The first-in-class angiotensin receptor neprilysin inhibitor LCZ696—compared with the gold standard treatment of enalapril—significantly reduced the composite primary outcome of cardiovascular (CV) death or heart failure (HF) hospitalization in patients with HF and reduced ejection fraction in the prospective trial Efficacy and Safety of LCZ696 Compared With Enalapril on Morbidity and Mortality of Patients With Chronic Heart Failure [PARADIGM-HF; McMurray JJ et al. N Engl J Med. 2014]. The components of the primary outcome, as well as the secondary outcome of all-cause mortality, were also significantly reduced.

New results from analyses of prespecified outcomes showed that HF progression is attenuated and fatal and that nonfatal worsening heart failure (WHF) is delayed or prevented with LCZ696 when compared with enalapril, according to John J. V. McMurray, MD, University of Glasgow, Glasgow, Scotland, UK. LCZ696 combines a neprilysin inhibitor prodrug (sacubitril) and the angiotensin receptor blocker valsartan, thereby blocking both the AT₁ receptor and inhibiting the enzyme neprilysin, which breaks down natriuretic peptides and other vasoactive substances with beneficial effects in HF, to obtain incremental benefits beyond blockade of the renin angiotensin system alone.

In the original study, the median follow-up was 27 months, and the average daily dose at the last visit was LCZ696, 375 mg, and enalapril, 18.9 mg. The patients were aged 63.8 years; 22% were women; 60% had ischemic cardiomyopathy; and the mean left ventricular ejection fraction was about 29%.

Based on patient and physician assessments, the proportion of patients with WHF at month 8 was lower with LCZ696 vs enalapril [Packer M et al. Circulation. 2014]. For each domain measured by the Kansas City Cardiomyopathy Questionnaire, fewer patients in the LCZ696 group reported ≥ 5 points in deterioration (level considered to be clinically meaningful). Regarding change in NYHA class from baseline, more patients in the LCZ696 group improved (16.7% vs 14.9% with enalapril; P = .0015), and fewer patients progressed to a higher NYHA class (5.4% vs 7.0%, respectively), while 78% of each group had no change.

LCZ696 had a favorable influence on a number of parameters that are a measure of WHF—including reductions in treatment failure (as measured by the need for treatment intensification), emergency department visits for HF, hospitalization for HF, intensive care unit admission, and use of inotropic drugs (Table 1).

The need for devices, ventricular assist devices, or heart transplant for WHF was numerically lower with LCZ696 vs enalapril (Table 2).

Notably, all-cause hospitalization was reduced with LCZ696 as compared with enalapril, at about 110 fewer hospitalizations per 1000 patients, stated Prof McMurray. The number of admissions for any cause, including repeat episodes, was reduced (RR, 0.84; 95% CI, 0.78 to 0.91; P < .001), as was the proportion of patients hospitalized (HR, 0.88; 95% CI, 0.82 to 0.94; P < .001).

The rate of death for WHF was lower with LCZ696 vs enalapril (HR, 0.79; P = .34) and was significant for all-cause death (HR, 0.84; P < .001), CV death (HR, 0.80; P = .00008), and sudden death (HR, 0.80; P =.008).