For patients with heart failure and preserved ejection fraction, sacubitril-valsartan therapy did not significantly lower risk for hospitalization or death from cardiovascular (CV) causes compared with valsartan alone, according to study results published in the New England Journal of Medicine.
The investigators of this randomized, double-blind clinical trial compared the effects of angiotensin receptor-neprilysin inhibition (sacubitril-valsartan) against angiotensin system inhibition alone (valsartan) in patients with heart failure with preserved ejection fraction (HFpEF).
The study included 4796 patients age ≥50 years with symptoms of heart failure (HF), ejection fraction ≥45%, New York Heart Association (NYHA) class II-IV, elevated natriuretic peptide levels, and evidence of structural heart disease. Researchers randomly assigned participants to receive sacubitril-valsartan (n=2407) or valsartan (n=2389) and were followed for a median of 35 (interquartile range, 30-41) months. A composite of total hospitalizations because of heart failure and deaths from CV causes was the primary outcome. Secondary outcomes reported at 8 months included NYHA class change, decline of renal function, score change in the Kansas City Cardiomyopathy Questionnaire, and death from any cause. Prespecified adverse events of interest were hypotension, renal dysfunction, hyperkalemia, and angioedema.
A total of 526 participants in the sacubitril-valsartan group reported 894 primary events (690 hospitalizations and 204 cardiovascular deaths); 557 participants in the valsartan group reported 1009 primary events (797 hospitalizations and 212 cardiovascular deaths). The rate ratio between the 2 groups was 0.87 (95% CI, 0.75-1.01; P =.06).
At 8 months, 15% of the sacubitril-valsartan group improved their NYHA class and 8.7% had a worsened NYHA class; in the valsartan group, 12.6% improved their NYHA class and 9.6% had a worsened NYHA class.
The odds ratio for NYHA class improvement was 1.45 (95% CI, 1.13-1.86). Renal function worsened in 33 patients (1.4%) in the sacubitril-valsartan group and in 64 patients (2.7%) in the valsartan group (hazard ratio [HR] 0.5; 95% CI, 0.33-0.77).
At 8 months, the mean change in Kansas City Cardiomyopathy Questionnaire scores was 1.6±0.4 points in the sacubitril-valsartan group vs 2.6±0.4 points in the valsartan group for a between-group difference of 1 point (95% CI, 0-2.1). Death from any cause was nearly identical between groups: 342 patients (14.2%) in the sacubitril-valsartan group and 349 patients (14.6%) in the valsartan group (hazard ratio 0.97; 95% CI, 0.84-1.13). The incidences of hypotension and angioedema were higher in the sacubitril-valsartan group, but the valsartan group was more likely to report hyperkalemia.
Limitations to the study included that most patients were receiving a renin-angiotensin system inhibitor before enrollment, making a placebo-controlled trial unrealistic. Furthermore, patients with HF and ejection fraction ≥45% represent a phenotypically heterogeneous group, limiting the generalizability of the findings to broader populations.
The researchers of the study concluded that because fewer primary outcome events were reported for sacubitril-valsartan than for valsartan alone, this therapy may benefit patients with HFpEF; however, there was no statistical difference in risk for CV death or hospitalizations between the 2 treatments, and future studies are needed.
Disclosure: This clinical trial was supported by Novartis Pharmaceuticals Corporation. Please see the original reference for a full list of authors’ disclosures.
Solomon SD, McMurray JJV, Anand IS, et al. Angiotensin–neprilysin inhibition in heart failure with preserved ejection fraction. N Eng J Med. 2017;5(7):471-482.