: PARADIGM-HF. Angiotensin-neprilysin inhibition versus enalapril in heart failure.

The the novel agent LCZ696 (Novartis) that has effects both within and beyond the renin-angiotensin system, was tested against of the ACE inhibitor enalapril, showing fewer HF hospitalizations and mortality from cardiovascular causes, acccording a phase 3 trial PARADIGM-HF.
In this double-blind trial, 8442 patients with class II – IV heart failure and an ejection fraction of 40% or less were randomized 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 other guidelines-based therapies. The primary outcome was a composite of death from cardiovascular causes or hospitalisation for heart failure.
The trial was stopped early, with a median follow-up of 27 months, due to an overwhelming benefit with the new agent. The primary outcome had occurred in 914 patients (21.8%) in the LCZ696 group and 1117 patients (26.5%) in the enalapril group (HR 0.80; 95% 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 (HR 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 (HR 0.80; 95% CI, 0.71 to 0.89; P<0.001). As compared with enalapril, LCZ696 also reduced the risk of hospitalisation for heart failure by 21% (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.
LCZ696 is the first successful drug in the angiotensin receptor-neprilysin inhibitor (ARNI) class, an inhibitor of angiotensin that can also potentiate endogenous natriuretic peptides, which are vasodilators. Chemically, it is composed of the angiotensin-receptor blocker (ARB) valsartan affixed to the neprilysin inhibitor sacubitril.
The editorial accompanying the PARADIGM-HF results, pointed out that LCZ696 “may prove to be the first disruptive agent to the heart-failure treatment algorithm, which has remained essentially unchanged for a decade”; and “ the beneficial results seen in PARADIGM-HF may apply to a wide spectrum of patients, even those who are currently receiving the best possible therapy”, concluded the editorialist Dr Mariell Jessup (University of Pennsylvania, Philadelphia).
PARADIGM-HF is a trial of great significance that will likely have a deep influence on the way we treat patients with symptomatic heart failure.

Authors: McMurray JJ, et al
Posted: August 30; 2014 (N Engl J Med. 2014 Sep 11;371(11):993-1004)

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