Novel Heart Failure Drug Combo Cuts CV Mortality More Than Enalapril

By Joe Elia

Edited by Susan Sadoughi, MD, and Richard Saitz, MD, MPH, FACP, FASAM

LCZ696, an experimental compound that inhibits both angiotensin and neprilysin, "may well represent a new threshold" in treating heart failure, according to an editorialist in the New England Journal of Medicine. Neprilysin is an endopeptidase that degrades certain endogenous vasoactive peptides; its inhibition increases levels of these peptides, offsetting the neurohormonal overactivation seen in heart failure.

In the phase III PARADIGM-HF trial, also published in NEJM, some 8400 patients with class II to IV disease and ejection fractions of 40% or lower were randomized to LCZ696 or the ACE inhibitor enalapril. LCZ696 comprises the angiotensin-receptor blocker valsartan and the neprilysin inhibitor sacubitril.

After a median follow-up of roughly 2 years, the composite primary outcome of cardiovascular mortality or first hospitalization for heart failure was reduced by 20% with LCZ696 relative to enalapril. In particular, cardiovascular death occurred in 13.3% of the LCZ696 group versus 16.5% of the enalapril group (hazard ratio, 0.80).

The number of patients needed to be treated with LCZ696 to prevent one cardiovascular death was 32.

In NEJM Journal Watch Cardiology, Harlan Krumholz writes: "This trial provides welcome news for patients with chronic heart failure and reduced systolic function. On first look, these are stunning results, although whether they are generalizable to more-typical older patients with HF (compared with an average age of 64 in this cohort) remains to be seen. It would be nice to see validation in another trial before this drug becomes a standard of care — but many people will consider this evidence to be more than adequate to support its use."

PARADIGM-HF was conducted with the participation of LCZ696's manufacturer.