Sir James Black was a pioneer in medicine when he realized that Alquist’s theory of ‘sympathins’ could be used in drug development, and antagonizing these would reduce myocardial oxygen demand in patients with obstructive coronary artery disease.1 The invention of propranolol, a novel beta-blocker, and its use in alleviating angina pectoris symptoms is considered one of the most important contributions in medicine.2 For his work, Sir James Black was awarded the Nobel Prize in Medicine. Landmark trials undertaken during the late 1970s and early 1980s introduced early oral beta-blocker therapy as a treatment in patients with acute myocardial infarction (MI) with the publication of the Norwegian Timolol study and Swedish ‘Gothenburg-study’ in 1981,3,4 and the BHAT study in 1982.5
Due to the convincing effect of beta-blockers in patients with MI on reinfarction and death,6 they have since then remained a cornerstone in the pharmaceutical weaponry of every cardiologist in the care of MI patients. Of note from these early studies, however, the short-term mortality in patients treated with placebo was high, 15%, and the greatest benefit was seen in patients with heart failure.5 There was no reporting on left ventricular ejection fraction (LVEF) among the patients included.
Since the introduction of beta-blockers for treatment of MI patients, mortality and morbidity have decreased substantially due to development of additional therapies for both patients with non-STsegment elevation myocardial infarction (NSTEMI)7 and STEMI:8 reperfusion therapy, early revascularization, dual antiplatelet therapy, angiotensin-converting enzyme (ACE) inhibition, and statins. Also, the introduction of high-sensitivity troponins for the detection of myocardial injury has led to smaller MIs being detected. Altogether, this has probably attenuated the effect of beta-blocker therapy following MI. Indeed, a systematic review from Bangalore et al. did not find an effect of beta-blocker treatment from randomized trials9 in the reperfusion era. Despite the paucity of data on the effect of betablocker therapy in MI patients in the reperfusion era, contemporary guidelines from the American Heart Association/American College of Cardiology (AHA/ACC) and the European Society of Cardiology (ESC) still recommend their use in patients with STEMI10,11 without contraindications, and in those with NSTEMI12,13 for all patients in the AHA/ACC guidelines and for patients with reduced ejection fraction (LVEF of 40%) in the ESC guidelines. Data from contemporary trials are lacking and the two main studies are the CAPRICORN14 study which showed the effect of carvedilol in patients with MI, but included only patients with LVEF of <_40%, and the COMMIT study in 45 852 patients without LVEF restrictions that could not find evidence of an effect of beta-blocker therapy for the two co-primary outcomes. Thus, uncertainty exists as to the effect of beta-blocker treatment for patients with MI and normal ejection fraction, defined as an LVEF of >40%.
In this issue of the European Heart Journal – Cardiovascular Pharmacotherapy, Seung-Jae Joo15 and colleagues suggest that the effect of beta-blocker therapy in patients with MI may be influenced by an interaction with LVEF and that the true equipoise may be in patients with LVEF >50%. The authors should be congratulated for their study, which provides new insights into beta-blocker therapy in patients with MI and mildly reduced ejection fraction. Their study is an observational registry study from the Korea Acute Myocardial Infarction Registry-National Institute of Health (KAMIR-NIH) investigating the effect of beta-blockers following MI in 12 200 patients with contemporary MI management. All patients survived index hospitalization and had echocardiographic data on LVEF.
Joo et al. divided patients into groups according to their LVEF and found that the beneficial effects of beta-blockers after MI was only present in patients with reduced (LVEF <40%) or mid-range LVEF (40% <LVEF <50%), and not in patients with LVEF >50%. The associations found were mainly driven by lower cardiac deaths in patients with LVEF <_40% and a lower rate of MI in patients with 40% <LVEF<50%.
There are several studies indicating that patients with LVEF 40–50% are different from patients with LVEF >_50%. In a recent meta-analysis of randomized beta-blocker trials in heart failure, there was no effect in patients with LVEF >50%, whereas in patients in the 40%<LVEF<50% group, treatment with a beta-blocker reduced the risk of cardiovascular death16. However , in this group, the median was closer to 40% than 50% due to inclusion of trials with exclusion criteria of LVEF>40%. There are also a number of trials examining the effect of other drugs that have noted the heterogeneity of patients with heart failure and preserved ejection fraction and suggested a treatment effect in patients with LVEF of 40–55%.17–19 Following the study by Joo et al. it appears that ‘50 is the new 40’ may also be true when deciding whether an MI patient should have treatment with a beta-blocker or not.
CAPITAL-RCT is a recently published randomized trial in reperfused STEMI patients with normal LVEF (>40%) that did not show an effect of carvedilol on mortality.20 However, in the CAPITAL-RCT trial, mean LVEF in both groups was ~60%, indicating a high degree of selection bias and, furthermore, the trial was stopped prematurely after inclusion of 801 patients due to slow recruitment, limiting power and generalizability. Therefore, the current study by Joo and colleagues adds valuable new information on the effect of beta-blocker treatment in patients following MI with mid-range LVEF (40% <LVEF<50%).
Despite advanced statistics, the study by Joo et al. is an observational study with the inherent limitation of not being able to exclude residual confounding. Therefore, changes in practice cannot be done without appropriate randomized trials. Several ongoing trials are recruiting patients to evaluate the effect of betablocker treatment in patients with MI and ‘normal’ LVEF in the reperfusion era. The majority of trials have set an LVEF cut-off of 40%, and only the REDUCe-trial is excluding patients with mildly reduced LVEF. Results from these trials will inform us about the effect of beta-blockers both in those with LVEF >_50% and in those with LVEF 40–50%.
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