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(Circulation. 1997;95:351-356.)
© 1997 American Heart Association, Inc.
Articles |
TNK-Tissue Plasminogen Activator in Acute Myocardial Infarction
Results of the Thrombolysis in Myocardial Infarction (TIMI) 10A Dose-Ranging Trial
the Cardiovascular Division, Department of Medicine, Brigham and Women's Hospital and Harvard Medical School, Boston, Mass (C.P.C., C.H.M., E.B.); West Roxbury Veterans Administration Medical Center, West Roxbury, Mass (C.M.G.); Iowa Heart Center (Des Moines) (M.G.); Jackson Memorial Hospital, Miami, Fla (R.F.S.); Rhode Island Hospital, Providence, RI (G.R.M.); Genentech Inc, South San Francisco, Calif (J.B., N.B.M., N.L.F., T.W.L.); and University of Vermont (Colchester) (R.P.T.).
Correspondence to Eugene Braunwald, MD, Department of Medicine, Brigham and Women's Hospital, 75 Francis St, Boston, MA 02115. E-mail timi{at}bwh.harvard.edu
Background TNK-tissue plasminogen activator (TNK-TPA) is a genetically engineered variant of TPA, which in experimental models has a slower plasma clearance and greater fibrin specificity and is 80-fold more resistant to plasminogen activator inhibitor-1 than alteplase TPA.
Methods and Results The Thrombolysis in Myocardial Infarction (TIMI) 10A trial was a Phase 1, dose-ranging pilot trial designed to evaluate the pharmacokinetics, safety, and efficacy of TNK-TPA in patients with acute myocardial infarction. One hundred thirteen patients with acute ST-segment elevation myocardial infarction presenting within 12 hours and without contraindications to thrombolysis were enrolled and treated with a single bolus of TNK-TPA over 5 to 10 seconds with doses ranging from 5 to 50 mg. TNK-TPA demonstrated a plasma clearance of 151±55 mL/min and a half-life of 17±7 minutes. Comparable values for wild-type TPA are 572±132 mL/min and 3.5±1.4 minutes, respectively. Systemic fibrinogen and plasminogen levels fell by only 3% and 13%, respectively, at 1 hour after TNK-TPA administration. TIMI grade 3 flow at 90 minutes was achieved in 57% to 64% of patients at the 30- to 50-mg doses. Seven patients (6.2%) experienced a major hemorrhage, which occurred at a vascular access site in six patients.
Conclusions TNK-TPA has a prolonged half-life so it can be administered as a single bolus. TNK-TPA appears to be very fibrin specific, and the initial patency and safety profiles are encouraging. Further study of this new thrombolytic agent is ongoing.
Key Words: myocardial infarction • thrombolysis • reprefusion • plasminogen activators
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