Comparative fibrinolytic activity of front-loaded alteplase and the single-bolus mutants tenecteplase and lanoteplase during treatment of acute myocardial infarction

Background Quantification of fibrinolytic activity (FAct) in clinical practice has been abandoned because of the complexity of existing assays. The relationship between thrombolytic drug concentration and FAct is complex. FAct profiles of currently used thrombolytic drugs were not characterized. Methods By use of a system that quantifies FAct by shortening of clot lysis onset time (LOT), we measured LOT in vitro with incremented concentrations of alteplase (t-PA) and tenecteplase (TNK-tPA) and ex vivo in patients with acute myocardial infarction who were receiving front-loaded t-PA (n = 3 1), 30 to 40 mg TNK-tPA (n = 19), and 120 kU/kg lanoteplase ([n-PA] n = 23). Results In vitro, FAct depended on drug concentration by means of a double exponential model revealing 2 distinct activity zones (weak/strong). Ex vivo, no FAct was detected before agent administration (LOT > 1200 seconds). Ten minutes after a bolus was given, FAct was sharply increased in all patients, but it increased more with TNK-tPA than with t-PA or n-PA (mean LOT of 109, 125, and 130 seconds, respectively, P < .05). At 90 minutes, accelerated infusion of t-PA resulted in FAct that remained stronger than that observed for TNK-tPA (P < .0001) or n-PA (P = .011). At 180-minutes, significant FAct (LOT <600 seconds) was only observed in patients who received n-PA. Conclusion This study provides the first direct comparison of FAct between t-PA, TNK-tPA, and n-PA by use of the LOT test, the results of which are reliably related to drug concentration. The ideal FAct profile would combine an immediate strong FAct of relatively short duration, as seen with TNK-tPA, that may contribute to its better efficacy/safety profile in the Assessment of Safety and Efficacy of a New Thrombolytic Agent-2 (ASSENT-2) trial. Prolonged FAct after n-PA may contribute to increased hemorrhagic complications, as seen in the Intravenous n-PA for Treatment of Infarcting Myocardium Early-2 (InTIME-2) trial. Thus, characterizing FAct profiles might provide insights in developing more efficient thrombolytic regimens.