By Michael H. Crawford, MD, Editor
A large, multicenter, international, randomized clinical trial of long-term beta-blocker therapy vs. no such therapy in contemporary acute myocardial infarction patients who had coronary artery angiography-guided therapy and left ventricular ejection fractions ≥ 50% found no differences in the primary endpoint of all-cause mortality and recurrent myocardial infarction.
Yndigegn T, Lindahl B, Mars K, et al. Beta-blockers after myocardial infarction and preserved ejection fraction. N Eng J Med 2024;390:1372-1381.
Although of proven value in heart failure with reduced ejection fraction (EF), recent meta-analyses of studies in the current era have suggested that beta-blockers are not beneficial in post-myocardial infarction (MI) patients despite their almost universal recommendation in guidelines. Thus, the Randomized Evaluation of Decreased Usage of Beta-Blockers after Acute Myocardial Infarction (REDUCE-AMI) trial is of interest. REDUCE-AMI is a prospective, open-label, parallel group, randomized clinical trial conducted in 45 centers, largely in Sweden, with contributions from centers in New Zealand and Estonia, from 2017-2023. Patients one to seven days post-MI who had an invasive coronary angiogram and an echocardiogram with an EF ≥ 50% with no contraindications to beta-blockers were randomized to a beta-1 selective blocker or no beta-blocker therapy. The beta-blocker was either metoprolol 100 mg/day (62%) or bisoprolol 5 mg/day as minimum targets.
The primary endpoint was a composite of all-cause mortality or new MI. Secondary endpoints included the two primary endpoints separately, atrial fibrillation (AF) hospitalization, and heart failure (HF) hospitalization. Safety endpoints included bradycardia, second- or third-degree heart block, pacemaker placement, hypotension, syncope, asthma, or stroke hospitalization. A total of 5,020 patients (95% from Sweden) were randomized; median age was 65 years, 23% were women, and 35% had ST elevation MI. Of the patients enrolled, 96% had a percutaneous coronary intervention (PCI) and 4% had coronary artery bypass surgery (CABG). After a median follow-up of 3.5 years, 8% of patients in each group had experienced the primary endpoint, and there were no differences in any of the secondary or safety endpoints. The authors concluded that, in this cohort of patients with an acute MI who underwent coronary angiography-guided treatment and with an EF of ≥ 50% by echocardiogram, long-term beta-blocker therapy did not reduce the incidence of recurrent MI or all-cause death compared to those randomized to no beta-blocker therapy.
COMMENTARY
Current guidelines recommend indefinite prophylactic beta-blocker therapy after acute MI based on trials largely done in the 1980s in patients with large MIs and low EFs. These trials predate the use of thrombolysis, PCI, statins, and renin-angiotensin system inhibitors. Even in these old trials, there was a suggestion that the benefits of beta-blockers were seen mainly in those with low EFs and HF. Thus, given the advances in therapy in the last 30 years, it is not surprising that the value of beta-blockers post-MI has diminished.
In the REDUCE-AMI study, patients with indications for beta-blockers were excluded. The most likely reason for this exclusion was probably AF, given the age of the study population. Some of those excluded may have been taking non-selective or beta-blockers with vasodilatory properties that are used mainly for HF and hypertension. The older post-MI trials predominantly used beta-1 selective blockers, hence their use in REDUCE-AMI. The beta-blocker doses selected for the trial were robust, no doubt to avoid the underdosed straw man criticism. However, most of the patients taking beta-blockers post-MI I see now are on much lower doses. This may be to avoid quality of care criticism yet avoid any potential side effects of beta-blockers. Perhaps now the guidelines will be updated to eliminate this recommendation.
There are weaknesses of the REDUCE-AMI study to be considered. The annual event rates were low (2.4% on beta-blockers, 2.5% not on beta-blockers), so a larger study may have seen a small but significant difference. This is much lower than the older trials, which reported 7.5% yearly event rates. Part of the reason for the low event rates was excellent patient care (> 95% were on aspirin, P2Y12 inhibitors, and statins, and 80% were on renin-angiotensin system inhibitors). Also, the only safety endpoints were those that required hospitalization. In addition, at one year, 14% of the group randomized to no beta-blockers were taking them. Finally, the study population was largely white Europeans. Despite these weaknesses, this was a large, well-conducted study that should occasion confirmatory studies and influence guideline committees.
