Thrombolysis, anticoagulation, and reocclusion

Abstract

Based on apparent higher recanalization rates of the infarct-related artery, preferential use of thrombolytic agents with high clot specificity has been proposed for treating patients with acute myocardial infarction. In the Thrombolysis in Myocardial Infarction (TIMI-I) and European Cooperative Group studies, higher reperfusion rates were observed with alteplase compared with streptokinase, causing many to assume that the former would achieve a greater reduction in early hospital mortality. However, the Gruppo Italiano per lo Studio della Streptochinasi nell'Infarto Miocardico (GISSI-2) and its associated International Study Group failed to show any differences in 15-day mortality between these agents in more than 20,000 patients. This apparent lack of correlation between reperfusion rates and early mortality may be explained in part when one considers that recanalization or patency rates measured at a given point in time, such as 90 minutes after onset of therapy, fail to define the subsequent vessel status. Early reocclusion is the major reason for this and is a major limitation to the clinical efficacy of thrombolytic drugs. Following recanalization, residual fibrin-bound thrombin adherent to the site of arterial injury from plaque rupture strongly promotes rethrombosis. Although antiplatelet and antithrombin agents such as aspirin and heparin help to decrease rethrombosis, these agents are far from ideal. Thrombolytic agents that produce a significantly prolonged systemic thrombolytic state, such as streptokinase and anistreplase, are likely to result in less rethrombosis. Therefore, a systemic fibrinolytic state would appear to be an advantage rather than a disadvantage, particularly because the incidence of intracerebral hemorrhage does not appear to be greater with their use compared with agents producing less systemic fibrinolysis. Although relatively clot-specific agents producing only mild systemic fibrinolysis are associated with higher initial patency rates, they are also more likely to be associated with higher initial rethrombosis rates. Future therapy may be directed to the combined use of agents such as alteplase and streptokinase, alteplase and urokinase, or perhaps anistreplase alone to take advantage of early and higher recanalization rates produced by increased clot specificity combined with the advantage of a prolonged systemic lytic state. Results of the Third International Study of Infarct Survival (ISIS-3) and the currently planned Global Utilization of Streptokinase and t-PA for Occluded Arteries (GUSTO) trial may help to substantiate this approach.