Frans J Van de Werf
Professor and Chairman
Department of Cardiology
Gasthuisberg University Hospital
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)
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.(5–7) 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.(8) That trial, however, failed to show a significant reduction in 30-day mortality, and there was a significant increase in noncerebral bleeding complications.
The treatment of acute myocardial infarction requires combination of several therapies. This article summarises 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 seven days; the second was the platelet glycoprotein IIb/IIIa inhibitor abciximab for 12 hours; and the third was weight-adjusted unfractionated heparin for 48 hours according to the guidelines of the American College of Cardiology and the American Heart Association (ACC/AHA).(9)
A total of 6,095 patients with acute myocardial infarction of less than 6 hours were randomly assigned one of the three regimens. The primary endpoints were the composites of 30-day mortality, in-hospital reinfarction, or in-hospital refractory ischaemia (efficacy endpoint), and the above endpoint plus in-hospital intracranial haemorrhage or in-hospital major bleeding complications (efficacy plus safety endpoint). Analysis was by intention to treat.
There were significantly fewer efficacy endpoints in the enoxaparin and abciximab groups than in the unfractionated heparin group: 11·4% versus 15·4%; relative risk 0·74 (95% CI 0·63–0·87), p=0·0002 for enoxaparin, and 11·1% versus 15·4%; 0·72 (0·61–0·84), p<0·0001 for abciximab. The same was true for the efficacy plus safety endpoint: 13·7% versus 17·0%; 0·81 (0·70–0·93), p=0·0037 for enoxaparin, and 14·2% versus 17·0%; 0·84 (0·72–0·96), p=0·01416 for abciximab.
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 hours 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 bleeding complications (2·2% vs 4·7%) and less need for blood transfusion (2·3% vs 4·3%) in the present trial than in ASSENT-2. These results indirectly support the use of a more fully weight-adjusted dose of unfractionated heparin together with earlier monitoring of the partial thromboplastin time.
Compared with unfractionated heparin, adjunctive therapy with abciximab or enoxaparin reduces ischaemic complications of acute myocardial infarction treated with tenecteplase. These reductions were found to be present early after the start of treatment. The results obtained with half-dose tenecteplase plus abciximab are very similar to those with half-dose reteplase and abciximab seen in GUSTO-V, and support the hypothesis that a more potent antiplatelet agent increases flow in the infarct-related coronary artery. In both trials, these benefits are obtained at the cost of a higher rate of thrombocytopenia, major bleeding complications and blood transfusions. No benefit, and perhaps even harm, was seen in patients older than 75 years and in diabetics. Results from both trials suggest that caution should be exercised regarding the use of conjunctive therapy with abciximab in elderly patients with an acute myocardial infarction treated with a fibrinolytic agent.
The reductions in ischaemic complications in the full-dose tenecteplase plus enoxaparin group were similar to those seen in the abciximab group, but were more consistent. Importantly, no increase in intracranial haemorrhage rate, no excess in thrombocytopenia, and only a modest and nonsignificant increase in major bleeding complications was seen despite the length of treatment. In view of the present data and the ease of administration, enoxaparin might be regarded as an attractive alternative anticoagulant treatment when given in combination with tenecteplase. Whether enoxaparin is a desirable anticoagulant in conjunction with less fibrin-specific agents, whether enoxaparin can replace unfractionated heparin in combination with a platelet glycoprotein IIb/IIIa inhibitor and a reduced dose fibrinolytic, and what role various pharmacological combinations will ultimately have in conjunction with early coronary intervention need to be determined.
The overall 30-day mortality rates in the study were low and probably result from selection of patients and an improvement in associated medical treatment and intervention. However, time to treatment remained similar to that of other large trials of fibrinolytic therapy, emphasising the opportunity provided by prehospital therapy with simple regimens.
The study had some limitations. Ascertainment of selected components of the composite endpoints in this open trial was investigator-determined and subject to bias. Nonetheless, the strength and consistency of the results suggest that they are probably not due to bias or chance. The different duration of heparin therapy in the enoxaparin versus the unfractionated heparin group also deserves comment. A seven-day course of enoxaparin was chosen to conform with previous studies in the hope of reducing recurrent ischaemic complications and preventing reocclusion; the 48-hour infusion of unfractionated heparin is a standard antithrombotic strategy used in previous trials. The longer exposure to enoxaparin possibly contributed to its increased efficacy and to the increased trend for bleeding.
Taking into account efficacy and safety, the combination of full-dose tenecteplase and long-term administration of enoxaparin emerged as the best treatment in this trial. Because of additional advantages, such as the ease of administration and the lack of need for monitoring of anticoagulation, this combination should be regarded as an attractive alternative pharmacological reperfusion strategy deserving further study.
- Assessment of the Safety and Efficacy of a New Thrombolytic (ASSENT-2) Investigators. Single-bolus tenecteplase compared with front-loaded alteplase in acute myocardial infarction: the ASSENT-2 double-blind randomised trial. Lancet 1999;354:716-22.
- White H, Van de Werf F. Thrombolysis for acute myocardial infarction. Circulation 1998;97:1632-46.
- Armstrong PW, Collen D. Fibrinolysis for acute myocardial infarction. Current status and new horizons for pharmacological reperfusion, part I. Circulation 2001;103:2865-66.
- Turpie AGG, Antman EM. Low molecular weight heparins in the treatment of acute coronary syndromes. Arch Intern Med 2001;161:1484-90.
- Antman EM, Giugliano RP, Gibson CM, et al, for the TIMI 14 Investigators. Abciximab facilitates the rate and extent of thrombolysis: results of the Thrombolysis in Myocardial Infarction (TIMI) 14 Trial. Circulation 1999;99:2720-32.
- The SPEED Group (Strategies for the Patency Enhancement in the Emergency Department). Randomized trial of abciximab with and without low-dose reteplase for acute myocardial infarction. Circulation 2000;101:2788-94.
- Brener SJ, Vrobel TR, Lopez JF, et al. INTRO AMI: marked enhancement of arterial patency with eptifibatide and low-dose t-PA in acute myocardial infarction. Circulation 1999;100(Suppl):I-649 (abstract).
- GUSTO V investigators. Reperfusion therapy for acute myocardial infarction with fibrinolytic therapy or combination reduced fibrinolytic therapy and platelet glycoprotein IIb/IIIa inhibition: the GUSTO V randomised trial. Lancet 2001;357:1905-14.
- Ryan TJ, Antman EM, Brooks NH, et al. 1999 update: ACC/AHA guidelines for the management of patients with acute myocardial infarction: executive summary and recommendations. A report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Committee on Management of Acute Myocardial Infarction). Circulation 1999;100:1016-30.
European Society of Cardiology
Topol E, editor. Acute coronary syndromes. New York: Dekker Publishing; 2000