Withholding beta-blockers after myocardial infarction: reasons to be cautious

Recently, two large, randomized trials suggested that withholding beta-blockers after an acute myocardial infarction in carefully selected patients at low cardiovascular risk was safe, with no increase in myocardial infarction or death, provided the left ventricular ejection fraction (LVEF) was ≥50%.1 A further trial suggested that withholding beta-blockers increased the risk of a further myocardial infarction (one additional event per 100 patients in the first year), although this did not translate into an increase in unplanned coronary revascularization, heart failure, or deaths.1 The trials also suggested that a subgroup of patients with a LVEF between 41% and 49% fared better if randomized to beta-blockers, with a reduction in a composite of recurrent myocardial infarction, heart failure, or all-cause mortality.2 Given that, echocardiography does not reliably distinguish between an LVEF of 46% and 54%, a great deal of cross-contamination between LVEF subgroups is certain. How should these results be generalized for clinical practice? Is it wise to try to identify patients at low risk who are unlikely to benefit from a beta-blocker? What else might these trials tell us about the practice of evidence-based medicine? More than 95% of patients in these trials underwent percutaneous coronary intervention (PCI), although only 48% presented with an ST-segment elevation myocardial infarction (STEMI). All trials had an open-label, pragmatic design, allowing investigators to choose the beta-blocker and dose. Most investigators chose bisoprolol or metoprolol, despite the lack of a substantial trial of bisoprolol after myocardial infarction and no convincing evidence of benefit in trials of metoprolol.3 Only trials of non-selective beta-blockers have shown reductions in mortality after myocardial infarction, although pre-dating the widespread introduction of PCI and therefore including many more patients with a reduced LVEF. However, trials of non-selective beta-blockers showed a reduction in recurrent myocardial infarction, an effect that is unlikely to be related to LVEF. Investigators also chose to treat patients with low doses of beta-blockers. No information on post-randomization heart rate, the physiological marker of beta-blockade, was reported to confirm adherence to therapy or the effectiveness of blockade. Moreover, within 1 year, about 15% of those assigned to the control group were known to have started taking beta-blockers, rising to almost 30% with longer-term follow-up, which may be underestimates due to under-reporting. Obviously, physicians considered that a high proportion of patients assigned to the control group should receive a beta-blocker. In the current trials, events accumulated in a near-linear fashion over a follow-up of three or more years, with no evidence of the vulnerable period usually encountered in the immediate aftermath of a myocardial infarction. For those with an LVEF ≥50%, 75 years and with an LVEF >50%. Whether non-selective agents would offer better protection is unknown. Given the high rate of events in the weeks following a myocardial infarction in clinical practice, the potential confusion caused by deviation from well-defined treatment protocols in the acute setting and inaccuracies in the assessment of LVEF, is it wise to try to identify a small minority of patients who will not benefit from a beta-blocker when recent trials show no adverse effect of beta-blockers on quality of life or outcomes. The ABYSS trial took a different approach, randomizing low-risk patients at least six months after a myocardial infarction.10 The trial showed that there were slightly more cardiology encounters for those who had beta-blockers withdrawn, but neither disability nor mortality increased. After surviving the onset of a myocardial infarction, getting to hospital, and having a percutaneous coronary intervention, taking a beta-blocker for a few weeks is probably not a ‘big deal’ for most patients. Indeed, beta-blockers may reduce anxiety and stress. Re-assessment 6–12 weeks after the event, being told that all is well and that some medicines are no longer needed might even have a psychological benefit. But who persuaded cardiologists to use bisoprolol and metoprolol after a myocardial infarction? Commercial entities, those who wrote the guidelines, or perhaps it is just uncritical perseveration of poor decisions made by our forebears? None. Not applicable. John Cleland is Professor of Cardiology at the University of Glasgow, United Kingdom. He helped establish the European Society of Cardiology’s (ESC) Task Force on Heart Failure in the 1990’s. He wrote the very first ESC guideline in 1995 (on the diagnosis of heart failure) and has contributed to many others (most recently in 2023). He initiated the European Journal of Heart Failure and was its editor-in-chief from 1999–2006. He is currently a deputy editor of the European Heart Journal. Special interests are diagnostic criteria for and epidemiology of heart failure (a cardio-renal syndrome) and randomized trials for preventing and treating heart failure. He has received many international awards, including the James Mackenzie medal of the British Cardiovascular Society and the William Stokes medal of the Irish Cardiac Society. He is a Clarivate highly-cited researcher (top 1% in the world). He has authored >1200 peer-reviewed papers and reviews. Ben Hurdus is a cardiology registrar in Bradford, West Yorkshire. He is part of the Leeds cardiovascular epidemiology research group led by Professor Chris Gale, with particular interests in post myocardial infarction outcomes and heart failure. Chris Gale is Professor of Cardiovascular Medicine, Honorary Consultant Cardiologist, and Co-Director of the Leeds Institute for Data Analytics at the University of Leeds and Leeds Teaching Hospitals NHS Trust. He practices clinical cardiology with particular interests in general cardiology, post-myocardial infarction survivorship, and chronic heart failure. He Co-Chairs The Lancet Regional Health—Europe Commission on Inequalities and Disparities in Cardiovascular Health and is the Clinical Lead for the UK national heart attack register, MINAP. He is a trialist and health services researcher, focusing on atrial fibrillation, heart failure, and acute coronary syndrome.