The initial work on
thrombolytic therapy for acute
myocardial infarction (AMI) focused on intracoronary administration of
streptokinase. Continuing research has given rise to the development of both second- and third-generation agents and consequent refinements in thrombolytic regimens. Intravenous recombinant
tissue plasminogen activator (t-PA, or
alteplase) proved superior to both intracoronary and intravenous
streptokinase with regard to reperfusion efficacy and impact on survival. An accelerated dosage regimen was later devised to allow the administration of t-PA over a shorter period of time. Unfortunately, t-PA failed to lessen the risk of
bleeding complications that had plagued the use of
streptokinase. The wild-type t-PA molecule has since been modified in an attempt to achieve improved lytic characteristics with less
bleeding risk. Among these third-generation agents is
reteplase (r-PA); compared with
alteplase,
reteplase has a prolonged half-life and seems to offer more rapid thrombolysis. Promising results have been obtained in large, randomized trials of
reteplase. Another new agent is the TNK mutant of t-PA, which also has a prolonged half-life and seems to produce more rapid and complete thrombolysis, as well as less risk of intracranial
bleeding than with
alteplase in animal models. Although large, randomized trials have not yet been conducted, encouraging results have emerged from preliminary dose-ranging trials with TNK. A third new agent, n-PA, has an even longer half-life and has shown improved lytic activity in animal models. A dose-ranging trial of n-PA is currently under way. Despite the fact that each of the third-generation drugs has shown considerable potential with regard to improving the efficacy of
thrombolytic therapy, the risk of intracranial
bleeding remains problematic and will need to be assessed in large, randomized trials.