Entresto in Heart Failure with Preserved Ejection Fraction (HFpEF)
Entresto (sacubitril/valsartan) has limited evidence in HFpEF and receives only a Class 2b recommendation (may be considered) from current guidelines, with the strongest potential benefit in women and patients with ejection fractions in the lower preservation range (45-57%). 1
Primary Evidence and Guideline Recommendations
The PARAGON-HF trial, the pivotal study for Entresto in HFpEF, failed to meet its primary endpoint of reducing cardiovascular death or heart failure hospitalizations (rate ratio 0.87; 95% CI 0.75-1.01; P=0.06). 1, 2 Importantly, there was no mortality benefit demonstrated, with cardiovascular death showing a hazard ratio of 0.95 and all-cause mortality showing a hazard ratio of 0.97. 1, 3
The 2022 AHA/ACC/HFSA guidelines assign Entresto a Class 2b recommendation for HFpEF (LVEF ≥50%), meaning it "may be considered" but is not strongly recommended. 3 This contrasts sharply with its Class 1 recommendation in HFrEF where it significantly reduces mortality and morbidity. 1, 4
Patient Selection: Who Benefits Most
Subgroups with Potential Benefit
Women with HFpEF showed the most compelling benefit in prespecified subgroup analysis, with a rate ratio of 0.73 (95% CI 0.59-0.90), primarily driven by reduced heart failure hospitalizations. 1, 3 This represents a 27% risk reduction. 4
Patients with LVEF 45-57% (the lower range of preservation) demonstrated benefit with a rate ratio of 0.78 (95% CI 0.64-0.95). 1, 3 This suggests Entresto may be more effective as ejection fraction approaches the mildly reduced range.
Treatment Hierarchy
SGLT2 inhibitors should be prioritized over Entresto in most HFpEF patients, as they carry a stronger Class 2a recommendation with more robust evidence for benefit. 3 Entresto should be considered only after SGLT2 inhibitor therapy in patients who remain symptomatic and meet specific criteria: female sex, LVEF 45-57%, elevated natriuretic peptides, and symptomatic disease. 3
Clinical Outcomes Beyond the Primary Endpoint
While the primary endpoint was not met, exploratory analyses showed:
- Heart failure hospitalizations trended toward reduction (rate ratio 0.85; 95% CI 0.72-1.00; P=0.056). 1
- NYHA class improvement occurred in 15.0% of Entresto patients versus 12.6% on valsartan alone (odds ratio 1.45; 95% CI 1.13-1.86). 2
- Renal function preservation was better with Entresto, with worsening renal function in only 1.4% versus 2.7% on valsartan (hazard ratio 0.50; 95% CI 0.33-0.77). 2
- Quality of life showed minimal improvement with only a 1.0 point higher KCCQ score at 8 months. 2
Safety Considerations and Monitoring
Hypotension and angioedema occurred more frequently with Entresto, while hyperkalemia was less common compared to valsartan alone. 1, 2 A mandatory 36-hour washout period is required when transitioning from ACE inhibitors to avoid angioedema. 3
Contraindications include history of angioedema related to previous ACE inhibitor or ARB therapy. 4
Practical Dosing Approach
Start with 24/26 mg twice daily in patients ≥75 years, those with severe renal impairment, or moderate hepatic impairment. 3 Titrate gradually, doubling every 2-4 weeks as tolerated, targeting 97/103 mg twice daily. 3 Monitor blood pressure closely during initiation, particularly in patients with borderline blood pressure. 3 Check renal function and electrolytes within 1-2 weeks after initiation and with each dose increase. 3
Clinical Bottom Line
For most HFpEF patients, Entresto is not first-line therapy. The evidence supports considering it primarily in symptomatic women or patients with LVEF 45-57% who remain symptomatic despite SGLT2 inhibitor therapy. 1, 3 The lack of mortality benefit and marginal reduction in hospitalizations, combined with increased hypotension and angioedema risk, limits its role compared to its transformative impact in HFrEF. 1, 2