ESC Report 2014: LCZ696 could change heart failure treatment paradigm

Report from the European Society of Cardiology Annual Congress in Barcelona by Bruce Sylvester – Results from the PARADIGM-HF trial, presented at ESC 2014 on August 30,2014 and published simultaneously in the New England Journal of Medicine, are “…an astonishing result and a real breakthrough for patients with heart failure,” said John McMurray, MD,  co-primary author, from the University of Glasgow, UK.

Investigative LCZ696, an angiotensin receptor-neprilysin inhibitor (ARNI), has already been granted Fast Track status by the United States Food and Drug Administration (FDA). The manufacturer, Novartis, said it expects to complete the submission of its new drug application in the US by the end of 2014, and in Europe in early 2015.

The trial presented at ESC 2014, PARADIGM-HF (Prospective comparison of ARNI with ACEI to Determine Impact on Global Mortality and morbidity in Heart Failure) was halted early by an independent data monitoring committee in the United States due to evidence of the efficacy of LCZ696 when compared to enalapril, an ACE inhibitor.

“The magnitude of the advantage of LCZ696 over enalapril on cardiovascular mortality was at least as large as that of enalapril over placebo during long-term treatment,” said Milton Packer, MD, co-primary author of the study from University of Texas Southwestern Medical Center, in Dallas, Texas. “This robust finding provides strong support for using this new approach instead of ACE inhibitors or ARBs in the treatment of chronic heart failure,” he added.
In PARADIGM-HF the researchers randomized 8,399 patients with class II to IV heart failure and an ejection fraction if 40% or less to either LCZ696 200 mg twice daily (n=4,187), or enalapril 10 mg twice daily (n=4,212), plus recommended therapy.

The trial was stopped early after a median follow-up of 27 months. The primary outcome, death from cardiovascular causes or hospitalization for heart failure, appeared in 21.8% of the LCZ696 group and 26.5% of the enalapril group (hazard ratio [HR] 0.80; p=0.0000002).

When compared to enalapril, LCZ696 lowered the risk of death from cardiovascular causes by 20% (13.3% vs 16.5%; HR 0.80; p<0.0001), and the risk of hospitalization for heart failure by 21% (12.8% vs 15.6%; HR 0.79; p<0.0001). The findings remained consistent across all pre-specified patient sub-populations.

LCZ696 subjects also achieved significantly improved secondary outcomes compared to enalapril subjects, including all-cause mortality (17.0% vs 19.8%, respectively; HR 0.84; p<0.001) and symptoms and physical limitations of heart failure measured on the Kansas City Cardiomyopathy Questionnaire (p=0.001).

“The superiority of LCZ696 over enalapril was not accompanied by important safety concerns,” said Dr. Packer.