Another Beta-blocker Blow: REDUCE-AMI Confirms No Benefit After Acute MI

ATLANTA, GA—The latest study to assess the long-term use of beta-blockers in patients with acute MI and preserved ejection fraction has again suggested that, in the modern era of post-MI care, these agents do nothing to reduce the risk of death or recurrent MI.

Troels Yndigegn, MD (Lund University/Skane University Hospital, Sweden), who led the trial, presented the results of the registry-nested REDUCE-AMI randomized trial today at the American College of Cardiology (ACC) 2024 Scientific Session, with the data showing that the Kaplan-Meier curves for the primary endpoint of death or recurrent MI were “intermingling, virtually overlapping” between the two treatment groups.  

The REDUCE-AMI study is not the first to challenge the use of beta-blockers in the modern era of post-MI patients, with several observational studies—among them REACH and CLARIFY—suggesting there is no benefit of beta-blockers given on top of contemporary medical therapy. As far back as 2014, investigators published a meta-analysis of more than 60 trials with 100,000 patients that found beta-blockers prescribed following acute MI did not reduce the risk of all-cause mortality in the reperfusion era.

Sripal Bangalore, MD (NYU Langone Health, New York, NY), who led that meta-analysis, is pleased there are finally randomized data to address this clinical question.

“When you think about it, there have been a number of therapies that have been handed down to us,” he told TCTMD. Each advance results in this new treatment being added to what’s worked in the past, resulting in patients taking multiple drugs after MI. However, “if you closely look at the data, you wonder if many of the [older] trials would pass muster in this day and age,” said Bangalore.

One of the biggest challenges after a heart attack is you're on a gazillion medications. Wayne Batchelor

Wayne Batchelor, MD (Inova Heart and Vascular Institute, Fairfax, VA), chair of the ACC interventional council, agreed that REDUCE-AMI allows physicians to take a “somewhat reductionist” approach to treatment. “One of the biggest challenges after a heart attack is you're on a gazillion medications,” said Batchelor. “We can finally start to say with some degree of confidence that if your LV ejection fraction is preserved, over 50%, and you don't have any other reason to be on a beta-blocker, you probably don't need to throw that in.”

The new study was published in the New England Journal of Medicine to coincide with the ACC presentation.

Registry-Nested Randomized Trial

To TCTMD, Jernberg explained that there are “very solid data” showing that beta-blockers reduce the risk of mortality after a large MI in patients with impaired left ventricular function, but those trials were conducted in the 70s and 80s and preceded the modern era of PCI, high-sensitivity troponin testing, and modern medical management with statins, antithrombotic therapy, and ACE inhibitors/ARBs.

In the European guidelines, beta-blockers are a class Ia recommendation in ACS patients with LVEF ≤ 40% while the routine use in all ACS patients carries a 2a endorsement. US guidelines recommend that physicians initiate beta-blockers in ACS patients with STEMI (class I recommendation, level of evidence B) and in NSTE-ACS patients with and without impaired systolic function (class I, level of evidence C and class IIa, level of evidence C, respectively).   

To study the effectiveness of beta-blocker therapy in a more contemporary era, the REDUCE-AMI investigators performed a parallel-group, open-label trial at 45 hospitals in Sweden, Estonia, and New Zealand using registry data. More than 95% of patients were from Sweden, with data on MI collected from the SWEDEHEART registry and mortality through a linked national database. In Estonia and New Zealand, baseline data were collected using electronic case-report forms similar to those used in SWEDEHEART and through hospital health records for follow-up.

Patients with acute MI (median age 65 years; 22.5% female) who underwent coronary angiography and who had obstructive CAD and a preserved LVEF (≥ 50%) were randomized to treatment with a beta-blocker or no treatment. Between 2017 and 2023, 2,508 were treated with metoprolol succinate (62.2%) to a target dose of 100 mg or bisoprolol (37.8%) to a target dose of 5.0 mg and 2,512 were not treated with any beta-blocker. More than one-third (35%) presented with STEMI and more than 95% underwent PCI. At discharge, 97% were treated with aspirin, approximately 96% were treated with a P2Y12 receptor antagonist, and nearly all patients received a statin.

Among more than 5,000 patients who presented with either STEMI or NSTEMI and who underwent coronary angiography during the hospitalization, all-cause mortality or MI occurred in 7.9% of those treated with a beta-blocker and in 8.3% of those who did not receive a beta-blocker (HR 0.96; 95% CI 0.79-1.16) over a median follow-up of 3.5 years. Additionally, there was no benefit in any of the secondary endpoints or in any prespecified subgroups.

To TCTMD, Batchelor said REDUCE-AMI largely addresses a historical issue, noting that LVEF was usually impaired following MI before the advent of coronary revascularization and other treatments.

“We’re not seeing as often these really low ejection fractions that we used to,” he told TCTMD. “They're still out there, and many of them unfortunately go into cardiogenic shock, but the ones who have preserved heart function used to all get treated with beta-blockers largely because the guidelines supported the global use after myocardial infarction. What this study has done is allowed us to refine that.”

Regarding the beta-blockers used in the study, Batchelor said these are the most efficacious agents, but he’s uncertain how hard the drugs were pushed, noting that investigators only have data on use out to 1 year. Additionally, safety endpoints, such bradycardia and any other arrhythmias, were equal between treatment arms, meaning it’s possible the drugs weren’t used at their maximal doses.

“If they weren't pushed to the max, then there's a possibility that we could be missing a little bit of therapeutic value there,” he said.

Bangalore, Batchelor, and others pointed out that the incidence of the primary endpoint—2.4% and 2.5% per year in the beta-blocker and no beta-blocker arms, respectively—was much lower than anticipated by the investigators, likely because these were patients with near-normal LVEF who’d undergone revascularization and received top-shelf care.

“It's emblematic of how well we're treating patients otherwise,” said Batchelor. “These patients got excellent interventional care. They were all on statins, all on aspirin, and on P2Y12 inhibitors. So, in the realm of all those interventions, it's just impossible to detect a signal from a beta-blocker.”

“It just shows you how far we’ve come along in treating MI,” said Bangalore.

Maybe Not Finished Yet?

In an editorial, P. Gabriel Steg, MD (Hôpital Bichat, Assistance Publique-Hôpitaux de Paris, France), emphasizes that the results only apply to those studied, not to higher-risk patients, such as those with LVEF < 50% or those who haven’t undergone revascularization.

Steg points out that a double-blind randomized trial is preferable to an open-label design, noting that crossover at 1 year was not negligible: 18% of those taking beta-blockers stopped in the first year while 14% of those randomized to no treatment started. Moreover, he reminds physicians that “absence of evidence is not evidence of absence,” adding that confidence intervals do include a potential 21% lower risk with beta-blockers.

“Given the difficulty of unambiguously showing an absence of benefit with beta-blocker therapy and the limitations of a single, somewhat underpowered, open-label trial, it may be too early to cut beta-blockers from the secondary prevention team’ definitively. While we await the results of the multiple upcoming trials reevaluating the role of beta-blockers in contemporary care, it may be prudent to place routine beta-blocker therapy after myocardial infarction on ‘injured reserve.’”

More randomized studies of beta-blockers post-MI should help clarify things further, with DANBLOCK, BETAMI, REBOOT, and AβYSS all expected in 2024, as well as SMART-DECISION and ABBREVIATE to come after that, writes Steg.

Five or 10 years ago, beta-blockers were considered the bedrock of evidence, the cornerstone of treatment for MI. Sripal Bangalore

To TCTMD, Bangalore acknowledged that REDUCE-AMI does have limitations given that it’s a registry-based randomized trial, but nonetheless should change minds when it comes to the reflexive habit of prescribing beta-blockers after acute MI.

“In acute MI, at least in our clinical practice, we will start patients on other therapies, and maybe prescribe a beta-blocker towards the end, maybe before discharge,” he said. “This trial comes at a time when people are open-minded about [stopping beta-blockers]. Five or 10 years ago, beta-blockers were considered the bedrock of evidence, the cornerstone of treatment for MI. But I think it’s the right time—I’m hopeful things will change.” 

“I think it’s going to change practice,” Batchelor agreed. “I think there’ll be a sort of peel-back of this knee-jerk response to prescribing beta-blockers in anyone and everyone who comes in with a heart attack.”