Efficacy of Beta-blocker Therapy in Post-myocardial Infarction Patients with Preserved or Mildly Reduced Ejection Fraction: A Systematic Review and Meta-analysis

Protocol and search strategy

Following Preferred Reporting Items for Systematic reviews and Meta-Analyses guidelines [Supplementary Table 1] and PROSPERO protocol registration (CRD420251173887), we conducted a systematic search of four electronic databases: Cochrane Central Register of Controlled Trials, Scopus, EMBASE, and PubMed, between September 1 and September 30, 2025.^[12] The search strategy was confined to interventional trials evaluating the efficacy and safety of beta-blocker therapy in patients without heart failure with reduced ejection fraction (HFrEF) after acute MI (AMI). Full search queries are available in Supplementary Table 2. No language or date restrictions were applied. Reference lists of included studies were also screened.

Eligibility and exclusion criteria

Eligible studies were RCTs evaluating the initiation of long-term beta-blocker therapy after AMI in patients with a LVEF ≥40%, on top of optimized standard therapy, compared with patients not receiving beta-blockers. Included studies were required to report at least one of the predefined primary outcomes.

The primary outcomes of interest were all-cause mortality during follow-up and new MI. Secondary outcomes included CV mortality, heart failure hospitalization (HFH), malignant ventricular arrhythmias, ischemic stroke, and unplanned coronary revascularization.

Studies were excluded if they were not RCTs, lacked a control group, failed to provide sufficient data for outcome extraction, investigated alternative therapeutic interventions, or included control groups other than placebo or usual medical therapy alone.

Selection process and data collection

Two reviewers (EM and BR) independently screened all titles and abstracts for potential eligibility after duplicate records were removed. Full texts of potentially eligible studies were then retrieved and assessed independently by the same reviewers to determine inclusion based on the predefined criteria described above. Discrepancies at the full-text level were resolved through consensus. No automation tools were used in any phase of the screening process. All references were managed using EndNote X9 (Clarivate Analytics).

Three reviewers (EM, BR, and AMP) independently extracted data from each eligible study, using a standardized data extraction form with information regarding study characteristics, population, key demographics, clinical characteristics, interventions, and outcomes. For studies with multiple sequential publications, measures were taken to avoid the duplication of results. Whenever available, data were analyzed according to the intention-to-treat principle; otherwise, an as-treated approach was applied. All data relevant to the study are included in the article and its supplementary materials.

Quality assessment

Two authors (EM and BR) independently assessed risk of bias using the Cochrane Risk of Bias tool version 1. Publication bias was assessed using funnel plot analysis and Egger’s test. Symmetrical funnel plots and non-significant Egger’s test results were interpreted as indicating a low risk of publication bias. Regarding the certainty of evidence, the Grading of Recommendations, Assessment, Development, and Evaluation framework was used.

Synthesis methods

A narrative synthesis approach was primarily used to describe and interpret findings across studies, particularly when analysis was limited by heterogeneity in outcome reporting, study populations, or outcome definitions. Meta-analysis was conducted by pooling data using a random-effects model to account for expected variability in treatment effects across studies. Summary outcome measures were reported either as risk ratio (RR) or hazard ratio (HR), in accordance with the effect measures used and reported in the included studies. All estimates were calculated using an inverse variance method with the corresponding 95% confidence intervals (CIs). Statistical heterogeneity was evaluated by the visual inspection of forest plots and the I² statistical index (<25% low, 25–50% moderate, and >50% high heterogeneity). The software package used for the meta-analysis was Review Manager version 5.4.1 (the Cochrane Collaboration). All data were evaluated at a 5% significance level (p < 0.05). A leave-one-out analysis was also performed for the primary outcomes to evaluate the robustness of the findings. In addition, the planned random-effect meta-regression analysis using LVEF as a moderator could not be performed because LVEF was not consistently reported as a continuous variable across studies.

Search results

Figure 1 presents the study selection process. After duplicates were removed, 3616 records were screened according to pre-defined criteria. Four multicenter RCTs conducted between 2010 and 2024 met the inclusion criteria, including 9892 patients in the beta-blocker group and 9934 in the control group.^[8,9,13,14] Table 1 summarizes the characteristics of the included studies. The included RCTs were conducted across Italy, Spain, Denmark, Norway, Japan, Sweden, New Zealand, and Estonia, reflecting diverse contemporary healthcare settings and consistent reperfusion-era management. Across the four RCTs, the median follow-up duration ranged between 3.5 and 3.7 years.

Close

Figure 1: Literature search flow diagram.

Export to PPT

Table 2 summarizes the baseline characteristics of patients enrolled. The prevalence of previous PCI varied from 6% to 8%, whereas prior coronary artery bypass grafting (CABG) varied from 1% to 4%. A history of heart failure was reported in 0.5–3% of patients, and previous beta-blocker use ranged between 8% and 11%. Baseline LVEF was generally preserved across studies, with median values around 55–58%, and approximately 12–15% of participants presented with mildly reduced systolic function (LVEF 40–49%).

Regarding the index event, ST-segment elevation MI accounted for roughly 35–78% of cases, while non-ST-segment elevation MI represented the remainder. Rates of PCI performed during the index hospitalization were high across trials (>90%, up to 100% in carvedilol post-intervention long-term administration in large-scale [CAPITAL]-RCT), whereas CABG during the index event was rare (≤4%).

Among the beta-blockers used, bisoprolol and metoprolol predominated, accounting for approximately 80–95% of prescriptions, while carvedilol, nebivolol, and atenolol were prescribed only in a minority of patients (<10%).

Primary outcomes

For the primary outcomes, beta-blocker therapy in post-MI patients with mrEF or pEF was not associated with a significant reduction in all-cause mortality compared with usual care (HR 0.98, 95% CI 0.85–1.12; I² = 0%). Similarly, no significant difference was observed in the incidence of new MI (HR 0.88, 95% CI 0.74–1.05; I² = 32 %) [Figure 2]. Heterogeneity across studies was low.

Close

Figure 2: (A-B) Effect of long-term beta-blocker therapy in post-myocardial infarction patients with preserved or mildly reduced left ventricular ejection fraction on primary outcomes. Effect estimates are presented as hazard ratios with 95% confidence intervals, using inverse variance random-effect meta-analysis.

Export to PPT

The leave-one-out sensitivity analysis demonstrated consistency of the pooled results of the primary outcomes across all iterations.

Secondary outcomes

Across the included trials, beta-blocker therapy was not associated with significant differences in any of the secondary endpoints when compared to usual care. There was no reduction in CV mortality (HR 1.15, 95% CI 0.88– 1.52; I² = 0%) or HFH (HR 0.85, 95% CI 0.61–1.19; I² = 0%). Likewise, no significant differences were observed in the incidence of malignant ventricular arrhythmias (RR 0.87, 95% CI 0.51–1.48; I² = 0%), ischemic stroke (RR 1.13, 95% CI 0.77–1.65; I² = 52%), or unplanned coronary revascularization (HR 1.00, 95% CI 0.85–1.18; I² = 0%). Three-month all-cause mortality was also comparable between groups (RR 0.99, 95% CI 0.86–1.14; I² = 0%) [Figure 3]. Overall, heterogeneity across outcomes was low to moderate, and no consistent benefit of beta-blocker therapy was demonstrated in this population.

Close

Figure 3: (A-F) Effect of long-term beta-blocker therapy in post-myocardial infarction patients with preserved or mildly reduced left ventricular ejection fraction on secondary outcomes. Effect estimates are presented as hazard ratios or risk ratios with 95% confidence intervals, using inverse variance random-effect meta-analysis.

Export to PPT

Quality assessment

All included studies were rated as having moderate overall risk of bias, primarily due to their open-label design with the CAPITAL-RCT trial having additional concerns due to the randomization process and outcome measurement [Supplementary Table 3]. Although Egger’s test results were non-significant and no clear asymmetry was observed in funnel plots (implying low risk of publication bias), the small number of included studies precludes firm conclusions [Supplementary Figure 1]. Based on methodological quality and consistency of results, the certainty of evidence was rated high for the primary outcomes and moderate for most secondary outcomes, except for ischemic stroke, which was rated low due to inconsistency and imprecision [Supplementary Table 4].

Main findings and historical context

In this meta-analysis of contemporary RCTs, beta-blocker therapy initiated after AMI in patients with mrEF or pEF was not associated with a significant reduction in all-cause mortality or recurrent MI compared with usual care. No consistent benefit was evident across secondary outcomes (CV mortality, HFH, arrhythmias, stroke, or revascularization). The results demonstrated a high degree of consistency with low statistical heterogeneity. These findings are in stark contrast to the benefits observed in the prereperfusion era, prompting a reappraisal of routine post-MI beta-blockade in the modern setting.

In the pre-reperfusion era, the benefits of beta-blocker therapy after MI were unequivocal. Landmark RCTs such as the BHAT (1982), NMSG (1982), and Hjalmarson et al. demonstrated substantial reductions in all-cause and CV mortality, ranging from 26% to over 40%.^[3-5] The CAPRICORN trial (2001) further confirmed these benefits in patients with LVEF <40%,^[15] while the meta-analysis by Freemantle et al. reported a 23% reduction in long-term mortality across 31 RCTs.^[16] These findings underpinned decades of guideline recommendations advocating long-term beta-blocker therapy after MI, regardless of LVEF. In that historical context, beta-blockers conferred robust anti-ischemic and anti-arrhythmic protection in patients frequently exposed to large infarcts, recurrent ischemia, and malignant ventricular arrhythmias.

However, with the advent of contemporary reperfusion strategies and medical therapy, the clinical landscape has changed substantially. Patients in modern RCTs experience smaller infarct sizes, lower arrhythmic burden, and improved ventricular remodeling, potentially diminishing the incremental benefit of beta-blockade. The recent reperfusionera RCTs have consistently failed to show mortality or reinfarction benefits in patients with pEF or mrEF, even with adequate power and long-term follow-up.^[8,9,13,14] Consistent with these findings, our meta-analysis demonstrated no significant reduction in all-cause mortality or recurrent MI among patients with mrEF or pEF. Moreover, results from a recent individual patient data meta-analysis further support this conclusion, suggesting that any potential benefit of beta-blocker therapy may be confined to patients with mrEF.^[17]

Evidence from contemporary observational registries

Observational registry data provide additional, nuanced insights into the contemporary role of beta-blockers after MI. Several registries, including COREA-AMI, CORONOR, and ePARIS, reported lower mortality and MACE rates among beta-blocker users.^[18-20] Likewise, analyses from large Korean nationwide datasets such as KNHIS and KAMIRNIH have suggested potential clinical benefits; however, these effects were predominantly observed in patients with reduced or mildly reduced LVEF.^[21,22] In contrast, large-scale registries including FAST-MI (France), SWEDEHEART (Sweden), and MINAP (United Kingdom) consistently demonstrated no mortality advantage among patients with preserved LVEF receiving contemporary secondary prevention therapy.^[23-25] Similarly, the MIG registry (Australia) underscored an LVEF-dependent association, showing survival benefits confined to those with LVEF <50%. This reinforces that the prognostic impact of beta-blockers in the reperfusion era is likely limited to subgroups with residual ventricular dysfunction.^[26-29]

ABYSS trial: Discontinuation of beta-blockers after MI

Notably, the ABYSS trial (2024) specifically evaluated the strategy of discontinuing beta-blockers 1 year after MI in stable patients with LVEF ≥40%.^[10] The trial failed to demonstrate non-inferiority of beta-blocker withdrawal compared with continuation. Patients who discontinued therapy experienced a non-significant uptick in CV hospitalizations (particularly for angina) without any improvement in quality of life. These findings suggest that the protective effect of beta-blockade may be confined to the early post-MI period, when sympathetic activation and arrhythmic risk are most pronounced. Beyond the acute phase, beta-blockers did not significantly influence hard outcomes such as mortality or recurrent MI, reinforcing the notion that prolonged therapy may offer limited benefit in contemporary, well-treated post-MI populations.

Collectively, current data imply that routine long-term beta-blocker therapy might no longer confer a broad mortality benefit in MI patients with mrEF or pEF, especially once the high-risk early period has passed.

Clinical implications

In light of current evidence, future guidelines may refine recommendations, potentially limiting the routine long-term use of beta-blockers to patients with HFrEF or at least mrEF. Clinicians may also be encouraged to periodically re-evaluate the need for continued therapy beyond the 1^st year after MI. Collectively, these findings underscore the importance of a more individualized, risk-based approach to post-MI management, reserving chronic beta-blockade for patients with persistent left ventricular dysfunction or other clear clinical indications. For those who are fully revascularized, hemodynamically stable, and have pEF, discontinuation of beta-blockers after the early post-event period may be both safe and appropriate. This approach may help minimize unnecessary adverse effects, improve quality of life, and reduce polypharmacy in the contemporary era of optimized secondary prevention.