Desai AS, McMurray JJ, Packer M et al.
Eur Heart J. 2015 May 28. pii: ehv186. [Epub ahead of print]

Background

In 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 [3].
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.

Main results

• 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.

Conclusion

These 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.

Find this article online at European Heart Journal

References

1. Vardeny O, Tacheny T, Solomon SD. First-in-class angiotensin receptor neprilysin inhibitor in heart failure. Clin Pharmacol Ther 2013;94:445–448.
2. Gu J, Noe A, Chandra P, et al. Pharmacokinetics and pharmacodynamics of LCZ696, a novel dual-acting angiotensin receptor-neprilysin inhibitor (ARNi). J Clin Pharmacol 2010; 50:401–414.
3. McMurray JJ, Packer M, Desai AS, et al. PARADIGM-HF Investigators and Committees. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014;371:993–1004.