A Review of Treatment Options, Guidelines for Heart Failure With Preserved Ejection Fraction

Heart failure with preserved ejection fraction (HFpEF), previously known as diastolic heart failure, is an impairment in the ventricular filling of blood characterized by a left ventricular ejection fraction (LVEF) of 50% or greater. HFpEF represents at least half of the population with heart failure and is associated with a high symptom burden, poor quality of life, and significant morbidity and mortality.¹

According to the 2013 Heart Failure Guidelines, the primary recommended treatment option for patients with HFpEF were diuretics to improve symptom management. Angiotensin receptor blockers (ARBs) were also included in the guidelines to help decrease hospitalization, although they were a weak recommendation due to conflicting evidence.² Additionally, the 2017 Focused Update of the 2013 Guidelines included a new, weak recommendation of mineralocorticoid receptor antagonists (MRAs) to decrease hospitalizations.³ With the release of the 2022 AHA/ACC Guidelines for the Management of Heart Failure, patients with HFpEF now have a wider range of treatment options.¹ A timeline of these updates is included in Figure 1.

Diuretics are commonly prescribed in patients with heart failure, regardless of ejection fraction, and remain a strong, Class 1 recommendation in the guidelines. Despite their frequent use in heart failure, evidence is lacking in regard to morbidity and mortality. Congestion and fluid retention are associated with severe symptoms and lead to frequent hospitalizations. Loop diuretics are preferred in most patients with physical signs of congestion or fluid retention, but thiazide diuretics may be added in cases of loop diuretic resistance. Maintenance diuretics should be considered in patients with a history of congestion to avoid recurrent symptoms which can reduce heart failure hospitalizations.¹

SGLT2 inhibitors block the reabsorption of glucose and sodium in the proximal convoluted tubule, leading to diuresis and natriuresis. They are suggested with a moderate, Class 2a recommendation by the 2022 guidelines in patients with HFpEF to reduce heart failure hospitalizations and cardiovascular mortality.¹ Empagliflozin (Jardiance, Boehringer Ingelheim) received FDA approval in February 2022 for use in HFpEF after the EMPEROR-Preserved trial demonstrated a significant benefit. The trial randomized participants with an LVEF ≥40% to receive either empagliflozin or placebo. Treatment with empagliflozin led to a 21% relative risk reduction in 100 patient-years, and a 3.3% absolute risk reduction in the primary composite endpoint of cardiovascular death or hospitalization for heart failure. The reduction in the primary outcome was driven by the significant decline in heart failure hospitalization.⁴

Dapagliflozin (Farxiga, AstraZeneca) has not received FDA approval for HFpEF but is recommended in the guidelines following the PRESERVED-HF trial. The trial randomized participants with an LVEF of ≥45% to receive either dapagliflozin or placebo. Treatment with dapagliflozin significantly improved symptoms and physical limitations, as measured by the patient-reported Kansas City Cardiomyopathy Questionnaire Score (p=0.001).⁵ Additionally, patients saw significant improvements in distance during the 6-minute walk test and had greater weight loss than those receiving placebo.⁵ A second trial, DELIVER, was published in August 2022 after the release of the 2022 guidelines. The trial randomized participants with an LVEF >40% to receive either dapagliflozin or placebo. Dapagliflozin led to a 19% relative risk reduction in 100 patient-years and a 3.1% absolute risk reduction in the primary composite endpoint of worsening heart failure or cardiovascular death. Similar to the EMPORER-Preserved trial, this result was driven by a reduction in heart failure hospitalizations.⁶

Angiotensin receptor-neprilysin inhibitors (ARNi) may be considered in patients with HFpEF and are suggested with a weak, Class 2b strength of recommendation by the 2022 guidelines.¹ Sacubitril-valsartan (Entresto, Novartis), the only ARNi available on the market, received an expanded indication approval by the FDA for treatment of HFpEF patients in February 2021. It combines an ARB with a neprilysin inhibitor, which leads to vasodilation and natriuresis. The PARAGON-HF trial assigned patients with an LVEF of ≥45% to receive either sacubitril-valsartan or valsartan alone and found that the 2 groups did not differ significantly in the primary composite outcome of total hospitalizations for heart failure and death from cardiovascular causes. However, the subgroup analysis demonstrated that sacubitril-valsartan was significantly better in patients with an LVEF ≤57% with a rate ratio of 0.78 (0.64–0.95), which ultimately led to its FDA approval for HFpEF.⁷

Mineralocorticoid receptor antagonists inhibit the effects of aldosterone, leading to increased sodium and water excretion. They continue to be a weak, Class 2b recommendation in the 2022 guidelines.¹ The TOPCAT trial randomized patients with an LVEF of ≥45% from Russia, Georgia, and the Americas to receive either spironolactone or placebo, but no significant benefit was observed in the primary composite outcome of cardiovascular death, aborted cardiac arrest, or heart failure hospitalization.⁸ However, a post hoc analysis identified regional differences in their response to treatment with spironolactone. Participants in the Americas had a significantly lower relative risk reduction by 14% in the composite primary outcome, with a 25% relative risk reduction in cardiovascular death and a 15% reduction in hospitalizations, compared to patients from Russia and Georgia.⁹

Angiotensin receptor blockers inhibit aldosterone secretion and angiotensin II, resulting in vasodilation, reduced sympathetic outflow, and preservation of kidney function. They continue to be a weak, Class 2b recommendation in the 2022 guidelines.¹ In the CHARM-Preserved trial, patients with an LVEF of ≥40% were randomized to receive either candesartan or placebo. While the trial did not reach significance in its primary endpoint of cardiovascular death or heart failure hospitalization, they identified a significant reduction in the total number of admissions for heart failure in the candesartan group (p=0.014).¹⁰

Patients with heart failure with reduced ejection fraction have many treatment options, but few therapies have proven to be effective for patients with preserved ejection fraction, until recently. Diuretics continue to be efficacious in reducing symptoms and improving quality of life. Evidence from randomized clinical trials suggest that MRAs may reduce cardiovascular death and hospitalization rates, and ARBs may reduce hospitalizations in certain populations. The 2022 AHA/ACC Guidelines have added SGLT2 inhibitors as a class 2a recommendation and ARNi as a class 2b recommendation to the list of treatment options for HFpEF patients, presenting an opportunity for pharmacists to improve patient outcomes.

References

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