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Adobe Flash Player is required to view this feature. If you are using an operating system that does not support Flash, we are working to bring you alternative formats. Original Article Angiotensin–Neprilysin Inhibition versus Enalapril in Heart Failure John J.V.

McMurray, M.D., Milton Packer, M.D., Akshay S. Desai, M.D., M.P.H., Jianjian Gong, Ph.D., Martin P. Lefkowitz, M.D., Adel R. Rizkala, Pharm.D., Jean L. Rouleau, M.D., Victor C.

Shi, M.D., Scott D. Solomon, M.D., Karl Swedberg, M.D., Ph.D., and Michael R. Zile, M.D., for the PARADIGM-HF Investigators and Committees N Engl J Med 2014; 371:993-1004 DOI: 10.1056/NEJMoa1409077 open through September 17, 2014. 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. Figure 1 Screening Criteria, Run-in Periods, and Randomization. The proportion of patients who withdrew from the study because of adverse events was higher during the enalapril run-in period than during the LCZ696 run-in period after adjustment for the longer duration of LCZ696 exposure. The most common reasons for withdrawal from the study during the run-in period were hypotension, cough, hyperkalemia, and renal dysfunction. During the run-in period, 8 patients did not take enalapril and took only LCZ696.

IQR denotes interquartile range, and GCP Good Clinical Practice. Angiotensin-converting–enzyme (ACE) inhibitors have been the cornerstone of the treatment for heart failure and a reduced ejection fraction for nearly 25 years, since enalapril was shown to reduce the risk of death in two trials.

Long-term treatment with enalapril decreased the relative risk of death by 16% among patients with mild-to-moderate symptoms. The effect of angiotensin-receptor blockers (ARBs) on mortality has been inconsistent, and thus, these drugs are recommended primarily for patients who have unacceptable side effects (primarily cough) while receiving ACE inhibitors. Subsequent studies showed that the use of beta-blockers and mineralocorticoid-receptor antagonists, when added to ACE inhibitors, resulted in incremental decreases in the risk of death of 30 to 35% and 22 to 30%, respectively. Neprilysin, a neutral endopeptidase, degrades several endogenous vasoactive peptides, including natriuretic peptides, bradykinin, and adrenomedullin. Inhibition of neprilysin increases the levels of these substances, countering the neurohormonal overactivation that contributes to vasoconstriction, sodium retention, and maladaptive remodeling.

Combined inhibition of the renin–angiotensin system and neprilysin had effects that were superior to those of either approach alone in experimental studies, but in clinical trials, the combined inhibition of ACE and neprilysin was associated with serious angioedema. LCZ696, which consists of the neprilysin inhibitor sacubitril (AHU377) and the ARB valsartan, was designed to minimize the risk of serious angioedema. In small trials involving patients who had hypertension or heart failure with a preserved ejection fraction, LCZ696 had hemodynamic and neurohormonal effects that were greater than those of an ARB alone.