Long-term beta-blocker treatment is not associated with a lower risk of death from any cause or new myocardial infarction (MI) in patients with acute MI with preserved left ventricular ejection fraction (EF) (≥50%), a new study shows. Findings from the 5,020 patients enrolled onto the parallel-group, open-label REDUCE-AMI trial, presented Sunday at the American College of Cardiology (ACC) Scientific Sessions 2024 in Atlanta, also found that beta-blocker treatment was not associated with a lower cumulative incidence of secondary efficacy end-point events or symptoms. “Although the neutral result that we found in this trial does not rule out either a small beneficial or detrimental effect, the overlapping time-to event curves that were observed throughout the follow-up period and the consistent results in all the prespecified subgroups and for the secondary end points make a clinically relevant difference unlikely,” said the authors of a manuscript that was simultaneously published online in The New England Journal of Medicine. “Our findings are also consistent with the results of several large observational studies and meta-analyses of such studies.” ACC presentation Presenting at ACC 24, study team member Troels Yndigegn, MD, from the Department of Clinical Sciences at Lund University in Sweden, revealed that a primary end-point event occurred in 199 of 2,508 patients (7.9%) in the beta-blocker group and in 208 of 2,512 patients (8.3%) in the no–beta-blocker group (hazard ratio [HR], 0.96; 95% confidence interval [CI], 0.79 to 1.16; P=0.64). Beta-blocker treatment did not appear to lead to a lower cumulative incidence of the secondary end points. Death from any cause was calculated at 3.9% in the beta-blocker group and 4.1% in the no beta-blocker group. Other incidences as a result of secondary end points include death from cardiovascular causes, (beta-blocker 1.5% and no beta-blocker 1.3%); myocardial infarction, (4.5% and 4.7%); hospitalization for atrial fibrillation, (1.1% and 1.4%); and hospitalization for heart failure, (0.8% and 0.9%). Safety end points In findings regarding safety end points, the researchers found hospitalization for bradycardia, second- or third-degree atrioventricular block, hypotension, syncope, or implantation of a pacemaker occurred in 3.4% of the patients in the beta-blocker group and in 3.2% of those in the no beta-blocker group. Hospitalization for asthma or chronic obstructive pulmonary disease occurred in 0.6% of patients in the beta-blocker group and 0.6% in the no beta-blocker group and hospitalization for stroke (1.4% and 1.8%). “The doses of beta-blockers that were used in our trial were lower than those in previous trials,” the paper’s authors said. “However, the doses that were used in our trial mirror the current practice of beta-blocker treatment, and no apparent association between the planned target dose of beta-blocker treatment and the primary end point was observed. “Results from contemporary observational studies comparing various doses of beta-blockers have not shown any clear association with outcome.” Results in context Writing in an accompanying editorial, P. Gabriel Steg, MD, of the Université de Paris, commented on the need for the results to be put in context. Steg pointed out that the observed incidence of primary end-point events was much lower than had been anticipated by the investigators. This reflected the selection of a cohort of patients with near-normal left ventricular ejection fraction who had undergone revascularization and received excellent care. “This is a reminder that the trial results should not be applied to higher-risk patients, such as those with a left ventricular ejection fraction below 50% or those who have not undergone revascularization,” he said. “With the lower-than-expected incidence of events, the trial was powered to detect a 25% lower risk with beta blockers than with no beta blocker therapy — admittedly, an ambitious goal.” Double-blind design preferable Moving on to the study’s methodology, Steg said a double-blind design was preferable to the study’s parallel-group, open-label trial design. He said it was inevitable that some patients stopped treatment in the beta-blocker group and others started treatment in the no beta-blocker group – a situation that tended to bias results toward the null. Steg concluded that as the confidence interval for the effect of beta-blockers included a potential 21% lower risk, an actual benefit with beta blockers could not be ruled out. 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, Steg said it may be too early to cut beta-blockers from the “secondary prevention team” definitively. “While we await results of upcoming trials reevaluating the role of beta-blockers in contemporary care, it may be prudent to place routine beta-blocker therapy after MI on “injured reserve.” Study methodology The Randomized Evaluation of Decreased Usage of Beta-Blockers after Acute Myocardial Infarction [REDUCE-AMI] trial enrolled a total of 5,020 patients. Patients with an acute MI who had undergone coronary angiography and with EF ≥50% were randomized to long-term treatment with beta-blockade or not. Patients who were randomly assigned to the beta-blocker group were administered metoprolol (first choice) or bisoprolol (alternative) The treating physician was encouraged to aim for a dose of at least 100 mg daily for metoprolol and at least 5 mg daily for bisoprolol. In the beta-blocker group (n=2,508) the median age was 65 years (interquartile range [IQR]: 57-73) with 563 (22.4%) female participants. In the non-beta blocker group (n=2,512) the median age was also 65 (IQR: 57–73), with 568 (22.6%) female participants. The primary endpoint was defined as the composite endpoint of death of any cause or new non-fatal MI. There were several secondary endpoints, including all-cause death, cardiovascular death, new MI, readmission because of heart failure and atrial fibrillation, and symptoms. Safety endpoints were bradycardia, AV-block II-III, hypotension, syncope or need for pacemaker, asthma or chronic obstructive pulmonary disease and stroke. Sources: Yndigegn T, Lindahl B, Mars K, et al. Beta-Blockers after Myocardial Infarction and Preserved Ejection Fraction. N Engl J Med. 2024 Apr 7 (Article in press). Steg PG. Routine Beta-Blockers in Secondary Prevention — On Injured Reserve. N Engl J Med. 2024 Apr 7 (Article in press). Photo Credit: Jason Wermers/CRTonline.org Photo Caption: Troels Yndigegn, MD, presents results from the REDUCE-AMI trial Sunday at ACC.24 in Atlanta.