Heart Failure with preserved ejection fraction (HFpEF) is currently defined as HF with left ventricular ejection fraction (LVEF) ≥50% and elevated LV filling pressures at rest or during exercise, diagnosed after careful exclusion of conditions that may mimic HFpEF.¹ What was initially thought to result from LV diastolic dysfunction alone, is now increasingly being recognized as a multi-organ, systemic syndrome.² The complex pathophysiology of HFpEF makes it a diagnostic and therapeutic challenge. As our understanding of HFpEF continues to evolve, so does our approach to treatment. Management of HFpEF ranges from lifestyle interventions, (diet, exercise training), management of modifiable risk factors and comorbidities (hypertension, coronary artery disease, atrial fibrillation, obesity, diabetes, cigarette smoking), to pharmacologic therapies, and health services.¹ As LVEF increases in HF, non-cardiac comorbidities account for an increasing proportion of death and hospitalizations. The pharmacologic interventions that have demonstrably reduced all-cause or cardiovascular (CV) mortality in HFrEF with LVEF <40% have not had the same effect as EF increases but have decreased HF hospitalizations in this group. Broad, multi-organ, multi-disciplinary interventions may be required to improve overall survival in HFpEF.

Unlike heart failure with reduced ejection fraction (HFrEF), there are no medical therapies that reduce mortality in HFpEF. Diuretics have remained the mainstay of HFpEF management as they help mitigate volume overload. Beta blockers are often prescribed to these patients for management of comorbidities such as coronary artery disease or atrial fibrillation, but there is no clinical trial evidence to support its use at the higher range of the LVEF spectrum.¹ In an individual patient-level meta-analysis of double-blind randomized trials, beta blockers improved outcomes in patients in HF, sinus rhythm, and LVEF ≤49%, but there was no evidence to support their use in HF with LVEF >50%. Furthermore, the benefit of beta blockers in HF and atrial fibrillation across LVEF is equivocal.³ Observations from a large-scale registry suggested that in patients with HFpEF and a heart rate of ≥70 beats per minute, high dose beta blocker use was associated with lower all-cause mortality.⁴ However, recent research suggests that beta-blocker withdrawal is in fact associated with improved functional capacity of patients with HFpEF.⁵ To make matters more complicated, there is some evidence that the type of beta blocker (non-selective and vasodilating, such as nebivolol and carvedilol, vs. rate controlling only) may have differential effects in different HFpEF phenotypes.¹ Randomized controlled trials (RCTs) of beta blockers in HFpEF are a major unmet need.

Angiotensin converting enzyme inhibitors (ACEi) and angiotensin II receptor blockers (ARB), historically important in the management of HFrEF, have demonstrated a reduction in HF hospitalizations, but no reduction in all-cause or CV mortality in HFpEF.¹ The TOPCAT (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) trial of the mineralocorticoid receptor antagonist, spironolactone, in HFpEF failed to show an overall benefit in the primary composite outcome of all-cause mortality and HF hospitalizations. This was followed by an exploratory analysis of the trial, including only patients from the Americas, which did show a small benefit in the primary outcome. Spironolactone did, however, show an improvement in rates of HF hospitalizations.

The angiotensin receptor neprilysin inhibitor (ARNi) sacubitril-valsartan was compared to valsartan in an RCT which included patients with HF and LVEF ≥45%. Relative to valsartan, sacubitril-valsartan did not significantly reduce the composite endpoint of CV death and total hospitalizations for HF but did reduce HF hospitalizations. In prespecified subgroup analysis, there was a suggestion of benefit in patients with LVEF <57% and in women (benefits of sacubitril-valsartan in women were sustained up to LVEF 60%, while for men the benefit was restricted to LVEF 45%).⁶ Based on these findings, the United States Food and Drug Advisory granted an expanded indication for the use of sacubitril-valsartan in patients with "LVEF below normal" with an added mention of the variability in LVEF measurement and use of clinical judgement as appropriate.⁷ A multicenter RCT examining changes in NT-proBNP, and outcomes, safety and tolerability of sacubitril-valsartan in patients admitted with an acute exacerbation of HFpEF who have been stabilized and initiated on sacubitril-valsartan in-hospital or within 30 days of discharge is currently underway.

More recently, the sodium-glucose cotransport-2 inhibitors (SGLT2i) have emerged as promising therapies for HFpEF. First, the SGLT2i empagliflozin showed a reduction in the risk of composite CV death or total HF hospitalization in HF with LVEF >40%. This benefit was driven by a reduction in HF hospitalizations. A post-hoc analysis of treatment effect size across pre-specified LVEF subgroups showed that the beneficial effects of empagliflozin were limited to LVEF <60%.⁸ Notably, the magnitude of the effect of empagliflozin on HF hospitalizations in HFpEF was similar to that on hospitalizations for HFrEF.^8,9 Subsequently, among patients hospitalized for symptomatic HF across the LVEF spectrum, the combined SGLT2 and SGLT1 inhibitor sotagliflozin reduced the primary outcome of CV death and hospitalizations for HF in patients with diabetes and worsening HF. This effect was consistent across the prespecified subgroup stratified by LVEF <50 or ≥50%.¹⁰ The benefit, however, was once again driven by a reduction in hospitalizations and urgent visits for HF.¹⁰ Most recently, results of the multicenter randomized controlled SGLT2i empagliflozin in patients hospitalized for acute HF (EMPULSE) trial showed that more patients treated with empagliflozin than placebo experienced clinical benefit and met the primary endpoint (stratified win ratio, 1.36; 95% confidence interval, 1.09–1.68; P = 0.0054). Clinical benefit was defined as a hierarchical composite of death from any cause, number of HF events and time to first HF event, or a 5 point or greater difference in change from baseline in the Kansas City Cardiomyopathy Questionnaire Total Symptom Score at 90 days, as assessed using a win ratio. Benefits were consistent regardless of LVEF or diabetes status.¹¹ Finally, a trial testing the efficacy of dapagliflozin in HF with LVEF >40%, including recovered LVEF, is currently underway.

To date, no medication classes have reduced CV or all-cause mortality in chronic HF at the higher range of the EF spectrum.¹ As LVEF increases, the proportion of deaths due to CV causes and proportion of hospitalizations due to HF decreases, and the burden of non-cardiac comorbidities increases.¹ Drug therapies that reduce mortality in HF at the lower range of LVEF are less effective at doing so in higher range of LVEF. There are several lines of evidence that give pause to reconsider the current classification of HF into three groups based on arbitrary LVEF cut-off points. It may be more appropriate to managing LVEF as a continuum until an LVEF of approximately 50-55%. Beyond this range, it is crucial to investigate and exclude conditions that mimic HFpEF, target therapies to the underlying cause or phenotype, and address non-cardiac comorbidities that have an incremental contribution to disease burden and prognosis.^1,12

References

1. Gevaert AB, Kataria R, Zannad F, et al. Heart failure with preserved ejection fraction: recent concepts in diagnosis, mechanisms and management. Heart 2022;Jan 12:[Epub ahead of print].
2. Shah SJ, Borlaug BA, Kitzman DW, et al. Research priorities for heart failure with preserved ejection fraction. Circulation 2020;141:1001-26.
3. Cleland JGF, Bunting KV, Flather MD, et al. Beta-blockers for heart failure with reduced, mid-range, and preserved ejection fraction: an individual patient-level analysis of double-blind randomized trials. Eur Heart J 2018;39:26-35.
4. Lam PH, Gupta N, Dooley DJ, et al. Role of high-dose beta-blockers in patients with heart failure with preserved ejection fraction and elevated heart rate. Am J Med 2018;131:1473-81.
5. Palau P, Seller J, Domínguez E, et al. Effect of beta-blocker withdrawal on functional capacity in heart failure and preserved ejection fraction. J Am Coll Cardiol 2021;78:2042-56.
6. Solomon SD, McMurray JJV, et al. Angiotensin–neprilysin inhibition in heart failure with preserved ejection fraction. N Eng J Med 2019;381:1609-20.
7. Novartis Entresto® granted expanded indication in chronic heart failure by FDA (novartis.com). 2021. Available at: https://www.novartis.com/news/media-releases/novartis-entresto-granted-expanded-indication-chronic-heart-failure-fda. Accessed 02/10/2022.
8. Packer M, Zannad F, Anker SD. Heart failure and a preserved ejection fraction: a side-by-side examination of the PARAGON-HF and EMPEROR-Preserved trials. Circulation 2021;144:1193-95.
9. Packer M, Anker SD, Butler J, et al. Cardiovascular and renal outcomes with empagliflozin in heart failure. N Engl J Med 2020;383:1413-24.
10. Bhatt DL, Szarek M, Steg PG, et al. Sotagliflozin in patients with diabetes and recent worsening heart failure. N Engl J Med 2020;384:117-28.
11. Voors AA, Angermann CE, Teerlink JR, et al. The SGLT2 inhibitor empagliflozin in patients hospitalized for acute heart failure: a multinational randomized trial. Nat Med 2022;Feb 28:[Epub ahead of print].
12. Gevaert AB, Tibebu S, Mamas MA, et al. Clinical phenogroups are more effective than left ventricular ejection fraction categories in stratifying heart failure outcomes. ESC Heart Fail 2021;8:2741-54.

Clinical Topics: Arrhythmias and Clinical EP, Cardiovascular Care Team, Dyslipidemia, Heart Failure and Cardiomyopathies, Prevention, Atherosclerotic Disease (CAD/PAD), Atrial Fibrillation/Supraventricular Arrhythmias, Lipid Metabolism, Statins, Acute Heart Failure, Heart Failure and Cardiac Biomarkers, Diet, Hypertension

Keywords: Stroke Volume, Mineralocorticoid Receptor Antagonists, Heart Failure, Angiotensin Receptor Antagonists, Carvedilol, Nebivolol, Neprilysin, Sodium-Glucose Transporter 2, Spironolactone, Patient Discharge, Double-Blind Method, Atrial Fibrillation, Clinical Reasoning, Coronary Artery Disease, Heart Rate, Ventricular Function, Left, Angiotensin-Converting Enzyme Inhibitors, Valsartan, Risk Factors, Registries, Receptors, Angiotensin, Cost of Illness, Cardiomyopathies, Hypertension, Life Style, Phenotype, Diabetes Mellitus, Hospitals, Glucose, Obesity, Diet

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