Angiotensin-neprilysin inhibition versus enalapril in heart failure

Background: We compared the angiotensin receptor–neprilysin inhibitor LCZ696 with enalapril in patients who had heart failure with a reduced ejection fraction. In previous studies, enalapril improved survival in such patients. Methods: In this double-blind trial, we randomly assigned 8442 patients with class II, III, or IV heart failure and an ejection fraction of 40% or less to receive either LCZ696 ( at a dose of 200 mg twice daily ) or enalapril ( at a dose of 10 mg twice daily ), in addition to recommended therapy. The primary outcome was a composite of death from cardiovascular causes or hospitalization for heart failure, but the trial was designed to detect a difference in the rates of death from cardiovascular causes. Results: The trial was stopped early, according to prespecified rules, after a median follow-up of 27 months, because the boundary for an overwhelming benefit with LCZ696 had been crossed. At the time of study closure, the primary outcome had occurred in 914 patients ( 21.8% ) in the LCZ696 group and 1117 patients ( 26.5% ) in the enalapril group ( hazard ratio in the LCZ696 group, 0.80; 95% confidence interval [CI], 0.73 to 0.87; P < 0.001 ). A total of 711 patients ( 17.0% ) receiving LCZ696 and 835 patients ( 19.8% ) receiving enalapril died ( hazard ratio for death from any cause, 0.84; 95% CI, 0.76 to 0.93; P < 0.001 ); of these patients, 558 ( 13.3% ) and 693 ( 16.5% ), respectively, died from cardiovascular causes ( hazard ratio, 0.80; 95% CI, 0.71 to 0.89; P < 0.001 ). As compared with enalapril, LCZ696 also reduced the risk of hospitalization for heart failure by 21% ( P < 0.001 ) and decreased the symptoms and physical limitations of heart failure ( P=0.001 ). The LCZ696 group had higher proportions of patients with hypotension and nonserious angioedema but lower proportions with renal impairment, hyperkalemia, and cough than the enalapril group. Conclusions: LCZ696 was superior to enalapril in reducing the risks of death and of hospitalization for heart failure. ( Funded by Novartis; PARADIGM-HF ClinicalTrials.gov number, NCT01035255. )