New heart failure drug reduces both sudden cardiac death and fatal worsening of heart failure
Effect of the angiotensin-receptor-neprilysin inhibitor LCZ696 compared with enalapril on mode of death in heart failure patients
Desai AS, McMurray JJ, Packer M et al.
Eur Heart J. 2015 May 28. pii: ehv186. [Epub ahead of print]
BackgroundIn patients with heart failure (HF), conventional drugs can improve the incidence of death from progressive HF, but not from myocardial infarction (MI), stroke or non-cardiovascular causes. The first-in-class angiotensin-receptor-neprilysin inhibitor (ARNI) LCZ696 [1,2] was shown to reduce the composite primary endpoint of CV death or HF hospitalisation, as well as CV death and all-cause mortality, in the PARADIGM-HF study .
This study analysed the mode of death in PARADIGM-HF, in order to better understand the mortality reduction associated with LCZ696 treatment. In the prospective, randomised, double-blind PARADIGM-HF study, LCZ696 was compared with enalapril in 8399 subjects with chronic HF (NYHA classes II-IV) and left ventricular ejection fraction <40% who were treated with guideline-recommended therapy.
- Among CV deaths, the majority were categorised as sudden (44.8%) or HF-related (26.5%). Both death causes were less frequently seen in LCZ696 vs enalapril-treated patients (sudden death: HR: 0.80, 95%CI: 0.68-0.94, P=0.008, death due to worsening HF: HR: 0.79, 95%CI: 0.64-0.98, P=0.034).
- Resuscitated sudden deaths, resulting in a surviving patient occurred 16 times in the LCZ696 arm, as compared with 28 times with enalapril (HR: 0.57, 95%CI: 0.31-1.04, P=0.07).
- When combining resuscitated and non-resuscitated sudden death events, the risk of sudden death was 22% lower in those treated with LCZ696 (HR: 0.78, 95%CI: 0.66-0.92, P=0.002).
The magnitude of the treatment effect was similar (P=0.17) for patients with (HR: 0.49, 95%CI: 0.25-0.98) and without (HR: 0.82, 95%CI: 0.69-0.98) an implantable defibrillator.
- Fatal MI occurred in <1% of patients, accounting for 3.7% of all deaths. A similar, but not statistically significant difference between treatment arms was seen to that seen in HF death and sudden death.
- Less than 1% of patients experienced a fatal stroke, accounting for 4.1% of deaths, without a difference between treatment arms.
ConclusionThese data suggest that the mortality benefits of LCZ696 as compared with enalapril treatment observed during the PARADIGM-HF trial are mostly attributable to a lower incidence of both sudden death and death due to progressive heart failure. Previous placebo-controlled studies with renin-angiotensin system inhibition in heart failure showed larger reductions in hospitalisation for worsening HF than in CV death. The mechanism by which LCZ696 influences CV mortality requires further study.
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