How to Manage Heart Failure With Preserved Ejection Fraction

Practical Guidance for Clinicians

Akshay S. Desai, MD, MPH; Carolyn S.P. Lam, MBBS, PHD; John J.V. McMurray, MD; Margaret M. Redfield, MD

JACC Heart Fail. 2023;11(6):619-636.

Abstract and Introduction

Abstract

Although patients with heart failure with preserved ejection fraction (HFpEF) (left ventricular ejection fraction ≥50%) comprise nearly half of those with chronic heart failure, evidence-based treatment options for this population have historically been limited. Recently, however, emerging data from prospective, randomized trials enrolling patients with HFpEF have greatly altered the range of pharmacologic options to modify disease progression in selected patients with HFpEF. In the context of this evolving landscape, clinicians are increasingly in need of practical guidance regarding the best approach to management of this growing population. In this review, the authors build on the recently published heart failure guidelines by integrating contemporary data from recent randomized trials to provide a contemporary framework for diagnosis and evidence-based treatment of patients with HFpEF. Where gaps in knowledge persist, the authors provide "best available" data from post hoc analyses of clinical trials or data from observational studies to guide management until more definitive studies are available.

Introduction

Although patients with heart failure with preserved ejection fraction (HFpEF) comprise nearly half of those with heart failure (HF), evidence-based treatment options have historically been limited.^[1] Treatment guidelines have accordingly emphasized symptomatic management through relief of congestion and treatment of comorbidities.^[2,3] However, recent data from prospective, randomized trials enrolling patients with HFpEF have now informed pharmacologic approaches to modify disease progression in selected patients. In this review, we have integrated emerging data (including evidence from trials published subsequent to the most recent guideline updates) to provide contemporary, practical guidance regarding the management of HFpEF. Where gaps in knowledge persist, we provide "best available" data from post hoc analyses of clinical trials or data from observational studies to guide management until more definitive studies are available.

Although various left ventricular ejection fraction (LVEF) thresholds have been used to describe different HF phenotypes over time, the recently published Universal Definition of HF and guideline updates currently define 3 groups (Table 1): 1) patients with LVEF ≤40% (ie, heart failure with reduced ejection fraction [HFrEF]); 2) those with ejection fraction between 41% and 49% (ie, heart failure with mildly reduced ejection fraction [HFmrEF]); and 3) those with ejection fraction ≥50% (HFpEF), with patients with prior HFrEF who improve to an ejection fraction >40% classified separately as heart failure with improved ejection fraction (HFimpEF).^[4] Additional phenotypes, including the subset with HF and "supra-normal" ejection fraction have been proposed, but are not yet well-characterized. Because the data suggest that patients with HFmrEF derive similar benefit from treatments proven to be effective in HFrEF, consensus guidelines now favor treatment of these patients with the same combination of angiotensin-receptor-neprilysin inhibitors (ARNIs) (in preference to angiotensin-converting enzyme [ACE] inhibitors or angiotensin receptor blockers [ARBs]), beta-adrenergic receptor blockers, mineralocorticoid receptor antagonists (MRAs), and sodium-glucose cotransporter-2 (SGLT2) inhibitors that are recommended for HFrEF.^[2,3,5–9] Similarly, guidelines strongly recommend continuation of HFrEF evidence-based therapies in patients with HFimpEF. Accordingly, this review emphasizes the approach to management of patients with HFpEF defined at the threshold of LVEF ≥50%, acknowledging the significant residual clinical heterogeneity in this population and possible overlap with the syndrome of HFrEF in terms of therapeutic responsiveness.

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Table 1. Overview of HF Therapy According to LVEF
Initial Classification	LVEF, %	Diagnostic Contingencies	Initial Approach	Potential LVEF Trajectories and Treatment Implications
HFpEF	≥50	Symptoms of HF and evidence of elevated filling pressure (congestion) at rest or with exercise^a	Treat as HFpEF	LVEF may stay stable or decline Treat as HFrEF if LVEF declines <50%
HFmrEF	41–49	Symptoms of HF and evidence of elevated filling pressure (congestion) at rest or with exercise^a	Treat as HFrEF	LVEF may improve or decline Treat as HFrEF even if LVEF subsequently improves
HFrEF	≤40	Symptoms of HF or asymptomatic	Treat as HFrEF	LVEF may improve to >40% (HFimpEF) Treat as HFrEF even if LVEF subsequently improves

Categories defined as per Universal Definition of HF.⁴ Shown are specific diagnostic considerations, initial treatment strategy, and treatment implications of changes in EF over time. ^aCorroborating evidence of elevated filling pressure can be provided by: 1) physical examination: elevated jugular venous pressure, S₃ gallop, rales; 2) chest radiography: pulmonary venous hypertension, pulmonary edema; 3) elevated brain natriuretic peptide levels outpatient setting: BNP ≥35 pg/mL or NT-proBNP >125 pg/mL; 4) elevated brain natriuretic peptide levels ED setting: BNP >100 pg/mL or NT-proBNP >300 pg/mL; 5) elevated filling pressures at rest or exercise Doppler-echocardiography; 6) elevated filling pressures at rest or exercise right or left heart catheterization; and 7) elevated (≥6) H₂FPEF Score (see Figure 2) or European Society of Cardiology Heart Failure Risk Score (see Figure 3).
BNP = B-type natriuretic peptide; ED = emergency department; EF = ejection fraction; HF = heart failure; HFimpEF = heart failure with improved ejection fraction; HFmrEF = heart failure with mildly reduced ejection fraction; HFpEF = heart failure with preserved ejection fraction; HFrEF = heart failure with reserved ejection fraction; LVEF = left ventricular ejection fraction; NT-proBNP = N-terminal pro–B-type natriuretic peptide.

Table 2. Management of Key Noncardiac and Cardiac Comorbidities in Patients With HFpEF
Condition	Recommended Strategies
Hypertension	• Management of BP to guideline-recommended targets, typically <130/80 mm Hg
Diabetes/dysglycemia	• Prioritize SGLT2 inhibitors (as in all patients)
	• ACE inhibitor/ARB for CKD/proteinuria
	• Finerenone for ongoing proteinuria despite ACE inhibitor/ARB
Obesity	• Routine recommendation for calorie restriction, aerobic exercise training
	• Screening and treatment of obstructive sleep apnea
	• Consider GLP-1 agonists, tirzepatide, bariatric surgery?
Chronic kidney disease	• ACE inhibitor/ARB for proteinuria
	• SGLT2 inhibitors
	• Finerenone (if diabetes and ongoing proteinuria despite ACE inhibitor/ARB)
Coronary artery disease/coronary microvascular dysfunction	• Antiplatelet therapy
	• Moderate-high intensity statin therapy for those with elevated LDL
	• Revascularization for patients with angina or ischemia on provocative testing
Atrial fibrillation	• Anticoagulation for stroke prophylaxis
Atrial fibrillation	• Consider trial of rhythm control
Chronotropic incompetence	• Avoid routine use of beta-blockers in absence of compelling indication

ACE = angiotensin-converting enzyme; ARB = angiotensin receptor blocker; BP = blood pressure; CKD = chronic kidney disease; GLP = glucagon-like peptide; LDL = low-density lipoprotein; SGLT2 = sodium-glucose cotransporter-2; other abbreviation as in Table 1.

Table 3. Randomized, Placebo-Controlled Trials Enrolling Patients With HF and LVEF ≥40%
	CHARM-Preserved (n = 3,023)	PEP-CHF (n = 850)	I-Preserve (n = 4,128)	TOPCAT (n = 3,445)	PARAGON-HF (n = 4,822)	EMPEROR-Preserved (n = 5,988)	DELIVER (n = 6,263)
Intervention	ARB (candesartan)	ACE inhibitor (perindopril)	ARB (irbesartan)	MRA (spironolactone)	ARNI (sacubitril/valsartan)	SGLT2 inhibitor (empagliflozin)	SGLT2 inhibitor (dapagliflozin)
Key inclusion criteria	• NYHA functional class II to IV • Prior CV hospitalization	• Age ≥70 y • HF signs and symptoms • LVH/LAE/impaired LV filling/AF (2 or more)	• NYHA functional class II to IV • Corroborating evidence of HF on echo/ECG (signs, LVH, LAE) • Prior HFH within 6 mo if NYHA functional class II	• HF signs and symptoms • Either elevated NP or prior HFH	• NYHA functional class II to IV • Elevated NP • Structural heart disease (LAE/LVH)	• NYHA functional class II to IV • Elevated NP • Structural heart disease (LAE/LVH) by echocardiography or prior HFH within 12 mo	• NYHA functional class II to IV • Elevated NP • Structural heart disease (LAE/LVH)
Eligible LVEF, %	>40	≥40 (wall motion index <1.4)	≥45	≥45	≥45	>40	>40
Eligible NP	NA	NA	NA	BNP >100 pg/mL or NT-proBNP >360 pg/mL within 60 d	If HFH within 9 mo: NT-proBNP >200 pg/mL (SR), or >600 pg/mL (AF) If no prior HFH: NT-proBNP >300 pg/mL (SR), or >900 pg/mL (AF)	NT-proBNP >300 pg/mL (SR), or >900 pg/mL (AF)	NT-proBNP ≥300 pg/mL (SR), or ≥600 pg/mL (AF)
Primary composite endpoint	CV death or HFH (time to first)	All cause death or HFH (time to first)	All-cause death or CV hospitalization (time to first)	CV death, RSD, or HFH (time to first)	CV death and total HFH (first and recurrent)	CV death or HFH	CV death or worsening HF
Median follow-up, mo	36.6	25.2	49.5	39.6	35	26.2	27.6
Treatment effect (primary endpoint)	Unadjusted HR 0.89 [95% CI: 0.77–1.03]; P = 0.118; covariate adjusted HR: 0.86 [95% CI: 0.74–1.00]; P = 0.051	HR: 0.919 [95% CI: 0.700–1.208]; P = 0.545	HR: 0.95 [95% CI: 0.86–1.05]; P = 0.35	HR: 0.89 [95% CI: 0.77–1.04]; P = 0.14	Rate ratio: 0.87 [95% CI: 0.75–1.01]; P = 0.06	HR: 0.79 [95% CI: 0.69–0.90]; P < 0.001	HR: 0.82 [95% CI: 0.73–0.92]; P < 0.001
Overall efficacy	Neutral, reduction in HFH	Neutral	Neutral	Neutral	Borderline, favorable results in EF ≤57%	Positive	Positive

AF = atrial fibrillation; ARNI = angiotensin receptor neprilysin inhibitor; CHARM-Preserved = Candesartan in Heart Failure Assessment of Reduction in Mortality and Morbidity–Preserved; CV = cardiovascular; DELIVER = Dapagliflozin Evaluation to Improve the Lives of Patients With Preserved Ejection Fraction Heart Failure; ECG = electrocardiogram; EMPEROR-Preserved = EMPagliflozin outcomE tRial in Patients With chrOnic heaRt Failure With Preserved Ejection Fraction; HFH = heart failure hospitalization; I-Preserve = Irbesartan in Heart Failure With Preserved Systolic Function; LAE = left atrial enlargement; LV = left ventricular; LVH = left ventricular hypertrophy; MRA = mineralocorticoid receptor antagonist; NA = not available; NP = natriuretic peptide; NYHA = New York Heart Association; PARAGON-HF = Efficacy and Safety of LCZ696 Compared to Valsartan, on Morbidity and Mortality in Heart Failure Patients With Preserved Ejection Fraction; PEP-CHF = Perindopril in Elderly People with Chronic Heart Failure trial; RSD = resuscitated sudden death; SR = sinus rhythm; TOPCAT = Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist; other abbreviations as in Tables 1 and 2.

Authors and Disclosures

Akshay S. Desai, MD, MPH^a, Carolyn S.P. Lam, MBBS, PHD^b,c, John J.V. McMurray, MD^d and Margaret M. Redfield, MD^e

^aCardiovascular Division, Brigham and Women's Hospital, Boston, Massachusetts, USA; ^bNational Heart Centre, Singapore; ^cDuke-National University of Singapore, Singapore; ^dBritish Heart Foundation Cardiovascular Research Centre, University of Glasgow, Glasgow, Scotland, United Kingdom; and the ^eDepartment of Cardiovascular Disease, Mayo Clinic, Rochester, Minnesota, USA.

Address for Correspondence
Dr Akshay S. Desai, Center for Advanced Heart Disease, Cardiovascular Division, Brigham and Women's Hospital, PBB-A3-AB370, 75 Francis Street, Boston, Massachusetts 02115, USA. E-mail: adesai@bwh.harvard.edu.

Funding Support and Author Disclosures
Dr Desai has received institutional research grants from AstraZeneca, Abbott, Alnylam, Bayer, and Novartis; has received consulting fees from Abbott, Alnylam, AstraZeneca, Axon Therapeutics, Avidity Biopharma, Bayer, Biofourmis, Cytokinetics, GlaxoSmithKline, Medpace, Merck, New Amsterdam, Novartis, Parexel, Roche, Regeneron, Veristat, and Verily. Dr Lam has received a Clinician Scientist Award from the National Medical Research Council of Singapore; has received research support from Bayer and Roche Diagnostics; has served as consultant or on the advisory board/steering committee/executive committee for Actelion, Alleviant Medical, Allysta Pharma, Amgen, AnaCardio AB, Applied Therapeutics, AstraZeneca, Bayer, Boehringer Ingelheim, Boston Scientific, Cytokinetics, Darma Inc, EchoNous Inc, Eli Lilly, Impulse Dynamics, Intellia Therapeutics, Ionis Pharmaceutical, Janssen Research and Development LLC, Medscape/WebMD Global LLC, Merck, Novartis, Novo Nordisk, Prosciento Inc, Radcliffe Group Ltd, ReCor Medical, Roche Diagnostics, Sanofi, Siemens Healthcare Diagnostics, and Us2.ai; and serves as cofounder and nonexecutive director of Us2.ai. Dr McMurray has received a British Heart Foundation Centre of Research Excellence Grant RE/18/6/34217; has received payments through Glasgow University from work on clinical trials; has received fees for consulting and other activities from Alnylam, Amgen, AstraZeneca, Bayer, Boehringer Ingelheim, BMS, Cardurion, Cytokinetics, Dal-Cor, GlaxoSmithKline, Ionis, KBP Biosciences, Novartis, Pfizer, and Theracos; and has received personal lecture fees from Corpus, Abbott, Hikma, Sun Pharmaceuticals, Medscape/Heart.Org, Radcliffe Cardiology, Servier Director, and Global Clinical Trial Partners (GCTP). Dr Redfield has reported that she has no relationships relevant to the contents of this paper to disclose.