New developments in thrombolytic therapy

Abstract

Thrombotic complications of cardiovascular disease are a main cause of death and disability and, consequently, thrombolysis could favorably influence the outcome of such life-threatening diseases as myocardial infarction, cerebrovascular thrombosis and venous thromboembolism. Thrombolytic agents are plasminogen activators that convert plasminogen, the inactive proenzyme of the fibrinolytic system in blood, to the proteolytic enzyme plasmin. Plasmin dissolves the fibrin of a blood clot, but may also degrade normal components of the hemostatic system and predispose to bleeding. Currently, five thrombolytic agents are either approved for clinical use or under clinical investigation in patients with acute myocardial infarction. These include streptokinase, urokinase, recombinant tissue-type plasminogen activator (rt-PA), anisoylated plasminogen streptikinase activator complex (APSAC) and single chain urokinase-type plasminogen activator (scu-PA, prourokinase). The first generation thrombolytic agents, streptokinase (and probably also urokinase), are only moderately efficacious and their administration is associated with extensive systemic fibrinogen breakdown. In comparative studies performed in patients with acute myocardial infarction, recombinant tissue-type plasminogen activator (rt-PA) is a more effective and fibrin-specific thrombolytic agent than streptokinase. The acylated plasminogen streptokinase activator complex (APSAC) has a profile of thrombolytic efficacy and fibrin-specificity that is similar or somewhat better than that of streptokinase, but has the advantage that it can be administered by bolus injection. Single chain urokinase-type plasminogen activator is more fibrin-specific than urokinase. Comparative data on the efficacy and safety of this agent are limited as it is in the early stage of clinical investigation. Reduction of infarct size, preservation of ventricular function and/or reduction in mortality has been observed with streptokinase, rt-PA and APSAC. Therefore, thromboyltic therapy will probably become routine therapy for early acute myocardial infarction. In patients with acute myocardial infarction, intravenous streptokinase recanalizes 40–45 percent of occluded coronary arteries and reduces mortality by 25 percent; it costs approximately $ 200 for a therapeutic dose of 1,500,000 units. Recombinant tissue-type plasminogen activator (rt-PA) is more potent for coronary arterial thrombolysis, producing both more rapid and more frequent (65–70 percent) reperfusion, but it costs over $ 1,000 for a therapeutic dose of 100 mg. Side effects (mainly bleeding) and the incidence of reocclusion associated with the use of streptokinase and rt-PA are not markedly different. Whether the higher efficacy of rt-PA will translate into a comparably larger reduction of mortality remains to be determined in large comparative clinical trials. Both agents are available for clinical use. The choice of agent for the treatment of acute myocardial infarction at present must be based on considerations of lower cost of streptokinase versus the higher efficacy for coronary recanalization of rt-PA. Recent reviews of thrombolytic agents have reached apparently contradictory conclusions with respect to the comparative properties of thrombolytic agents (1–3). In particular, the data on the relative efficacy for coronary thrombolysis, the speed of reperfusion, the frequency of reocclusion, the occurrence of bleeding complications, and the impact on mortality have been presented and interpreted differently. All available thrombolytic agents still suffer significant shortcomings, including the need for large doses to be therapeutically efficient, a limited fibrin-specificity and residual toxicity in terms of bleeding complications. New developments towards further improved efficacy and fibrin-specificity of thrombolytic therapy include the use of combinations of synergistic thrombolytic agents, mutants of t-PA and scu-PA, chimeric t-PA/scu-PA molecules, antibody-targeted thrombolytic agents, and/or combinations of fibrin-dissolving agents with anti-platelet strategies. In this communication, we will briefly review the components of the fibrinolytic system, the mechanism of fibrin-specific thrombolysis, the present state of clinical trials with thrombolytic agents in acute myocardial infarction, and finally, new trends in thrombolytic therapy.