Heart failure with preserved ejection fraction

Abbreviations

ACC – American College of Cardiology
ARB – angiotensin-receptor blockers
ESC – European Society of Cardiology
FDA – U.S. Food and Drug Administration HFMREF – heart failure with midrange ejection fraction
HFPEF – heart failure with preserved ejection fraction
HR – hazard ratio
HFREF – heart failure with reduced ejection fraction
LV – left ventricle
LVEF – left ventricular ejection fraction MRA – mineralocorticoid receptor antagonist RR – relative risk
SGLT-2 – sodium-glucose co-transporter 2

Introduction

Heart failure with preserved ejection fraction (HFPEF) is characterised by normal left ventricular (LV) systolic function and makes up at least half of all cases of chronic heart failure¹. Despite the significant morbidity associated with HFPEF², there have been limited breakthroughs in its management, relying instead on the treatment of co-morbidities and use of diuretics to ease congestion. Despite the chasm in available treatments compared with heart failure with reduced ejection fraction
(HFREF), there are potential new drug treatments on the horizon as well as an emerging appreciation of of HFPEF subgroups for which existing heart failure therapies may be effective.

This review article will briefly summarise the epidemiology, diagnosis and current treatments available for HFPEF, before discussing potential novel therapies available in the near future.

Epidemiology

Observational studies have consistently demonstrated that HFPEF accounts for at least 40- 50% of all heart failure patients depending on the population studied, with higher incidences in older populations^{1, 3, 4}. While the incidence of heart failure has declined overall, the declines have been greater in HFREF than HFPEF, with a resulting widening gap in prevalence. It is estimated that the incidence and prevalence of HFPEF is rising by 10% relative to HFREF every 10 years⁵. Furthermore, increasing prevalence of comorbidities associated with HFPEF (including but not limited to hypertension, elevated BMI and metabolic syndrome, and aging) will likely result in yet higher proportions of HFPEF in the overall heart failure population.

Outcomes in HFPEF vary depending on the population studies (outpatient, inpatient) and LVEF threshold using to define HFPEF. In general, community-based studies have showed that 5-year mortality is at least 50%, though in 30-50% of cases this is from non-cardiovascular reasons¹. When compared to HFREF, observational studies suggest little difference in outcomes even after adjustment, while in randomised studies the annualised mortality in HFPEF is significantly lower than in HFREF¹.

Diagnosis

The diagnosis of HFPEF requires signs and symptoms of heart failure, preserved LV systolic function (defined by the European Society of Cardiology [ESC] as an LV ejection fraction  [LVEF] ≥50% and by the American College of Cardiology [ACC] as ≥ 40%), elevated cardiac biomarkers (BNP and NT-proBNP) and echocardiographic features (LV hypertrophy or left atrial enlargement, and/or diastolic dysfunction). Gold standard evaluation of haemodynamic abnormalities in HFPEF (elevated LV filling pressures) can be achieved using invasive right heart catheterisation during cardiopulmonary exercise testing, though is not routinely recommended in guidelines and is rarely done due to invasiveness, cost and availability.

The accurate diagnosis of HFPEF and attribution of symptoms to the condition can be a challenge given the high prevalence of existing co-morbidities that can mimic it (e.g. chronic respiratory disease, obesity, and atrial fibrillation). Two scoring systems (H2PEF and HFA-PEFF) have been designed with the aim of improving the diagnostic accuracy for HFPEF in individuals with unexplained dyspnoea^{6, 7}. H2PEF, a score derived from invasive haemodynamic exercise testing, includes co-morbidities (obesity, hypertension [on at least 2 antihypertensive medications], and atrial fibrillation) together with age >60 years and measures of LV filling pressures (septal E/e’ >9 and estimated pulmonary artery systolic pressure  >35mmHg). The score has been independently validated in a stable chronic HFPEF population enrolled in the TOPCAT trial, for its association with the primary composite endpoint  (cardiovascular death, aborted cardiac arrest or heart failure hospitalisation)⁸. The HFA-PEFF is an expert consensus algorithm that includes biomarker levels and echocardiographic measures for diastolic dysfunction and structural abnormalities.

Existing therapies

Current ESC and ACC guidance recommends use of loop diuretics to alleviate symptoms arising from congestion (1B recommendation) and the screening and treatment of co-morbidities (1C recommendation)^{9, 10}. It is reasonable to use therapies licensed for HFREF (e.g. ACE inhibitors, angiotensin receptor blockers [ARB], and beta-blockers) for the management of co-morbidities, while the ACC provides a tentative 2B recommendation based on secondary endpoints in the TOPCAT study for the use of mineralocorticoid receptor antagonists (MRA) to reduce heart failure hospitalisation¹¹. The absence of strong and consistent recommendations for specific pharmacological therapies reflects the consistently neutral results of major phase-3 RCTs in HFPEF².

The role of remote monitoring in guiding diuretic dosage is given a 2B recommendation by the ESC for individuals with heart failure (HFREF and HFPEF) based on promising results in the CHAMPION trial using pulmonary arterial pressure changes detected with the CardioMEMS device¹². Heart failure hospitalisations were reduced by around half in those with HFPEF (using both LVEF thresholds of 40 and 50%), highlighting the importance of judicious diuretic dosing in reducing events.

The importance of lifestyle changes including exercise-based rehabilitation should not be overlooked. Guidelines consistently recommend that regular aerobic exercise be encouraged in those with heart failure (including HFPEF), with enrolment in rehabilitation programmes if available.

A recent study of 349 older patients (mean age 73 years, 97% frail or prefrail) recently hospitalised for decompensated heart failure demonstrated that a tailored 12 week physical rehabilitation course targeting strength, balance, mobility and endurance, was associated with improvements in physical function compared with usual care. Improvements were greater in the 53% of patients who had HFPEF, highlighting the value of physical rehabilitation in this older and more co-morbid cohort¹³.

On the horizon

Expansion of LV ejection fraction thresholds for existing evidence-based therapies

Current guidelines recommend the use of heart failure therapies up to an LVEF of 40%. This has been based on the consistent use of this LVEF threshold in clinical trials. The most recent ESC heart failure guideline update in 2016 defined the lower LVEF for HFPEF as 50%, and introduced the concept of heart failure with mid-range ejection fraction (HFMREF) for those with LVEF 40-50%. Indeed, the 2020 British Society of Echocardiography update defines an LVEF of 36-49% as being impaired, 50-54% as borderline low, and only ≥55% being normal. This introduction of heterogeneity in definitions (ACC continues to use an LVEF of 40%) and non-uniformity across clinical trials introduces complexity for practising clinicians when deciding on introducing therapies in those with borderline LV systolic function.

Post-hoc analysis of randomised clinical trials provide evidence that benefits from existing heart failure therapies extend beyond those patients with LVEF <40%, with efficacy maintained in those with an LVEF of 40-50%^14-16. An individual-patient data meta-analysis of 11 trials demonstrated nominally lower mortality and cardiovascular death or heart failure hospitalisation in those with sinus rhythm in the mid-range category who were treated with beta-blockers¹⁴. The main limitation of this study was that the majority of patients in this mid-range category had LVEFs in the low 40s, and included patients enrolled into largely historic HFREF studies. Post-hoc analysis of the CHARM programme that randomised heart failure participants to candesartan or placebo, demonstrated significant reductions in cardiovascular death or heart failure hospitalisation (hazard ratio [HR] 0.76, P 0.02) in those with LVEF in the mid-range, with improvements in outcome up until well over 50%¹⁵. Post-hoc analysis of the TOPCAT trial, which randomised 3444 patients with HFPEF (LVEF ≥45%) to spironolactone or placebo, demonstrated that while the overall trial was unequivocally neutral, the efficacy of spironolactone interacted with LVEF (interaction P 0.04, with greater effects in those with lower LVEF)¹⁶. In individuals with LVEF <50%, the HR for cardiovascular mortality or heart failure hospitalisation was 0.72 (upper confidence interval 1.05), compared with 0.97 in those with LVEF ≥60%.

It should not be surprising that therapies of proven efficacy in HFREF (beta-blockers, ARB and MRA) appear to have some efficacy in those with borderline LV systolic function given that individuals in the HFMREF group tend to have characteristics intermediate between HFREF and HFPEF¹⁷. This may be related to the precision of the method of LVEF estimation using echocardiography (HFREF misclassified as HFMREF), or that a proportion of individuals with HFMREF be transitioning into or recovering from HFREF. A prospective longitudinal study of heart failure patients demonstrated that 36.5% and 23.6% of HFMREF patients demonstrated worsening or improvement of LVEF, respectively, highlighting that HFMREF may represent a transitional state in many patients¹⁸.

ARNI (sacubitril-valsartan)

PARADIGM-HF demonstrated significant reductions in morbidity and mortality in symptomatic (NYHA 2-3) individuals with HFREF (LVEF<40%) treated with sacubitril-valsartan as compared with enalapril¹⁹. As the first participants were recruited into PARADIGM-HF in late 2009, recruitment began on a considerably smaller phase-2 RCT (PARAMOUNT) evaluating sacubitril-valsartan compared with valsartan in symptomatic individuals with HFPEF (defined using LVEF ≥45%)²⁰. The primary trial endpoint was change in NT-proBNP after 12-weeks. PARAMOUNT demonstrated that in 301 randomised participants, sacubitril-valsartan resulted in significant reductions in NT-proBNP compared with valsartan. These favourable results provided the rationale to proceed to a larger phase-3 cardiovascular outcome study (PARAGON-HF).

PARAGON-HF randomised 4,822 symptomatic (NYHA 2-4) individuals with HFPEF (LVEF ≥45%) to sacubitril-valsartan or valsartan²¹. After a median of 35 months, sacubitril-valsartan was associated with a nominal reduction in the primary outcome of total heart failure hospitalisations or cardiovascular death (relative risk [RR] 0.87, 95% confidence interval 0.75 to 1.01, P = 0.06), driven largely by reductions in heart failure hospitalisation (RR 0.85) rather than cardiovascular death (RR 0.95). Additional secondary endpoints including patient-reported symptoms, physician-assessed functional status and renal endpoints demonstrated directionally consistent albeit modest benefits with sacubitril-valsartan. While the headline conclusions of PARAGON-HF predominantly focused on borderline heart failure benefits in the HFPEF population, pre-specified and hypothesis-generating sensitivity analyses suggested that there were subgroups that could potentially benefit. Any effectiveness of sacubitril-valsartan appeared to be present only in those with sub-normal LVEF, with those with LVEF less than the median of 57% demonstrating benefit (HR 0.78 for the primary study outcome) compared with those above the median (HR 1.00). Post-hoc analysis pooling individual-participant data from PARADIGM-HF and PARAGON-HF showed consistent reductions in the primary outcome across a range of LVEF up to around 60%²². Intriguingly, sacubitril-valsartan was associated with improvements in the primary outcome in women (RR 0.73) but not in men (RR 1.03, P for interaction 0.017), even after adjustment for baseline differences²³.

The PARALLAX study (NCT03066804), requested by the German health technology assessment board and presented at the ESC Congress 2020, was an active-controlled RCT comparing sacubitril-valsartan with an individualised comparator in 2,572 symptomatic individuals (NYHA 2-4) with LVEF ≥40%. The rationale was that in clinical practice, not all HFPEF patients will be on an ARB, as was the case in the control arm of PARAGON-HF. The individualised comparator in PARALLAX depended on what the participant was already on at recruitment: enalapril if on ACE inhibitors, valsartan if on ARB and placebo if not on either. The two primary outcomes were change in NT-proBNP and 6-minute walk distance after 24 weeks of treatment. The trial met one of its co-primary endpoints, demonstrating greater reductions in NT-proBNP level with sacubitril-valsartan compared with comparator therapy (16% greater reduction), a difference consistent with what was seen in PARAGON-HF (19% greater reduction after 16 weeks of treatment). No differences were seen in 6-minute walk distance, or any of the secondary endpoints including quality of life, and other measures of functional status. Post-hoc analysis of clinical events showed that there was a 42% reduction in heart failure hospitalisation with sacubitril-valsartan (HR 0.52, 95% CI 0.37 to 0.91)²⁴.

On the basis of PARAGON-HF, the Food and Drug Administration (FDA) advisory committee voted in favour of expanding the indication of Entresto to include reducing worsening heart failure in patients with HFPEF with an LVEF below normal (60%), an important step if it is to be formally approved by the FDA. No decision has been made by either The National Institute for Health and Clinical Excellence or The European Medicines Agency.

SGLT-2 inhibitors

Sodium-glucose co-transporter-2 (SGLT-2) inhibitors are the newest drug therapy to demonstrate impressive improvements in clinical outcomes in HFREF. Both dapagliflozin (DAPA-HF) and empagliflozin (EMPEROR-Reduced) showed significant benefits in survival and heart failure events in HFREF regardless of diabetes status²⁵, opening the door to a new class of agents for HFREF. Although similar phase-3 studies are currently ongoing in participants with HFPEF (dapagliflozin in DELIVER and empagliflozin in EMPEROR-Preserved), several existing phase-3 SGLT-2 inhibitor trials included and subsequently reported data on participants with HFPEF. While HFPEF definitions varied in these studies, they generally included a group distinct from HFREF who would not meet guideline criteria for evidence-based HFREF therapies. Our own meta-analysis of trial-level data of 4,557 participants with HFPEF (defined as LVEF ≥40%) recruited to four SGLT-2 inhibitor trials (DECLARE-TIMI 58, SCORED, SOLOIST-WHF and VERTIS-CV) suggests that SGLT-2 inhibitor use is associated with reductions in heart failure hospitalisation or cardiovascular death (HR 0.72, 95% credible interval 0.61 to 0.85, unpublished data from Zheng SL and Roddick AJ) compared with placebo, a difference driven by reductions in heart failure hospitalisation. The magnitude of benefit appeared similar in HFPEF (defined as LVEF>50% and HFREF (HR 0.72 and 0.76 respectively, unpublished data) with no evidence of interaction, suggesting that SGLT-2 inhibitor effects in heart failure are irrespective of LVEF. The ongoing DELIVER and EMPEROR-Preserved studies, each recruiting approximately 6000 participants with HFPEF with or without diabetes, are scheduled to complete this year and will determine whether agents in this drug class can be the first to reduce hard endpoints in HFPEF.

Conclusions

As of now, there are no evidence-based therapies recommended to improve survival in the treatment of HFPEF in clinical guidance. Post-hoc analyses of existing trials suggest that patients in the mid-range (LVEF 40-50%) could benefit from the use of HFREF therapies (beta-blockers, ARB and MRA). Promising results with sacubitril-valsartan in PARAGON-HF and eagerly anticipated trials with SGLT-2 inhibitors in HFPEF suggest that the current dearth of treatments for this condition may soon be behind us.

Disclosures

None to disclose.

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