Designing thrombolytic agents: focus on safety and efficacy

Thrombolytic therapy for evolving acute myocardial infarction (AMI) reduces infarct size, preserves ventricular function, and reduces mortality. Intravenous streptokinase is commonly followed by approximately 50% patency of coronary arteries within 90 minutes and by reduction of mortality by 25%. Recombinant tissue plasminogen activator (rt-PA) is more potent for coronary arterial thrombolysis, producing both more rapid and more frequent recanalization (approximately 75% patency at 90 minutes) with a dose of 100 mg given over 3 hours. Side effects (mainly bleeding) associated with the use of streptokinase and rt-PA are not markedly different. That the higher efficacy of rt-PA would translate into a larger reduction of mortality is suggested by the results of several small trials but remains to be confirmed in well-designed comparative clinical trials. This question has not been adequately answered by the recent International rt-PA/streptokinase mortality trial and the International Study on Infarct Survival (ISIS-3) study, because of concerns with respect to the role of conjunctive intravenous heparin administration and the dose of rt-PA used in ISIS-3. All available thrombolytic agents still have significant shortcomings, including the need for large doses to be maximally efficient, a limited fibrin specificity, and a significant associated bleeding tendency. New developments toward improved efficacy and fibrin-specificity of thrombolytic agents include the use of mutants of rt-PA, chimeric rt-PA or single chain urokinase plasminogen activator molecules, and antibody-targeted thrombolytic agents. Some of these artificial plasminogen activators have a 5- to 10-fold increased potency (thrombolytic activity per unit dose), but whether they are safe enough to be clinically useful remains to be established. The conjunctive use of anticoagulants and antiplatelet agents with thrombolytic agents increases their efficacy to an extent that monotherapy with a plasminogen activator alone is no longer tenable. Heparin and aspirin are only moderately efficient for acceleration of lysis and prevention of reocclusion, but are relatively safe. More selective thrombin inhibitors and antiplatelet agents are more potent, but their safety remains to be confirmed. Continued investigation in this area will provide new insights and promote progress toward the development of the ideal thrombolytic therapy, characterized by maximized stable coronary arterial thrombolysis with minimal bleeding.