Efficacy and Safety of Valsartan/Sacubitril in Heart Failure

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The MD Magazine Peer Exchange “Managing Heart Failure Today: Current Best Practices and New Treatment Options” features a panel of physician experts discussing key factors to consider when making treatment decisions for patients with heart failure and their own clinical experiences with recently approved medications for the treatment of heart failure.

This Peer Exchange is moderated by Peter Salgo, MD, professor of medicine and anesthesiology at Columbia University College of Physicians and Surgeons, and an associate director of Surgical Intensive Care at New York-Presbyterian Hospital.

The panelists are:

• Michael Felker, MD, MHS, professor of medicine and chief of the Heart Failure Section at Duke University School of Medicine, in Durham, NC
• Milton Packer, MD, Distinguished Scholar in Cardiovascular Science, Baylor Heart and Vascular Hospital, Baylor University Medical Center, in Dallas, TX
• Scott Solomon, MD, Senior Physician and director of Non-Invasive Cardiology at Brigham and Women’s Hospital, and Edward D. Frohlich Distinguished Chair and professor of medicine at Harvard Medical School, in Boston, MA
• John R. Teerlink, MD, director of Heart Failure at San Francisco Veterans Affairs Medical Center and professor of medicine at UCSF in San Francisco, CA

Peter Salgo, MD: I want to get back to the ARNIs (angiotensin receptor/neprilysin inhibitors) a bit in terms of, as you said, the granular stuff—safety, efficacy, indications, contraindications. Can you walk me through that?

Scott Solomon, MD: Yeah. First of all, let me make clear [that we are discussing] sacubitril/valsartan. Let me use that term.

I’m going to use that term because I think it’s the most descriptive. We know what valsartan is, it’s an ARB (angiotensin-receptor blocker). And, we know how it works. It blocks the AT1 receptor.

Sacubitril is a neprilysin inhibitor. Neprilysin is an enzyme that is responsible for the breakdown of a whole host of vasoactive peptides, including the biologically active natriuretic peptides like ANP (atrial natriuretic peptide), CNP (C-type natriuretic peptide), and BNP (brain natriuretic peptide), as well as a whole bunch of other things.

When we give this drug (and by the way, it is essentially a crystalline compound that contains both valsartan and neprilysin), it comes apart when you ingest it. When we give it, we’re blocking the AT1 receptor and we’re doing exactly what Milton [Milton Packer, MD] just said—we’re increasing these vasoactive peptides and affecting this other system that we didn’t really have a good way to affect previously, [which] helps counteract some of the deleterious effects of both the sympathetic nervous system and the renin-angiotensin system’s abnormal activation.

We did a large trial. Dr. Packer led this trial [and] I had the honor of working with him on this for the last 7 or 8 years. [The trial was] called the PARADIGM Heart Failure study. This is a trial in which we treated 8500 patients with either sacubitril/valsartan or the previous gold standard therapy in heart failure, which was enalapril. We randomized patients to receive either the 200-mg dose of sacubitril/valsartan, or an evidence-based dose of enalapril, which was 10 mg twice a day. We followed them to see if they would live longer and stay out of the hospital.

The study was stopped early by the data and safety monitoring board because of overwhelming efficacy. This doesn’t happen very often in our business, unfortunately. What we saw was a 20% reduction in a composite endpoint of cardiovascular death or heart failure hospitalization—that was including both a 20% reduction in cardiovascular death and a 20% reduction in heart failure hospitalization, as well as a 16% reduction in all-cause mortality.

Peter Salgo, MD: Let me stop you right there, because that number is simply ridiculous. When you read a lot of research it’s, “Oh, we got a 2% or a 5% [reduction].” Twenty percent? You’re kidding me. Twenty percent? That’s huge!

Michael Felker, MD, MHS: It’s important to remember that this is on top of an already effective treatment. This is what’s very different about PARADIGM than most of the trials we’ve traditionally done, where we’ve compared standard of care to a new drug plus placebo on top of standard of care. This is comparing a new drug plus an already highly effective drug.

Peter Salgo, MD: A known effective therapy.

Scott Solomon, MD: It’s a gold standard therapy.

Peter Salgo, MD: Right.

Michael Felker, MD, MHS: I think it’s a major breakthrough in chronic heart failure care, in terms of outcomes.

Milton Packer, MD: A way to think about this is that what we really have been expecting to be able to give [patients with heart failure is] a drug that reduces mortality by, let’s say about 30% to 35%. When you put them together, the effect is even more. When you give a beta-blocker, you reduce mortality by about 35%. When you give an aldosterone antagonist, [there is] about a 30% reduction in mortality. The problem is that when we gave an ACE (angiotensin-converting enzyme) inhibitor, or an angiotensin-receptor blocker, we were only reducing mortality by about 5% to 15%. There was something missing. Now, when you use an angiotensin receptor/neprilysin inhibitor instead of an ACE inhibitor, you bring that level of survival to a 30% or 35% reduction, compared to placebo.

Peter Salgo, MD: That’s very, very impressive. So [let’s discuss] safety, indications, and contraindications?

Scott Solomon, MD: We pay a lot of attention to safety in these trials. In fact, this drug, in general, was quite safe in comparison to enalapril. There was more symptomatic hypotension, but when you looked at the number of patients who discontinued the study drug for hypotension, there was no difference between the 2 groups.

But, 2 of the side effects that really plague both patients and physicians were actually reduced with sacubitril/valsartan compared to enalapril—elevation of serum creatinine and hyperkalemia. We saw less of that with sacubitril/valsartan than with enalapril.

The overall rates of angioedema were very low in the trial. Numerically, a little bit more in the sacubitril/valsartan, but we’re talking about very small numbers. And importantly, [there were] no cases of severe, life-threatening angioedema.