New developments in thrombolytic therapy

Abstract

Thrombotic complications of cardiovascular disease are a main cause of death and disability and, consequently, thrombolytic therapy with plasminogen activators could favorably influence the outcome of such life-threatening diseases as acute myocardial infarction (AMI). Five thrombolytic agents are either available or under clinical investigation: streptokinase (SK), urokinase (UK), recombinant tissue-type plasminogen activator (rt-PA), anisoylated plasminogen streptokinase activator complex (APSAC) and single chain urokinase-type plasminogen activator (scu-PA, pro-urokinase). The first generation thrombolytic agents, SK (and probably also UK), are only moderately efficacious; rt-PA is a more effective and fibrin-specific thrombolytic than SK; APSAC has a thrombolytic efficacy and fibrin-specificity that is probably similar or somewhat superior to that of SK and can be administered by bolus injection; scu-PA is more fibrin-specific than UK but it is only in the early stage of clinical investigation. Reduction of infarct size, preservation of ventricular function and/or reduction in mortality has been observed with SK, rt-PA and APSAC, but comparative trials with mortality endpoints are not yet available. Intravenous SK recanalizes 40-45 percent of occluded coronary arteries in patients with AMI and reduces mortality by 25 percent. rt-PA produces both more rapid and more frequent (65-70 percent) reperfusion. The choice of agent for the treatment of AMI at present must be based on considerations of lower cost of streptokinase versus higher efficacy for coronary recanalization of rt-PA. All available thrombolytic agents suffer shortcomings, including submaximal efficacy, limited fibrin-specificity and bleeding side effects. New developments towards improved efficacy and fibrin-specificity include combinations of synergistic thrombolytic agents, mutants of t-PA or scu-PA, chimeric t-PA/scu-PA molecules, antibody-targeted thrombolytic agents, and/or combinations of fibrin-dissolving agents with anti-platelet strategies.