Early intravenous β-blocker combined with thrombolytic therapy for acute myocardial infarction: The thrombolysis in myocardial infarction (TIMI-2) trial

Abstract

The early administration of thrombolytic and antiplatelet therapy reduces mortality from acute myocardial infarction (MI) by approximately 20% to 25% during the first week after treatment.’ Such treatment has become the standard of care for patients with acute MI who do not have contraindications. The role of long-term oral administration of p-adrenergic-blocking agents (P-blockers) for secondary prevention after MI is also well established from individual trials and pooled results that reveal reduced long-term mortality by up to 25%.1,2 Early intravenous (IV) P-blockers as primary treatment for acute MI reduce short-term mortality by approximately 15%1,3 and are also generally recommended. Although benefit has been shown for thrombolytic therapy and IV p-blocker treatments individually, little is known about combined use. There is a compelling rationale for considering early thrombolytic and antiplatelet treatment in combination with IV P-blocker. First, the agents presumably work by different mechanisms: the former achieves and maintains coronary reperfusion, restoring myocardial blood flow, and protects against reocelusion and reinfarction, whereas the latter reduces myocardial oxygen demand. Second, evidence gathered in larger trials suggests that the peak effects of the two interventions occur at different times during the clinical course of MI. In the First International Study of Infarct Survival (ISIS-l) trial, early intravenous atenolol reduced mortality, primarily during the first 24 hours of presentation.3 Review of the Gruppo Italian0 per lo Studio della Streptochinasi nell’ Infarto Miocardico4 and ISIS-2 trials of IV streptokinase showed a 20% to 33% excess of deaths during the first 24 hours, although overall, l-week mortality was significantly lower.5 A recent meta-analysis examining six large thrombolytic trials showed the relative risk (RR) of death was 1.27 +- 0.07 on day 0, insignificantly lower on day 1, and significantly lower on days 2 through 35 (RR 0.72 ? 0.03) and overall (RR 0.81 & 0.03) when thrombolytic-treated patients were compared with placebo or control patients.‘j In addition, the combination is free of any recognized negative interaction. Furthermore, P-blocking agents have been shown to reduce in vitro measurements of platelet aggregability,’ a theoretically desirable property. Thus the combination of thrombolytic treatment and IV P-blocker may be complementary and potentially further reduce mortality as compared with either agent used alone. Despite the theoretical appeal of the combined use of thrombolytic agents with IV P-blockers, little prospective data support such an approach. The purpose of this review is to consider briefly IV P-blocker trials performed before the widespread use of thrombolytic agents, examine nonrandomized studies of the combined approach, and then consider in detail the findings of the Thrombolysis in Myocardial Infarction (TIMI-2) Study,a the only published trial in which patients receiving thrombolytic therapy were randomized to early IV P-blocker or control groups.