Effect of the angiotensin-receptor-neprilysin inhibitor LCZ696 compared with enalapril on mode of death in heart failure patients

Aims: The angiotensin-receptor-neprilysin inhibitor (ARNI) LCZ696 reduced cardiovascular deaths and all-cause mortality compared with enalapril in patients with chronic heart failure in the prospective comparison of ARNI with an Angiotensin-Converting Enzyme Inhibitor to Determine Impact on Global Mortality and Morbidity in Heart Failure (PARADIGM-HF) trial. To more completely understand the components of this mortality benefit, we examined the effect of LCZ696 on mode of death. Methods and results: PARADIGM-HF was a prospective, double-blind, randomized trial in 8399 patients with chronic heart failure, New York Heart Association Class II–IV symptoms, and left ventricular ejection fraction ≤40% receiving guideline-recommended medical therapy and followed for a median of 27 months. Mode of death was adjudicated by a blinded clinical endpoints committee. The majority of deaths were cardiovascular (80.9%), and the risk of cardiovascular death was significantly reduced by treatment with LCZ (hazard ratio, HR 0.80, 95% CI 0.72–0.89, P < 0.001). Among cardiovascular deaths, both sudden cardiac death (HR 0.80, 95% CI 0.68–0.94, P = 0.008) and death due to worsening heart failure (HR 0.79, 95% CI 0.64–0.98, P = 0.034) were reduced by treatment with LCZ696 compared with enalapril. Deaths attributed to other cardiovascular causes, including myocardial infarction and stroke, were infrequent and distributed evenly between treatment groups, as were non-cardiovascular deaths. Conclusions: LCZ696 was superior to enalapril in reducing both sudden cardiac deaths and deaths from worsening heart failure, which accounted for the majority of cardiovascular deaths.