Therapy for acute myocardial infarction involves rapid restoration of blood flow through a coronary artery that has been occluded by a ruptured atherosclerotic plaque. Thrombolytic therapy, the pharmacologic standard to achieve this outcome, significantly improves survival; however, current regimens have limitations: they can fail to achieve complete reperfusion, they can cause significant bleeding events, and they can result in reocclusion. In addition, complex regimens of some agents can cause dosing errors. Accordingly, newer compounds were developed to address some of these issues, and alternative strategies are being implemented. The combination of platelet glycoprotein IIb-IIIa receptor inhibitors plus thrombolytic agents produced promising results in clinical trials, including faster clot lysis and greater flow rates than either therapy alone. The addition of unfractionated heparin or low-molecular-weight heparin to thrombolytic-antiplatelet therapy is being evaluated, as is administration of thrombolytic-antiplatelet before percutaneous coronary intervention.
The etiology of acute myocardial infarction is a ruptured atherosclerotic plaque with thrombotic occlusion of the coronary artery. The theory that rapid and complete restoration of blood flow in the occluded artery is directly related to reduced mortality is widely accepted, and success is evaluated in terms of achieving Thrombolysis in Myocardial Infarction (TIMI) flow grades (Table 1). Significant reductions in morbidity and mortality are associated with restoration of high TIMI flow grade. In the first Global Utilization of Streptokinase and Tissue Plasminogen Activator for Occluded Coronary Arteries (GUSTO I) study, the mortality rate in patients with TIMI 3 flow at 90 minutes was less than half that in patients with grade 0 or 1 flow (4.4% and 8.9%, respectively). Patients with grade 2 flow had an intermediate mortality rate of 7.4%. The survival advantage may be seen up to 5 years after myocardial infarction.
Although thrombolytics enhance survival and preserve left ventricular function after myocardial infarction, current reperfusion strategies have significant limitations. The drugs can fail to achieve TIMI 3 flow, may result in reocclusion, and are ineffective in patients with non-ST segment elevation. The explanation for their limitations may lie in the composition of the thrombus, which is made up of fibrin, thrombin, and activated platelets. Thrombolytics lyse the fibrin component, which results in exposure of thrombin, one of the most potent platelet proaggretory substances. Bleeding events, including intracranial hemorrhage (ICH), are associated with these agents. Thrombolytics are less effective in patients who are not treated within 6 hours of symptom onset. In those treated within 6 hours, mortality decreases to 30/1000 patients. After 6 hours, the mortality benefit begins to decline. Accordingly, newer strategies to achieve rapid, sustained reperfusion focus on administering thrombolytic agents in conjunction with glycoprotein (GP) IIb-IIIa receptor antagonists and unfractionated (UFH) or low-molecular-weight heparins (LMWH). Complementary measures, including critical pathways and revised evaluation to reduce delays in treatment and time to reperfusion, as well as combined pharmacologic and mechanical intervention, offer additional promising avenues for improving outcomes.