Weight-adjusted dosing of TNK-tissue plasminogen activator and its relation to angiographic outcomes in the thrombolysis in myocardial infarction 10Btrial

Fixed doses of thrombolytic agents are generally administered to patients o f varying body weights, and the dose-response relation may be confounded by the variability in patient weight. We hypothesized that higher doses of TN K-tissue plasminogen activator (tPA) per unit body weight would be related to improved flow at 90 minutes after thrombolytic administration, A fetal o f 886 patients with acute myocardial infarction were randomized to receive either a single bolus of 30, 40, or 50 mg of TNK-tPA or front-loaded tPA in the Thrombolysis In Myocardial Infaction (TIMI) 10B trial. The dose of TNK -tPA administered was divided by the patient's weight to arrive at the TNK- tPA dose (mg) per unit body weight (kg), and patients were stratified into tertiles based on mg/kg of TNK-tPA: low dose, 0.2 to 0.39 mg/kg; mid-dose, 0.40 to 0.51 mg/kg; high dose, 0.52 to 1.24 mg/kg. Flow in the culprit and nonculprit arteries was analyzed using the TIMI flow grades and the correct ed TIMI frame count (CTFC). The median CTFC in culprit arteries differed be tween the tertiles (3-way p = 0.007), with the CTFC being 7.2 frames faster in high-dose than in low-dose patients (43.1 +/- 30.1, median 31.2, n = 17 1 vs 54.6 +/- 34.8, median 38.4, n = 166, 2-way p 0.002). patients in the m id- and high-dose tertiles achieved patency more frequently (TIMI grade 2 o r 3 flow) by 60 minutes (p = 0.02), and the 90-minute percent diameter sten osis was less severe in patients in the high- versus low-dose tertile (p = 0.03). In nonculprit arteries, the CTFC was faster in high- than in low-dos e tertiles (29.6 +/- 13.4, median 26.9, n = 130 vs 34.7 +/- 16.3, median 32 .8, n = 108, 3-way p = 0.03, 2-way p = 0.008). In patients who underwent pe rcutaneous transluminal coronary angioplasty (PTCA), the CTFC in culprit ar teries after PTCA was fastest in the high- and mid-dose tertiles than in th ose receiving low doses (2-way p = 0.05), Thus, higher doses per unit body weight of TNK-tPA result in not only faster culprit artery flow, but also f aster nonculprit, global, and post-PTCA flow, which may reflect earlier ope ning, reduced stunning, or improved microvascular function. The greater eff ectiveness of thrombolysis must be weighed against any increase in risk. (C ) 1999 by Excerpta Medica, Inc.