Angiotensin–Neprilysin Inhibition versus Enalapril in Heart Failure
Comprehensive Overview
Published in the New England Journal of Medicine in 2014, this study, known as the PARADIGM-HF trial, asked whether a newer drug combining a neprilysin inhibitor with an angiotensin receptor blocker, called LCZ696, could outperform enalapril, an ACE inhibitor that had already been shown to improve survival, in patients with chronic heart failure and a reduced ability of the heart to pump blood. Researchers randomly assigned 8,442 patients with class II, III, or IV heart failure and an ejection fraction of 40% or less to receive either LCZ696 at 200 milligrams twice daily or enalapril at 10 milligrams twice daily, on top of other recommended heart failure therapy, in a double-blind design. The primary outcome was a composite of death from cardiovascular causes or hospitalization for worsening heart failure, though the trial was specifically powered to detect a difference in cardiovascular death alone. The topline result was that LCZ696 reduced this composite outcome, as well as the risk of death from any cause, to such a striking degree that the trial was stopped early, after a median follow-up of 27 months, because the prespecified boundary for overwhelming benefit had already been crossed.
Outcomes and Implications
The most important finding was that the primary composite outcome of death from cardiovascular causes or hospitalization for heart failure occurred in 21.8% of patients receiving LCZ696 compared with 26.5% of those receiving enalapril, a 20% relative risk reduction. LCZ696 also reduced death from any cause, 17.0% versus 19.8%, and death specifically from cardiovascular causes, 13.3% versus 16.5%, along with a 21% reduction in the risk of hospitalization for heart failure. Patients on LCZ696 additionally reported fewer symptoms and physical limitations related to their heart failure. These benefits emerged early in the trial and were consistent across nearly every one of the 18 prespecified subgroups examined, and they proved large enough that the independent data and safety monitoring committee stopped the trial ahead of schedule for overwhelming efficacy. LCZ696 did carry a distinct side-effect profile: patients on the drug had higher rates of symptomatic low blood pressure and nonserious swelling reactions, but notably lower rates of dangerous kidney impairment, elevated potassium, and cough than those on enalapril, with fewer LCZ696 patients stopping their medication overall because of side effects. The authors conclude that combined inhibition of the angiotensin receptor and neprilysin was superior to ACE inhibition alone at reducing death and hospitalization in patients with chronic heart failure and reduced ejection fraction, a magnitude of benefit they note was at least as large as that of enalapril's own landmark improvement over placebo, supporting LCZ696 as a replacement for ACE inhibitors and ARBs in this population.