New Combination Improves Heart Failure Outcomes

A new product combining an angiotensin-receptor blocker (ARB) and a neprilysin inhibitor lowers mortality and hospitalization rates in patients with heart failure, compared with enalapril, concludes a trial in the New England Journal of Medicine.

The PARADIGM-HF trial enrolled 8442 patients with class II, III, or IV heart failure and an ejection fraction of 40 percent or less. The patients were randomly assigned to treatment with LCZ696, consisting of the neprilysin inhibitor sacubitril and the ARB valsartan, 200 mg twice daily, or the angiotensin-converting enzyme inhibitor enalapril, 10 mg twice daily. Study medications were given in addition to recommended therapy. The main outcome of interest was a composite of cardiovascular death and heart failure hospitalization.

The study was halted early at a median follow-up time of 27 months, with evidence of “overwhelming benefit” in the LCZ696 group. The rates of the primary outcome were 21.8 percent with LCZ696 versus 26.5 percent with enalapril: hazard ratio (HR) 0.80 in the LCZ696 group.

All-cause mortality was 17.0 percent with LCZ696 and 19.8 percent with placebo, HR 0.84. The rates of death resulting from cardiovascular causes were 13.3 percent and 16.5 percent, respectively, HR 0.80. Treatment with LCZ696 was also associated with a reduced risk of heart failure hospitalization, HR 0.79. There was also significant improvement in heart failure–related symptoms and physical limitations, with about a 1-point difference in clinical summary score on the Kansas City Cardiomyopathy Questionnaire. LCZ696 was associated with higher rates of hypotension and nonserious angioedema but with lower rates of renal impairment, hyperkalemia, and cough.

Naprilysin inhibition increases levels of endogenous vasoactive peptides, counteracting the adverse effects of neurohormonal overactivation. The new study shows significant improvement in morbidity and mortality with LCZ696 in patients with heart failure and reduced ejection fraction, compared with enalapril. The PARADIGM-HF study “provides strong evidence that combined inhibition of the angiotensin receptor and neprilysin is superior to inhibition of the renin-angiotensin system alone in patients with chronic heart failure,” the investigators conclude [McMurray JJ, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014: 371:993–1004].