Fast track — ArticlesEfficacy and safety of tenecteplase in combination with enoxaparin, abciximab, or unfractionated heparin: the ASSENT-3 randomised trial in acute myocardial infarction
Introduction
Tenecteplase—a genetically engineered variant of alteplase—has provided a new standard of fibrinolytic therapy by virtue of its equivalent efficacy with regard to 30-day mortality, its reduced propensity for systemic bleeding complications, and its simple administration as a bolus.1 Despite these advantages, however, there are still substantial challenges, including suboptimal macroperfusion and microperfusion, recurrent ischaemia, and reinfarction and intracranial haemorrhage, in the optimum care of patients with acute myocardial infarction.2, 3
Antithrombotic agents are an important component of pharmacological reperfusion therapy for acute myocardial infarction. At present, unfractionated heparin and aspirin are routinely given to most patients. Low-molecular-weight heparins have only recently been studied with fibrinolytics. Unlike unfractionated heparin, low-molecular-weight heparins have more predictable kinetics, are less protein-bound, have less potential for platelet activation, and require no monitoring, providing a strong rationale for potentially better outcomes when given in combination with fibrinolytics.4 Most studies have shown either less reocclusion, enhanced late patency of the infarct-related vessel, or a reduction in reinfarction rate when compared with unfractionated heparin.5, 6, 7, 8 Largescale studies with low-molecular-weight heparins have not previously been done.
Pilot studies with platelet glycoprotein IIb/IIIa inhibitors and reduced-dose fibrinolytic agents have shown better patency of the epicardial infarct-related artery, and signs of improved tissue reperfusion.9, 10, 11 The phase III Global Use of Strategies to Open Occluded Coronary Arteries (GUSTO)-V trial showed a reduction in ischaemic complications of acute myocardial infarction with half-dose reteplase and abciximab compared with full-dose reteplase.12 That trial, however, failed to show a significant reduction in 30-day mortality and there was a significant increase in non-cerebral bleeding complications.
The treatment of acute myocardial infarction requires combination of several therapies. We therefore did a large exploratory trial to develop evidence about whether specific combinations might provide clinical benefit. The aim of the study was to compare the efficacy and safety of three antithrombotic conjunctive therapies with tenecteplase: the first was the low-molecular-weight heparin enoxaparin given up to discharge or revascularisation for a maximum of 7 days; the second was the platelet glycoprotein IIb/IIIa inhibitor abciximab for 12 h; and the third was weight-adjusted unfractionated heparin for 48 h according to the guidelines of the American College of Cardiology and the American Heart Association (ACC/AHA).13
Section snippets
Patients
We recruited patients in 575 hospitals in 26 countries. Inclusion criteria were identical to those of the Assessment of the Safety and Efficacy of a New Thrombolytic Regimen (ASSENT)-2 trial:1 age 18 years or older, onset of symptoms less than 6 h before randomisation, ST-segment elevation of at least 0·1 mV in two or more limb leads or at least 0·2 mV in two or more contiguous precordial leads, or left bundle-branch block. Exclusion criteria on admission were: systolic blood pressure of more
Results
6095 patients were enrolled between May, 2000, and April, 2001, of whom 5989 received study medication (figure 1). The baseline characteristics were similar in the three groups (table 1). Overall, the study populations were similar to those of previous trials on thrombolytics. As expected, the time from randomisation to bolus tenecteplase was significantly longer in the abciximab group because of the complexity of the treatments and the need to give the boluses of heparin and abciximab before
Discussion
The results of the group treated with full-dose tenecteplase and weight-adjusted unfractionated heparin in this trial were very similar to those of ASSENT-2. In ASSENT-2, a higher and not fully weight-adjusted dose of unfractionated heparin was given and the first partial thromboplastin time was measured 6 h after start of treatment. Nonetheless, total mortality, reinfarction, total stroke, and intracranial haemorrhage rates were almost identical in both trials. However, there were fewer major
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