Which agent(s) have demonstrated a reduction in mortality in patients with heart failure with preserved ejection fraction (HFpEF)?

Mortality Benefits in Heart Failure with Preserved Ejection Fraction (HFpEF)

None of the agents listed (carvedilol, spironolactone, or sacubitril/valsartan) have demonstrated a reduction in mortality in patients with heart failure with preserved ejection fraction (HFpEF).

Evidence Summary on Mortality Benefits in HFpEF

Beta-Blockers (Carvedilol)

• No evidence supports mortality reduction with carvedilol or other beta-blockers in HFpEF
• Beta-blockers have established mortality benefits in HFrEF but these benefits do not extend to patients with preserved ejection fraction 1
• Beta-blockers may be used in HFpEF for other indications such as hypertension, history of MI, or rate control in atrial fibrillation 1

Mineralocorticoid Receptor Antagonists (Spironolactone)

• Spironolactone has not demonstrated mortality reduction in HFpEF patients
• The 2022 AHA/ACC/HFSA guidelines indicate that MRAs may be considered in selected HFpEF patients to decrease hospitalizations, but not for mortality benefit 1
• Meta-analyses suggest a trend toward mortality reduction with spironolactone compared to placebo, but results did not reach statistical significance 2
• MRAs may be considered primarily for patients with LVEF in the lower range of preservation (50-60%) 3

Sacubitril/Valsartan

• The PARAGON-HF trial showed only a numerical reduction in the composite endpoint of total HF hospitalizations and CV death (RR 0.87; 95% CI [0.75,1.01], p = 0.06) 4
• The treatment effect was primarily driven by reduction in HF hospitalizations, not mortality
• No significant effect on cardiovascular death was observed (HR = 0.95; 95% CI [0.79,1.16]) 4
• May be considered in selected patients, particularly those with LVEF ≤57% and women, but not for mortality benefit 3

Current Evidence-Based Approaches for HFpEF

Medications with Some Evidence of Benefit (Not Mortality)

1. SGLT2 inhibitors (empagliflozin, dapagliflozin):

   • First-line disease-modifying therapy with strongest evidence
   • Reduce HF hospitalizations (HR: 0.71 for empagliflozin) 3
   • Improve quality of life and exercise capacity
   • No proven mortality benefit 5, 6

2. Diuretics:

   • First-line therapy for symptom relief in volume overload
   • Goal is achieving euvolemia with lowest effective dose 3
   • No mortality benefit

3. MRAs (spironolactone):

   • May reduce hospitalizations in selected patients
   • Requires monitoring of potassium and renal function 3

4. ARBs (candesartan):

   • May be considered for patients with hypertension and HFpEF
   • Showed borderline benefit in CHARM-Preserved trial (HR: 0.86) 3

Management of Comorbidities

• Aggressive management of comorbidities is crucial:
  • Hypertension (target systolic BP <130 mmHg)
  • Atrial fibrillation (rate or rhythm control)
  • Diabetes (optimize glycemic control)
  • Obesity (weight reduction for BMI ≥30)
  • Sleep apnea (screening and treatment) 3

Pitfalls and Caveats

1. Heterogeneity of HFpEF:

   • HFpEF represents a heterogeneous syndrome with multiple pathophysiological mechanisms 7, 5
   • This heterogeneity may explain why treatments effective in HFrEF have failed in HFpEF

2. Medication Avoidance:

   • Avoid medications known to worsen HF:
     • NSAIDs
     • Most antiarrhythmic drugs
     • Non-dihydropyridine calcium channel blockers (verapamil, diltiazem)
     • Routine use of nitrates or phosphodiesterase-5 inhibitors 3

3. Diagnostic Challenges:

   • HFpEF diagnosis is more challenging than HFrEF
   • Requires demonstration of cardiac structural/functional abnormalities beyond just preserved LVEF 1

4. Endpoint Considerations:

   • While mortality remains unchanged, improvements in quality of life and reduction in hospitalizations are important outcomes in this predominantly elderly population 8

In conclusion, current evidence does not support the use of carvedilol, spironolactone, or sacubitril/valsartan specifically for mortality reduction in HFpEF patients. Management should focus on symptom relief, reducing hospitalizations, and addressing underlying comorbidities.