Weight-Adjusted Dosing of TNK-Tissue Plasminogen Activator and Its Relation to Angiographic Outcomes in the Thrombolysis In Myocardial Infarction 10B Trial C. Michael Gibson, MD, Christopher P. Cannon, MD, Sabina A. Murphy, MPH, A.A. Jennifer Adgey, MD, Marc J. Schweiger, MD, Rafael F. Sequeira, MD, Gilles Grollier, MD, Norma Lynn Fox, PhD, Silvano Berioli, MD, W. Douglas Weaver, MD, Frans Van de Werf, MD, and Eugene Braunwald, MD, for the TIMI 10B Investigators Fixed doses of thrombolytic agents are generally admin- istered to patients of varying body weights, and the dose-response relation may be confounded by the vari- ability in patient weight. We hypothesized that higher doses of TNK-tissue plasminogen activator (tPA) per unit body weight would be related to improved flow at 90 minutes after thrombolytic administration. A total of 886 patients with acute myocardial infarction were random- ized 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 corrected TIMI frame count (CTFC). The median CTFC in culprit arteries differed between 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  171 vs 54.6  34.8, median 38.4, n  166, 2-way p  0.002). Patients in the mid- and high-dose tertiles achieved patency more frequently (TIMI grade 2 or 3 flow) by 60 minutes (p  0.02), and the 90-minute percent diameter stenosis 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-dose 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 percutaneous transluminal coronary angioplasty (PTCA), the CTFC in culprit arteries after PTCA was fastest in the high- and mid-dose tertiles than in those 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 faster nonculprit, global, and post-PTCA flow, which may reflect earlier opening, reduced stunning, or improved microvascular function. The greater effective- ness of thrombolysis must be weighed against any in- crease in risk. 1999 by Excerpta Medica, Inc. (Am J Cardiol 1999;84:976 –980) I n dose-finding thrombolytic trials, several fixed doses of a thrombolytic agent are usually adminis- tered. 1–3 Within each dose regimen, however, the body weight may vary significantly among patients which may confound ascertainment of a dose-re- sponse relation. For instance, a 50-kg patient admin- istered a 30-mg dose of a thrombolytic agent might respond with greater efficacy to this relatively small dose than a 100-kg patient administered a higher dose of 40 mg because of the higher dose per unit body weight administered to the 50-kg patient (dose/ weight = 0.6 vs 0.4 mg/kg). The Thrombolysis In Myocardial Infarction (TIMI) 10B trial was a dose- ranging trial with the new bolus thrombolytic, TNK- tissue plasminogen activator (tPA). 2 To examine the dose-response relation with greater precision, the dose of TNK-tPA per unit body weight (kg) was deter- mined, and patients were stratified into tertiles. We hypothesized that higher doses of TNK-tPA per unit body weight would be related to improved indexes of coronary perfusion such as the corrected TIMI frame From the Cardiovascular Division, Department of Medicine, Allegheny General Hospital, Pittsburgh, Pennsylvania; Brigham and Women’s Hospital and Harvard Medical School, Boston, Massachusetts; Royal Victoria Hospital, Belfast, Northern Ireland, United Kingdom; Baystate Medical Center, Springfield, Massachusetts; University of Miami/ Jackson Memorial Hospital, Miami, Florida; CHU Cote de Nacre, Caen, France; Genentech Inc., South San Francisco, California; Boehringer Ingelheim, Milano, Italy; Henry Ford Hospital, Detroit, Michigan; and University Hospitals Leuven, Leuven, Belgium. This study was supported in part by Genentech, Inc. South San Francisco, California and Boehringer Ingelheim GmbH, Ingelheim Rhein, Ger- many. Manuscript received February 24, 1999; revised manuscript received and accepted May 24, 1999. Address for reprints: C. Michael Gibson, MS, MD, Allegheny General Hospital, 320 East North Avenue, Pittsburgh, Pennsylvania 15212. E-mail: perfuse@concentric.net. 976 ©1999 by Excerpta Medica, Inc. All rights reserved. 0002-9149/99/$–see front matter The American Journal of Cardiology Vol. 84 November 1, 1999 PII S0002-9149(99)00483-X