2025+CCS／CHFS指南：非射血分数降低心力衰竭的药物治疗（更新版）

Guidelines

Canadian Cardiovascular Society/Canadian Heart Failure Society 2025 Guideline Update for Pharmacologic Management of Heart Failure With Nonreduced Ejection Fraction (LVEF > 40%)

Primary Panel: Sean Virani, MD,(Co-chair),a Shelley Zieroth, MD,(Co-chair),b_Natasha Aleksova, MD,c Kim Anderson, MD,MSc,d Brian Clarke, MD,a Anique Ducharme, MD,e

Justin A. Ezekowitz, MBBCh, f Farid Foroutan, HBSc, PhD, g Nadia Giannetti, MD,

Rahul Jain, MD, ${}^{i}$ Douglas Lee, MD, PhD, ${}^{c}$ Serge Lepage, MD, ${}^{j}$ Kristin Lyons, MDCM, ${}^{k}$

Michael McDonald, MD, ${ }^{c}$ Caroline McGuinty, $MD, { }^{l}$ Lisa Mielniczuk, $MD, { }^{l, m}$

Eileen O'Meara, MD,° Stephanie Poon, MD,° Kyla Siatecki, MN, NP, Elizabeth Swiggum, MD,

Mustafa Toma, MD,° Ricky D. Turgeon, PharmD,°

Review Panel: Marc Bains, P' Margot K. Davis, MD, SM, a Sabe De, MD, q Nowell Fine, MD, SM,

Jodi Heshka, MD, Sabina Keen, MD, § Alexandra King, MD, {} Andrea Lavoie, MD,

Susanna Mak, MD, PhD, Lynn McCleary, RD, PhD, w Oussama Outbih, MD,

Rodolfo Pike, RN, BN, MN, NP, ${}^{y}$ Abhinav Sharma, MD, PhD, ${}^{x}$

Harriette G.C. Van Spall, MD, MPH, and Amelia Ming Ching Yip, MD

"University of British Columbia, Vancouver, British Columbia, Canada,"Sction of Cardiologic, Max. Rady College of Medicine, University of Manitoba, Winnipeg,Manitoba, Canada;"Peter Munk Cardiac Centre, Toronto General Hospital, University Health Network, Toronto, Ontario, Canada;"Dalbousie University QEII HealthBci Science Centre, Halifax, Nova Scotia, Canada;"Institut de Cardiologic de Montreal, Université de Montreal, Montreal, Québec, Canada;"University of Alberta,Edmonton, Alberta, Canada;"S Ted Rogers Centre for Heart Research, Toronto, Ontario, Canada;"McGill University, Montreal, Québec, Canada;"Sunnybrook Health Sciences Centre, University of Toronto, Toronto, Ontario, Canada;"Uiversite de Sherbrooke, Sherbrooke, Québec, Québec, Canada;"Cumming School of Medicine, University of Calgary, Libm Cardivascular Institute, Calgary, Alberta, Canada;"Uotanyus of Ontaway Institute, Ontaria, Canada;"Mayo Clinic, Rochester,Minnesota,USA;"a Royal Jubilee Hospital, University of British Columbia, Victoria, Cambridge, Canada;"Ulosubia University of British Columbia, St Paul's Hospital PHARM-HF Clinic, Vancouver, British Columbia, Canada;"HeartLife Foundation, Vancouver, British Columbia, Canada;"London Health Sciences, Western University, London, Ontario, Canada;"Oattwota, Ontario, Canada;"Mancoldish Sciences, McMaster University, University of Ottawa, University of Ottawa, Ottawa, Ontario, Hamilton,University, Canada;"Department of Medicine, and Pawesstehun Indigenous Wellness Research Group, College of Medicine, University of Saskatchewan, Saskatoon, Canada;"Saskatchewan, Canada;"College of Medicine, University of Saskatchewan, Regina, Saskatchewan, Canada;"University of Toronto, Sinai Health, Toronto, Ontario,Canada;"Brock University, S. Cherstein, Ontario, Canada;"The Ottawa Hospital Health Team, University of Ottawa, Ottawa, Ontario, Canada;"Bakerhner, Ontario, Canada;"S.Chem's University, and的新hman, and H. Sertman, University, Hamilton Health Sciences Centre, Hamilton, Ontario, Canada;"McMaster University, Hamilton Health Sciences Centre, Hamilton, Ontario, Canada;"Baim Institute for Clinical Research, Boston, Massachusetts, USA."St Mary's General Hospital, McMater University, Kitchener, Ontario, Canada

See Systematic Review and Meta-Analysis Article by Aleksova et al, CJC Open,pages 1332-1344, Volume 7, Issue 10, 2025.

Keywords: heart failure; guideline; Canadian Cardiovascular Society

Corresponding author: Dr Sean Virani, Division of Cardiology, Uni-versity of British Columbia, A44-1081 Burrard Street, Vancouver, British Columbia V6Z 1Y6, Canada. Tel.:+1-604-806-9139.

E-mail: Sean.Virani@phsa.ca.

The disclosure information of the authors and reviewers is available from the CCS on their guidelines library at www.ccs.ca.

This statement was developed following a thorough consideration of medical literature and the best available evidence and clinical experience. It represents the consensus of a Canadian panel comprised of multidisciplinary experts on this topic with a mandate to formulate disease-specific

recommendations. These recommendations are aimed to provide a reason-able and practical approach to care for specialists and allied health pro-fessals obliged with the duty of bestowing optimal care to patients and families, and can be subject to change as scientific knowledge and technology advance and as practice patterns evolve. The statement is not intended to be a substitute for physicians using their individual judgement in managing clinical care in consultation with the patient, with appropriate regard to all the individual circumstances of the patient, diagnostic and treatment options available and available resources. Adherence to these recommendations will not necessarily produce successful outcomes in every case.

Received for publication March 10, 2025. Accepted July 14, 2025.

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ABSTRACT

Heart failure with nonreduced ejection fraction(HFnrEF), defined as signs and symptoms of heart failure(HF) with a left ventricular ejection fraction(LVEF) of> 40%, continues to increase in prevalence with significant effects to patients, their care givers, and the health care system broadly. Historically, this population has been divided into HF with mildly reduced(HFmrEF) or HF with preserved ejection fraction(HFpEF). However, contemporary evidence Indicates that patients across the spectrum of LVEF> 40% experience similar clinical outcomes and, importantly, respond consistently to several key pharmacotherapies. Adoption of the term HFnrEF provides a practical and unified framework for clinical decision-making, reducing ambiguity and promoting consistent application of evidence-based therapies.

To support clinicians in translating evidence into practice, the Cana-dian Cardiovascular Society(CCS) and the Canadian Heart Failure Society(CHFS) present this guideline, which is focused on pharma-cological management of symptomatic heart failure with nonreduced ejection fraction(HFnEF).

Underpinned by Grading of Recommendations, Assessment, Devel-opment, and Evaluation(GRADE) methodology and meta-analyses,outcomes of interest include pharmacotheres shown to reduce the risk of HF hospitalization(HFH) and improve patient well-being in this population. The guideline offers concise recommendations for 4 key classes of pharmacological therapies: sodium-glucose cotrans-porter-2 inhibitors(SGLT2i), mineralocorticoid receptor antagonists(MRAs), angiotensin receptor-nerplisys inhibitors(ARNIs), and evidence-based drugs with glucagon-like peptide-1(GLP-1) receptor agonist activity. Recommendations are complemented by practical tips to guide the initiation, titration, and maintenance of these foundational treatments.

By emphasizing therapeutic consistency across the> 40% LVEF spectrum, this guideline aims to streamline care pathways and enhance the delivery of guideline-directed medical therapy for pa-tients with symptomatic HFnrEF in real-world settings.

1. Introduction

HFnrEF, defined as signs and symptoms of HF with an LVEF of> 40%, is an increasing clinical and public health challenge. It affects a growing number of Canadians while placing substantial burdens on patients, caregivers, and health care systems. To simplify and consolidate existing definitions,we have unified HFnrEF and HFpEF under the new term"HFnrEF"(Figure 1). Within this framework, we have developed guidelines to address the unique needs of this diverse patient population.

Unlike HF with reduced ejection fraction(HFrEF), for which established therapies have shown clear benefits,pharmacologic options for HFnrEF have historically been limited. This population often includes older adults with multiple comorbidities and unique phenotypes2 such as obesity, diabetes, and hypertension, which complicate man-agement and contribute to a high burden of morbidity and mortality.

Clinicians have expressed an urgent need for clearer guidance on optimal pharmacologic strategies for managing patients who suffer from HFpEF and HFmrEF. This need is

RESUME

La prevalence de l'insuffisance cardiacque avec fraction d'ejection non reduite(ICFEnr), définie comme les signes et symptomes d'insuffisance cardiaque(IC) avec une fraction d'ejection ventriculaire gauche(FEVG)>40%,continue d'augmenter, avec des répercussions importantes pour les patients, leurs soignants et le systeme de sante en général.

Historiquement, cette population aété divisée en deux groupes: l'IC avec fraction d'ejection légèrement réduite et l'IC avec fraction d'ejection preservée. Cependant, les données actuelles indiquent que les patients presentant toute la gamme de FEVG présentent des con-sequences cliniques similaires et, surtout, répondent de maniere coherenteà plusieurs pharmacothérapies clés.

L'adoption du terme ICFnour fournit un cadre pratique et unifié pour la prise de decision clinique, reduisant l'ambiguite et favorisant l'applica-tion cohérence de thérapies fondées sur des données probantes.

Afin d'ader les clinicians a intégrer les données scientificues dans leur pratique la clinique, la Société Canadienne de Cardiologie et la SocietéCanadienne d'Insuffisance Cardiague présentent cette ligne directice axée sur la prise en charge pharmacologique de l'ICFEnr symptomatique.s'uyappant sur la methodologie GRADE et des méta-analyses, les criteres de jugement d'interet comprennent les pharmacotherapies qui ont démontré leur efficatie pour réduire le risque d'hospitalisation pour insuffisance cardiaque et ameliérer le bien-etre des patients dans cette population. La directive propose des recommandations concises pour quatre grandes classes de traitements pharmacologiques:les inhibiteurs du cotransporteur sodium-glucose de type 2, les antagonistes des récepteurs aux mineralcorticoides, les inhibiteurs du récepteur de l'an-gliotensine et de la rénilysine et les médicaments fondés sur des données probantes ayant une activite agoniste du récepteur du peptide-1 de type glucagon. Ces recommandations sont complétées par des consels pra-tiques pour guider l'initiation, l'ajustement posologique et le maintien de ces traitements de base.

le spectre des FEVG> 40%, cette ligne directrice vise a rationaliser les parcours de soins et a Ameliorer l'administration des traitements con-formes aux recommandations cliniques pour les patients atteints d'ICFRnwr symptomatique.

especially pressing because of the rising prevalence of these conditions and their associated burden, including mortality and hospitalization as well as declining symptom and func-tional status. In response to these needs, the CCS/CHFS guideline on pharmacological management of HFnrEF aims to synthesize data from high-quality contemporary clinical trials that would inform meta-analyses in this patient popu-lation, and in turn, provide evidence-based recommenda-tions. These recommendations are complemented by practical tips on 4 therapies that have emerged as promising options for improving outcomes in this population: SGLT2i,MRAs, ARNI, and evidence-based drugs with GLP-1 recep-tor agonist activity.

A new treatment paradigm for the management of patients with HFnrEF, specifically aimed at reducing HFH, is out-lined in Figure 2. The sequencing of treatments is based on the strength of recommendation for each pharmacological class, the quality of available evidence, and patient-specific factors. While acknowledging that no algorithm can fully capture the complexities and patient-specific factors involved in tailored pharmacological therapy, our approach emphasizes

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pragmatism within an evidence-based framework that high-lights practice considerations to support patients and pro-viders in shared decision-making. Table 1 includes the evidence-based medications for which recommendations are provided in this guideline including drug name, therapeutic class, starting dose, and target dose.

Our HF treatment algorithm is focused on therapies that reduce HFH because of the significant effect of these ad-missions on patients, caregivers, and the health care system.Hospitalizations not only indicate disease progression but also come with a high associated mortality; the unadjusted 1-year mortality after any HFH is approximately 27%,3,4 which underscores the severe prognosis linked to recurrent admis-sions. Furthermore, approximately 20% of patients with HF in Canada are readmited within 30 days, resulting in a costly and burdensome cycle of care. The average length of stay for those admitted with an HFH in Canada approxi-mates 7 days and patients face an average of 2.8 rehospi-talizations in the subsequent year, which contributes to the condition's designation as one of the most resource-intensive in Canadian hospitals. Conservatively estimated, direct costs associated with HFH are expected to grow to CAD$1 billion through 2040.6

As such, the algorithm presented in Figure 2 seeks to disrupt the cycle of HFH and improve quality of life(QoL)for patients who suffer from HFnrEF. Effective application of this tool might also support health care system sustainability by lessening the strain on hospital resources and reducing overall expenditures. However, it is critical to recognize that these benefits cannot be equitably achieved without address-ing the significant disparities faced by Indigenous peoples and other marginalized populations within the health care system.For Indigenous peoples, the experience of HF is often complicated by systemic barriers, including limited access to timely and culturally safe health care, mistrust stemming from historical injustices and the pervasive impact of Indigenous-specific racism in care settings. These inequities might contribute to delayed diagnosis, suboptimal treatment,and disproportionately higher rates of HFH.

2. Scope of the 2025 Pharmacologic Management of HFnrEF Guideline Update

The scope of this guideline is restricted to key phar-macologic therapies for chronic HFnrEF management of symptomatic patients in the ambulatory care setting.Although the panel acknowledges the critical role of non-pharmacologic management as an essential component of comprehensive HF care, this document is limited to pharmacologic strategies and does not address non-pharmacologic interventions. Likewise, the management of significant comorbidities and their interactions with HF are recognized as important but are not included in this guideline. For additional guidance on nonpharmacological management of HF and treatment of associated comor-bidities, we direct the reader to the 2017 Comprehensive Update of the Canadian Cardiovascular Society Guidelines for the Management of Heart Failure. ${}^{7}$

We have limited our subgroup analyses to specific populations of special interest for each drug class, which

were identified by the primary panel a priori. Although there are any number of subgroups worth exploring as part of our meta-analyses, the limited scope of this guideline precluded an in-depth review of all. Although some trials specifically included and/or excluded patients with recov-red HF, the lack of consistent reporting of this key characteristic among baseline demographic characteristics in many clinical trials precluded our ability to assess this subgroup a priori.

3. Guideline Development

The guideline development process is described in detail in Supplemental Appendix S1. The Primary and Review Panels,including the co-chairs were appointed by the CCS Guide-lines Committee. Two journal reviewers for the Canadian Journal of Cardiology were nominated to join the Review Panel. Two methodologies from the methodology subcom-mittee of the CCS Guidelines Committee joined the primary panel to conduct systematic reviews and meta-analyses of the literature for each clinical question addressed. The topics were selected by the co-chairs and approved by the Primary Panel and CCS Guidelines Committee. Each topic was addressed in the form of a“PICO” question: patient population of interest(P), intervention(I), comparator(C), and outcomes(O). The GRADE approach was used to synthesize evidence. Members of the Primary Panel who did not have direct conflicts of interest with the substance of a specific PICO were allowed to vote on that PICO. All recommendations in the guideline reached a majority(75%) agreement of eligible voters. A summary of the systematic reviews and meta-analyses con-ducted plus GRADE evidence-to-decision frameworks for this guideline document for the 4 key classes of pharmaco-logical therapies are available online in Supplemental Appendix S2(ARNIs), Supplemental Appendix S3(MRAs),Supplemental Appendix S4(SGLT2i), and Supplemental Appendix S5(Agents with GLP-1 Receptor Agonist Activity).The guideline manuscript was peer-reviewed before submis-sion by the Review Panel, which included 2 people with lived experience of HF and the CCS Guidelines Committee.

4. SGLT2i

4. SGLT2i

SGLT2i exert their beneficial effects in patients with HF through several interconnected mechanisms. Originally developed to manage hyperglycemia in patients with type 2 diabetes mellitus(T2DM) by reducing renal glucose reabsorption and promoting glycosuria, their benefits in patients with HF extend beyond glycemic control. SGLT2i improve cardiac function by reducing preload and afterload through osmotic diuresis and natriuresis, thereby decreasing intravascular volume and blood pressure. They also enhance myocardial efficiency by shifting substrate utilization from glucose to ketones, a more energy-efficient fuel for the heart under stress. Additionally, SGLT2i have anti-inflammatory and antifibrotic effects, reduce oxidative

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CCS Terms:HF according to LVEF

HFrEF(HFrEF(LVEF≤40%)

Previous Terms:HF according to LVEF

 Figure 1. The Canadian Cardiovascular Society (CCS)/Canadian Heart Failure Society (CHFS) nomenclature for heart failure (HF) stratified ac-cording to left ventricular ejection fraction (LVEF). The CCS has consolidated the 2 terms, heart failure with mildly reduced ejection fraction(HFmrEF) and heart failure with preserved ejection fraction (HFpEF) into a single unified term, heart failure with nonreduced ejection fraction(HFnrEF). Heart failure with improved ejection fraction, which includes patients with HF and LVEF, which has improved to >40%, is not specifically addressed in this guideline. HFrEF, heart failure with reduced ejection fraction.

  Figure 2. Simplified evidence-based treatment approach for reducing heart failure hospitalization(HHF) in people with heart failure with nonreduced ejection fraction(HFnrEF). Only evidence-based medications should be used for the treatment of heart failure(HF). The literature currently does not support a specific sequence to initiating therapy within a given treatment tier. The order of prescribing should be individualized on the basis of patient characteristics and through a shared decision-making approach.AF,atri fibrillation; ARNI,angiotensin receptor-nepriyslin inhibitor; BMI,body mass index;BP,blood pressure;CCS,Canadian Cardiovascular Society;CKD,chronic kidney disease;GLP-1,glucagon-like peptide-1;LVEF,left ventricular ejection fraction; MRA,mineralocorticoid receptor antagonist; SGLT2i, sodium-glucose cotransporter-2 inhibitor; VHD, valvular heart disease.

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Table 1. Evidence-based medications for the management of HFnrEF including starting and optimal target dose

|Drug class|Specific agent*|Starting dose|Target dose| |---|---|---|---| |SGLT2i|Dapagliflozin|10 mg daily|10 mg daily| ||Empagliflozin|10 mg daily|10-25 mg daily| |ARNI|Sacubitril-valsartan|24/26 mg or 49/51 mg twice daily|97/103 mg twice daily| |ARB|Candesartan|4-8 mg daily|32 mg daily| |MRA|Spironolactone|12.5-25 mg daily|25-50 mg daily| ||Eplerone|25 mg daily|50 mg daily| ||Finerenone|10-20 mg daily|20-40 mg daily| |GLP-1 receptor agonists|Semaglutide|0.25 mg once weekly|2.4 mg once weekly| ||Tirzepatide|2.5 mg once weekly|15 mg once weekly|

ARB, angiotensin receptor blocker; ARNI, angiotensin receptor-neprilysin inhibitor; GLP-1, glucagon-like peptide-1; HFnrEF, heart failure with nonreduced ejection fraction; MRA, mineralocorticoid receptor antagonist; SGLT2i, sodium-glucose cotransporter-2 inhibitors.

*Only specific evidence-based medications should be used for the treatment of patients with HF.

stress, and improve endothelial function, which collectively contribute to reverse cardiac remodelling.

Early trials, conducted in persons with T2DM and concomitant cardiovascular(CV) risk factors or established CV disease showed that SGLT2i, compared with placebo,reduced the risk of HFH and CV death. Subsequent ran-domized controlled trials(RCTs) showed benefits of this therapy for persons with established HF irrespective of dia-betes status, across a broad range of LVEF, and in those hospitalized for HF decompensation.

In the Dagapliflozin and Prevention of Adverse Outcomes in Heart Failure(DAPA-HF) ${}^{10}$ trial and the Empagliflozin Outcome Trial in Patients with Chronic Heart Failure and a Reduced Ejection Fraction(EMPEROR-Reduced),11 the efficacy and safety of SGLT2i in people with HFrEF irre-spective of diabetes status were evaluated. The results of these trials showed significant reductions in HFH and CV death among participants treated with SGLT2i, which established their role as a cornerstone of guideline-directed medical therapy for HFrEF.12

4.2. Relevant data in patients with HFnrEF

Building on the evidence for SGLT2i in patients with HFrEF, a second tranche of RCTs provided insight into the role of SGLT2i across a broader range of LVEF, including for persons with HF and improved LVEF(previously reduced); a cohort that had been excluded from previous trials.13

The Empagliflozin Outcome Trial in Patients with Chronic Heart Failure with Preserved Ejection Fraction(EMPEROR-PRESERVED) was the first phase 3 random-ized double-blind placebo-controlled trial to achieve its pri-mary end point in people with symptomatic HFnrEF.14 The composite of CV death or HFH was reduced in the cohort of patients randomized to empaglifzoin(hazard ratio[HR],0.79; 95% confidence interval[CI], 0.69-0.90). A total of 5988 participants were randomized with a median follow-up of 26 months. The primary end point was driven by a 29%reduction in first HFH without a significant reduction in CV death.

In the Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure

(DELIVER) trial dapagliflozin was compared with placebo in patients with symptomatic HFnrEF.15 The trial ran-domized 6263 participants with a median duration follow-up of 2.3 years. The primary outcome was a composite of unplanned HFH, an urgent visit for HF, or CV death. The primary outcome occurred in 16.4% of participants in the dapagliflozin group compared with 19.5% in the placebo group(HR, 0.82; 95% CI, 0.73-0.92). The primary end point was driven by a significant reduction in worsening HF events(HR, 0.79; 95% CI, 0.69-0.91) with a nonsignificant reduction in CV death. There was no heterogeneity in treatment effect for the primary end point according to sex,LVEF, or the presence of diabetes.

4.3. Meta-analysis for the guidelines

Our meta-analysis of SGLT2i included 7 RCTs and 13,454 participants with HFnrEF. Forest plots for outcomes of interest and adverse events(AEs) are shown in Supplemental Appendix S4.

There was no significant effect of SGLT2i on CV mor-tality. Treatment with SGLT2i was associated with a reduc-tion in HFH compared with standard of care(HR, 0.76;95% CI, 0.69-0.84), corresponding to 11 fewer HFHs per 1000 patients(95% CI, 14 fewer to 7 fewer).

There was a statistically significant improvement in functional status compared with standard of care, although the mean difference in the Kansas City Cardiomyopathy Questionnaire(KCCQ) overall summary score(OSS) of 1.70(95% CI, 0.33-3.07) was below what is accepted as a clini-cally important difference.

Six-minute walk distance(6MWD) was numerically improved by 7.15 m(95% CI,-4.1 to 18.4) in favour of SGLT2i, although only a small number of RCTs met criteria for inclusion and the magnitude of this improvement in 6MWD is also unlikely to be clinically meaningful.

Among participants with HFnrEF, there were no signifi-cant interactions between diabetes status, sex, or LVEF, and the effect of SGLT2i on the various outcomes evaluated in this meta-analysis.

Treatment with SGLT2i among participants with HFnrEF was not associated with a significant increase in AEs

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or serious AEs compared with standard of care(serious AEs HR, 0.95; 95% CI, 0.88-1.04). ${}^{16}$

4.4. Controversies and considerations

The Effect of Sotagliflozin on Cardiovascular Events in Patients with Type 2 Diabetes Post Worsening Heart Failure(SOLOIST-WHF) trial examined the role of sotagliflozin, a combination sodium-glucose cotransporter-1 inhibitor and sodium-glucose cotransporter-2 inhibitor, versus placebo in patients with T2DM and recently decompensated HF.16 The trial included patients who began therapy in the inpatient or outpatient setting. Most(79.1%) had an LVEF< 50%,however, outcomes specific to patients with HFnrEF were not reported. The primary end point was the total number of deaths from CV causes, HFH, and urgent visits for HF. The rate of primary end point events was 51.0 per 100 patient-years in the sotagliflozin group compared with 76.3 per 100 patient-years in the placebo group(HR, 0.67; 95% CI,0.52-0.85). The incidence of death from CV causes or death from any cause did not significantly differ between groups.Notably, data from the SOLOIST-WHF was not included in our meta-analysis. Sotagliflozin is not currently available in Canada.

The certainty of evidence regarding the clinical benefits of SGLT2i in patients with acute HF across the range of LVEF will be strengthened by several ongoing trials, including the large Dapagliflozin and Effect on Cardiovascular Events in Acute Heart Failure- Thrombolysis in Myocardial Infarction 68 (DAPA ACT HF-TIMI 68, NCT04363697).

RECOMMENDATION

1. We recommend the use of SGLT2i for people with symptomatic HF and LVEF> 40% to reduce the risk of HFH(Strong Recommendation; High-Quality Evidence).

Values and preferences. The Primary Panel's judge-ment was that the balance of desirable and undesirable effects was in favour of treatment with SGLT2i. Specif-ically, we believe that many patients with HFnrEF will place high value on reduction in HFH and this will outweigh potential AEs and costs that might be attributed to treatment with SGLT2i. ${}^{17,18}$ Additional data are needed to ensure we have accurately reflected the per-spectives of individuals with lived experience of HFnrEF regarding the risks and benefits of SGLT2i treatment.Similarly, contemporary Canadian data on the cost-effectiveness of SGLT2i as therapy across the spectrum of LVEF, and specifically for treatment of HFnrEF, are lacking and must be generated.

Practical tips:

● SGLT2i have a favourable safety profile in patients with HF across the spectrum of LVEF, with low to rare rates of AEs such as hypoglycemia, ketoacidosis,and renal impairment.

- The CCS has developed resources to support patients and providers on the safe prescribing and monitoring of patients receiving SGLT2i. Tools are available at https://ccs.ca/guideline/cardiorenal-2022.

5. MRAs

5.1. Why is this therapy relevant and what is its clinical significance?

Although HFnrEF is represented by heterogeneous patient phenotypes and disease processes, diastolic dysfunction is a common and consistent finding in many of these patients.MRAs improve diastolic function.19-21 Elevated aldosterone levels in the setting of HF result in significant pathophysio-logic effects on the heart, blood vessels, and kidneys. Aldo-sterone interacts with mineralocorticoid receptors (MRs) in the heart and blood vessels, which leads to endothelial dysfunction, myocardial fibrosis, and pathologic cardiac remodelling, which contributes to the development of HFnrEF. In the kidneys, aldosterone interacts with MRs,which leads to congestion by up-regulation of tubular sodium and water reabsorption, and excretion of potassium and magnesium. ${ }^{22}$ By interrupting these counter-regulatory cycles and physiologic processes, MRAs improve diastolic function and have established plausibility as an entity for further investigation in patients with HFnrEF.

5.2. Relevant data in patients with HFnrEF

The Treatment Of Preserved Cardiac function heart fail-ure with an Aldosterone anTagonist(TOPCAT) trial was designed to test the clinical benefit of spironolactone in symptomatic patients with HFpEF. The primary end point of CV death, HFH, or resuscitated cardiac arrest over 6 years was similar between the spironolactone and placebo arms(18.6% vs 20.4%; HR, 0.89; 95% CI, 95% 0.77-1.04).23A post-hoc analysis 24 showed a striking regional difference in the placebo event rates: 31.8% in the Americas vs 8.4% in Eastern Europe, which led to controversy about trial design,inclusion criteria, and the overall efficacy of MRAs in the treatment of patients with HFpEF.

The Finereneon in Heart Failure with Mildly Reduced or Preserved Ejection Fraction(FINEARTS-HF) trial was un-dertaken in the context of ongoing equipoise about the role of MRAs in patients with HFnrEF. FINEARTS-HF was a phase 3, randomized, double-blind, placebo-controlled, event-driven study in which the efficacy and safety of finerenone,a nonsteroidal MRA, was evaluated in patients with symp-tomatic HFnrEF. Treatment with finerenone significantly reduced the composite primary end point of CV death and total(first and recurrent) HF events compared with placebo.Over a median follow-up of 32 months, the rate ratio for the primary end point was 0.84(95% CI, 0.74-0.95), with the reduction primarily driven by fewer total worsening HF events(rate ratio, 0.82; 95% CI, 0.71-0.94).25

5.3. Meta-analysis for the guidelines

In our systematic review we identified 13 studies(see Supplemental Appendix S3); 9 RCTs were included in our meta-analysis and 4 studies were used for predetermined

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subgroup analyses. Epleroneen and spironolactone were the 2 steroidal MRAs tested in the included trials, and fineroneen was the only nonsteroidal MRA tested.

On the basis of our meta-analysis of patients with HFnrEF, MRA use did not improve CV mortality(HR,0.93; 95% CI, 0.85-1.02).

Because of its large study population and event rate, in-clusion of the recently published FINEARTS-HF trial25 improved precision and therefore certainty in the evidence for reduction of HFH with MRAs compared with placebo or standard of care. Before FINEARTS-HF, our meta-analysis showed a reduction in HFH favouring MRAs(HR, 0.82;95% CI, 0.69-0.98), corresponding to an absolute reduction of 25 fewer HFHs per 1000 patients with HFnRF(95% CI,42 fewer to 3 fewer). With the addition of FINEARTS-HF to our meta-analysis, the HR for HFH was essentially un-changed at 0.83(95% CI, 0.76-0.91) in favour of MRAs,corresponding to 29 fewer HFHs per 1000 patients(95% CI,41 fewer to 15 fewer).

MRA use did not improve New York Heart Association(NYHA) functional class(HR, 1.02; 95% CI, 0.91-1.13) or 6MWD(4.5 m; 95% CI,-21.03 to 30.03). There was a nonclinically significant improvement in QoL measured ac-cording to the KCCQ clinical summary score(CSS) among patients treated with MRAs vs placebo(1.71 points higher;95% CI, 0.95-2.47).

Compared with placebo or standard of care, MRA treat-ment was associated with more hyperkalemia(HR, 2.08;95% CI,1.85-2.34) and worsening renal function(HR, 1.57;95% CI,1.33-1.85); however, there was no difference in the rate of MRA withdrawal compared with placebo for adverse effects(HR, 1.04; 95% CI, 0.97-1.12). The absence of increased mortality(and trend toward reduced mortality)associated with MRAs is reassuring in the context of the observed risk of hyperkalemia and renal dysfunction.

Overall credibility for subgroup analysis was deemed low using the Instrument to assess the Cibility of Effect Modification Analyses(ICEMAN) instrument. A meta-analysis that pooled individual patient-level data including TOPCAT and FINEARTS-HF showed nonsig-nificant P values for interaction on the basis of sex, LVEF<50% vs≥50%, and geographic region.26 In the TOPCAT trial, there was heterogeneity in mortality benefit with MRA use vs placebo for women compared with men; in our anal-ysis, CV mortality did not reach statistical significance for a subgroup effect according to sex.

In the TOPCAT trial, LVEF had a significant effect modification on HFH and on the combined primary end point with the greatest risk reduction at a lower range of LVEF.27 This benefit was not observed in our meta-analysis. For a previous subgroup analysis regarding geographic variation in the TOPCAT trial, we refer the reader to the CCS 2017 HF guidelines, in which this topic is specifically discussed.

The final subgroup of interest focused on patients with diabetic kidney disease(DKD). The Finerenone in Reducing Cardiovascular Mortality and Morbidity in Dia-betic Kidney Disease(FIGARO-DKD) trial enrolled pa-tients with T2DM and albuminuric chronic kidney disease period. The study demonstrated a reduction in the com-posite primary endpoint of death from CV causes, nonfatal myocardial infarction, nonfatal stroke, or HFH in patients randomized to finerenone. In a prespecified subgroup analysis, the beneficial effects of finerenone were not modified by a history of HF.28,29

5.4. Controversies and considerations

Overall, the primary panel believes the balance of desirable and undesirable effects for symptomatic patients with HFnrEF favours MRAs over the comparator, placebo or standard of care, to reduce HFH.

Our understanding of the resources required for imple-mentation of MRAs in clinical care are informed by existing practice patterns and established care processes; steroidal MRAs are widely accessible, affordable, and already used routinely in the management of patients with HF across the spectrum of LVEF(Figure 3).23,25,30,31

A US cost-effectiveness study assigned high value to the use of spironolactone in this population, after modelling their analysis on the TOPCAT trial.32 The costs and accessibility of finerenone remain unclear, and the lack of head-to-head comparisons between steroidal and nonste-roidal MRAs prevented the panel from assessing their rela-tive cost-effectiveness.

Two RCTs designed to assess the efficacy of spi-ronolactone in patients with HFnrEF are currently under way: Spironolactone in the Treatment of Heart Failure(SPIRIT-HF; NCT04727073) and Spironolactone Initia-tion Registry Randomized Interventional Trial in Heart Failure With Preserved Ejection Fraction(SPIRRIT; NCT 02901184). A Study to Determine the Efficacy and Safety of Finerenone and SGLT2i in Combination in Hospitalized Patients With Heart Failure(CONFIRMATION-HF;NCT06024746) will establish data on the potential benefit of SGLT2i in reducing hyperkalemia when used in combi-nation with MRAs among patients with HFnrEF and may guide our understanding of optimal combination regimens and prescribing strategies. Along with A Study to Ran-domized Trial to Determine the Efficacy and Safety of Finerenone on Morbidity and Mortality Among Heart Failure Patients With Left Ventricular Ejection Fraction Greater Than or Equal to 40% Hospitalized Due to an Episode of Acute Decompensated Heart Failure (REDE-FINE-HF; NCT06008197), these studies will inform our approach to patients with HFnrEF and HFH in guiding the optimal timing of treatment initiation.

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|Population|Spironolactone|Eplerenone|Finerenone|Up-titration and Monitoring Considerations| |---|---|---|---|---| |Starting dose for patients with normal kidney function (eGFR≥ 60 mL/min/1.73 m2)|12.5-25 mg daily|25 mg daily|20 mg daily|Perform bloodwork for renal function and electrolytes 1 week after initiation and after any dose change.| |Starting dose for patients with impaired kidney function (eGFR 30-59 mL/min/1.73 m2)|12.5 mg daily|12.5 mg daily|10 mg daily|Check renal function and electrolytes after any change in other medication or intercurrent illness that could influence renal function and/or electrolytes.| |Starting dose for patients with impaired kidney function (eGFR 30-59 mL/min/1.73 m2)|12.5 mg daily|12.5 mg daily|10 mg daily|Regular surveillance of renal function and electrolytes in the stable patient receiving stable dose of MRA is recommended; consider checking these parameters every 3 months. Consider increasing the dose of MRA every 2-4 weeks until target dose achieved, if: ● Serum and/or plasma potassium<5.0 mmol/L and, ● eGFR>30 mL/min/1.73 m2 and, ● Systolic BP>95 mm Hg without symptoms of hypotension| |Target dose|25-50 mg daily|50 mg daily|eGFR≥ 60 mL/min/1.73 m2 40 mg daily eGFR 30-59 59 mL/min/1.73 m2 20 mg daily|• Serum creatinine increases by >30%, or • Potassium >5.4 mmol/L, or Symptomatic hypotension|

Figure 3. Mineralocorticoid receptor antagonist(MRA) dosing and up-titration schedule for patients with heart failure with nonreduced ejection fraction(HFEnrE). ${}^{23,25,30,31}$ eGFR, estimated glomerular filtration rate.

RECOMMENDATION

2. We recommend the use of MRAs for people with symptomatic HF and LVEF> 40% to reduce the risk of HFH(Strong Recommendation; High-Quality Evidence).

Values and preferences. Steroidal MRAs directly block MRs; spironolactone, in particular, has a strong affinity for other steroid receptors including androgen and progesterone receptors, which lead to well-known adverse effects including gynecomastia and impotence. In contrast, finer-enone, a nonsteroidal MRA, has different pharmacologic properties including greater selectivity for MRs, thus mini-mizing off-target effects. ${}^{33,34}$ The absence of head-to-head trials preclude our ability to distinguish whether steroidal vs nonsteroidal MRAs are different from an efficacy perspective and whether their benefits extend to a class effect.Similarly, there are no cost-effective analyses, in the Cana-dian context, that have compared these agents to guide our values and preferences. The panel acknowledges that ste-roidal MRAs are widely accessible and generally affordable.

Practical tips:

● Close surveillance of renal function and potassium is recommended for patients receiving steroidal and nonsteroidal MRAs, because both are associated with a risk of hyperkalemia.

● The CCS has developed a suggested approach for management of hyperkalemia. This resource can be found as Table 13 at https://onlinecjc.ca/article/S0828-282X(17)30973-X/fulltext.7

● The starting dose, titration, and monitoring schedule for MRAs as well as additional practical tips for providers are highlighted in Figure 3.

● Spironolactone and eplerone should not be initi-ated in patients with an estimated glomerular filtration rate(eGFR)<30 mL/min/1.73 m2 and finerone should not be initiated in patients with and eGFR< 25 mL/min/1.73 m2. MRAs should not be initiated in patients with a serum and/or plasma potassium level> 5.0 mmol/L.

● Monitoring of serum creatinine and potassium should occur within 1 week of treatment initiation or dose change.

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● MRAs can increase serum potassium levels, especially during an acute dehydrating illness in which renal dysfunction can worsen. Closer monitoring of renal function and potassium is required in these situations.

● Most trials that have compared MRAs with placebo in patients with HF followed creatinine and elec-trolytes levels every 3 months. Regular surveillance of potassium and renal function in the stable patient receiving a stable dose of MRA should be adapted to individual risk of hyperkalemia and renal dysfunction.

● In patients with DKD, finnerone may be prioritized as the MRA of choice, if accessible and affordable,because there is high-quality evidence to support the use of this agent in improving CV and kidney outcomes.

- In patients with an eGFR< 60 mL/min/1.73 m2 the starting dose of finnerone is 10 mg orally daily with a maximum dose of 20 mg orally daily. In patients with an eGFR≥ 60 mL/min/1.73 m2 the dose of finnerone is 20 mg orally daily with a maximum dose of 40 mg orally daily. Target doses in HFnrEF are higher than for patients with DKD without HFnrEF.

At the time this guideline was submitted for publi-cation, finerenone was under Health Canada review for indication as a treatment for HF.

6. ARNI

6.1. Why is this therapy relevant and what is its clinical significance?

Sacubitril-valsartan, a first-in-class ARNI, represents an important advance over angiotensin-converting enzyme in-hibitors(ACEi) or angiotensin II receptor blockers(ARBs)alone. In addition to angiotensin II receptor blockade, ARNIs increase natriuretic peptide(NP) levels, resulting in addi-tional vasodilation, diuresis, and natriuresis; they have bene-ficial effects in cardiac remodelling and enhance cardiomyocyte survival. 35,36 ARNI is more effective than enalapril at decreasing CV death, HFH, and symptom burden, in patients with either de novo or chronic HFEr.37-39 Although renin-angiotensin-aldosterone system activation is a purported pathophysiological mechanism in patients with HFnrEF, clinical trials to date have not shown definitive benefits in patients with symptoms and an LVEF> 40%.41-43

6.2. Relevant data in patients with HFnrEF

To our knowledge, there is no specific trial of ARNIs in patients comprising the full HFnrEF spectrum that examined our outcomes of interest. The efficacy of ARNIs in our analysis is extrapolated on the basis of post hoc or subgroup analyses of clinical trials that included patients with HF and LVEF> 40%. Notably, patients who initially had HFrEF

and subsequently realized improvement in LVEF to> 40%were excluded from these trials.

6.3. Meta-analysis for the guidelines

Our meta-analysis showed that ARNI use did not improve CV death(HR, 0.83; 95% CI, 0.52-1.32) in patients with HFnrEF(Supplemental Appendix S2).

With respect to HFH, 4 trials were included in our meta-analysis; the 3 largest studies were Changes in NT-proBNP and Outcomes, Safety, and Tolerability in HFEF Patients With Acute Compensated Heart Failure Who Have Been Stabilized During Hospitalization and Initiated In-hospital or Within 30 Days Post-discharge(Prospective comparison of ARNI with ARB Given following stabilization In DEcompensated HFpEF [PARAGLIDE]) trial,41 Angio-tensin Receptor Neprysulin Inhibition in Heart Failure With Preserved Ejection Fraction (PARAGON-HF) trial,42 and the Prospective Comparison of ARNI vs Comorbidity-Associated Conventional Therapy on Quality of Life and Exercise Ca-pacity (PARALLAX) trial.43 The results of our meta-analysis showed moderate certainty that use of ARNI leads to a small reduction in HFH (HR, 0.89; 95% CI, 0.81-0.98) corre-sponding to 20 fewer HFHs per 1000 patients (95% CI: from 34 fewer to 4 fewer HFHs per 1000 patients).

With respect to symptoms, we showed no statistically significant benefit for ARNI with respect to NYHA func-tional class, 6MWD, or QoL.

Prespecified subgroup analyses of the PARAGON-HF trial suggested there might be differences in the effect of ARNI on the basis of LVEF and sex.42 In our analysis, sex was a moderately credible subgroup, suggestive that ARNI might be of more benefit in women than in men with respect to reducing HFH. This finding was primarily related to a reduction in recurrent HFH in women compared with that in men. In contrast, a treatment effect with ARNI is consistent across LVEF subgroups, although exploratory analyses from trials suggest that treatment effect is attenuated as EF increases.

Our meta-analysis of PARAGLIDE, PARAGON-HF, and PARALLAX showed that ARNI use is associated with more hypotension(HR, 1.80; 95% CI, 1.23-2.63) compared with use of ACEi/ARBs, and angioedema(HR, 2.15; 95% CI,1.00-4.65) compared with ACEi treatment alone. Notably,use of ARNI resulted in comparable rates of hyperkalemia(HR,0.95;95% CI,0.82-1.10) and worsening renal function(HR, 0.88; 95% CI, 0.68-1.14) compared with use of ACEi/ARBs in this population.

6.4. Controversies and considerations

Access to treatment with ARNI varies across Canada with differential coverage on the basis of provincial formularies and drug plans; cost of the medication might be a barrier for many people living with HF. Cost-effectiveness modelling suggests an incremental cost-effective ratio for treatment with sacrilubartan vs renin-angiotensin-aldosterone system inhibitors consistent with high economic value for patients with LVEF≤ 50% and intermediate value at the current undiscounted wholesale acquisition cost price for those with an LVEF≤ 60%. In the United States, cost-effectiveness

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modelling in the HFEF population showed that use of ARNI was low value; however, projections with generic pricing substantially increased its value. ${ }^{32}$ In the absence of a robust Canadian cost-effectiveness analysis, it is unknown whether universal access to ARNI for patients with HFnEF is cost-effective at a system level through reduction in HFH and whether this assessment might be further attenuated with access to generic formulations.

RECOMMENDATION

3. We suggest the use of ARNI for people with symptomatic HF and LVEF> 40%, who are at low risk of symptomatic hypotension to reduce the risk of HFH(Weak Recommendation; Moderate-Quality Evidence).

Values and preferences. There is little evidence con-cerning patient values and preferences in this population.One small study of 48 patients with HFpEF suggested that survival and avoidance of unplanned hospitalizations are valued more than avoidance of medication side effects. ${ }^{17}$ As such, we believe that reducing HFH by an estimated 20 per 1000 is likely to be more valuable to patients than an increased risk of hypotension by 74 per 1000, particularly because the blood pressure-lowering effects of ARNI can be mitigated by other strategies. Although frailty is a growing concern with an aging population, and the risk-benefit profile of ARNI might be perceived as less favourable in frail individuals, evidence suggests that the use of ARNI in this population might result in a greater reduction in total HFHs and CV deaths compared with valstaran alone.47 When the frailty index was examined as a continuous variable, interaction with treatment was significant for the primary outcome(P for interaction = 0.002) and total HFH(P for interaction< 0.001); in lay terms, the fralest derived the greatest benefit from treatment with ARNI.Overall, we believe that the balance of desirable and un-desirable effects for people who have symptomatic HFnrEF favours ARNI over the comparison.

Practical tips:

● The starting dose, titration, and monitoring schedule for patients receiving ARNI as well as additional practical tips for providers are highlighted in Figure 4.7,48-50

● Because of concerns regarding hypotension with the use of ARNI, caution should be used in starting ARNI treatment if the patient's systolic blood pres-sure is $<100~mm Hg.{}^{51}$

● Medications that might decrease blood pressure should be staggered to avoid symptomatic hypotension.

● Consider either reducing or discontinuing antihiy-pertensive medications, particularly if they have no other indication beyond blood pressure-lowering. ${ }^{20}$

● Because of the diuretic effect of ARNI, consider decreasing or discontinuing loop diuretics in patients who are already euolemic or hypovolemic before starting ARNI therapy, to prevent symptomatic hypo-tension and renal dysfunction from dehydration.

● Drug tolerability, side effects, and laboratory moni-toring of patients receiving ARNI is similar to that for patients receiving ACEi or ARBs.

•Appropriate clinical and laboratory follow-up(renal function and electrolytes) is essential after initiating or titrating ARNI therapy to monitor for AEs

● To our knowledge, to date no clinical trial has informed a strong recommendation for use of ACEi in this patient population. Consider candesartan, per existing CCS HF guidelines, if sacubitril-valsartan is not available, accessible, or tolerated.

7. Evidence-Based Drugs With GLP-1 Receptor Agonist Activity

7.1. Why is this therapy relevant and what is its clinical significance?

GLP-1 receptor agonists, initially developed for the management of T2DM, have recently generated significant interest for their potential benefits in patients with HFnrEF,particularly among those with an associated obesity car-diometabolic phenotype. ${}^{52}$ Notably, approximately 80% of patients with HFnrEF are overweight (body mass index[BMI] $\geq 25$ ) or obese (BMI $\geq 30$ ) ${}^{53}$ and one-third have diabetes.

Individuals with obesity and HFnrEF have excessive epicardial adipose tissue55 and more advanced right ventricular dysfunction than nonobese patients. The role of adipose tissue is central in cardiometabolic HFnrEF pathophysiology,56 it induces systemic inflammation with uptake of fatty acids by cardiomyocytes, which leads to myocardial dysfunction.Excessive epicardial adipose tissue might also contribute to mechanical pericardial constraint, 55 promote fibrosis though secretion of soluble factors, and increase plasma volume due to disproportionate systemic vasodilation and sodium retention. 57 Furthermore, obesity itself contributes to several adverse physiologic effects, including increased left ventricular stiffness and hypertrophy, elevated intracardiac filling pressures,58,59 increased incidence of atrial fibrillation,60 impaired systolic reserve with exercise, 57,58,61 and decreased longitudinal strain 55 suggestive of subclinical systolic dysfunction.

increased incidence of atrial fibrillation, ${}^{60}$ impaired systolic reserve with exercise, ${}^{57,58,61}$ and decreased longitudinal strain ${}^{55}$ suggestive of subclinical systolic dysfunction.

GLP-1 is an incretin hormone that stimulates insulin secretion in response to glucose, which leads to improved glycemic control. Drugs with GLP-1 receptor agonist activity mimic this action, reduce glucagon secretion, delay gastric emptying, and augment satiety, with beneficial effects on CV risk factors. ${ }^{62}$ Drugs with GLP-1 receptor agonist activity

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|Population|Starting Dose of Sacubitril-Valsartan|Up-titration and Monitoring Considerations| |---|---|---| |Patients receiving high dose ACEi:● Enalapril≥10 mg/daily ● Lisinopril≥10 mg/daily ● Perindopril≥4 mg/daily ● Ramipril≥5 mg/daily ● Lisinopril≥10 mg/daily|36-Hour washout, then start 49/51 mg twice daily|Check serum creatinine, potassium, and blood pressure 1 week after ARNI initiation| |Patients receiving high dose ARB:● Candesartan≥16 mg/daily ● Irbesartan≥150 mg/daily ● Losartan≥50 mg/daily ● Olmesartan≥10 mg/daily ● Telmisartan≥40 mg/daily ● Valsartan≥160 mg/daily|Start 49/51 mg twice daily (No washout period needed for patients already receiving an ARB)|Check serum creatinine, potassium, and blood pressure 1 week after ARNI initiation $$\begin{array}{l}\text{ Check serum creatinine, potassium, and}\\ \text{ blood pressure 1 week after ARNI initiation}\\ \text{ If stable creatinine, potassium, and}\\ \text{ SBP}\geq 100~mm\text{ Hg, increase dose every}\\ 2-4\text{ weeks to target dose of 97/103 mg}\\ \text{ twice daily}\end{array}$$| |Patients receiving low- or medium-dose ACEi, low- or medium-dose ARB, or those who are ACEi/ARB naive|36-Hour washout if on ACEi then start 24/26 mg twice daily (No washout period needed for patients already receiving an ARB)|Consider decreasing or stopping sacubitril-valsartan, if: ● Serum creatinine increases by >30%, or ● Potassium>5.4 mmol/L ● Symptomatic hypotension| |Severe kidney impairment (eGFR<30 mL/min/1.73 m2)|24/26 mg twice daily|| |Elderly patients(age>75 years)|24/26 mg twice daily|24/26 mg twice daily| |Moderate hepatic impairment (Child-Pugh class B)|24/26 mg twice daily|24/26 mg twice daily| |Systolic blood pressure ≥120 mm Hg|49/51 mg twice daily 24/26 mg twice daily|| |≥100-120 mm Hg|24/26 mg twice daily|24/26 mg twice daily|

Figure 4. Angiotensin receptor-neprilysin inhibitor(ARNI) dosing and up-titration schedule for patients with heart failure with nonreduced ejection fraction(HFnrEF). 7,48-50 ACEi, angiotensin converting enzyme inhibitors; ARB, angiotensin II receptor blocker; eGFR, estimated glomerular filtration rate; SBP, systolic blood pressure.

have been shown to reduce major adverse CV events in pa-tients with T2DM, who are at high risk for atherosclerotic CV events. More recently, in the Semaglutide Effects on Cardiovascular Outcomes in People with Overweight or Obesity(SELECT) trial, semaglutide was shown to reduce the risk of the combined end point of CV death or nonfatal myocardial infarction or stroke $(HR, 0.80; 95\% CI, 0.72-$ 0.90) among patients without T2DM who had a BMI $>27$ and preexisting atherosclerotic CV disease. ${}^{63}$

7.2. Relevant data in patients with HFnrEF

Drugs with GLP-1 receptor agonist activity have been pro-spectively tested in the management of patients with HFnrEF in 2 double-blind RCTs: Semaglutide Treatment Effect in People with Obesity and HFpEF (STEP-HpEF) and Semaglutide Treatment Effect in People with Obesity and HFpEF EM) in people without and with T2DM, respectively. ${}^{64-66}$ Both trials included

patients with obesity, symptomatic HF(NYHA class 2-4), and LVEF≥45%, plus either elevated intracardiac filling pressures,elevated NP levels with echocardiographic abnormalities, or HFH within the previous 12 months. Patients in both trials were mostly white, approximately half were female, with a mean age of 69 years, and median BMI of 37(median weight, 103-105 kg). Patients were randomized to placebo or semaglutide 0.25 mg subcutaneously(sc) once weekly and titrated every 4 weeks according to the Health Canada-approved dosing regimen for weight management(available at https://pdf.hres.ca/dpd_pm/00071443.PDF).

Co-primary outcomes were weight loss and change in heart failure-related symptoms and physical limitations measured using the KCCQ CSS. In pooled results from the 2 trials, at 1 year smelulotide use reduced weight by an average of 8.4%(-9.2% to-7.5%) and improved the KCCQ CSS by 7.5(95% CI, 5.3-9.8) points vs placebo. The major adverse effect noted was increased rate of semaglutide discontinuation because of gastrointestinal side effects(10.7 per 100 person-

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years) compared with placebo(3.3 per 100 patient-years).67 In an exploratory analysis, semagulotide also improved the secondary end point of 6MWD by 17.1 m(95% CI, 9.2-25.0) compared with placebo, and reduced HF events(HFH or urgent outpatient visit for HF) by 3.6 per 100 patient-years(HR, 0.27; 95% CI, 0.12-0.56).

An additional pooled analysis that included the HFpEF subgroups of the SELECT trial(2273/17,604 patients[12.9% of the study population]), the smaller Evaluate Renal Function with Semaglutide Once Weekly(FLOW) trial and patients enrolled in the STEP-HpEF/STEP-HpEF EM trials, suggested a beneficial effect of semaglutide on HF events. This post hoc analysis showed a reduction in the risk of the combined end point of CV death or worsening HF events favouring semaglutide compared with placebo(HR, 0.69;95% CI, 0.53-0.89). ${}^{68}$

7.3. Meta-analysis for the guidelines

Our meta-analysis of drugs with GLP-1 receptor agonist activity initially included 9 RCTs and 3527 patients with HF,irrespective of LVEF.67 We focused on the subgroup of pa-tients with HFnrEF, which included the STEP-HFpEF and STEP-HFpEF DM RCTs. Both trials enrolled patients with an LVEF≥ 45%. Forest plots for outcomes of interest and AEs are shown in Supplemental Appendix S5.

Results were congruent with the previously published pooled analysis of the STEP-HFpEF and STEP-HFpEF DM trials. Specifically, there was no significant effect of sem-aglulide on overall mortality or CV mortality. Semaglutide treatment was associated with a reduction in HFH compared with placebo(relative risk, 0.24; 95% CI, 0.06-0.99) corre-sponding to 52 fewer HFHs per 1000 patients(95% CI,from 64 fewer to 1 fewer).

There was a statistically significant improvement in heart failure-related overall health status compared with placebo,with a mean difference in KCCQ OSS of 7.39(95% CI,4.79-10), which is believed to be a clinically important difference.

Use of drugs with GLP-1 receptor agonist activity among patients with LVEF≥ 45% was not associated with a sig-nificant increase in serious AEs compared with placebo or drug discontinuation due to AEs.

7.4. Controversies and considerations

After completion of our systematic review, the Tirzepa-tide in Participants with Heart Failure with Preserved Ejection Fraction and Obesity(SUMMIT) trial showed a reduction in a composite of HF outcomes(urgent outpa-tient visit for HF, HFH, oral diuretic intensification, or CV death) among patients with LVEF≥ 50% and BMI≥ 30 who were receiving tirepatide, a dual GLP-1 receptor agonist and glucose-dependent insulinotropic polypeptide receptor agonist, compared with standard of care. This therapy showed a 38% relative risk reduction in time to first occurrence of HF event at a median follow-up of 104 weeks(HR, 0.62; 95% CI, 0.41-0.95). KCCQ CSS was also significantly improved. ${}^{69}$

Although existing data provide valuable insight into the benefit of drugs with GLP-1 receptor agonist activity for improving functional outcomes and symptoms in patients with obesity and HFnrEF, further research is needed to better define subgroups of patients for whom this class of medications might be most appropriate. It remains unclear whether benefits observed in the current clinical trials relate to the degree of weight loss per se, changes in intracardiac pressures and volume status in obese patients, or yet-to-be-elucidated effects on the underlying pathophysiology responsible for HFnrEF. The significant decrease in NP levels despite decrease in body weight suggest a mechanistic benefit beyond pure weight loss.Further mechanistic insight would be useful for understanding the potential role of drugs with GLP-1 receptor agonist activity in nonobse patients, those with lesser degrees of weight loss during treatment, and even among those with HFrEF.

Current trials have shown promise in well-characterized populations of patients with the overweight and/or obese HFnrEF phenotype.65,66,69 As is the case in many RCTs,trials to date have included predominantly white patients,which limits the generalizability of findings. Among patients without established T2DM, rates of concomitant treatment with SGLT2i have been very low, and it is unclear whether broader uptake of SGLT2i in patients with HFnrEF will attenuate the observed benefits of drugs with GLP-1 receptor agonist activity in this group.

Further studies will be required to address these areas of uncertainty, and results will likely influence the strength of any further recommendation for drugs with GLP-1 receptor agonist activity in the management of patients with HFnrEF.It is highly probable that additional clinical trial data will be generated to support the use of novel agents within this class for the treatment of patients with HFnrEF.

RECOMMENDATION

4. We suggest the use of evidence-based drugs with GLP-1 receptor agonist activity and with proven efficacy for people with symptomatic HF, LVEF≥45%, and body mass index≥30 kg/m2 to reduce the risk of HFH and to improve QoL(Weak Recommendation; Moderate-Quality Evidence).

Values and preferences. This recommendation places high value on interventions to reduce the risk of wors-ening HF events and improve QoL in patients with obesity and HFnrEF relative to the risks of adverse treatment-related effects. We acknowledge that there is uncertainty with respect to cost-effectiveness and acces-sibility for all patients in Canada with HFnrEF.

This recommendation also assumes that patients will place a high value on achieving the clinical outcomes observed in RCTs of drugs with GLP-1 receptor agonist activity including weight loss, reduced risk of HFH, and improved QoL, balanced against the requirement for pa-tients to receive an injectable therapy.

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Practical tips:

- Figure 4 highlights a practical approach to the use of evidence-based drugs with GLP-1 receptor agonist activity in people with HFnrEF. 7,48-50,70

● Clinicians should become comfortable discussing the potential benefits of treatment with drugs that have GLP-1 receptor agonist activity for all patients with obesity and HFnrEF; they should offer treatment for appropriate patients, and work with them to overcome barriers to receive therapy, including cost and insur-ance coverage.

● The 5As framework(ask, assess, advise, agree, and assist) provides a useful foundation for clinicians when discussing weight management with patients.Please also refer to the Obesity Canada guidelines. ${}^{71}$

● Individuals prescribed evidence-based drugs with GLP-1 receptor agonist activity can lose 10\% or more of their muscle mass. This is an evolving area of research, and some clinicians are advising healthy di-etary intake as well as regular exercise in an attempt to avoid muscle loss. Further research will better inform this strategy.

- In RCTs, $>80\%$ of patients with obesity and HFpEF achieved the target dose of semaglutide 2.4 mg weekly with protocolized, standardized titration. The starting dose of semaglutide in clinical trials was 0.25 mg weekly and titrated every 4 weeks as tolerated, with the target dose achieved by 16 weeks. If side effects such as gastrointestinal upset limit tolerability, dose reduction or a slower titration schedule can be considered with clinical reassessment. Although 2.4 mg weekly of sem-aglitude was the target dose in clinical trials, the mini-mally effective dose that leads to clinical benefit in obese patients with HFnEF is currently unknown. A typical titration scheduled is as follows(per Health Canada-approved dosing and titration schedule for overweight and/or obesity indication):

● 0.25 mg once weekly sc for 4 weeks

● 0.5 mg once weekly sc for 4 weeks

-1 mg once weekly sc for 4 weeks

● 1.7 mg once weekly sc for 4 weeks

● 2.4 mg once weekly sc

The up-titration schedule for tirepatide in the SUMMIT trial protocol is as follows (pending Health Canada approval for overweight and/or obesity indication at time of guideline submission):

● 2.5 mg once weekly sc for 4 weeks

● 5 mg once weekly sc for 4 weeks

● 10 mg once weekly sc for 4 weeks

● 12.5 mg once weekly sc for 4 weeks

● 15 mg once weekly sc

8. Other Pharmacological Considerations in Patients With HFnrEF

Only pharmacological therapies with proven efficacy for improving outcomes should be used for the purpose of treating patients with HFnrEF.

There is no indication for $\beta$ -blockers (BB) in the man-agement of HFnrEF. Specifically, no RCT of BB has shown benefit in a population of HF patients with an LVEF> 40%.Nonetheless, baseline characteristics in contemporary clinical trials continue to reflect high utilization of BB in patients with HFnrEF,14,15,25,42,64 likely related to the treatment of cardiac comorbidities such as atrial fibrillation and coronary artery disease.

Hypertension is a well established cause and exacer-bating condition in patients with HFnrEF. A previous iteration of the CCS HF guidelines highlighted the importance of controlling systolic and diastolic blood pressure on the basis of contemporary hypertension treat-ment guidelines.7 Landesartan specifically has shown effi-cacy as a blood pressure-lowering agent ${}^{72}$ and for reducing HFH.73,74 As such, candesartan should be considered the preferred renin-angiotensin system inhibitor in patients with HFnrEF who are ineligible or unable to be treated with ARNI.

RECOMMENDATION

We draw the reader's attention to established recom-mendations for treatment of HFpEF as well as the un-derpinning evidence for these recommendations, which can be found at https://onlinejc.ca/article/S0828-282X(17)30973-X/fulltext. The following recommendations are unchanged and for ease of reference are numbered to align with the 2017 Comprehensive Update of the Ca-nadian Cardiovascular Society Guidelines for the Man-agement of Heart Failure":

46. We suggest candesartan be considered to reduce HFH in patients with HFpEF (Weak Recom-mendation; Moderate-Quality Evidence).

47. We recommend and systolic and/or diastolic hyperten-sion be controlled according to current Canadian Hypertension Education Program hypertension guidelines(2017; http://www.onlinejc.ca/article/S0828-282X(17)30110-1/abstract) to prevent and treat HFpEF (Strong Recommendation; High-Quality Evidence).

48. We recommend loop diuretics be used to control symptoms of congestion and peripheral edema(Strong Recommendation; Moderate-Quality Evidence).

Practical tips

● Every attempt should be made to use specific evidence-based drugs, proven to be beneficial in clinical trials, at their target doses as optimal guideline-directed medical therapy (GDMT). If these doses cannot be achieved, the maximally tolerated dose is acceptable.

- Table 2 includes a list of common drugs to be avoided in patients with HF. ${ }^{75}$

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Table 2. Medications that can cause or worsen HF

|Type|Medications| |---|---| |Medications that can cause fluid retention|● Corticosteroids ● COX-2 inhibitors (eg, clecoxib) ● Gabapentinoids (eg, gabapentin and pregabalin) ● Thiazolidinediones (eg, pilogitazone) ● NSAIDs (including ASA at doses of≥325 mg/d, but excluding topical products) ● Black licorice ● Kelp| |Medications that can cause fluid retention|● BLC| |Medications that can cause fluid retention|● Certain antiarrhythmic drugs (eg, dro-nedarone, flecanide, profapenone) ● Certain calcium-channel blockers (eg, diltiazem, verapamil) ●β-blocker eye drops (rare, but usually associated with incorrect use) ● Carbamazepine(overdose) ● Itraconazole ●Tricyclic antidepressants (overdose)| |Oral medications with high sodium content|Sodium polystyrene sulfonate (1500 mg of sodium per 15 g dose) ● Sodium zirconium cytosilicate (800 mg of sodium per 10 g dose) ● Polyethylene glycol-electrolyte solution (1500 mg of sodium per 1 L)| |Medications with a miscellaneous mechanism of toxicity|● Central nervous system Bromopriptine (eg, doxorubicin) Clozapine (myocarditis) Lithium Sympathomimetics (eg, amphet-amines, methylphenidate, cocaine)| |Medications with a miscellaneous mechanism of toxicity|● Diabetes Saxagliptin (other DPP4 inhibitors have not been associated with an increased risk of HF) ● Rheumatology Hydroxychloroquine (acquired lyso- somal storage disorder) Tumour necrosis factor inhibitors (eg, infliximab)| |Oncology drugs|● Anthracyclines (eg, doxorubicin) Antimetabolites (eg, 5-fluorouracil) Alkylating agents (eg, cyclophosphamide) Anti-HER2 agents (eg, trastuzumab, pertuzumab) Interferons ● Interleukin-2 ●Taxanes (eg, paclitaxel)|

ASA, acetylsalicylic acid; COX-2, cyclooxygenase 2; DPP4, dipeptidyl peptidase; HER2, human epidermal growth factor receptor 2; NSAID, non-steroidal anti-inflammatory drug.

Adapted from Canadian Family Physician (75). Copyright 2025 (c) The College of Family Physicians of Canada. Reproduced with permission.

Conclusion

The 2025 CCS/CHFS guideline for the pharmacological management of HFnrEF(LVEF> 40%) introduces a transformative approach to managing this increasingly prev-alent condition, specifically addressing a previously under-treated population at high risk of adverse outcomes. This guideline provides an innovative and structured approach to treatment with 4 targeted pharmacological therapies, each

Table 3. Effect of contemporary therapies for treatment of HFnrEF on important outcomes of interest

|Agent|HFH|KCCQ|6MWD| |---|---|---|---| |SGLT2i|||| |MRA|√||| |ARNI|√||| |Evidence based GLP-1 receptor agonists|√|||

Effect is determined on the basis of statistically significant end points from meta-analyses (please refer to Supplementary Material). Refers to efficacy for indicated outcome.

ARNI, angiotensin receptor-neprilysin inhibitor; GLP-1, glucagon-like peptide-1; HHF, heart failure hospitalization; HFnrEF, heart failure with nonreduced ejection fraction; KCCQ, Kansas City Cardiomyopathy Ques-tionnaire; MRA, mineralocortic receptor antagonist; 6MWD, six-minute walk distance; SGLT2i, sodium-glucose cotransporter-2 inhibitors.

offering potential to significantly alter the care landscape for these patients by reducing HFH and/or improving QoL.

Drawing upon evidence from recent trials and meta-analyses, this guideline emphasizes the thoughtful inclusion of SGLT2i, MRAs, ARNI, and evidence-based drugs with GLP-1 receptor agonist activity as core components of HFnrEF management. SGLT2i and MRAs show strong ev-idence for reducing HFH with favourable safety profiles.Meanwhile, ARNI and evidence-based drugs with GLP-1 receptor agonist activity represent innovative stepwise addi-tions: ARNI as a selective option for patients at lower risk of symptomatic hypotension, and evidence-based GLP-1 re-ceptor agonists for individuals with obesity and LVEF≥ 45%(Tables 3 and 4). This therapeutic mix underscores a para-digm shift by providing practitioners with a structured al-gorithm to guide care plans, creating a template for treatment milestones and a mechanism to standardize quality improvement measures.

The guideline advances an integrated, patient-centred care model, that emphasizes shared decision-making and indi-vidualized treatment plans. It encourages clinicians to align therapeutic choices with patient values and preferences,acknowledging the varying risks, side effects, and costs of these therapies. By reducing treatment variability and addressing care gaps, this approach aims to ensure all eligible patients can access the benefits of modern HFnrEF therapies.

The complementary mechanisms of these therapies have been shown to significantly reduce HFH and CV mortality.However, challenges remain in determining the optimal sequencing and timing of drug initiation. While current practices prioritize clinical stability and patient-specific fac-tors, the development of bespoke algorithms for combination therapy is an unmet need. Future research should address these gaps, focusing on sequencing strategies, mitigating risks such as hypotension and hyperkalemia, enhancing adherence,and evaluating the incremental cost-effectiveness of these therapies when used in combination.

Additionally, this guideline presents a forward-looking view, integrating therapies into a flexible framework that can be iterated with evolving clinical trial and real-world evidence. This model invites further exploration of pharma-cologic strategies and cost-effectiveness data to support optimal use of these agents across a spectrum of clinical HFnrEF phenotypes. As ongoing research continues to refine

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Table 4. Summary of new recommendations

1. We recommend the use of SGLT2i for people with HF and LVEF $>40\%$ to reduce the risk of HFH (Strong Recommendation; High-Quality Evidence).

2. We recommend the use of MRAs for people with HF and LVEF $>40\%$ to reduce the risk of HFH (Strong Recommendation; High-Quality Evidence).

3. We suggest the use of ARNI for people with symptomatic HF and LVEF> 40%, who are at low risk of symptomatic hypotension to reduce the risk of HFH (Weak Recommendation; Moderate-Quality Evidence).

4. We suggest the use of evidence-based drugs with GLP-1 receptor agonist activity and with proven efficacy for people with symptomatic HF, LVEF≥45%, and body mass index ≥ 30 to reduce the risk of HFH and to improve QoL (Weak Recommendation; Moderate-Quality Evidence).

ARNI, angiotensin receptor-neprilysin inhibitor; GLP-1, glucagon-like peptide-1; HF, heart failure; HFH, heart failure hospitalization; LVEF, left ventricular ejection fraction; MRA, mineralocorticoid receptor antagonist;QoL, quality of life; SGLT2i, sodium-glucose cotransporter-2 inhibitors.

our understanding of patient values and preferences, we seek to create an adaptable, patient-focused paradigm of care,which is responsive to outcomes prioritized by those with lived experience.

We recognize that equitable access to HFnrEF therapies requires addressing the unique challenges faced by those in rural or remote settings, and by individuals for whom sys-temic barriers to care persist. Furthermore, culturally safe and responsive care must be the standard for Indigenous pop-ulations and other marginalized groups, embracing the importance of trust-building, and respecting diverse healing practices. Incorporating these principles is essential to ensure that the benefits of modern HF therapies are equitably and distributed and tailored to meet the needs of all populations.

Ultimately, the guideline is aimed to serve as a compre-hensive resource for clinicians and bridge longstanding treatment gaps with novel pharmacologic options. It lays the foundation for a modernized, patient-centred care paradigm that is clinically effective, equitable, and responsive to the needs of a growing, high-risk population.

Declarations of Generative Al and Al-Assisted Technologies in the Writing Process

During the preparation of this work the author(s) used ChatGPT to improve language and readability. After using this tool/service, the co-Chairs reviewed and edited the con-tent as needed and take full responsibility for the content of the publication.

Acknowledgements

The authors thank:

● Dr David Birnie, CCS Guidelines Committee member who provided support, guidance, and advice through the duration of development of this guide-line as Guidelines Committee Liaison;

● Ms Carolyn Gallase for contributions and support to the co-chairs, and primary and review panels, and the document preparation process:

● Christopher De Luca, Cen Goa, Arnav Gupta,Daniel Rayner, Meghan Ross, and Wimonchat

Tangamornsulsan; trainees who supported the assessment of evidence and preparation of systematic reviews.

The authors acknowledge and recognize the ongoing volun-teer contributions of all writing panel members, the CCS Guidelines Committee, CCS members, and CCS staff involved in the development, publication, and dissemination of CCS guidelines.

Ethics Statement

All research reported in the current article adhered to the relevant ethical guidelines.

Patient Consent

The authors confirm that patient consent is not applicable to this article because this is a guidelines document; no pa-tients were involved in the development of the guideline.

Funding Sources

The CCS verifies that funding for systematic review ser-vices was provided from its general Guidelines Administra-tion budget. The CCS gratefully acknowledges the annual contribution of $10,000$ from the CCS Academy (CCSA) to support in part, the development of high-quality Guidelines and Clinical Practice Updates. Please read about the impor-tant work of the CCSA at https://ccs.ca/canadian-cardiovascular-society-academy/.

No external funding was received for the systematic review services of this project nor directly for the development or publishing of this guideline.

The CCS provided grant-in-aid support to McMaster and University for stipend payments to methodology trainees.

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Supplementary Material

To access the supplementary material accompanying this article, visit the online version of the Canadian Journal of Cardiology at www.onlinecjc.ca and at https://doi.org/10.1016/j.cjca.2025.07.027.

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