Potential for a New Coronary Thrombolytic Plateau.
The GUSTO-I trial provided definitive evidence that early and complete thrombolysis are closely associated with clinical outcome. However, in this trial the best thrombolytic strategy, consisting of accelerated t-PA, aspirin, and heparin, only yielded restoration of brisk flow (TIMI 3) in 54% of patients at 90 minutes after therapy. There are a variety of new strategies aimed at improving the rate of early TIMI flow, consisting of new plasminogen activators, anticoagulants, and platelet inhibitors, The third generation plasminogen activators include reteplase (r-PA), n-PA, bat-PA, staphylokinase, and TNK. To date, none of these molecules have been clearly associated with superior rates of infarct vessel patency, but comparative trials are in progress. Potent inhibitors of thrombin are recombinant hirudin, the most potent naturally occurring anticoagulant known, and synthetic direct thrombin inhibitors such as hirulog and argatroban. In the years ahead, agents that block the generation of thrombin, a step higher up in the coagulation cascade, such as factor Xa inhibitors, will be clinically pursued. The platelet glycoprotein Ilb/Illa inhibitors are a potent class of agents directed against the final common pathway for platelet aggregation, and pilot studies suggest excellent potential for facilitating early thrombolysis. Accordingly, a multitiered strategy of improved plasminogen activators, thrombin inhibitors, and antiplatelets is likely to result in far better clinical outcomes for myocardial reperfusion therapy in the future.
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Joseph J. Jacobs Center for Thrombosis and Vascular Biology and the Department of Cardiology, Cleveland Clinic Foundation, Cleveland, Ohio.