Angiotensin Receptor Neprilysin Inhibition in Heart Failure

Peter L. Salgo, MD: What about the angiotensin receptor neprilysin inhibitors (ARNIs)? That’s another class of drug. We’re getting into some strange territory around here. What are they and when do they get used?

Sheryl Chow, PharmD, BCPS: I actually want to refer to Scott on this because he’s done extensive studies on ARNIs, in particular.

Scott Solomon, MD: An angiotensin receptor neprilysin inhibitor is a new class of drugs. Of course, there’s only 1 drug, so far, in that class, and it’s sacubitril/valsartan. Sacubitril/valsartan is essentially a compound that contains both valsartan, which is an angiotensin receptor blocker (we know it well, it blocks the AT1 receptor), and sacubitril, which is a prodrug neprilysin inhibitor. They’re together in a crystal, essentially. You ingest it and these come apart into the component parts. The ARB (angiotensin receptor blocker) blocks the AT1 receptor and is then converted to the active form and that inhibits neprilysin.

What is neprilysin? Neprilysin is a ubiquitous enzyme that is responsible for the breakdown of a number of vasoactive peptides, including the biologically active natriuretic peptides like ANP (atrial natriuretic peptide), BNP (B-type natiuretic peptide), and CNP (C-type natriuretic peptide). We were talking before about BNP as a marker, and now we remember that BNP is also a hormone that, as Sheryl said very early in the program, goes up in the setting of heart failure. It goes up as a compensation. When you give a neprilysin inhibitor, you both block the renin angiotensin system and you make natriuretic peptides go up. You’re doing 2 things at once.

Peter L. Salgo, MD: Do you remove the usefulness of BNP as a marker at the same time you’re modifying it from a therapeutic effect?

Scott Solomon, MD: It turns out you do. Because BNP goes up when you give a neprilysin inhibitor, it’s no longer going to be as good a marker of the severity of heart failure. It’s going to be confusing, because if you start a patient on this drug, BNP will go up. But remember before that we talked about NT- (or N-terminal) proBNP. NT-proBNP is not a substrate for neprilysin, and so it’s still a really good marker of the severity of heart failure, even in the setting of neprilysin inhibition.

Sheryl Chow, PharmD, BCPS: But just, also, to clarify: I don’t think you’re suggesting that hospitals that use BNP should switch over to NT-proBNP because of the effect of this ARNI. Or are you?

Scott Solomon, MD: I might be. If you’re going to use an ARNI, and you’re going to want to follow some metric that you can measure in the blood, it’s going to be very, very difficult to follow BNP.

Peter L. Salgo, MD: Let’s look at some of the research that’s out there on these ARNIs in head-to-head studies. There’s the PARADIGM-HF trial, which was a head-to-head trial with an ARNI (sacubitril/valsartan) versus the ACE inhibitor (enalapril). What did it show? Where were the implications?

Scott Solomon, MD: PARADIGM-HF was the largest heart failure trial that we’ve ever done so far. A total of 8500 patients were randomized to either this ARNI, sacubitril/valsartan, or enalapril, which has been considered the gold standard of treatment in heart failure. PARADIGM was actually stopped early by the Data Safety Monitoring Board for overwhelming efficacy because there was a 20% reduction in a composite endpoint of cardiovascular death and heart failure hospitalization, a 20% reduction in cardiovascular death alone, and a 16% reduction in all-cause mortality. All of these were highly statistically significant.

Peter L. Salgo, MD: It was an important study, a big study. What about a 30-day readmission study comparing sacubitril/valsartan versus enalapril?

Akshay Desai, MD: Readmissions are a big problem in heart failure. I think we’re all concerned that patients who leave the hospital come back. And because Medicare has now set penalties for hospitals with higher than expected 30-day readmission rates, this is a target. So, we looked at this in the PARADIGM-HF study and looked at patients allocated to sacubitril/valsartan versus those with enalapril after their first hospitalization during the trial, and then asked the question, “How many of them were readmitted at 30 days and then beyond?” And it turns out that the rates of 30-day readmissions among the sacubitril/valsartan treated patients, after a first heart failure hospitalization, are lower by a substantial amount (by about 20%) than in patients who were treated with enalapril.

Peter L. Salgo, MD: Twenty percent is a big number.

Akshay Desai, MD: Yes.

Peter L. Salgo, MD: When you hear 20%, that’s verified statistically significant and you kind of perk up. That’s an impressive result. And there’re results of a post hoc analysis of PARADIGM-HF with diabetes patients, too.

Akshay Desai, MD: Yes. I think that what we know is a couple of things about diabetes. One is that diabetics benefit equally as nondiabetics with therapy with sacubitril/valsartan, and there are consistent benefits. That’s important because a large fraction of our heart failure with reduced ejection fraction patients are diabetic. The other is this interesting observation from the trial, which is that although the rates of new onset diabetes were not changed by treatment with sacubitril/valsartan in preference to enalapril, the glycemic control was better in the patients treated with sacubitril/valsartan than enalapril. And hemoglobin A1C levels were actually lower.

Peter L. Salgo, MD: I know we’re on the clock, but I have got to ask. Why?

Scott Solomon, MD: It’s not completely clear, but it turns out that stimulation of the natriuretic peptide system may actually play a role in glycemic control. And, very interestingly, GLP-1 (glucagon-like peptide-1), which we actually stimulate as a way to control blood sugars in patients, is a substrate for neprilysin. So, if you give a neprilysin inhibitor, that can actually go up and that might be a good thing.

Peter L. Salgo, MD: So, it’s kind of a win-win?

Scott Solomon, MD: We’re not entirely sure why. This is a post hoc finding, so I wouldn’t want to make too much of it, but it says that if you have a patient who has diabetes and heart failure, this therapy is certainly not going to make the diabetes worse and it may improve glycemic control. We had a 30% reduction in new use of insulin in diabetic patients.

Peter L. Salgo, MD: This is ridiculously interesting, and I’m sure that there’s another textbook coming on all of this as we go forward. But if you can make the diabetes better and simultaneously treat heart failure, then that’s a massive win if it holds up going forward.

Scott Solomon, MD: Well, it’s important to remember that a diabetic patient with heart failure has about twice the risk of a nondiabetic patient. So, anything we can do to improve both the heart failure substrate and also the metabolic substrate would be useful.