Can we improve on front-loaded alteplase (r-TPA)?

The method of administration of alteplase has evolved since its introduction to clinical practice in the late 1980s. The initial dosage regimen of a graded administration of 100 mg was replaced by the front- loaded weight adjusted regimen, the efficacy of which was demonstrated in the GUSTO 1 trial. Double bolus administration was shown to achieve superior TIMI 3 patency of the infarct related artery in a small angiographic study, but the COBALT trial failed to show equivalence and indeed showed a slightly higher mortality and incidence of stroke, so cannot be recommended. Reteplase, a deletion mutant of alteplase, also showed superior efficacy in achieving coronary patency but no clinical superiority in outcomes in the 15,000 patient GUSTO 3 trial. The case of administration of reteplase, however, has some attraction as an alternative to alteplase. Trials of newer agents based on further modifications of alteplase are ongoing, but at present the front-loaded alteplase regimen remains the standard for clinical practice.