoba T, Nakamura M, et al.; AFIRE Investigators. Antithrombotic therapy for atrial fibrillation with stable coronary disease. N Engl J Med 2019; 381: 1103–1113. 424. Kaikita K, Yasuda S, Akao M, Ako J, Matoba T, Nakamura M, et al. Bleeding and subsequent cardiovascular events and death in atrial fibrillation with stable coronary artery disease: Insights from the AFIRE Trial. Circ Cardiovasc Interv 2021; 14: e010476. 425. Matsuzawa Y, Kimura K, Yasuda S, Kaikita K, Akao M, Ako J, et al.; AFIRE Investigators. Antithrombotic therapy for atrial fibrillation and coronary artery disease in patients with prior atherothrombotic disease: A post hoc analysis of the AFIRE Trial. J Am Heart Assoc 2021; 10: e020907. 426. Yazaki Y, Nakamura M, Iijima R, Yasuda S, Kaikita K, Akao M, et al.; AFIRE Investigators. Clinical outcomes of rivaroxaban monotherapy in heart failure patients with atrial fibrillation and stable coronary disease: Insights from the AFIRE Trial. Circulation 2021; 144: 1449–1451. 427. Ishii M, Akao M, Yasuda S, Kaikita K, Ako J, Matoba T, et al.; AFIRE Investigators. Rivaroxaban monotherapy in patients with atrial fibrillation and coronary stenting at multiple vessels or the left main trunk: The AFIRE Trial Subanalysis. J Am Heart Assoc 2022; 11: e027107. 428. Matoba T, Yasuda S, Kaikita K, Akao M, Ako J, Nakamura M, et al.; AFIRE Investigators. Rivaroxaban monotherapy in patients with atrial fibrillation after coronary stenting: Insights from the AFIRE Trial. JACC Cardiovasc Interv 2021; 14: 2330–2340. 429. Själander S, Själander A, Svensson PJ, Friberg L. Atrial fibrillation patients do not benefit from acetylsalicylic acid. Europace 2014; 16: 631–638. 430. Hindricks G, Potpara T, Dagres N, Arbelo E, Bax JJ, BlomströmLundqvist C, et al. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J 2021; 42: 373–498. 431. Okumura K, Akao M, Yoshida T, Kawata M, Okazaki O, Akashi S, et al.; ELDERCARE-AF Committees and Investigators. Low-dose edoxaban in very elderly patients with atrial fibrillation. N Engl J Med 2020; 383: 1735–1745. 432. Akashi S, Oguri M, Ikeno E, Manita M, Taura J, Watanabe S, et al. Outcomes and safety of very-low-dose edoxaban in frail patients with atrial fibrillation in the ELDERCARE-AF randomized clinical trial. JAMA Netw Open 2022; 5: e2228500. 433. Okazaki O, Higashino Y, Yokoya K, An Y, Tanizawa K, Imamura Y, et al. Prognosis of elderly non-valvular atrial fibrillation patients stratified by B-type natriuretic peptide: ELDERCARE-AF subanalysis. Am Heart J 2022; 250: 66–75. 434. Mikami T, Hirabayashi K, Okawa K, Betsuyaku T, Watanabe S, Imamura Y, et al. Laboratory test predictors for major bleeding in elderly $\scriptstyle\geq80$ years) patients with nonvalvular atrial fibrillation treated with edoxaban 15mg: sub-analysis of the ELDERCARE-AF trial. J Am Heart Assoc 2022; 11: e024970. 435. Ide Y, Ogawa H, Ishigami K, Ikeda S, Doi K, Hamatani Y, et al.; Fushimi AF Registry Investigators. Clinical characteristics and outcomes of very elderly patients with atrial fibrillation at high bleeding risk: The Fushimi AF Registry. Circ Rep 2021; 3: 629–638. 436. Okumura K, Yamashita T, Akao M, Atarashi H, Ikeda T, Koretsune Y, et al. Oral anticoagulants in very elderly nonvalvular atrial fibrillation patients with high bleeding risks: ANAFIE Registry. JACC Asia 2022; 2: 720–733. 437. Connolly SJ, Crowther M, Eikelboom JW, Gibson CM, Curnutte JT, Lawrence JH, et al.; ANNEXA-4 Investigators. Full study report of andexanet alfa for bleeding associated with factor Xa inhibitors. N Engl J Med 2019; 380: 1326–1335. 438. Milling TJ Jr, Middeldorp S, Xu L, Koch B, Demchuk A, Eikelboom JW, et al.; ANNEXA-4 Investigators. Final study report of andexanet alfa for major bleeding with factor Xa inhibitors. Circulation 2023; 147: 1026–1038. 439. Gómez-Outes A, Alcubilla P, Calvo-Rojas G, Terleira-Fernández AI, Suárez-Gea ML, Lecumberri R, et al. Meta-analysis of reversal agents for severe bleeding associated with direct oral anticoagulants. J Am Coll Cardiol 2021; 77: 2987–3001. 440. Pollack CV Jr, Reilly PA, van Ryn J, Eikelboom JW, Glund S, Bernstein RA, et al. Idarucizumab for dabigatran reversal: Full cohort analysis. N Engl J Med 2017; 377: 431–441. 441. Lu G, Conley PB, Leeds JM, Karbarz MJ, Levy GG, Mathur VS, et al. A phase 2 PK/PD study of andexanet alfa for reversal of rivaroxaban and edoxaban anticoagulation in healthy volunteers. Blood Adv 2020; 4: 728–739. 442. Vamos M, Erath JW, Hohnloser SH. Digoxin-associated mortality: A systematic review and meta-analysis of the literature. Eur Heart J 2015; 36: 1831–1838. 443. Elayi CS, Shohoudi A, Moodie E, Etaee F, Guglin M, Roy D, et al.; AF-CHF Investigators. Digoxin, mortality, and cardiac hospitalizations in patients with atrial fibrillation and heart failure with reduced ejection fraction and atrial fibrillation: An AF-CHF analysis. Int J Cardiol 2020; 313: 48–54. 444. Whitbeck MG, Charnigo RJ, Khairy P, Ziada K, Bailey AL, Zegarra MM, et al. Increased mortality among patients taking digoxin: Analysis from the AFFIRM study. Eur Heart J 2013; 34: 1481–1488. 445. Fauchier L, Grimard C, Pierre B, Nonin E, Gorin L, Rauzy B, et al. Comparison of beta blocker and digoxin alone and in combination for management of patients with atrial fibrillation and heart failure. Am J Cardiol 2009; 103: 248–254. 446. Japanese Circulation Society and the Japanese Heart Failure Society Joint Working Group. JCS/JHFS 2021 Guideline focused update on diagnosis and treatment of acute and chronic heart failure. Circ J 2021; 85: 2252–2291. 447. Kotecha D, Bunting KV, Gill SK, Mehta S, Stanbury M, Jones JC, et al. Effect of digoxin vs bisoprolol for heart rate control in atrial fibrillation on patient-reported quality of life: The RATE-AF Randomized Clinical Trial. JAMA 2020; 324: 2497–2508. 448. Rathore SS, Curtis JP, Wang Y, Bristow MR, Krumholz HM. Association of serum digoxin concentration and outcomes in patients with heart failure. JAMA 2003; 289: 871–878. 449. Kotecha D, Holmes J, Krum H, Altman DG, Manzano L, Cleland JG, et al.; Beta-Blockers in Heart Failure Collaborative Group. Efficacy of $\beta$ blockers in patients with heart failure plus atrial fibrillation: An individual-patient data meta-analysis. Lancet 2014; 384: 2235–2243. 450. Ziff OJ, Lane DA, Samra M, Griffith M, Kirchhof P, Lip GY, et al. Safety and efficacy of digoxin: Systematic review and meta-analysis of observational and controlled trial data. BMJ 2015; 351: h4451. 451. Japanese Circulation Society Joint Working Group. JCS 2020 Guideline on diagnosis and treatment of cardiac amyloidosis. Circ J 2020; 84: 1610–1671. 452. Ettinger PO, Wu CF, De La Cruz C Jr, Weisse AB, Ahmed SS, Regan TJ. Arrhythmias and the “Holiday Heart”: Alcoholassociated cardiac rhythm disorders. Am Heart J 1978; 95: 555–562. 453. Liang Y, Mente A, Yusuf S, Gao P, Sleight P, Zhu J, et al.; ONTARGET and TRANSCEND Investigators. Alcohol consumption and the risk of incident atrial fibrillation among people with cardiovascular disease. CMAJ 2012; 184: E857– E866. 454. Conen D, Albert CM. Alcohol consumption and risk of atrial fibrillation: How much is too much? J Am Coll Cardiol 2014; 64: 290–292. 455. Larsson SC, Drca N, Wolk A. Alcohol consumption and risk of atrial fibrillation: A prospective study and dose-response meta-analysis. J Am Coll Cardiol 2014; 64: 281–289. 456. Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJ, Lip GY. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: The Euro Heart Survey. Chest 2010; 138: 1093–1100. 457. Overvad TF, Rasmussen LH, Skjøth F, Overvad K, Albertsen IE, Lane DA, et al. Alcohol intake and prognosis of atrial fibrillation. Heart 2013; 99: 1093–1099. 458. Voskoboinik A, Kalman JM, De Silva A, Nicholls T, Costello B, Nanayakkara S, et al. Alcohol abstinence in drinkers with atrial fibrillation. N Engl J Med 2020; 382: 20–28. 459. Prineas RJ, Jacobs DR Jr, Crow RS, Blackburn H. Coffee, tea and VPB. J Chronic Dis 1980; 33: 67–72. 460. Cheng M, Hu Z, Lu X, Huang J, Gu D. Caffeine intake and atrial fibrillation incidence: Dose response meta-analysis of prospective cohort studies. Can J Cardiol 2014; 30: 448–454. 461. Krittanawong C, Tunhasiriwet A, Wang Z, Farrell AM, Chirapongsathorn S, Zhang H, et al. Is caffeine or coffee consumption a risk for new-onset atrial fibrillation? A systematic review and meta-analysis. Eur J Prev Cardiol 2021; 28: e13–e15. 462. Bodar V, Chen J, Gaziano JM, Albert C, Djoussé L. Coffee consumption and risk of atrial fibrillation in the physicians’ health study. J Am Heart Assoc 2019; 8: e011346. 463. Robertson D, Frölich JC, Carr RK, Watson JT, Hollifield JW, Shand DG, et al. Effects of caffeine on plasma renin activity, catecholamines and blood pressure. N Engl J Med 1978; 298: 181–186. 464. Menezes AR, Lavie CJ, De Schutter A, Milani RV, O’Keefe J, DiNicolantonio JJ, et al. Lifestyle modification in the prevention and treatment of atrial fibrillation. Prog Cardiovasc Dis 2015; 58: 117–125. 465. Baldesberger S, Bauersfeld U, Candinas R, Seifert B, Zuber M, Ritter M, et al. Sinus node disease and arrhythmias in the long-term follow-up of former professional cyclists. Eur Heart J 2008; 29: 71–78. 466. Molina L, Mont L, Marrugat J, Berruezo A, Brugada J, Bruguera J, et al. Long-term endurance sport practice increases the incidence of lone atrial fibrillation in men: A follow-up study. Europace 2008; 10: 618–623. 467. Nielsen JR, Wachtell K, Abdulla J. The relationship between physical activity and risk of atrial fibrillation-A systematic review and meta-analysis. J Atr Fibrillation 2013; 5: 789. 468. Malmo V, Nes BM, Amundsen BH, Tjonna AE, Stoylen A, Rossvoll O, et al. Aerobic interval training reduces the burden of atrial fibrillation in the short term: A Randomized Trial. Circulation 2016; 133: 466–473. 469. Luo N, Merrill P, Parikh KS, Whellan DJ, Piña IL, Fiuzat M, et al. Exercise training in patients with chronic heart failure and atrial fibrillation. J Am Coll Cardiol 2017; 69: 1683–1691. 470. Japanese Circulation Society/the Japanese Association of Cardiac Rehabilitation Joint Working Group. JCS/JACR 2021 Guideline on rehabilitation in patients with cardiovascular disease. Circ J 2022; 87: 155–235. 471. Krijthe BP, Kunst A, Benjamin EJ, Lip GY, Franco OH, Hofman A, et al. Projections on the number of individuals with atrial fibrillation in the European Union, from 2000 to 2060. Eur Heart J 2013; 34: 2746–2751. 472. Burdett P, Lip GYH. Atrial fibrillation in the UK: Predicting costs of an emerging epidemic recognizing and forecasting the cost drivers of atrial fibrillation-related costs. Eur Heart J Qual Care Clin Outcomes 2022; 8: 187–194. 473. Proietti M, Romiti GF, Olshansky B, Lane DA, Lip GYH. Improved outcomes by integrated care of anticoagulated patients with atrial fibrillation using the simple ABC (Atrial Fibrillation Better Care) pathway. Am J Med 2018; 131: 1359–1366. 474. Yoon M, Yang PS, Jang E, Yu HT, Kim TH, Uhm JS, et al. Improved population-based clinical outcomes of patients with atrial fibrillation by compliance with the simple ABC (Atrial Fibrillation Better Care) pathway for integrated care management: A nationwide cohort study. Thromb Haemost 2019; 119: 1695– 1703. 475. Pastori D, Pignatelli P, Menichelli D, Violi F, Lip GYH. Integrated care management of patients with atrial fibrillation and risk of cardiovascular events: The ABC (Atrial fibrillation Better Care) pathway in the ATHERO-AF Study Cohort. Mayo Clin Proc 2019; 94: 1261–1267. 476. Pastori D, Farcomeni A, Pignatelli P, Violi F, Lip GY. ABC (Atrial fibrillation Better Care) pathway and healthcare costs in atrial fibrillation: The ATHERO-AF Study. Am J Med 2019; 132: 856–861. 477. Wyse DG, Waldo AL, DiMarco JP, Domanski MJ, Rosenberg Y, Schron EB, et al.; Atrial Fibrillation Follow-up Investigation of Rhythm Management (AFFIRM) Investigators. A comparison of rate control and rhythm control in patients with atrial fibrillation. N Engl J Med 2002; 347: 1825–1833. 478. Kim D, Yang PS, You SC, Sung JH, Jang E, Yu HT, et al. Treatment timing and the effects of rhythm control strategy in patients with atrial fibrillation: Nationwide cohort study. BMJ 2021; 373: n991. 479. Schnabel RB, Marinelli EA, Arbelo E, Boriani G, Boveda S, Buckley CM, et al. Early diagnosis and better rhythm management to improve outcomes in patients with atrial fibrillation: The 8th AFNET/EHRA consensus conference. Europace 2023; 25: 6–27. 480. Rienstra M, Hobbelt AH, Alings M, Tijssen JGP, Smit MD, Brügemann J, et al.; RACE 3 Investigators. Targeted therapy of underlying conditions improves sinus rhythm maintenance in patients with persistent atrial fibrillation: Results of the RACE 3 trial. Eur Heart J 2018; 39: 2987–2996. 481. Huxley RR, Misialek JR, Agarwal SK, Loehr LR, Soliman EZ, Chen LY, et al. Physical activity, obesity, weight change, and risk of atrial fibrillation: The Atherosclerosis Risk in Communities study. Circ Arrhythm Electrophysiol 2014; 7: 620–625. 482. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: The Framingham Study. Stroke 1991; 22: 983–988. 483. Pisters R, Lane DA, Marin F, Camm AJ, Lip GY. Stroke and thromboembolism in atrial fibrillation: Systematic review of stroke risk factors and risk stratification schema. Circ J 2012; 76: 2289–2304. 484. Ganesan AN, Chew DP, Hartshorne T, Selvanayagam JB, Aylward PE, Sanders P, et al. The impact of atrial fibrillation type on the risk of thromboembolism, mortality, and bleeding: A systematic review and meta-analysis. Eur Heart J 2016; 37: 1591–1602. 485. Killu AM, Granger CB, Gersh BJ. Risk stratification for stroke in atrial fibrillation: A critique. Eur Heart J 2019; 40: 1294–1302. 486. Alkhouli M, Friedman PA. Ischemic stroke risk in patients with nonvalvular atrial fibrillation: JACC review topic of the week. J Am Coll Cardiol 2019; 74: 3050–3065. 487. Cosedis Nielsen J, Johannessen A, Raatikainen P, Hindricks G, Walfridsson H, Kongstad O, et al. Radiofrequency ablation as initial therapy in paroxysmal atrial fibrillation. N Engl J Med 2012; 367: 1587–1595. 488. Lip GYH. The ABC pathway: An integrated approach to improve AF management. Nat Rev Cardiol 2017; 14: 627–628. 489. Lip G, Freedman B, De Caterina R, Potpara TS. Stroke prevention in atrial fibrillation: Past, present and future. Comparing the guidelines and practical decision-making. Thromb Haemost 2017; 117: 1230–1239. 490. Lip GYH, Banerjee A, Boriani G, Chiang CE, Fargo R, Freedman B, et al. Antithrombotic therapy for atrial fibrillation: CHEST guideline and expert panel report. Chest 2018; 154: 1121–1201. 491. Kotalczyk A, Mazurek M, Kalarus Z, Potpara TS, Lip GYH. Stroke prevention strategies in high-risk patients with atrial fibrillation. Nat Rev Cardiol 2021; 18: 276–290. 492. Khan MN, Jaïs P, Cummings J, Di Biase L, Sanders P, Martin DO, et al.; PABA-CHF Investigators. Pulmonary-vein isolation for atrial fibrillation in patients with heart failure. N Engl J Med 2008; 359: 1778–1785. 493. Muhammad ZK, Safi U K, Adeel A, Muhammad SZ, Muhammad U K, Muhammad SK, et al. Meta-analysis of catheter ablation versus medical therapy in patients with atrial fibrillation without heart failure. J Atr Fibrillation 2020; 12: 2266. 494. Kim D, Yang PS, You SC, Jang E, Yu HT, Kim TH, et al. Age and outcomes of early rhythm control in patients with atrial fibrillation: Nationwide cohort study. JACC Clin Electrophysiol 2022; 8: 619–632.

Appendix 1. Details of Members

Chairs

• Yu-ki Iwasaki, Department of Cardiovascular Medicine, Nippon Medical School • Takashi Noda, Department of Cardiology, Tohoku University Hospital (Deputy Chief)

Members

• Masaharu Akao, Department of Cardiology, National Hospital Organization Kyoto Medical Center • Tadashi Fujino, Department of Cardiovascular Medicine, Toho University Faculty of Medicine • Teruyuki Hirano, Department of Stroke Medicine, Kyorin University School of Medicine • Koichi Inoue, Department of Cardiology, National Hospital Organization Osaka National Hospital • Takashi Kurita, Division of Cardiovascular Center, Kindai University School of Medicine • Kengo Kusano, Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center • Toshiyuki Nagai, Department of Cardiovascular Medicine, Faculty of Medicine and Graduate School of Medicine, Hokkaido University • Kazuhiro Satomi, Department of Cardiology, Tokyo Medical University Hospital • Wataru Shimizu, Department of Cardiovascular Medicine, Nippon Medical School • Tetsuji Shinohara, Department of Cardiology and Clinical Examination, Faculty of Medicine, Oita University • Kyoko Soejima, Department of Cardiovascular Medicine, Kyorin University School of Medicine • Yohei Sotomi, Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine • Shinya Suzuki, Department of Cardiovascular Medicine, The Cardiovascular Institute • Hiroshi Tada, Department of Cardiovascular Medicine, Faculty of Medical Sciences, University of Fukui • Teiichi Yamane, Department of Cardiology, The Jikei University School of Medicine

Collaborators

• Tsukasa Kamakura, Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center • Hiroyuki Kato, Department of Cardiology, Japan Community

Healthcare Organization Chukyo Hospital • Arimi Katsume, Department of Cardiovascular Medicine, Kyorin University School of Medicine • Yusuke Kondo, Department of Cardiovascular Medicine, Chiba University Graduate School of Medicine • Kenji Kuroki, Department of Cardiology, Faculty of Medicine, University of Yamanashi • Hisaki Makimoto, Division of Cardiovascular Medicine, Department of Internal Medicine, Data Science Center, Jichi Medical University • Hiroshige Murata, Department of Cardiology, Nippon Medical School Hospital • Takafumi Oka, Department of Cardiovascular Medicine, Osaka University Graduate School of Medicine • Nobuaki Tanaka, Department of Cardiology, Cardiovascular Center, Sakurabashi Watanabe Hospital • Nobuhiko Ueda, Department of Cardiovascular Medicine, National Cerebral and Cardiovascular Center • Hiro Yamasaki, Department of Cardiology, Institute of Medicine, University of Tsukuba • Seigo Yamashita, Department of Cardiology, The Jikei University School of Medicine • Ryobun Yasuoka, Department of Cardiology, Kindai University School of Medicine • Kenji Yodogawa, Department of Cardiology, Nippon Medical School Hospital

Independent Assessment Committee

• Kazutaka Aonuma, Department of Cardiology, Mito Saiseikai General Hospital • Takanori Ikeda, Department of Cardiology, Toho University Medical Center Omori Hospital • Toru Minamino, Department of Cardiovascular Medicine, Juntendo University Graduate School of Medicine • Hideo Mitamura, National Public Service Mutual Aid Federation Tachikawa Hospital • Akihiko Nogami, Tokyo Heart Summit Tokyo Cardiac Arrhythmia Hospital • Ken Okumura, Department of Cardiology, Cardiovascular Center, Saiseikai Kumamoto Hospital

(Listed in alphabetical order; affiliations as of March 2024)

Appendix2. Disclosure of Potential Conflicts of Interest (COI): JCS/JHRS 2024 Guideline Focused Update on Management of Cardiac Arrhythmias (2021/1/1–2023/12/31)

||||||||||| COI of the marital partner, first-degree family members, or those who shareincome and property | COI of the head of the organization/department to whichthememberbelongs (if the member is in a position to collaborate with the head of the organization/department) |||| |---|---|---|---|---|---|---|---|---|---|---|---|---|---|---| || Employer/ leadership position (private company) |Stakeholder| Patent royalty |Honorarium| Payment for manuscripts |Research grant| Scholarship (educational) grant |Endowed chair| Other rewards | Employer/ leadership position (private company) |Stakeholder| Patent royalty' | Research grant | Scholarship (educational) grant | | Chair: Takashi Noda (Deputy Chief) |||| Medtronic Japan Co., Ltd. BIOTRONIK Japan, Ine. Bayer Yakuhin, Ltd. || Johnson Johnson KK. ||||||||| | Members: Masaharu Akao* |||| Daiichi Sankyo Company. Limited. Bayer Yakuhin, Ltd. Bristol-Myers Squibb ||| Daiichi Sankyo Company. Limited. Bayer Yakuhin, Ltd. |||||||| | Members: Teruyuki Hirano |||| Daiichi Sankyo Company. Limited. Bayer Yakuhin, Ltd. Pfizer Japan Inc. NipponBoehringer Ingelheim Co., Itd. Otsuka Pharmaceutical Co., Ltd. ||||||||||| | Members: Koichi Inoue |||| KK. Medtronic Japan Co., Ltd. Japan Lifeline Co.,Ltd. Nippon Boehringer Ingelheim Co., Itd_ Bayer Yakuhin, Ltd. Pfizer Japan Inc. Boston Scientific Japan K.K. Daiichi Sankyo Company, Limited. Bristol-Myers Squibb ||||||||||| | Members: Takashi Kurita* |||| MedtronicJapan Co., Ltd. Bayer Yakuhin, Ltd. BIOTRONIK Japan, Inc. Daiichi Sankyo Company. Limited. TOA EIYO LTD. Abbott Medical Japan LLC. Japan Lifeline Co.,Ltd. ||||||||||| | Members: Kengo Kusano* |||| Medtronic Japan Co., Ltd. Daiichi Sankyo Company, Limited. Bayer Yakuhin, Ltd. Nippon Boehringer Ingelheim Co., Ltd. Pfizer Japan Inc. || Hitachi, Ltd. Daiichi Sankyo Company, Limited. Medtronic Japan Co., Ltd. BIOTRONIK Japan, Inc. Mebix, Inc. JSRCorporation IQVIA Services Japan K.K. Boston Scientific Japan K.K. Abbott Medical Japan LLC. GE Precision Healthcare EPS Corporation ||||||||| | Members: Toshiyuki Nagai |||| Kyowa Kirin Co., 工td. Bayer Yakuhin, Ltd. Viatris Inc. Nippon Boehringer Ingelheim Co., Itd_ ||| Mitsubishi Tanabe Pharma Corporation ||||||||

|Author|||||||||| COI of the marital partner, first-degree family members, or those who share income andproperty | COI of the head of the organization/department to which the member belongs (if the member is in a position to collaborate with the head of the organization/department) |||| |---|---|---|---|---|---|---|---|---|---|---|---|---|---|---| |Author| Employer/ leadership position private company) |Stakeholder| Patent royalty |Honorarium| Payment for manuscripts |Research grant| Scholarship (educational) grant |Endowed chair| Other rewards | Employer/ leadership position (private company) |Stakeholder| Patent royalty | Research grant | Scholarship (educational) grant | | Members: Kazuhiro Satomi |||| Medtronic Japan .Co., Ltd. Abbott Medical Japan LLC. Japan Lifeline Co.,Ltd. TERUMO CORPORATION Bayer Yakuhin, Ltd. Boston Scientific Japan K.K. || Johnson Johnson K-K. | Abbott Medical .Japan LLC. Nippon Boehringer Ingelheim Co., Itd. |||||||| | Members: Wataru Shimizu |||| Dajichi Sankyo Company, Limited. Nippon Boehringer Ingelheim Co., Itd_ Bayer Yakuhin, Ltd. Bristol-Myers Squibb Pfizer Japan Inc. Ono Pharmaceutical Co.,Ltd. K.K. Otsuka eutical Co., Ltd. Medtronic Japan Co., Ltd. AbbottMedical JapanLLC. Johnson K.K. ||||||||||| | Members: Kyoko Soejima* |||| Daiichi Sankyo Eomrarye Abbott Medical JapanLLC. Medtronic Japan Co., Ltd. Johnson K.K. Nippon Boehringer Ingelheim Co., Ltd. BIOTRONIK Japan, Inc. Boston Scientific Japan K.K. ||||||||||| | Members: Yohei Sotomi* |||| Bristol-Myers Squibb Abbott Medical JapanLLC. BostonScientific Japan K.K. || Abbott Medical Japan LLC... TOAEIYOLTD. Johnson Johnson K.K. Roche Diagnostics IK.K. Bristol-Myers Squibb || TOAEIYOLTD. TERUMO CORPORATION Nipro Corporation SHIMADZU CORPORATION ASAHIINTECC CO.,LTD. ||||||| | Members: Shinya Suzuki |||| Bristol-Myers Squibb Dajichi Sankyo Company. Limited. ||||||||||| | Members: Hiroshi Tada |||| Medtronic Japan Co., Ltd. BIOTRONIK Japan, Inc. Boston Scientific JapanK.K. Daiichi Sankyo Company. Limited. Bristol-Myers Squibb Novartis Pharma K.K. ||| Abbott Medical Japan LLC. DAICHI SANKYO COMPANY, Ltd. NipponBoehringer Ingelheim Co., Itd. Otsuka Pharmaceutical Co., Ltd. Eli Lilly Japan K.K. Marubun Tsusyo K.K. |||||||| | Members: Teiichi Yamane |||| MedtronicJapan Co.,Ltd. Abbott Medical Japan LLC. BEG Co.,Ltd. ||| JapanLifeline Co.,Ltd. |||||||| | Collaborators: Tsukasa Kamakura |||| Johnson Johnson K.K. Medtronic Japan Co.,Ltd. BIOTRONIK Japan, In. ||||||||||| ||||||||||||||||

Advance Publication

JCS/JHRS 2024 Guideline Focused Update on Management of Cardiac Arrhythmias

|Author|||||||||| COI of the marital partner, first-degree familymember, or those who share income and property | COI of the head of the organization/department to which the member belongs (if the member is in a position tocollaborate withteheadof the organization/department) |||| |---|---|---|---|---|---|---|---|---|---|---|---|---|---|---| |Author| Employer/ leadership position (private company) |Stakeholder| Patent royalty |Honorarium| Payment for manuscripts |Research grant| Scholarship (educational) grant |Endowed chair|Other| Employer/ leadership position (private company) |Stakeholder| Patent royalty' | Research grant | Scholarship (educational) grant | | Collaborators: Hiroyuki Kato |||| MedtronicJapan Co., Ltd. Abbott Medical Japan LLC. ||||||||||| | Collaborators: Yusuke Kondo |||| oston Scientific Japan K.K. Abbott Medical Japan LLC. BIOTRONIK Japan,Inc. Daiichi Sankyo Company. Limited. Bayer Yakuhin, Ltd. ||||||||||| | Collaborators: Kenji Kuroki |||||| MedtronicJapan Co, Ltd. Abbott Medical JapanLLC. ||||||||| | Collaborators: Hisaki Makimoto |||||| Mitsubishi Electric MCorporation ||||||||| | Collaborators: Hiroshige Murata ||||Pfizer Japan Inc.||||||||||| | Collaborators: Nobuaki Tanaka |||| Bayer Yakuhin, Ltd. Johnson K.K. Nippon Boehringer Ingelheim Co., Ltd... AstraZeneca K.K. Medtronic Japan Co., Ltd. ||||||||||| | Collaborators: Nobuhiko Ueda |||| Medtronic Japan Co., Ltd. ||||||||||| | Collaborators: Hiro Yamasaki |||| MedtronicJapan Co., Ltd. Abbott Medical JapanLLC. Boston Scientific Japan K.K. | TORAY INDUSTRIES, INC. |||||||||| | Independent Assessment Committee: Takanori Ikeda |||| Bayer Yakuhin, Ltd. Daiichi Sankyo Company. Limited. Pfizer Japan Inc. ||||||||||| | Independent Fukuda Denshi Assessment Co., Ltd. Committee: Toru Minamino ||| Bayer Yakuhin, Ltd. Daiichi Sankyo Company. Limited. Nippon Boehringer Ingelheim Co., Ltd. AstraZeneca K.K. Novo Nordisk Pharma Ltd. Novartis Pharma K.K. SumitomoPharma ||| Medical Hearts co.,Ltd. Crosswill Medical co.,Ltd. Eisai Co., Ltd. BIOTRONIK Japan, Inc. Daiichi Sankyo Company, Limited. Boston Scientific Japan K.K. Otsuka Pharmaceutical Co-, Ltd. PPD-SNBL K.K. MC, Inc. Ingelheim Co., Itd. Active Medical Co.,Ltd. MedtronicJapan Co., Ltd. Abbott Medical Japan LLC. JapanLifeline Co.,Ltd. ALVAUS Inc. Shionogi Co., Ltd. Mitsubishi Tanabe Pharma Corporation Roche Diagnostics ||||||||| | Independent Fukuda Denshi Assessment Co., Ltd. Committee: Toru Minamino ||| Co., Ltd. Kowa Company. Ltd. ||| Medical Hearts co.,Ltd. Crosswill Medical co.,Ltd. Eisai Co., Ltd. BIOTRONIK Japan, Inc. Daiichi Sankyo Company, Limited. Boston Scientific Japan K.K. Otsuka Pharmaceutical Co-, Ltd. PPD-SNBL K.K. MC, Inc. Ingelheim Co., Itd. Active Medical Co.,Ltd. MedtronicJapan Co., Ltd. Abbott Medical Japan LLC. JapanLifeline Co.,Ltd. ALVAUS Inc. Shionogi Co., Ltd. Mitsubishi Tanabe Pharma Corporation Roche Diagnostics ||||||||| | Independent Fukuda Denshi Assessment Co., Ltd. Committee: Toru Minamino ||| Co., Ltd. Kowa Company. Ltd. ||| _K.K- Ono Medical Research Foundation |||||||||

|Author|Member's own declaration items| COI of the marital partner, first-degree family memer, or those who share income and property | COI of the head of the organization/department to which themember belongs (if the member isin a position to collaborate with the head of the organization/department) |||||||||||| |---|---|---|---|---|---|---|---|---|---|---|---|---|---|---| |Author| Employer/ leadership position (private company) |Stakeholder| Patent royalty |Honorarium| Payment for manuscripts |Research grant| Scholarship (educational) grant |Endowed chair| Other rewards | Employer/ leadership position (private company) |Stakeholder| Patent royalty | Research grant | Scholarship (educational) grant | | Independent Assessment Committee: Akihiko Nogami |||| Johnson Johnson K.K. Abbott Medical Japan LLC. Nippon Boehringer Ingelheim Co., Ltd. Medtronic Japan Co., Ltd. |||| Medtronic Japan Co., Ltd. DVx Inc. ||||||| | Independent Assessment Committee: KenOkumura | Japan Lifeline Co.,Ltd. Medtronic Japan Co., Ltd. ||| Daiichi Sankyo Company, Limited. Bristol-Myers Squibb Nippon Boehringer Ingelheim Co., Ltd. Johnson Johnson KK. Bayer Yakuhin, Ltd. |||||||||||

Notation of corporation is omitted.

The following persons have no conflict of interest to declare: Chair: Yu-ki Iwasaki Members: Tadashi Fujino Members: Tetsuji Shinohara Collaborators: Arimi Katsume Collaborators: Takafumi Oka Collaborators: Seigo Yamashita Collaborators: Ryobun Yasuoka Collaborators: Kenji Yodogawa Independent Assessment Committee: Kazutaka Aonuma Independent Assessment Committee: Hideo Mitamura

In accordance with “The JAMS COI Management Guidance on Eligibility Criteria for Clinical Practice Guideline Formulation 2023”, all members have submitted their COIs for the past 3 years. Some members (\*) reported under the category of “Amount Category 3” or “Endowed departments established through donations by a company” and therefore do not have a vote in the guideline formulation process, to ensure fairness and transparency of the guidelines.

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