Guideline implications of REBOOT: beta-blockers therapy in post-MI patients with preserved LVEF

HIGHLIGHTS No clear benefit in preserved LVEF: In over 8500 post-MI patients with LVEF >40%, beta-blockers did not reduce mortality, recurrent MI, or heart-failure hospitalization, aligning with findings from other contemporary trials. Potential signal in mildly reduced LVEF (40–49%): Patients in this range showed numerically lower event rates on beta-blockers, suggesting possible benefit and highlighting the need for pooled analyses or dedicated studies. Subgroup and phenotype-specific considerations: Women and STEMI patients appeared to fare worse on beta-blockers, emphasizing the importance of sex-specific and phenotype-specific analyses to guide individualized therapy and future guidelines. The REBOOT trial offers a timely reappraisal of one of the most established therapies in cardiovascular medicine: beta-blockers after myocardial infarction (MI). For decades, beta-blockers have been prescribed nearly universally following MI, largely based on trials conducted before the advent of routine reperfusion, modern dual antiplatelet therapy, statins, and renin–angiotensin system inhibitors. In that earlier era, the mortality benefits were unequivocal. However, the contemporary relevance of these findings in patients with preserved or mildly reduced left ventricular ejection fraction (LVEF) has remained uncertain. The REBOOT trial directly addressed this knowledge gap by randomizing over 8500 patients with MI and LVEF >40% to beta-blocker therapy or no beta-blocker therapy, with a median follow-up of 3.7 years[1]. This study was conducted and reported in compliance with the TITAN 2025 Guidelines on transparent integration of AI in academic work in line with current publishing standards on responsible AI usage and reporting[2]. The trial’s primary finding that beta-blocker therapy did not reduce the incidence of all-cause mortality, recurrent MI, or hospitalization for heart failure has major implications for clinical practice and guidelines. Event rates were nearly identical between groups, with a hazard ratio of 1.04 (95% CI: 0.89–1.22)[1]. Furthermore, the lack of benefit was consistent across major subgroups, including those defined by age, prior MI, and revascularization strategy. These findings are concordant with those of the REDUCE-AMI trial, which similarly found no prognostic advantage of beta-blocker therapy in patients with LVEF ≥50%, and with results from the CAPITAL-RCT, ABYSS, and multiple observational studies[1,3–5]. Together, these trials suggest that the historical rationale for prescribing beta-blockers broadly to all post-MI patients with preserved systolic function may no longer be justified in the modern era[1,3–5]. An important nuance lies in the subgroup of patients with mildly reduced LVEF (40–49%)[1]. In REBOOT, these patients showed a numerically lower event rate when treated with beta-blockers, though the sample size (<1000) limited statistical power and interpretability. The possibility that beta-blockers may provide value in this intermediate-risk group warrants consideration and underscores the importance of pooled analyses across recent trials. REBOOT also raises questions regarding heterogeneity and differential responses. Women in the beta-blocker group experienced more primary-outcome events than women in the no-beta-blocker group[1]. A similar signal appeared in a Canadian registry, suggesting sex-specific differences in drug metabolism, comorbidities, or adverse effect profiles may contribute to variable outcomes[1]. Likewise, STEMI patients, but not NSTEMI patients, fared worse on beta-blockers, echoing findings from a registry of 43 000[1]. While exploratory, these subgroup findings highlight the need for sex- and phenotype-specific analyses in cardiovascular trials. The trial incorporated blinded adjudication of outcomes, an essential safeguard in open-label trials absent from REDUCE-AMI[1,3]. The pragmatic design, allowing physician discretion in beta-blocker type and dosing, mirrors real-world practice and enhances validity. Bisoprolol was most frequently prescribed, yet no outcome differences emerged between agents or doses, suggesting a class effect rather than agent-specific differences[1]. At the same time, the trial has limitations. The open-label design introduces potential bias, though mitigated by blinded adjudication. The overall event rate was lower than anticipated, reducing statistical power, though the near-equal distribution of events across groups minimizes the likelihood of a type II error. Additionally, the trial did not mandate titration to target doses or systematic heart-rate monitoring, precluding assessment of whether optimal dosing might have altered outcomes[1]. Finally, crossover occurred in both groups (12.9% in the beta-blocker group and 17.6% in the no-beta-blocker group at 15 months), though per-protocol analyses confirmed the intention-to-treat results[1]. From a guideline perspective, these findings are consequential. Current American guidelines give a Class I recommendation for beta-blocker use after MI regardless of LVEF, while European guidelines assign Class IIa for preserved function[1,3]. In light of REBOOT and related trials, there is little justification for continuing a blanket recommendation in preserved LVEF. Rather, guidelines should differentiate among reduced, mildly reduced, and preserved systolic function. For reduced LVEF (≤40%), the benefit is well established. For preserved LVEF (≥50%), routine use is unlikely to help. For mildly reduced LVEF (40–49%), evidence remains suggestive, and pooled analyses or dedicated trials are needed. In conclusion, REBOOT challenges long-standing dogma. Beta-blockers appear unnecessary in preserved LVEF, yet their potential value in mildly reduced LVEF warrants further study[1,4,5]. These findings argue for individualized, phenotype-specific therapy and guideline revisions reflecting evolving evidence. Until then, clinicians should carefully weigh risks and benefits of long-term beta-blocker therapy, reserving use for reduced or possibly mildly reduced LVEF[3–5]. In summary, REBOOT is a randomized trial of β-blocker therapy versus no β-blocker in patients discharged after acute MI with LVEF >40%, found no reduction in the composite of all-cause death, recurrent MI, or heart-failure hospitalization over a median follow-up of ~3.7 years. Importantly, randomized data are limited to this follow-up interval; no 5- or 10-year randomized data from REBOOT are available at present, and extrapolation beyond the reported follow-up would be speculative. REBOOT provides direct evidence relevant to withholding long-term β-blockers in carefully selected patients, but subgroup signals (notably an adverse signal observed in women with preserved EF, and benefit in patients with mildly reduced EF 40–49%) mandate cautious, individualized decision-making while additional pooled analyses and longer-term data mature. Finally, modern improvements in reperfusion, antiplatelet therapy, statins, and secondary prevention have lowered baseline event rates compared with prereperfusion trials, which plausibly attenuates the absolute benefit of routine long-term β-blockers in patients with preserved LV function.