Is Tresto (sacubitril/valsartan) indicated in patients with heart failure with preserved ejection fraction (HFpEF)?

Sacubitril/Valsartan (Tresto) in Heart Failure with Preserved Ejection Fraction

Sacubitril/valsartan has limited benefit in patients with heart failure with preserved ejection fraction (HFpEF) and is not strongly indicated for this population, with benefits most clearly evident in patients with left ventricular ejection fraction below normal. 1

Evidence Assessment

The evidence regarding sacubitril/valsartan in HFpEF comes primarily from the PARAGON-HF trial, which did not achieve statistical significance for its primary composite endpoint of cardiovascular death or heart failure hospitalizations in patients with LVEF ≥45% (rate ratio 0.87; 95% CI 0.75-1.01; p=0.06) 1.

Key findings from the guidelines and research:

• The 2022 AHA/ACC/HFSA guidelines give sacubitril/valsartan a Class 2b recommendation for HFpEF, indicating that it may be considered in selected patients but is not strongly recommended 1
• FDA approval language states that benefits are "most clearly evident in patients with left ventricular ejection fraction below normal" 2
• Post-hoc analyses suggest potential benefit in:
  • Patients with LVEF in the lower range of preservation (45-57%) 1
  • Women with HFpEF 1

Clinical Decision Algorithm

When to Consider Sacubitril/Valsartan in HFpEF:

1. Patient Selection:

   • LVEF at the lower end of the preserved range (closer to 50%)
   • Recent heart failure hospitalization within 9 months or elevated natriuretic peptide levels
   • eGFR ≥30 mL/min/1.73m²
   • Serum potassium <5.0 mEq/L
   • Creatinine <2.5 mg/dL

2. Prioritize Other Therapies First:

   • SGLT2 inhibitors (empagliflozin or dapagliflozin) have stronger evidence for HFpEF and should be considered first-line 1
   • Mineralocorticoid receptor antagonists (spironolactone) may be considered in appropriate patients 1

3. Monitoring Requirements:

   • Blood pressure (higher risk of hypotension)
   • Renal function
   • Potassium levels
   • Signs of angioedema

Efficacy Considerations

The evidence for sacubitril/valsartan in HFpEF shows:

• No significant benefit on cardiovascular death (HR 0.95) or total mortality (HR 0.97) 1
• Marginal benefit for heart failure hospitalizations (rate ratio 0.85; 95% CI 0.72-1.00; p=0.056) 1
• Small but significant improvement in Kansas City Cardiomyopathy Questionnaire Clinical Summary Score (mean difference 1.13; 95% CI 0.15-2.11) 3
• Improvement in NYHA class (OR 1.32; 95% CI 1.11-1.58) 3

Safety Considerations

When using sacubitril/valsartan in HFpEF patients:

• Higher incidence of hypotension compared to valsartan alone (OR 1.67; 95% CI 1.27-2.19) 3
• No increased risk of hyperkalemia or worsening renal function compared to valsartan 3
• Risk of angioedema, particularly in patients with history of angioedema or African American patients 1

Common Pitfalls

1. Misinterpreting the FDA label: The FDA approval does not specifically endorse use in HFpEF but rather acknowledges a gradient of benefit that decreases as EF increases 2

2. Inappropriate patient selection: Patients with very high EF (>60%) are unlikely to benefit

3. Inadequate monitoring: Failure to monitor for hypotension, particularly in patients with baseline low blood pressure

4. Ignoring stronger evidence-based therapies: SGLT2 inhibitors have stronger evidence for HFpEF and should generally be prioritized 1

5. Overlooking contraindications: History of angioedema, severe renal impairment, or pregnancy

In conclusion, while sacubitril/valsartan may provide modest benefits in selected HFpEF patients (particularly those with LVEF closer to 50% and women), it is not strongly indicated for the broad HFpEF population, and other therapies with stronger evidence should be considered first.