Combo heart failure drug promises to improve survival

A novel drug that combines an ARB with a neprilysin inhibitor proved superior to the ACE inhibitor enalapril, even when the latter was prescribed at its target dose, for reducing the risk of death and hospitalization for heart failure in patients with reduced ejection fraction.

The results of PARADIGM-HF trial (Prospective Comparison of ARNI [Angiotensin Receptor–Neprilysin Inhibitor] with ACEI [Angiotensin-Converting–Enzyme Inhibitor] to Determine Impact on Global Mortality and Morbidity in Heart Failure Trial) were published online Aug. 30 in the New England Journal of Medicine and presented simultaneously at the 2014 European Society of Cardiology Congress in Barcelona.  

The findings by John J.V. McMurray, MD, of the British Heart Foundation Cardiovascular Research Centre at the University of Glasgow in the U.K., and the other PARADIGM-AF researchers came as no surprise, given that the study’s sponsor, Novartis, stopped the trial early in March 2014 after meeting a prespecified boundary of overwhelming benefit of the drug LCZ696. LCZ696 is a combination of the neprilysin inhibitor AHU377 and the ARB valsartan.

PARADIGM-HF randomized 8,442 patients with New York Heart Association class II, III or IV heart failure and an ejection fraction of less than 40 percent (later lowered to 35 percent) who were taking an ACE inhibitor or ARB to either a twice daily dose of 200 mg LCZ696 or a twice daily dose of 10 mg enalapril. The patients were enrolled from 47 countries between Dec. 8, 2009, and Nov. 23, 2012, and screened for unacceptable side effects at the target dose before randomization.

The primary outcome was a composite of death from cardiovascular causes or first hospitalization for heart failure. After a median 27-month follow-up, 21.8 percent of the LCZ696 group and 26.5 percent of the enalapril group had died from cardiovascular causes or were hospitalized for heart failure. A total of 17 percent of the LCZ696 group died from any cause vs. 19.8 percent of the enalapril group. The use of LCZ696 reduced the risk of heart failure hospitalization by 21 percent.

Compared with enalapril patients, more patients in the LCZ696 group had symptomatic hypotension but fewer stopped taking medication overall or because of adverse events.

In clinical practice, physicians often prescribe enalapril at lower than the recommended 10 mg twice daily doses, although it has been shown at that dosage to reduce mortality. Based on PARADIGM-AF’s use of the ACE inhibitor at its target dose, McMurray et al deemed the advantage seen with LCZ696 to be “highly significant and clinically important.” They added that LCZ696 was well tolerated with a lower rate of adverse events compared with enalapril.

“Hence, our results are applicable to a broad spectrum of patients with heart failure, including those who are currently taking an ACE inhibitor or ARB or who are likely to be able to take such an agent without having unacceptable side effects,” they wrote.

In an accompanying editorial, Mariell Jessup, MD, of the Perelman School of Medicine at the University of Pennsylvania in Philadelphia, agreed, proposing that the results provide hope for heart failure. “The beneficial results seen in PARADIGM-AF may apply to a wide spectrum of patients, even those who are currently receiving the best possible therapy,” she wrote.

PARADIGM-AF was funded by Novartis.