What agents have demonstrated a reduction in mortality in patients with heart failure with preserved ejection fraction (HFpEF)?

Mortality Reduction in HFpEF: Current Evidence

No pharmacological agent has definitively demonstrated a reduction in all-cause or cardiovascular mortality as a standalone outcome in patients with HFpEF. However, SGLT2 inhibitors (dapagliflozin and empagliflozin) have shown the strongest evidence for reducing composite cardiovascular outcomes, driven primarily by reductions in heart failure hospitalizations rather than mortality alone 1.

Evidence for SGLT2 Inhibitors

SGLT2 inhibitors represent the only drug class with consistent Class I/IIa recommendations across major guidelines for HFpEF, though their benefit is predominantly on morbidity rather than mortality:

• Dapagliflozin (DELIVER trial): Reduced the composite of worsening HF and cardiovascular death (HR 0.82,95% CI 0.73-0.92), but cardiovascular death alone showed no significant reduction (HR 0.88,95% CI 0.74-1.05) 1, 2

• Empagliflozin (EMPEROR-PRESERVED trial): Reduced hospitalization for HF and cardiovascular death (HR 0.79,95% CI 0.69-0.90), but cardiovascular death alone was not significantly reduced (HR 0.91,95% CI 0.76-1.09) 1, 2

• Both agents received Class 2a recommendations from the American College of Cardiology, indicating they "can be beneficial in decreasing HF hospitalizations and cardiovascular mortality" in the composite endpoint 2

Evidence for Other Agents

Mineralocorticoid Receptor Antagonists (Spironolactone)

Spironolactone has not demonstrated mortality reduction in HFpEF:

• The TOPCAT trial showed no significant reduction in the primary composite outcome of cardiovascular death, aborted cardiac arrest, or HF hospitalization (HR 0.89,95% CI 0.77-1.04) 1
• Cardiovascular death alone was not reduced (HR 0.90,95% CI 0.73-1.12) 1
• HF hospitalizations were reduced (HR 0.83,95% CI 0.69-0.99), earning a Class 2b recommendation 1, 2
• Regional variation existed, with benefit seen in North America (HR 0.82,95% CI 0.69-0.98) but not Russia/Georgia 1

Angiotensin Receptor-Neprilysin Inhibitors (Sacubitril/Valsartan)

Sacubitril/valsartan failed to demonstrate mortality reduction in HFpEF:

• The PARAGON-HF trial did not achieve statistical significance for the primary composite endpoint of total HF hospitalizations and cardiovascular death (rate ratio 0.87,95% CI 0.75-1.01) 1, 2
• Cardiovascular death alone showed no benefit (HR 0.95% CI 0.79-1.16) 1
• Subgroup analyses suggested potential benefit in women and those with LVEF 45-57%, but these were post-hoc findings 2
• Received only a Class 2b recommendation ("may be considered") 2

Angiotensin Receptor Blockers

ARBs have not demonstrated mortality reduction in HFpEF:

• The CHARM-PRESERVED trial with candesartan showed no significant reduction in the composite of HF hospitalization and cardiovascular death (HR 0.86,95% CI 0.74-1.00) 1
• Cardiovascular death alone was not reduced (HR 0.95% CI 0.76-1.18) 1

Historical Context and Failed Trials

Multiple other agents have failed to show any mortality benefit in HFpEF, including:

• Perindopril, irbesartan, beta-blockers, nitrates, digoxin, ivabradine, sildenafil, and serelaxin all showed no benefit in completed trials 1
• As of 2015, no pharmacological agents had been shown to improve survival in HFpEF 1

Clinical Interpretation

The absence of mortality reduction in HFpEF trials reflects the complex pathophysiology of this syndrome:

• As LVEF increases, the proportion of deaths due to cardiac causes decreases, with non-cardiac comorbidities playing a larger role 3
• HFpEF is heterogeneous, with multiple cardiac and non-cardiac mechanisms contributing to the syndrome 3, 4
• Medications efficacious in HFrEF show diminishing effects as LVEF increases, reducing HF hospitalizations but not cardiovascular or all-cause death 3

Current Treatment Approach

Given the lack of mortality-reducing agents, treatment focuses on reducing morbidity and improving quality of life:

• First-line therapy: SGLT2 inhibitors (dapagliflozin 10 mg daily or empagliflozin 10 mg daily) for reducing HF hospitalizations 1, 2
• Symptom management: Loop diuretics titrated to relieve congestion 1, 2
• Comorbidity management: Aggressive treatment of hypertension, diabetes, obesity, atrial fibrillation, and coronary artery disease 1
• Consider adding: Spironolactone (25 mg daily) particularly in patients with LVEF 40-50% 1, 2

Critical caveat: The 2015 American Heart Association statement explicitly noted that "to date, no pharmacological agents have been shown to improve survival" in HFpEF, with goals of therapy being to alleviate symptoms, improve quality of life, and reduce hospitalizations 1. This remains largely true today, with SGLT2 inhibitors showing benefit on composite endpoints driven by hospitalization reduction rather than mortality alone.