Entresto - A New Treatment For Heart Failure

Cautious optimism is justified

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In July, 2015, the United States Food and Drug Administration approved a new drug, Entresto (also known as LCZ696, Novartis), for patients with heart failure. Entresto is creating a fair amount of excitement among heart failure experts not only because it is the first of a brand new class of drugs for heart failure (the angiotensin receptor-neprilysin inhibitors, or ARNI drugs), but more importantly, because in a head-to-head clinical trial, Entresto performed significantly better than enalapril, an ACE inhibitor that is a cornerstone of current therapy for this disease.

What Is An ARNI?

Entresto was created by combining molecules of two different drugs together - the angiotensin receptor blocker (ARB) valsartan, and the neprilysin inhibitor sacubitril (hence, an ARNI).

Neprilysin inhibitors block the effect of neprilysin, an enzyme that breaks down the body’s natriuretic peptides. The body produces more of these beneficial natriuretic peptides during heart failure, and they work by improving vascular tone and increasing diuresis (fluid loss via the kidneys, i.e., peeing). By blocking the effect of neprilysin, neprilysin inhibitors can improve heart failure by making the natriuretic peptides persist longer.

Unfortunately, neprilysin inhibitors also increase the body’s levels of angiotensin, which worsens heart failure. So, in order to use a neprilysin inhibitor safely, a drug that reduces angiotensin must be added.

In the case of Entresto, the ARB used is valsartan. So the combination of valsartan and sacubitril - Entresto - was created.

How Effective Is It?

After several preliminary trials whose results were very promising, Entresto was tested in PARADIGM- HF, a major randomized clinical trial that compared the new drug to enalapril in over 8000 patients with symptomatic heart failure.

Enlapril is an ACE inhibitor that had been proven to significantly improve outcomes in patients with heart failure, and is considered a cornerstone of therapy for this condition.

Over the first two to three years of therapy, the incidence of cardiovascular death or hospitalization for heart failure, as well as death due to cardiovascular disease, were 20% lower with Entresto. All-cause mortality was also reduced. All these results were highly significant on statistical analysis.

In summary, in the PARADIGM-HF trial using Entresto instead of a current mainstay of heart failure therapy resulted in significant improvements in clinical outcomes.

Side Effects of Entresto

The main reported side effects of Entresto were hypotension (low blood pressure), hyperkalemia (increased potassium levels), and reduced kidney function.

In addition, some patients developed angioedema, a serious allergic reaction causing swelling of the lips and face. Black patients may be more susceptible to this side effect.

In addition, the use of ACE inhibitors increases the risk of angioedema, and should not be prescribed with Entresto.

There are other concerns with Entresto that I have not seen written about elsewhere. Namely, neurologists are actually looking for drugs that potentiate neprilysin (instead of inhibiting it), because neprilysin can reduce the accumulation of undesirable proteins in the body that are associated with Alzheimer’s disease, amyloidosis, and prostate cancer. Will inhibiting neprilysin with ARNI drugs make these other conditions worse? Time will tell.

Note: I posed this question to representatives of Novartis, and reported on their reply in another article. You can read about that exchange here.

The Bottom Line

At this point the excitement being expressed by heart failure experts appears justifiable. If the findings of PARADIGM-HF are accurate, patients with heart failure will have improved clinical outcomes when Entresto is prescribed instead of the currently recommended therapy with enalapril, or other ACE inhibitors.

However, when any new drug appears on the market, and our experience with the drug suddenly increases from a few thousand patients to hundreds of thousands, discovering new problems is the rule rather than the exception. In my view we perhaps should be especially vigilant of this possibility with Entresto.

Furthermore, this new drug is likely to be quite expensive (although Novartis is said to be exploring novel payment options), and it remains to be seen how quickly payers will approve the drug for their subscribers, or what kinds of restrictions may be placed on its usage.

Nonetheless, at this stage of the game Entresto looks like it may turn out to be very beneficial to many if not most patients diagnosed with heart failure, and it (or some other ARNI drug) appears likely to become a cornerstone of therapy.


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.

Food and Drug Administration. FDA approves new drug to treat heart failure . Press release.. July 7, 2015. Available here. (Accessed July 10, 2015)

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