Beta Blockers Cut Cardiovascular Events by 25% in Post-MI Patients with Mildly Reduced LVEF: Meta-Analysis

Long-term oral Beta-blocker therapy, including bisoprolol, metoprolol, and carvedilol, reduces the composite endpoint of all-cause death, new myocardial infarction, or heart failure by 25% in patients with MI and mildly reduced left ventricular ejection fraction (LVEF 40-49%), a meta-analysis has reported.

The meta-analysis of four randomized controlled trials (REBOOT, BETAMI, DANBLOCK, and CAPITAL-RCT) published in The Lancet included 1,885 patients with acute MI and mildly reduced LVEF during index hospitalization. Of these, 991 patients were assigned to β-blockers and 894 to control (no β-blockers); where bisoprolol was used in 430 patients (44%), metoprolol in 485 patients (49%), and carvedilol in 46 patients (5%).

The key findings of the study include:

• β-blocker therapy reduced the composite endpoint of all-cause death, new myocardial infarction, or heart failure by 25%, with events occurring in 11% of patients compared to 14% in the no β-blocker group (β-blocker group: 32.6 events per 1,000 patient-years vs no β-blocker group: 43.0 events per 1,000 patient-years; HR 0.75, 95% CI 0.58-0.97; p=0.031) [as shown in Figure 1].

Figure 1: Cumulative Incidence of Primary Endpoint Over Time

• β-blocker therapy reduced all-cause death by 22%, with mortality of 6% compared to 8% in the no β-blocker group (β-blocker group: 17.1 events per 1,000 patient-years vs no β-blocker group: 21.9 events per 1,000 patient-years; HR 0.78, 95% CI 0.55-1.11; p=0.169)
• β-blocker therapy reduced cardiac death by 45%, occurring in 2% of patients compared to 3% in the no β-blocker group (β-blocker group: 5.6 events per 1,000 patient-years vs no β-blocker group: 10.1 events per 1,000 patient-years; HR 0.55, 95% CI 0.28-1.06; p=0.076)
• β-blocker therapy reduced new myocardial infarction by 23%, occurring in 4% of patients compared to 5% in the no β-blocker group (β-blocker group: 11.8 events per 1,000 patient-years vs no β-blocker group: 15.1 events per 1,000 patient-years; HR 0.77, 95% CI 0.50-1.18; p=0.230)
• β-blocker therapy reduced heart failure occurrence by 29%, occurring in 3% of patients compared to 4% in the no β-blocker group (β-blocker group: 9.0 events per 1,000 patient-years vs no β-blocker group: 12.7 events per 1,000 patient-years; HR 0.71, 95% CI 0.44-1.14; p=0.152)
• The analysis also revealed that the therapeutic benefit emerged at approximately 3 months after initiation of β-blocker therapy and continued to accrue throughout the study duration (median follow-up 3.5 years, IQR 2.3-4.5). This pattern of sustained separation of survival curves suggests that the clinical benefit derives from long-term continuous therapy rather than acute protective effects alone.

The benefit of β-blocker therapy was remarkably consistent across all four trials (REBOOT, BETAMI, DANBLOCK, and CAPITAL-RCT) with no evidence of heterogeneity (Cochran's Q test p=0.95, I²=0%). No evidence of heterogeneity in treatment effects by sex, type of myocardial infarction, LVEF category, β-blocker dosage, or country Spain, Italy, Norway, Denmark, and Japan (p interaction=0.98), demonstrating the universal applicability of these findings across diverse healthcare settings. The safety analysis demonstrated no significant increase in adverse events with β-blocker therapy. (Figure 2)

Figure 2: Forest Plot - Effect Estimates for Primary, Secondary, and Safety Endpoints

Expert Reactions to the Meta-analysis: Experts provide their perspectives below

For few years now, post-MI patients with mildly reduced LVEF (40–49%) have sat in a therapeutic grey zone. Does this study findings justify treating this group like HFrEF rather than preserved EF when it comes to long-term β-blocker therapy? What are the practical implications?

Responding to this, Dr. Sunip Banerjee, Sr. Consultant Interventional Cardiologist & Chairman, Kolkata Heart Lung Centre, Kolkata, said that post-MI patients, with or without heart failure and borderline ejection fraction <50% (also called mildly reduced ejection fraction), are common in clinical practice. A knowledge gap in this subset still persists, as most of them will not have clinical heart failure.

Keeping in mind the natural history of healing of myocardial scar—even after a small MI—adverse remodelling resulting in ventricular dilatation, aneurysm formation, and mitral regurgitation are inevitable. The present meta-analysis should encourage physicians to adopt routine use of maximum tolerated and cardioselective β-blockers, in particular metoprolol and bisoprolol, in this subgroup of patients.

The meta-analysis shows 30% of MI patients fall into the LVEF 40-49% range. In your practice, are you routinely prescribing β-blockers to these patients, or do you reserve them primarily for reduced EF cases? Tell us your experience about this intermediate EF group.

In reply, Dr. Rajiv Karnik, Sr. Consultant Cardiologist, Fortis, Mumbai, noted that in his practice he encounters a large number of patients in the mildly reduced category. In most such cases, he usually continues β-blockers lifelong unless there is a contraindication or significant side effect.

This, he explained, is because many of these patients carry one or more cardiovascular risk factors or established ASCVD, supporting continuation of therapy. Among β-blockers, his preference is for cardioselective agents such as bisoprolol. He added that he has also used β-blockers in HFpEF settings — although not for heart failure— but for hypertension, atrial fibrillation, and related indications.

Beyond mortality, there's a 29% reduction in new HF cases. Should we be considering β-blockers more as a HF prevention strategy in post-MI patients with LVEF 40-49%? How does this change our conversation with patients about long-term adherence?

Offering his perspective, Dr. T. Manikandan, Senior Consultant Cardiologist, MIOT Hospital, Chennai, stated that β-blocker therapy, especially bisoprolol, is effective in reducing post-myocardial infarction heart failure through its remodelling effect, coronary vasodilatation, and reduction of sympathetic drive. Being cardioselective, it can also be used in patients with bronchial asthma.

For post-MI patients, he emphasized starting at a low dose and maintaining therapy for a longer duration. He added that β-blockers also help prevent post-MI arrhythmias.

This study used bisoprolol in 44% of patients, metoprolol in 49%, and carvedilol in 5%. Given that bisoprolol is highly cardio-selective with a metabolically neutral profile, how does this influence your choice in patients with comorbidities like T2D or bronchial reactivity, commonly seen in Indian patients?

According to Dr. Narasa Raju Kavalipati, Sr. Consultant & Director – Interventional Cardiology, Hyderabad, bisoprolol’s cardioselectivity and metabolically neutral profile make it his preferred agent in post-MI Indian patients with diabetes or mild bronchial hyperreactivity. He typically starts low and uptitrates with close monitoring of glycaemia and symptoms.

In overt asthma or brittle diabetes, he individualizes therapy, but bisoprolol usually offers the most favourable risk–benefit balance.

This meta-analysis provides evidence that β-blocker therapy significantly reduces MACE by 25% in post-myocardial infarction patients with mildly reduced LVEF (40-49%), a population representing up to 30% of all MI patients.

Abbreviations: AHA = American Heart Association, ACC = American College of Cardiology, AV = Atrioventricular, BETAMI = Beta-blocker Treatment After acute Myocardial Infarction in patients without reduced left ventricular ejection fraction, CAPITAL-RCT = CArvedilol Post-Infarction survivaL controL In Left ventricular dysfunction - Randomized Controlled Trial, CI = Confidence Interval, DANBLOCK = DANish-norwegian trial on Beta-blocker therapy after myocardial infarction with preserved ejection fraction, ESC = European Society of Cardiology, HR = Hazard Ratio, IQR = Interquartile Range, LVEF = Left Ventricular Ejection Fraction, MI = Myocardial Infarction, PCI = Percutaneous Coronary Intervention, REBOOT = tREatment with Beta-blockers after myOcardial infarction withOut reduced ejection fracTion

Reference: Rossello X, Prescott EIB, Kristensen AMD, Latini R, Fuster V, Fagerland MW, Pocock SJ, Halvorsen S, Dominguez-Rodriguez A, Holmager TLF, Sanchez PL, Bakken A, Raposeiras-Roubin S, Jensen SE, Kimura T, Ottani F, Lambrechtsen J, Anguita M, Ozasa N, Atar D, Ibanez B, Munkhaugen J. β blockers after myocardial infarction with mildly reduced ejection fraction: an individual patient data meta-analysis of randomised controlled trials. Lancet. 2025 Sep 13;406(10508):1128-1137. doi: 10.1016/S0140-6736(25)01592-2.