ARNIs for the Treatment of Heart Failure


A panel of experts builds a discussion on the role of angiotensin receptor-neprilysin inhibitors for the management of heart failure and highlights the importance of considering patient adherence and cost burden.

Richard Mullvain, RPh, BCCP, BCPS, CCCC: It’s time to move on to the future. One of the breakthroughs has been the new class of drugs known as ARN [inhibitors]. It’s the angiotensin receptor valsartan with the neprilysin inhibitor. Those are combined together in a commercial product known as Entresto. I’m going to bring Ryan in for this. I was hoping you could discuss the role of the ARNI—the angiotensin receptor-neprilysin inhibitor—and the mechanism of action of specifically sacubitril, which is the component that is the neprilysin inhibitor. How do ARNIs fit into guideline-directed medical therapies? Ryan, if you could take off on that, we’d appreciate it.

Ryan Jacobsen, PharmD, BCPS: Our available ARNI is Entresto. It’s hard to believe that Entresto has been around since 2015. It’s unique in its mechanism of action. Neprilysin is a neutral endopeptidase. It activates several vasoactive peptides, including natriuretic peptides and bradykinin, which play an important role in the pathogenesis and progression of heart failure. The combination with valsartan is interesting. Valsartan, as you mentioned, is an angiotensin receptor blocker, and inhibition of neprilysin increases angiotensin levels. That explains the rationale for the coadministration of these 2 medications.

In terms of fitting into the guideline-directed medical therapy, the American Heart Association [AHA] and American College of Cardiology [ACC] has given Entresto a class 1 level of evidence A recommendation for treatment of heart failure with reduced ejection fraction in stage C. Alex in her earlier comments alluded to the backbone of heart failure therapy in this patient population. Entresto, or sacubitril and valsartan, are part of the backbone therapy. It’s recommended in the latest consensus decision pathway that this ARNI be considered either as initial therapy in place of an ACE or an AR [blocker] or switching from a patient who’s able to tolerate an ACE and an ARB. That is a bit of an update from the 2017 decision pathway, when we were more in a situation of switching patients. Now there’s good evidence of benefit and safety in terms of tolerability of initial therapy with ARNIs.

Of course, whether you’re starting in a naïve patient or switching, that determines some of the initial dosing. An important point for people to be aware of, especially a counseling point, is that if a patient is on an ACE inhibitor, it requires a minimum of a 36-hour washout period if switching. That’s because of risk of angioedema. Any history of angioedema is a contraindication to these medications. But over the last few years, this medication is a game changer in terms of added benefit in terms of mortality and other various heart failure outcomes of interest. I’d be curious to hear Alex’s comments too.

Richard Mullvain, RPh, BCCP, BCPS, CCCC: Alex, maybe you could weigh in. What are some of these challenges that we have with the ARNI? What do you see happening in the future with this drug or class of drug? Can you help us out?

Alexandra Goncharenko, PharmD, BCPS, BCCP: Yes. In the last couple years, as Ryan mentioned, as well as with the 2021 ACC/AHA update, there has definitely been support for the use of ARNIs in first-line instead of what it used to be: switching. Start the ACE or ARB first, as they did in the trial, and then consider switching to the ARNI. But now, that’s going to increase the uptake of ARNIs even more. It used to be more considered an outpatient medication, but we have more evidence to support initiation while in the hospital to promote adherence as well as decrease hospitalizations.

Some of the challenges still remain, like the cost of the medication. I work primarily in the South Side of Chicago where, especially when we’re using multiple brand-name medications, the co-pays can add up for patients. The cost is always a challenge with brand-name medications, but this is the best medication for a patient with heart failure with reduced ejection fraction on top of beta-blocker. In the future, it will be interesting to see increased uptake as well as more data to maybe support its use in HFpEF [heart failure with preserved ejection fraction] or in the midrange ejection fraction. Time will tell. I don’t know if Randy has something he wants to add.

Richard Mullvain, RPh, BCCP, BCPS, CCCC: I agree. We can define HFpEF as heart failure with preserved ejection fraction, just so people remember that. Did you have something else to weigh in with, Randy?

Randy McDonough, PharmD, MS, BCGP, BCPS, FAPhA: The thing I was going to mention was the cost issue. From a community pharmacy perspective, if someone were to pay out of pocket for a month’s supply at the top dose, you’re talking about easily $2000. What’s interesting, if you really look at the different formularies, is where they place it. What’s even more interesting is that when they came out and demonstrated the survival and the value of it, all of a sudden, we had to have prior authorization for some of the plans. But that’s not true across the board.

Depending on where it’s tiered on the formulary, whether it would be tier 2 or tier 3, the higher the tier, the more expensive it is for the patient. The frustrating thing is making sure these formularies get changed appropriately to fit the guideline-directed medical therapies. I’m on a P&T [pharmacy and therapeutics] committee myself, and we hit that hard to make it available, especially when it has that kind of value, to make it more available in a much easier way for both the prescriber and the pharmacist to get it to the patient.

Richard Mullvain, RPh, BCCP, BCPS, CCCC: Great answer. We’re going to see a lot more in the future on the ARNIs, but hopefully that was a good summary for us.

Transcript edited for clarity.

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