MADRID — Taken together, two new randomized trials and a meta-analysis showed that beta-blockers following a myocardial infarction (MI) offer a relatively modest benefit in contemporary practice when patients have a left ventricular ejection fraction (LVEF) of at least 40%.

Beta-blockers in this population are recommended in both the US and European guidelines, but these new studies might weaken rather than strengthen the mandate for routine use, according to Borja Ibáñez, MD, PhD, a professor at Universidad Complutense de Madrid, Madrid, Spain, and a principal investigator of one of the new trials.

These data are not relevant to those with an LVEF < 40%, but it remains unclear if beta-blockers are still helpful for those whose heart function is preserved, Ibáñez said.

The study led by Ibàñez, REBOOT-CNIC, was presented at European Society of Cardiology (ESC) Congress 2025. All addressing the same question, REBOOT-CNIC was presented alongside a Scandinavian trial called BETAMI-DANBLOCK and a meta-analysis that included data from both trials.

Value of Beta-Blockers After MI Reevaluated

Certain advances since the original beta-blocker trials were conducted have raised the question of whether beta-blockers are still relevant for improving outcomes after an acute MI in patients with a mildly reduced LVEF. These advances include routine reperfusion, complete revascularization, and multiple additional guideline-directed secondary preventive medicines.

Both REBOOT-CNIC and BETAMI-DANBLOCK were simultaneously published online in The New England Journal of Medicine. The meta-analysis was published online in TheLancet.

In the investigator-initiated, open-label REBOOT-CNIC trial, 4243 patients with an acute MI and an LVEF > 40% were randomly assigned to receive beta-blocker therapy and 4262 to receive no beta-blocker therapy at the time of discharge. Overall, 109 centers participated across Spain and Italy. The primary composite outcome was death from any cause, reinfarction, or hospitalization for heart failure.

After a median follow-up of 3.7 years, composite adverse event rates, expressed as number of events per 1000 patient-years, were 22.5 and 21.7 in the beta-blocker and no beta-blocker groups, respectively. The nonsignificant hazard ratio (HR) numerically favored no beta-blockers (HR, 1.04; P = .63).

There were no significant differences in any of the components of the primary outcome, Ibàñez said. For each, the CI crossed the line of unity, numerically favoring no beta-blockers for all-cause death (HR, 1.06) and reinfarction (HR, 1.01) but not for hospitalization for heart failure (HR, 0.89).

The investigator-initiated, open-label BETAMI and DANBLOCK trials had similar designs but were originally conceived as separate trials that could be combined for a pooled analysis. Ultimately, the trials were combined during the COVID-19 pandemic due to slow enrollment, explained senior investigator Dan Atar, MD, PhD, a professor of cardiology at Oslo University Hospital, Oslo, Norway.

As combined, 5574 patients with an acute MI and an LVEF ≥ 40% at 19 sites in Norway and 25 sites in Denmark were randomly assigned beta-blocker therapy or no beta-blocker therapy within 14 days of the index event. The primary outcome was a composite of death from any cause or major cardiovascular events, including new MI, unplanned coronary revascularization, ischemic stroke, heart failure, or malignant ventricular arrhythmia.

Significant Risk Reduction After Follow-Up

After a median follow-up of 3.5 years, a primary adverse outcome occurred in 14.2% of those in the beta-blocker group vs 16.3% of those in the no beta-blocker group, translating to a 15% risk reduction (HR, 0.85; P = .03).

When the individual components of the primary outcome were evaluated as secondary endpoints, rates were numerically lower in the beta-blocker group for death (4.2% vs 4.4%), recurrent MI (5.0% vs 6.7%), heart failure (1.5% vs 1.9%), and malignant ventricular arrhythmias (0.5% vs 0.6%) but were higher for stroke (1.6% vs 1.3%). None were statistically significant.

The meta-analysis was a systematic review of randomized controlled trials of beta-blockers started within 14 days of a recent MI in patients with a mildly reduced LVEF. Researchers compared the outcomes at an individual-patient level. Restricted to those with an LVEF ≥ 40% but < 49%, the meta-analysis included 979 (12%) of the 8505 patients in REBOOT-CNIC, 422 (15%) of the 2867 in BETAMI, 430 (16%) of the 2707 from DANBLOCK, and 54 (16%) of the 399 in CAPITAL-RCT, a study conducted in Japan and published in 2018.

For the primary composite endpoint of all-cause death, new MI, or heart failure, 32.6 events per 1000 patient-years occurred in the beta-blocker group and 43.0 per 1000 patient-years occurred in the no beta-blocker group. The result translated into a 25% reduction in risk (HR, 0.75; P = .031). The data revealed no statistically significant differences in any of the individual components of the primary outcome.

“There was no heterogeneity between trials or between countries of enrollment,” lead study author Xavier Rosselló, MD, PhD, a professor of cardiology at Hospital Universitari Son Espases in Mallorca, Spain, said during a presentation of the data.

In other words, the direction of benefit was consistent across all trials, he noted.

“Given this consistency, these data extend evidence of the previously known benefit of beta-blockers following an acute MI in patients with mildly reduced LVEF,” Rosselló said.

Interpretation of Data Complicated by Unknowns

The strength of these data lies in the studies’ lack of commercial support, but there are limitations, including the absence of a placebo control, according to John Cleland, MD, PhD, a professor of cardiology at the School of Cardiovascular and Metabolic Health at the University of Glasgow in Glasgow, Scotland.

Cleland, who served as a discussant for both trials and the meta-analysis, also noted that no study evaluated whether beta-blockers might differ by subclass. Although beta-blockers were selected by the participating investigator in both of the randomized trials, 86% of those in the beta-blocker arm in REBOOT-CNIC received bisoprolol, and more than 90% in BETAMI-DANBLOCK received metoprolol. All patients in CAPITAL-RCT who were assigned a beta-blocker received carvedilol.

Unlike the cardioselective beta-1 receptor blockers bisoprolol and metoprolol, carvedilol is a nonselective inhibitor of both beta-1 and beta-2 receptors, according to Cleland. He pointed out that there has never been a randomized trial with bisoprolol in post-MI patients, while a prior trial with metoprolol was neutral. Cleland questioned whether these drugs are interchangeable in this setting.

In addition to the fact that the researchers excluded most post-MI patients screened for inclusion in BETAMI-DANMARK because they already had an indication for a beta-blocker, Cleland said the trials raised many unanswered questions about subgroups that might not benefit from beta-blockers.

For example, there was no signal of benefit from beta-blockers in women relative to men in the REBOOT-CNIC trial, and there was a trend for a lack of benefit of beta-blockers in patients older than 75 years in the meta-analysis.

Overall, Cleland challenged the generalizability of these results in mildly reduced LVEF and noted that the overall 25% risk reduction in the primary endpoint in the meta-analysis was achieved with a less than robust P value. Still, he said the data do not dissuade consideration of a beta-blocker for post-MI care in a mildly reduced LVEF in contemporary practice.

“On balance, I think we should continue to offer beta-blockers following MI in patients with reduced LVEF, but it is reasonable to reevaluate whether to maintain beta-blockers after the dust has settled or about 4-6 weeks after the event,” he concluded.

Ibáñez reported having no conflicts of interest. Attar reported having financial relationships with Abbott, Amgen, Amarin, AstraZeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Chiesi, GlaxoSmithKline, Merck, Sharpe & Dohme, Novartis, Novo Nordisk, Pfizer, Pharmacosmos, Philips, Roche Diagnostics, Sanofi, Takeda, and Vifor. Prescott and Rosselló reported having no conflicts of interest. Cleland reported funding paid to his institution from Bristol Myers Squibb, Biopeutics, CSL Vifor, and Pharmacosmos.