Beta-blockers after acute myocardial infarction: an old drug in urgent need of new evidence!

This editorial refers to ‘Long-term β-blocker therapy and clinical outcomes after acute myocardial infarction in patients without heart failure: nationwide cohort study’†, by J. Kim et al., on page 3521. Developed more than half a century ago by Sir James Black in an effort to mitigate the effects of catecholamines, beta-blockers represent a remarkable advancement in pharmacotherapy. Beta-blockers are one of the most widely used class of drugs in cardiovascular medicine for patients with heart disease, arrhythmias, heart failure (HF), and hypertension. In patients post-myocardial infarction (MI), beta-blockers exert diverse cardioprotective effects, including attenuating the increased sympathetic drive and thereby reducing myocardial oxygen consumption, suppressing ventricular arrhythmias, and limiting adverse cardiac remodelling. The clinical use of beta-blockers after MI was introduced in the 1980s after several landmark randomized trials showed a reduction in both short- and long-term mortality associated with beta-blocker use in patients with MI.1 These studies were conducted in an era where primary percutaneous coronary intervention (PCI) was not the standard of care for acute MI (AMI). Similarly, adjunctive pharmacotherapy that is routinely used nowadays, including dual-antiplatelet therapy and high-potency lipid-lowering agents, was not available at the time. Therefore, extrapolating the results of those trials to contemporary practice presents important limitations. Subsequent studies established the efficacy of beta-blockers after MI in a particularly high-risk subgroup—patients with reduced ejection fraction (EF).2,3 Consequently, the routine use of beta-blockers in patients with ST-segment elevation myocardial infarction (STEMI) and reduced EF is strongly advocated for in the most recent iteration of the European Society of Cardiology (ESC) and American Heart Association/American College of Cardiology (AHA/ACC) guidelines.4,5 However, due to the paucity of data in patients with MI and preserved EF, the benefits of beta-blocker use in this population are uncertain. As such, although the guidelines generally advocate for their use, there is variability in their recommendation. For example, in patients with STEMI and preserved EF, routine long-term beta-blocker use is a Class I (level of evidence B) recommendation by the 2013 ACC/AHA guidelines and a Class IIa recommendation by the 2017 ESC guidelines.4,5 Similarly, in patients with non-ST segment elevation acute coronary syndromes and preserved EF, the 2014 ACC/AHA guidelines give a Class IIa (level of evidence C) recommenation for long-term beta-blocker use, while the 2015 ESC guidelines offer no such recommendations.6,7 In fact, the ESC guideline states: ‘beta-blocker therapy has not been investigated in a contemporary randomized controlled trial in patients after NSTE-ACS and no reduced LV function or heart failure’ and identifies this as a gap in evidence that needs to be investigated.7 In this issue of the European Heart Journal, Kim and colleagues evaluate the association between long-term beta-blocker use and clinical outcomes in patients without a history of HF who had an AMI.8 This nationwide cohort study of 28 970 patients who underwent coronary revascularization for AMI included those who were event free from death, recurrent MI, or HF at 1 year. The most important finding of the study is arguably the lower risk of all-cause death in patients who received a beta-blocker, an observation that persisted in some groups over a median follow-up of 3.5 years. In the analysis by Kim and colleagues, beta-blocker therapy for ≥1 year was associated with lower mortality compared with the group in whom beta-blocker therapy was used for <1 year [adjusted hazard ratio (HR) 0.81, 95% confidence interval (CI) 0.72–0.91; P < 0.001]. Similarly, among patients who were event free from death, recurrent MI, or hospitalization for HF at 2 years, lower all-cause death was observed in those who continued beta-blocker therapy for ≥2 years. (adjusted HR 0.86, 95% CI 0.75–0.99; P = 0.04). These findings were observed for carvedilol and bisoprolol, the two most commonly prescribed beta-blockers in the cohort. In the reperfusion era, data on a durable mortality benefit associated with beta-blocker therapy in patients with preserved EF are limited. In a propensity score-matched analysis of 424 patients with AMI and left ventricular EF (LVEF) >40%, beta-blocker use was associated with lower cardiac death and a 2.5-fold lower rate of fatal MI over a median follow-up of 4.7 years.9 Conversely, evidence to support a long-term benefit of beta-blocker therapy in patients with MI and preserved EF is disputed by findings from multiple studies. A post-hoc analysis of the Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance (CHARISMA) trial involving >4700 patients with prior MI and preserved EF found no difference in mortality with beta-blocker use at 28 months of follow-up.10 In an analysis from the Reduction in Atherothrombosis for Continued Health (REACH) registry involving >3000 patients with MI followed for a median of 43 months, we reported no difference in all-cause mortality or cardiovascular mortality associated with beta-blocker use.11 Notably, >70% of patients in this cohort did not have HF. The FAST-MI registry included >2600 patients with AMI and LVEF >40%. It was reported that patients who continued beta-blocker therapy after hospital discharge had lower risk of cardiovascular mortality at 1 year.12 However, continuing beta-blocker treatment after 1 year was not associated with a mortality difference at 5 years.12 Similarly, Dondo and colleagues failed to show a mortality benefit of beta-blocker therapy in an observational cohort study of close to 180 000 patients with MI and preserved EF.13 Two studies reported lower short-term (6 months) and long-term (3 years) mortality with beta-blocker therapy after AMI only in patients with reduced EF, whereas their counterparts with preserved EF derived no such reduction in mortality.2,14 Finally, contemporaneous meta-analyses also demonstrated no mortality benefit associated with beta-blocker use after MI.15,16 An interesting association between long-term beta-blocker therapy and the risk of recurrent MI emerges from the current analysis. Patients receiving a beta-blocker for ≥1 year showed a trend toward a lower risk of recurrent MI. In those patients who remained on a beta-blocker for ≥2 years, the trend became significant, with a HR of 0.67 (95% CI 0.51–0.87; P = 0.003). This observation offers a potential mechanistic explanation for the mortality benefit derived from long-term beta-blocker therapy. Notwithstanding, studies in the reperfusion era have yielded conflicting results on the association between beta-blocker therapy and recurrent MI. In a large meta-analysis, we reported a reduction in recurrent MI associated with beta-blockers, which appeared to be limited to the short term (30 days) and offset by an increase rate of HF, cardiogenic shock, and drug discontinuation.15 In a study including >81 000 patients with AMI treated with PCI and followed for 2 years, Won et al. reported a 30% risk reduction in recurrent MI and 38% reduction in all-cause death associated with regular beta-blocker use.17 The impressive benefits associated with beta-blocker therapy in a population with predominantly preserved EF, and widely treated with second-generation drug-eluting stents, renin–angiotensin–aldosterone system (RAAS) blockers, dual antiplatelet therapy, and statins have not been replicated in other studies and raise concerns about potential bias in the study. On the other hand, several studies have shown no benefit from beta-blocker therapy with respect to rates of recurrent MI.2,16,18 The management of AMI in the reperfusion era is characterized by rapid invasive revascularization, widespread use of latest generation drug-eluting stents, systematic use of potent antiplatelet agents, RAAS blockers, aggressive lipid-lowering therapy, and complete revascularization in patients with multivessel coronary artery disease. In this context, proving a mortality benefit with beta-blocker therapy, particularly in low-risk groups as is the case in patients with preserved EF, appears to be an elusive proposition. We commend Kim and colleagues for a remarkable study that yields important insights into the highly debated concept of beta-blocker use in patients with AMI and preserved EF. The findings presented by the authors, however, must be interpreted in the context of several limitations. First, the authors were unable to identify clear reasons for beta-blocker use in this population. It is therefore unclear if some patients receiving this therapy had an alternative compelling indication for beta-blockers that may have a favourable impact on their long-term survival. Secondly, patient clinical characteristics including type of AMI (i.e. STEMI vs. NSTEMI) and angiographic findings were not available, potentially introducing bias to the study. Finally, by virtue of missing data on LVEF, readers are cautioned to interpret the findings of the study in this context rather than generalizing the findings to patients with an LVEF above an arbitrary threshold. The study only excluded patients with a history of HF before the MI. LVEF data after MI were not available and, as such, the authors’ categorization of this study being predominantly comprised of patients with MI and preserved EF is therefore debatable. At present, multiple large, randomized clinical trials evaluating the clinical efficacy of beta-blocker therapy in patients with MI and preserved EF are in progress (Figure 1). As the scientific community eagerly await the results of these studies, mounting evidence shows that beta-blocker therapy in patients with MI and preserved EF is probably prognostically advantageous in the short term, but lacks definitive evidence with regards to long-term outcomes. A drug that has been widely used clinically for over half a century is now in urgent need of reappraisal from contemporary trials. Ongoing clinical trials evaluating beta-blocker therapy in patients with acute myocardial infarction and preserved ejection fraction. AMI, acute myocardial infarction; βB, beta-blocker; CV, cardiovascular; HF, heart failure; LVEF, left ventricular ejection fraction; MI, myocardial infarction; NSTEMI, non ST-segment elevation myocardial infarction; PCI, percutaneous coronary intervention; ; STEMI, ST-segment elevation myocardial infarction. *Type I MI as defined by the Universal Definition of MI. Ongoing clinical trials evaluating beta-blocker therapy in patients with acute myocardial infarction and preserved ejection fraction. AMI, acute myocardial infarction; βB, beta-blocker; CV, cardiovascular; HF, heart failure; LVEF, left ventricular ejection fraction; MI, myocardial infarction; NSTEMI, non ST-segment elevation myocardial infarction; PCI, percutaneous coronary intervention; ; STEMI, ST-segment elevation myocardial infarction. *Type I MI as defined by the Universal Definition of MI. Conflicts of interest: S.B. serves on the Advisory board for Amgen, Pfizer, Abbott Vascular, Biotronik, Meril, and Reata. R.H. has no conflicts to declare. The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.