The ideal fibrinolytic: can drug design improve clinical results?

Thrombolytic therapy has been a major milestone in the management of acute myocardial infarction. By restoring patency in the infarct-related vessel, early administration of thrombolytic therapy reduces the extent of myocardial damage, lowers the risk of morbidity, and prolongs survival. Importantly, however, the available thrombolytic agents have several limitations that may result in less than optimal outcomes. For instance, depending on the agent, only 30% to 60% of patients achieve TIMI (Thrombolysis in Myocardial Infarction) grade 3 flow at 90 min with the current regimens. The 30-day mortality rate has averaged 6 to 8% in clinical trials and is likely to be much higher in the practice setting. The rate of reinfarction stands at 4%. The risk of bleeding remains a concern as well, with the rate of intracranial haemorrhage averaging 0·5% to 0·9% and the rate of transfusion more than 2%. Another key issue is the need for more convenient administration. Because of their rapid clearance, both tissue type plasminogen activator and streptokinase must be administered by continuous intravenous infusion. To try to overcome these drawbacks, several newer thrombolytic therapies have been developed. The development of the second-generation agent, reteplase, was a first attempt. Clinical trials of equivalence have demonstrated that reteplase is at least as effective as streptokinase, but have failed to demonstrate superiority over the current gold standard therapy, accelerated tissue type plasminogen activator. Although reteplase can be given in two intravenous bolus doses, they must be administered precisely 30 min apart, somewhat mitigating convenience of administration.