Intravenous β-blockers in STEMI: what you are about to do, do it quickly

Acute myocardial infarction with ST-segment elevation (STEMI) is a life-threatening condition in which rapid response is essential. Most of the efforts in the acute setting are focused on achieving a rapid reperfusion, ideally by primary angioplasty, as long as it can be achieved within 2 hours from diagnosis.1 Quick initiation of dual antiplatelet therapy is the other intervention performed as soon as possible in the course of STEMI. For stable STEMI patients, most of the other interventions are initiated after reperfusion in the intensive cardiac care unit. β-Blockers have been shown to reduce mortality when used as secondary prevention after infarction,2 and are an established part of the pharmacological armamentarium, with a class I indication in clinical guidelines.1 However, early intravenous (i.v.) administration in the acute setting of STEMI is no longer in widespread use despite clinical practice guidelines recommending its use ‘at the time of presentation’ (class of recommendation IIa, level of evidence A).1 β-Blockers were one of the first class of agents tested in the STEMI setting, with overall positive results. A large proportion of the many trials performed in the 1970s and 1980s tested i.v. followed by oral β-blockers versus no β-blockers at all. The mortality benefits of β-blockers were observed mainly in trials with long-term follow-up.3 A meta-analysis including all trials testing early i.v. β-blockers in STEMI (most of them in the pre-reperfusion era) demonstrated benefits in terms of reductions in all-cause mortality and reinfarction rates.4 The trend in the use of i.v. β-blockers completely changed after the publication of the COMMIT trial.5 This mega trial enrolled more than 45,000 MI patients (>90% STEMI) and randomly allocated them to i.v. followed by oral metoprolol or placebo and followed them for 30 days. There were no differences in mortality. Metoprolol was associated with a reduced incidence of ventricular fibrillation and reinfarction at the cost of increasing the incidence of cardiogenic shock.5 That trial had a massive impact on practice because the use of early i.v. β-blockers was dramatically reduced after its publication. However, it is of utmost importance to understand the population recruited in that trial to put these results under scrutiny: half of the population never underwent reperfusion; patients receiving fibrinolysis (none underwent angioplasty) received the lytic agent very late (mean time from symptom onset 10.3 hours); most of the cardiogenic shock events were concentrated in those with a Killip III myocardial infarction (MI) on admission (in the subpopulation of Killip I/II, metoprolol strategy was associated with less all-cause mortality). In fact, in a meta-analysis, cardiogenic shock was not significantly increased patients receiving i.v. β-blockers.4 These data reinforce the fact that patients with acute heart failure (Killip III–IV) should not receive i.v. β-blockers. In the primary angioplasty era, four trials have tested the benefits of i.v. β-blockers. These trials compared i.v. β-blockers versus control, but in all patients enrolled (including controls), oral β-blockers were initiated within 1 day of STEMI according to clinical guidelines. Two trials tested metoprolol (METOCARD-CNIC (n=270)6 and EARLY-BAMI (n=683))7 one esmolol (BEAT-AMI (n=100))8 and one landiolol (Hanada et al. (n=96)).9 In a paper published in this issue of the journal, a patient-pooled meta-analysis of these four trials is reported.10 Infarct size was estimated in three out of four trials by different methodologies, and in two of them (METOCARD-CNIC and BEAT-AMI) i.v. β-blocker use was associated with smaller infarct sizes. In the largest trial (EARLY-BAMI), no sign of infarct-limiting effect was seen. In the pooled analysis, i.v. β-blocker use was not associated with less peak or area under the curve (AUC) cardiac damage biomarkers release. The 1-month left ventricular ejection fraction (LVEF) was only evaluated in EARLY-BAMI,7 and was not different between groups. Long-term LVEF (6 months) was evaluated in two trials (METOCARD-CNIC11 and Hanada et al.)9 and was significantly higher in patients receiving i.v. β-blockers. Of note, malignant ventricular arrhythmias (ventricular fibrillation or sustained ventricular tachycardia) during the acute phase of STEMI were significantly reduced (cut by half) consistently in METOCARD-CNIC, EARLY-BAMI and BEAT-AMI trials (in Hanada et al.9 no sustained ventricular tachycardia (VT) or ventricular fibrillation (VF) was noted in any group). No difference in clinical events was observed in the meta-analysis, despite i.v. metoprolol being associated with a significant reduction in long-term heart failure admissions in the METOCARD-CNIC trial.11 One very important result from the meta-analysis published in this issue of the journal10 relates to the safety of i.v β-blocker administration in the acute phase of STEMI: no safety concerns were observed in the pooled data (i.e. no increase in cardiogenic shock was observed). The latter is very important, and clearly demonstrates that when proper patients are included (i.e. those with Killip class