Review of the REDUCE-AMI trial

Beta-Blockers after Myocardial Infarction and Preserved Ejection Fraction

N Engl J Med 2024;390:1372-1381

Background: Beta-blockers are prescribed to the majority of patients with acute myocardial infarction. The bulk of evidence supporting this practice comes from trials published in the 1980s - BHAT and ISIS-I. Since the publication of these seminal trials, the care of patients with acute myocardial infarction has significantly changed with improvement in antiplatelet therapy, the addition of high-intensity statins and renin–angiotensin–aldosterone system antagonists in addition to early revascularization for STEMI patients. Furthermore, myocardial injury is now detected based on high-sensitivity troponin assays which can detect smaller myocardial infarctions. Therefore, there is a lack of evidence whether beta-blockers provide benefit for patients with acute myocardial infarction in the current era.

The Randomized Evaluation of Decreased Usage of Beta-Blockers after Acute Myocardial Infarction (REDUCE-AMI) trial sought to assess whether long-term oral beta-blocker treatment improves outcomes in patients with acute myocardial infarction and preserved left ventricular ejection fraction.

Patients: Eligible patients were adults, 1 to 7 days after myocardial infarction who underwent coronary angiography and echocardiography. Patients were required to have obstructive coronary artery disease on coronary angiography defined as stenosis of ≥50%, a fractional flow reserve of ≤0.80, or an instantaneous wave-free ratio of ≤0.89 at any time point before randomization. Left ventricular Ejection fraction on echocardiogram had to be ≥50%. Patients were excluded if they had contraindications to beta-blockers or if the treating physician determined that treatment with beta-blockers is indicated for other conditions.

Baseline characteristics: The trial randomized 2,508 patients to the beta-blockers group and 2,512 patients to the control group. The average age of patients was 65 years with 78% being men. About 20% were current smokers, 46% had hypertension, 14% had diabetes, 7% had prior myocardial infarction and < 1% had prior heart failure.

The index event was STEMI in 35% of the patients. About 96% underwent percutaneous coronary intervention. The median heart rate was 74 bpm and the median systolic blood pressure was 151 mm Hg.

Medications at discharge included aspirin in 97% of the patients, P2Y12 inhibitors in 96%, ACEi or ARBs in 80% and statins in 99%.

Procedures: Patients were randomized 1:1 to receive metoprolol succinate (first choice), bisoprolol (second choice) or no beta-blockers. The target doses were at least 100 mg daily for metoprolol succinate and at least 5 mg daily for bisoprolol. Patients in the control group were discouraged from using beta-blockers; they did not receive placebo. If a patient was on beta-blocker therapy at the time of enrollment and was randomly assigned to the no–beta-blocker group, the beta-blocker had to tapered off over a period of 2 to 4 weeks.

Endpoints: The primary end point was a composite of death from any cause or new myocardial infarction. Secondary end points were death from any cause, death from cardiovascular causes, myocardial infarction, hospitalization for atrial fibrillation as primary diagnosis, and heart failure hospitalization. There were three safety endpoints: 1- Hospitalization for bradycardia, second- or third-degree atrioventricular block, hypotension, syncope, or implantation of a pacemaker, 2- hospitalization for asthma or chronic obstructive pulmonary disease as a primary diagnosis and 3- hospitalization for stroke.

Data on clinical end points were not centrally adjudicated but rather obtained from the SWEDEHEART registry and the Swedish Population Registry.

Statistical analysis was performed based on the intention-to-treat principle. Before trial initiation, the estimated event rate in the control group was 7.2%/ year and at least 16.7% lower event rate in the beta-blocker group was considered clinically meaningful. During the trial, the actual event rate in control group was 3%/ year. Given this event rate, a 25% lower event rate in the beta-blocker group was considered clinically meaningful. A total of 379 primary end point events were needed in order to have 80% power at a two-sided alpha of 0.05, to detect the 25% lower event rate with beta-blockers. The estimated number of patients needed was about 5,000.

Results: Among the patients who attended the SWEDEHEART registry, 1500/1831 (81.9%) of the beta-blocker group were still taking beta-blockers after 11 to 13 months; compared to 269/ 1886 (14.3%) in the no beta-blocker group.

After a median follow up time of 3.5 years, beta-blockers did not the reduce the composite primary endpoint compared to no beta-blockers (7.9% vs 8.3%, HR: 0.96; 95% CI, 0.79 - 1.16; p= 0.64). There were no significant differences in death from any cause (3.9% vs 4.1%), death from cardiovascular causes (1.5% vs 1.3%), myocardial infarction (4.5% vs 4.7%), hospitalization for atrial fibrillation (1.1% vs 1.4%) or hospitalization for heart failure (0.8% vs 0.9%).

Safety endpoints were also not significantly different between both groups; 3.4% vs 3.2% for the bradyarrhythmia, syncope or hypotension endpoint, 0.6% in both groups for the hospitalization for asthma or COPD endpoint and 1.4% vs 1.8% for hospitalization for stroke.

There were no significant subgroup interactions.

Conclusion: In patients with acute myocardial infarction who underwent coronary angiography and had preserved left ventricular systolic function, treatment with beta-blockers did not improve outcomes over a 3.5-year follow-up. Events were infrequent in the trial; 1.4% for cardiovascular death, 4.6% for recurrent myocardial infarction and 0.8% for hospitalization for heart failure. The low event rate in this population in the current era makes it difficult to demonstrate additional benefit with more therapies.

The open-label design of the study may have introduced performance bias; however, this bias is expected to favor beta-blockers given the superiority design of the study. Another limitation, as noted by the authors, is that outcomes were obtained from the SWEDEHEART registry and the Swedish Population Registry and were not centrally adjudicated. However, this is expected to affect both groups equally.

We believe the divergent results between this trial and older beta-blocker trials in myocardial infarction patients such as BHAT and ISIS-1 which were published in the 1980s, is due to the significant improvement in the management of acute myocardial infarction over time including improved medical therapy in addition to early revascularization for STEMI patients. This improved patient care has led to significantly lower mortality rates over time. For instance, all-cause death in the control arm of REDUCE-AMI is significantly lower than that of BHAT and ISIS-1, at 4.1% vs 9.8% and 11.9%, respectively. This is despite REDUCE-AMI having a longer follow-up period of 3.5 years compared to 2.1 years and 1 year in the earlier trials.

In conclusion, this study does not provide evidence that beta-blockers improve outcomes for patients with acute myocardial infarction and preserved ejection fraction in the contemporary era.