A Breakthough In Heart Failure?

Looks Like It - But Questions Remain

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An article appearing in New England Journal of Medicine in late August, 2014 has raised the possibility of a new breakthrough in the treatment of heart failure. The article describes results from the PARADIGM-HF study, in which patients with heart failure were treated with a novel investigational drug. The drug, developed by Novartis, is so new that it hasn’t even been named yet - at the moment it is referred to as LCZ696.

LCZ696 actually consists of two drugs joined together - valsartan (which is a widely used ARB inhibitor) and a new agent, sacubitril. Sacubitril works by inhibiting the enzyme neprilysin, and as a result blood levels of natriuretic peptides increase. Because natriuretic peptides can be beneficial in heart failure, researchers postulated that LCZ696 could improve the outcome of patients with this condition. The results of the PARADIGM-HF study suggest that the researchers were right.

In this study, over 8000 patients with heart failure were randomized to receive either LCZ696, or standard therapy utilizing the ACE inhibitor enalapril. In patients who took LCZ696, after an average of 27 months the risk of hospitalizations for heart failure and the risk of death were both reduced by about 20%. This level of improvement, over what is currently considered good therapy for heart failure, is indeed remarkable.

Why This Study Is Important

The results of the PARADIGM-HF are important for at least two reasons. First, it suggests that the new drug LCZ696 should offer new hope for many patients with heart failure - once it is approved for use by the FDA.

And second, this study opens a whole new avenue for treating heart failure.

Accordingly, we can expect additional drugs to be developed that, like LCZ696, inhibit the enzyme neprilysin.

When Will LCZ696 Be Available?

The new drug cannot be prescribed until it passes a rigorous review by the FDA. Assuming all goes smoothly with this review, the earliest we could expect the drug to be approved for use would be some time in 2015.

Are There Potential Pitfalls With LCZ696?

At the moment, the PARADIGM-HF trial is being celebrated as a new breakthrough in the treatment of heart failure. And we all hope that turns out to be the case. However, there are at least three reasons for us to contain our enthusiasm for the moment. 

First, “new breakthroughs” are announced all the time after clinical trials with new drugs. And while sometimes it turns out that a genuine breakthrough has indeed occurred, more typically it happens that the new treatment may provide more a marginal benefit, and may be less a breakthrough, than it initially appeared.

Second, over a decade ago a drug called nesiritide (Natrecor) was also touted as a breakthrough in the treatment of heart failure.

This is relevant because nesiritide didn’t just indirectly increase the levels of natriuretic peptides as LCZ696 does; nesiritide was a natriuretic peptide. It took several years, and more clinical trials, to show that nesiritide actually had only a marginal benefit (if any) in treating heart failure. This history probably should temper a bit of the enthusiasm now being expressed for LCZ696.

And Third. . .

Neprilysin has several functions in addition to reducing the levels of natriuretic peptides, and some of these functions are beneficial. In particular, neprilysin may help to prevent certain diseases associated with the accumulation of undesirable proteins in the body, such as Alzheimer’s disease and amyloidosis, and even prostate cancer. So inhibiting neprilysin may not be a universally good thing to do. You can read more about this potential problem here.


McMurray JJV, Packer M, Desai AS, et al. Angiotensin-neprilysin inhibition versus enalapril in heart failure. N Engl J Med 2014; DOI:10.156/NEJMoa1409077.

Jessup M. Neprilysin inhibition—a novel therapy for heart failure. N Engl J Med 2014; DOI:10.1056/NEJMe1409898.

Nalivaeva NN,Belyaev ND,I. A. Zhuravin, IA, et al. The Alzheimer’s Amyloid-Degrading Peptidase, Neprilysin: Can We Control It? International Journal of Alzheimer’s Disease Volume 2012 (2012), Article ID 383796. Available at: http://dx.doi.org/10.1155/2012/383796 (accessed 9/2/2014).

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