A New Drug for Heart Failure

Since our most recent issue (August 3, 2015; 1474) includes an article on a new drug, sacubitril/valsartan (Entresto), for treatment of heart failure, we have asked our Contributing Editor, Dan M. Roden, MD, to be our guest blogger this week. Dr. Roden is Vice-Chancellor for Personalized Medicine and Professor of Medicine and Pharmacology at Vanderbilt University School of Medicine. His main research interest is in variability in clinical drug actions, notably in the treatment of cardiac arrhythmias.

From Dan M. Roden, MD

Angiotensin converting enzyme inhibitors were initially developed to treat hypertension, but seminal studies in rats in the 1980s suggested they might play a role in heart failure. A series of randomized placebo-controlled clinical trials then established their efficacy in human subjects, and ACE inhibitors have been first-line therapy in heart failure ever since.

The idea of manipulating neurohormones to therapeutic benefit in heart failure was incontrovertibly demonstrated by the success of the ACE inhibitors, and this success provided an impetus to development of other approaches to neurohormonal manipulation in heart failure. The now standard approaches of aldosterone antagonism, and indeed beta-blockade, are testament to the potential of this approach.

Rather than inhibiting detrimental neurohormonal pathways to treat heart failure, an alternate approach is to augment the activity of potentially beneficial pathways, such as the vasodilatory natriuretic peptides. One way to accomplish this goal would be to inhibit neprilysin, a neutral endopeptidase responsible for degradation of these potentially beneficial peptides. One early candidate molecule was omapatrilat, which was developed to retain neprilysin inhibition and add ACE inhibition. The drug was highly effective as an antihypertensive given once daily, but in heart failure it was only marginally more effective than enalapril. In a very large hypertension study, the risk of angioedema was very high, >5% of African-Americans exposed to the drug, compared to enalapril.

The next iteration in this strategy was LCZ696, which combines the angiotensin receptor blocker valsartan with the neprilysin inhibitor sacubitril, with the rationale that this should decrease the problem of angioedema while maintaining the efficacy of inhibiting the biological action of angiotensin and augmenting that of the vasodilatory peptides. The PARADIGM-HF study, which was designed to compare its effect to that of enalapril on the primary endpoint of death or first hospitalization for heart failure with reduced ejection fraction, was stopped early for very impressive efficacy. While the FDA usually requires demonstration of efficacy in two large clinical trials, the PARADIGM-HF result was so compelling that the combination was approved last month and is now marketed as Entresto.

There are a couple of small flies in the ointment. The incidence of hypotension was higher with LCZ696 than with enalapril, and the incidence of angioedema (termed “nonserious angioedema” in the NEJM paper in the fall of 2014) was higher with LCZ696 (17/4187) than with enalapril (10/4212). While these numbers are quite low, they reinforce the suggestion from the omapatrilat experience that angioedema may be a problem with the neprilysin moiety of the drug, and will mandate the same sorts of cautions we routinely give when patients are started on ACE inhibitors. The effect of LCZ696 in heart failure with preserved ejection fraction is still under evaluation. The very long-term effects of the drug are – as with any new therapy – not defined. The other likely fly in this ointment will be the cost of a new highly effective therapy for millions of subjects, weighed against the value of generic and effective ACE inhibitors. The development of this new therapy marks a triumph for the vision of targeting neurohormonal activation as a therapeutic modality, and in particular the tenacity of the heart failure and the drug development communities to build on expensive lessons learned to finally bring a new and effective treatment to market.

Dan M. Roden, M.D. has no disclosure or potential conflict of interest to report.

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