- Question
- To determine whether sacubitril-valsartan reduces heart failure hospitalizations and cardiovascular death in patients with heart failure with preserved ejection fraction, as it had in heart failure with reduced ejection fraction.
- Design
- Phase 3, randomized, double-blind, active-controlled, parallel-group trial enrolling 4822 patients, funded by Novartis. A run-in period preceded randomization, with follow-up of up to 57 months.
- Population
- Patients with NYHA class II to IV heart failure, ejection fraction of 45% or higher, elevated natriuretic peptides, and structural heart disease.
- Intervention
- Sacubitril-valsartan, with a target dose of 97 mg of sacubitril and 103 mg of valsartan twice daily.
- Control
- Valsartan, with a target dose of 160 mg twice daily.
- Primary outcome
- Composite of total (first and recurrent) hospitalizations for heart failure and death from cardiovascular causes.
- Results
- There were 894 primary events in 526 patients with sacubitril-valsartan and 1009 events in 557 patients with valsartan (rate ratio 0.87; 95% CI 0.75 to 1.01; P = 0.06). Cardiovascular death was 8.5% vs. 8.9% (HR 0.95; 95% CI 0.79 to 1.16). NYHA class improved in 15.0% vs. 12.6% (OR 1.45; 95% CI 1.13 to 1.86).
- Safety
- The sacubitril-valsartan group had a higher incidence of hypotension and angioedema and a lower incidence of hyperkalemia. Worsening renal function occurred in 1.4% vs. 2.7% (HR 0.50; 95% CI 0.33 to 0.77).
- Conclusion
- Sacubitril-valsartan did not significantly reduce total heart failure hospitalizations or cardiovascular death in patients with an ejection fraction of 45% or higher.
- Why it matters
- As the largest trial of a neprilysin inhibitor in heart failure with preserved ejection fraction, its neutral primary result, together with signals of possible benefit in subgroups with lower ejection fraction and in women, shaped the discussion about the drug's role in this syndrome.
Card generated automatically with AI from the abstract of the original publication and the trial registry; every figure was checked against those sources. It may contain errors: verify the data at the source before using it for clinical decisions.
Generated on October 7, 2026