Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment - ExTRACT-TIMI 25

Description:

The goal of the trial was to evaluate treatment with a strategy of enoxaparin compared with weight-based unfractionated heparin (UFH) among patients with ST-elevation myocardial infarction (STEMI).

Hypothesis:

Compared to UFH, adjunctive antithrombin therapy with enoxaparin reduces the composite endpoint of death and nonfatal reinfarction within 30 days in patients with STEMI receiving fibrinolytic therapy.

Study Design

Study Design:

Patients Enrolled: 20,506
Mean Follow Up: One year (30 days reported to date)
Mean Patient Age: Median 59 years
Female: 23

Patient Populations:

Age ≥18 years; at least 20 minutes of ischemic symptoms at rest within 6 hours before randomization; ST-segment elevation ≥0.1 mV in two limb leads or 0.2 mV in ≥2 contiguous precordial leads or left bundle branch block; and planned administration of fibrinolysis with either streptokinase, tenecteplase, alteplase, or reteplase

Exclusions:

Cardiogenic shock, pericarditis, symptoms of aortic dissection, contraindications to fibrinolysis, administration of a low molecular weight heparin within the prior 8 hours, known renal insufficiency, or anticipated survival <12 months

Primary Endpoints:

Death or nonfatal recurrent MI through 30 days

Secondary Endpoints:

Composite of death, nonfatal MI, or recurrent myocardial ischemia leading to urgent revascularization through 30 days

Drug/Procedures Used:

Patients were randomized to a strategy of enoxaparin throughout the index hospitalization (n = 10,256) or weight-based UFH (n = 10,223) for at least 48 hours. Enoxaparin dose was 30 mg intravenous (IV) followed by subcutaneous (SC) injection of 1.0 mg/kg every 12 hours in patients age <75 years; in patients age >75 years, IV bolus was not administered, and the SC injection was 0.75 mg/kg every 12 hours. UFH dose was IV bolus of 60 U/kg (maximum 4000 U) followed by 12 U/kg/h infusion (initial maximum 1000 U/h). Dosing of UFH was performed in an encrypted manner to maintain double-blinding.

Concomitant Medications:

Aspirin 150 to 325 mg orally or 500 mg IV for all patients

Other concomitant medications included beta-blockers (86%), angiotensin-converting enzyme inhibitors/angiotensin-receptor blockers (80%), and statins (70%).

Principal Findings:

Fibrin-specific lytic was used in 80% of patients, with 20% receiving streptokinase. Percutaneous coronary intervention was performed in 23.0% of patients, 74.3% were managed with medical therapy alone, and 2.8% underwent coronary artery bypass surgery. Median duration of therapy was 2.0 days in the UFH group and 7.0 days in the enoxaparin group.

The primary endpoint of death or MI at 30 days occurred less frequently in the enoxaparin group than the UFH group (9.9% vs. 12.0%, relative risk [RR] 0.83, p < 0.001). The secondary endpoint of death, MI, or myocardial ischemia leading to urgent revascularization was also lower in the enoxaparin group (11.7% vs. 14.5%, RR 0.81, p < 0.001), a finding that was evident by 48 hours (5.3% vs. 6.1%, p = 0.02). Likewise, nonfatal MI at 48 hours was significantly lower in the enoxaparin group (0.9% vs. 1.4%, p = 0.002).

TIMI major bleeding was higher in the enoxaparin group (2.1% vs. 1.4%, p < 0.001), as was TIMI minor bleeding (2.6% vs. 1.8%, p < 0.001). There was no difference in intracranial hemorrhage (0.8% vs. 0.7%, p = 0.14). Three net-clinical benefit endpoints were prespecified, all of which were lower with enoxaparin including death, MI, or disabling stroke (10.1% vs. 12.3%, RR 0.82, p < 0.001).

Interpretation:

Among patients with STEMI treated with fibrinolytic therapy, a strategy of enoxaparin for the duration of the index hospitalization was associated with a reduction in the primary endpoint of death or MI by 30 days compared with a strategy of UFH for 48 hours.

The reduction in death or MI with the enoxaparin strategy may be due to several factors, including a greater antithrombotic effect of enoxaparin, longer treatment duration with enoxaparin, or a rebound effect with increased events following discontinuation of UFH. While bleeding was higher with the enoxaparin strategy, all three of the net-clinical endpoints, which took into account the safety endpoints, showed benefit with enoxaparin over UFH. The significant reduction in MI was evident by 48 hours, when the two drugs (rather than the two strategies) could be compared in a head-to-head manner.

References:

Presented by Dr. Elliott M. Antman at the March 2006 ACC Annual Scientific Session, Atlanta, GA.

Antman EM, Morrow DA, McCabe CH, et al. Enoxaparin versus unfractionated heparin with fibrinolysis for ST-elevation myocardial infarction. N Engl J Med 2006;354:1477-88.

Clinical Topics: Anticoagulation Management, Arrhythmias and Clinical EP, Cardiac Surgery, Dyslipidemia, Invasive Cardiovascular Angiography and Intervention, EP Basic Science, Aortic Surgery, Cardiac Surgery and Arrhythmias, Lipid Metabolism

Keywords: Thrombolytic Therapy, Risk, Myocardial Infarction, Stroke, Heparin, Percutaneous Coronary Intervention, Intracranial Hemorrhages, Streptokinase, Enoxaparin, Fibrinolysis, Bundle-Branch Block, Tissue Plasminogen Activator, Coronary Artery Bypass


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