Abstract and Introduction
Abstract
Aims: We compared outcomes of ST-elevation myocardial infarction (STEMI) patients randomized to a strategy of either enoxaparin or unfractionated heparin (UFH) to support fibrinolysis.
Methods and Results: In the Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment-Thrombolysis in Myocardial Infarction Study 25 (ExTRACT-TIMI 25) trial, 20 479 patients undergoing fibrinolysis for STEMI with a fibrin-specific agent (N = 16 283) or streptokinase (SK) (N = 4139) were randomized to enoxaparin throughout their hospitalization or UFH for at least 48 h. The primary end point of death or nonfatal recurrent MI through 30 days occurred in 12.0% of patients in the UFH and 9.8% in the enoxaparin groups when treated with fibrin-specific lytics [odds ratioadjusted (ORadj) 0.78; 95% CI 0.700.87; P < 0.001] and 11.8 vs. 10.2%, respectively, when treated with SK (ORadj 0.83; 95% CI 0.661.04; P = 0.10; Pinteraction = 0.58). Major bleeding rates including intracranial hemorrhage within the fibrin-specific cohort were 1.2 and 2.0% in the UFH and enoxaparin groups, respectively (P < 0.001) and 2.0% in UFH and 2.4% in enoxaparin patients in the SK cohort (P = 0.16). Interaction tests between antithrombin- and lytic-type were non-significant (P = 0.20). Death, nonfatal MI, or major bleeding was significantly reduced with enoxaparin in the fibrin-specific cohort (ORadj 0.82; 95% CI 0.74-0.91; P < 0.001) and favoured enoxaparin in the SK cohort (ORadj 0.89; 95% CI 0.72-1.10; P = 0.29; Pinteraction = 0.53).
Conclusion: The benefits of an enoxaparin strategy over UFH were observed in both SK and fibrin-specific-treated STEMI patients. Therefore, an enoxaparin strategy is preferred over UFH to support fibrinolysis for STEMI regardless of lytic agent.
Introduction
Fibrinolysis remains the leading re-perfusion strategy around the world for patients with ST-elevation myocardial infarction (STEMI). Despite several advantages, including development of fibrin-specific lytics and bolus-administered agents, the benefits of fibrinolysis are compromised when re-occlusion of successfully re-perfused infarct arteries occurs.
The generation of thrombin via the coagulation cascade is pivotal in the formation of fibrin strands and activation of platelets at the site of a ruptured vulnerable plaque. Local production of thrombin is also paradoxically increased by the action of fibrinolytic agents. Enzymatically active thrombin plays a key role in re-occlusion following successful coronary re-perfusion, providing the rationale for adjunctive anticoagulant therapy in STEMI patients undergoing fibrinolysis.
Unfractionated heparin (UFH) is an anti-coagulant that has been widely used in the treatment of STEMI for > 40 years. Investigations have confirmed the benefits of UFH combined with fibrinolytic therapy. The addition of UFH to fibrinolysis with streptokinase (SK) has been demonstrated to reduce death and reinfarction, whereas in combination with fibrin-specific agents UFH is believed to help achieve and maintain coronary arterial patency. Low-molecular-weight heparins, such as enoxaparin, are an attractive potential replacement for UFH because of the convenient subcutaneous route of administration and reliable anticoagulation effects, eliminating the need for therapeutic monitoring.
The Enoxaparin and Thrombolysis Reperfusion for Acute Myocardial Infarction Treatment-Thrombolysis in Myocardial Infarction Study 25 (ExTRACT-TIMI 25) trial demonstrated that a strategy of adjunctive anticoagulant therapy with enoxaparin for the duration of the index hospitalization was superior to the standard two-day UFH regimen in patients with STEMI treated with fibrinolytic therapy. However, little information is available regarding the efficacy and safety of enoxaparin across a range of available lytics agents. In the ExTRACT-TIMI 25 trial, alteplase, tenecteplase, reteplase, or SK was administered to STEMI patients at the discretion of the treating physician, and 30-day outcomes were evaluated. We report a pre-specified subgroup analysis conducted to determine the efficacy and safety of the administration of a strategy of enoxaparin compared with UFH stratified by the type of lytic therapy used in the trial.