Using Beta Blockers for Quadruple Therapy in the Management of HFrEF


Gregg Fonarow, MD, relays pertinent information concerning the use of beta blockers in quadruple therapy in the management of heart failure with reduced ejection fraction.

James Januzzi, MD: We’re now going to move on to segment 2, which is the management of heart failure with reduced ejection fraction [HFrEF]. And you’ve already heard a bit of the background, the history of how we got to the conventional therapies for HFrEF, as we call it: vasodilators; β-blockers, including evidence-based drugs like carvedilol and metoprolol succinate; MRAs, mineralocorticoid receptor antagonists, also known as aldosterone antagonists; and SGLT2 [sodium-glucose co-transporter-2] inhibitors. We won’t go through that too much, but I really want to try to focus on the individual components of quadruple therapy, and the role of each in the management of heart failure with reduced ejection fraction. I’m just going to come at each of you with individual classes of drug, if that’s OK. I have a real affinity for some of these, and I will say that perhaps one of the really important drugs, time tested and time honored, let’s start with the evidence-based β-blocker class. Gregg, why don’t we start with you, you often give a great sort of historical context to β-blocker therapy and why it’s so important to get patients titrated up on these therapies. Can you give us a sense of how β-blockers fit in the guideline-directed medical therapy scheme and give us a sense of the challenges that are associated with using β-blocker therapy?

Gregg C. Fonarow, MD: It’s been quite an evolution with β-blockers for heart failure with reduced ejection fraction [EF], starting from absolutely contraindicated to one of the single most important life-prolonging therapies we have for heart failure with reduced EF. From a human dynamic standpoint, it doesn’t necessarily make a lot of sense to apply β-blockers, but it does from a neurohormonal standpoint of counteracting all of the adverse effects related to the chronic stimulation and activation of epinephrine, norepinephrine, and the beneficial effects on reversing the pathologic remodeling process. Initial studies were more in patients with mild to moderate heart failure, but as the trials evolved, even severe patients with left ventricular ejection fractions of 20% on average, class 4 symptoms, have been shown to benefit. The key to success is starting at a low dose, one-eighth, one-twelfth, the usual starting dose for hypertension and gradually uptitrating. But it’s been shown that you can actually, for a patient admitted to the hospital with volume overloaded decompensated heart failure, so long as it’s not in cardiogenic shock, safely and effectively initiate β-blocker therapy, and then carefully uptitrate that. And it can be tolerated from a heart rate and blood pressure standpoint. We see reversal of remodeling, where EF on average, once you get up around 12 weeks to the full target dose, will improve by 7%. Within 2 weeks, the survival curves begin to diverge, with reductions in mortality and hospitalizations in the first 30 days.

Now, it’s important to recognize there are only certain β-blockers that have shown this. You mentioned metoprolol succinate, carvedilol, bisoprolol is the other one. But specifically, with metoprolol tartrate and atenolol, some infrequently studied, but when studied did not have the same mortality benefits. So only certain guideline-recommended, evidence-based β-blockers are recommended, work well, and are additive to the other therapies. It’s part of our mainstay of treatment. Our contraindications are relatively few here. It’s going to be severe reactive airway disease, and even there, trying a beta-1 selective blocker. Second- or third-degree heart block without a pacemaker, those are going to be candidates for CRT [cardiac resynchronization therapy], and then treat with beta blockade, and irrespective of renal function. Thus, this is really a workhorse of our treatment of patients, and it can really have markable benefits. One of the challenges though, heart failure itself causes a lot of symptoms and fatigue. Often it gets confused, and clinicians attribute those adverse effects to the β-blocker rather than the heart failure itself. But in the clinical trials, there were more patients coming off placebo than the β-blocker for what the clinician thought was an adverse event of the study drug. These are very well-tolerated medications and very efficacious.

James Januzzi, MD: Great answer. And for the viewers, one thing that Dr Fonarow said that’s so important, β-blockers are very associated with dose and benefit. In other words, it’s not a single low dose for all. They really do require uptitration to get the maximum benefit from this class of treatment.

This transcript has been edited for clarity.

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