Foundations of Quadruple Therapy in Heart Failure

James Januzzi, MD: This gives us an opportunity to think about the newer updates on the guideline-directed medical therapies that we use in heart failure for management. Rob, in terms of the foundation, it’s a bit of a marketing tool that we use in heart failure. We talk about the 4 pillars of quadruplet-based guideline-directed medical therapies for heart failure with reduced ejection fraction [HFrEF]. Is this a standard of practice at this point?

Robert J. Mentz, MD: That’s exactly right. The language we use really matters, and when we see HFrEF, we need to think the 4 pillars of quad therapy: ARNI [angiotensin receptor–neprilysin inhibitor], 1of 3 evidence-based beta-blockers, MRAs [mineralocorticoid receptor antagonists], and now SGLT2 inhibitors being added as that fourth pillar.

James Januzzi, MD: Let’s go through each of those because for viewers who may be interested in this, they may not know what these drugs are. Or they do but they’re interested in hearing more. What’s an ARNI?

Robert J. Mentz, MD: ARNIis sacubitril/valsartan. Building on the rich history with ACEs and ARBs, ARNI is showing superiority in the PARADIGM-HF trial, which compares an ACE inhibitor with an ARNI and elevates ARNI to class 1.That should be the priority therapy as long as there isn’t a contraindication.

James Januzzi, MD: Perfect. What about the evidence-based beta-blockers?

Robert J. Mentz, MD: These are the long-acting version of metoprolol succinate, the bisoprolol, and carvedilol. It needs to be 1 of those 3, and we can make sure our patients with reduced EF [ejection fraction] are on 1 of those 3.

James Januzzi, MD: It comes up very frequently. You mentioned the term MRA. What’s an MRA?

Robert J. Mentz, MD: Historically the term had been aldosterone antagonists or mineralocorticoid receptor antagonists. This is looking as spironolactone or eplerenone in that class for HFrEF therapies.

James Januzzi, MD: Lastly, SGLT2 inhibitors. Some individuals may recognize these as therapies for diabetes. Why are we talking about them for heart failure?

Robert J. Mentz, MD: This is an important piece, and it comes up every day when we’re in clinic. These are medications initially developed for patients with diabetes, but these are cardiovascular and heart failure drugs across the spectrum.

James Januzzi, MD: Dr Butler, you were involved in the pivotal studies for some of these therapies. What’s your perspective on the 4 pillars but really 5 drugs? Ironically, sacubitril/valsartan is 2 drugs.

Javed Butler, MD, MPH, MBA: That’s absolutely correct. You were talking about slogans. The 1 that I like the best is from Muthiah. He said 4 pills, 5 drugs, 6 years because, on average, treatment can increase survival for patients by about 6.3 years. One thing I want to highlight is that sacubitril/valsartan is a combination of 2 drugs. It’s not 1 drug.

James Januzzi, MD: Why is that important?

Javed Butler, MD, MPH, MBA: It’s important because we sometimes call them RAS inhibitors. If you call them RAS inhibitors, then you might think ACE inhibitors and ARNI are interchangeable, but they’re not. We wouldn’t put beta-blockers and ivabradine in the same class. You need a separate class for ARNI, because these are 2drugs. Suppose beta-blockers are available only in combination with ACE inhibitors and there’s no such thing as a separate beta-blocker. Would you call an ACE inhibitor and an ACE inhibitor beta-blocker the same thing?

James Januzzi, MD: No, that’s a great point.

Javed Butler, MD, MPH, MBA: Absolutely not. ARNI is a different medication. When you compare an ARNI with an ACE inhibitor, at every level there is benefit that’s superior to an ACE inhibitor. We shouldn’t think of ARNI as a RAS blocker. It is RAS blocker plus and should be thought of as a separate category.

James Januzzi, MD: Plus neprilysin inhibition. Let’s give credit to Dr Vaduganathan for his work focusing on this: 4 pills, 5 pathways, 6 years. Explain that result, please.

Muthiah Vaduganathan, MD, MPH: We started by discussing the life expectancy in a natural history of a patient population on minimal drug therapies. They’re anticipated to survive 11 to 12 years. Based on randomized clinical trial evidence that supported each of the newer drug classes, we simulated what comprehensive drug therapy could benefit patients if patients took these therapies for their lifetimes. We estimated that they would survive about 18 years on average. The net difference or extension in survival with multidrug therapeutic implementation would be about 6 years. That’s a quantity that’s quite translatable at the bedside or in the clinic, where patients may wonder, “Why should I take this many drugs? I feel just fine, and I was just diagnosed. Can’t I start with 1drug and see how it goes?” This is a way to change that conversation.

James Januzzi, MD: What’s amazing about those results—I talk about them all the time with my patients—is that in my practice at Massachusetts General [Hospital Corrigan Minehan] Heart Center, I still see patients who come to me on an ACE inhibitor and a beta-blocker, and that’s it. There’s perceived contraindication to spironolactone or eplerenone without any effort to mitigate, for example, hyperkalemia. For whatever reason, an SGLT2 hasn’t been added. All of a sudden, the reaction is as you say, “But I feel fine, and I’m only taking these 2pills. Why should I be switched around to all these new medicines?”This exact result is very important. Practically speaking, Rob, as the director of heart failure at Duke University, what contraindications to these 4drugs might you consider before you go all out at trying to establish a treatment strategy? By the way, we’re all going to talk about our own approaches.

Robert J. Mentz, MD: This is an important piece as we work to get all our patients with HFrEF on quad therapy, making sure they don’t have some of these other contraindications. Things like angioedema for ARNI therapy or realizing renal dysfunction can be an issue specifically with RAS inhibitors. There are those absolute contraindications, things like dialysis with some of our therapies. There are also challenges around blood pressure and heart rate with things like ARNI and beta-blockers, where we need to pull those pieces in to tell the full story and take care of our patients.

James Januzzi, MD: I agree. The more important issue about contraindications is that they’re far less common than the indications. It’s overcoming inertia about making changes. Even if an individual is a borderline candidate for a drug, it’s worth the effort.

Transcript edited for clarity