Assessment of the Safety of a New Thrombolytic: TNK-tPA - ASSENT-1
The Assessment of the Safety of a New Thrombolytic: TNK-tPA (ASSENT-1) trial was a Phase II dose-ranging trial that was designed to test the clinical safety of three different doses of tenecteplase-tissue plasminogen activator (TNK-tPA) in ST-elevation myocardial infarction (MI).
The goal of this study was to establish the clinical safety of a new fibrinolytic agent specifically with regard to identifying rates of intracranial hemorrhage and major clinical events at 30 days.
Patients Enrolled: 3,301; 3,235 received study drug
Mean Follow Up: 30 days
Mean Patient Age: mean age 60.9; 11.9% of patients >75 years old
Age ≥18 years, ischemic discomfort ≥30 minutes seen within 12 hours of onset and with ST-segment elevation of 0.1 mV in two or more contiguous leads, or new left bundle branch block associated with 0.1 mV ST-segment elevation concordant with the QRS
Prior stroke, transient ischemic attack, or central nervous system structural damage; a history of dementia or major cognitive deficit; blood pressure >180/110 mm Hg; significant bleeding disorder within six months; cardiogenic shock; treatment of acute MI with thrombolytic therapy within the previous four days; major surgery, biopsy, or trauma within three months; prolonged cardiopulmonary resuscitation within two weeks; recent noncompressible vascular puncture; previous coronary artery bypass surgery; therapeutic oral anticoagulation, pregnancy, current lactation, or absence of reliable birth control methods (for women of childbearing age); allergy to heparin or history of multiple allergies; current cocaine abuse; other serious illness; current participation in another experimental drug or device protocol; or previous treatment with TNK-tPA. The use of abciximab within the preceding 96 hours was added as an exclusion criterion in September 1996.
Rates of intracranial hemorrhage at 30 days
Other major clinical events (death, recurrent MI, total stroke, cardiac revascularization, death and nonfatal stroke, and severe and moderate bleeding) at discharge and at 30 days
Three arms, each with different doses of TNK-tPA (30 mg, 40 mg, and 50 mg) were given as a bolus intravenously.
Aspirin and heparin bolus and infusion (the dosing protocol initially started with a 5000 U heparin bolus, which was changed early in the trial to a 4000 U bolus in patients ≤67 kg).
A total of 3,235 patients were given primarily the 30 mg and 40 mg doses of TNK-tPA (the 50 mg dosing arm was eliminated after increased bleeding was identified with this dose in the parallel TIMI-10B trial). There were 48 total strokes (1.5%), with 26 in the 30 mg arm (1.5%) and 22 in the 40 mg arm (1.5%).
Intracerebral hemorrhage was seen in 25 patients overall (0.77%), with 16 in the 30 mg arm (0.94%) and nine in the 40 mg arm (0.62%). Lower rates of intracerebral hemorrhage were seen in patients treated within six hours (0.56% vs. 1.19% for >6 hours). Death, death or nonfatal stroke, and severe bleeding complications occurred in 6.4%, 7.4%, and 1.6% of patients, respectively, and were balanced across the arms of the trial (6.9%, 7.8%, and 1.8% in the 30 mg arm; 6.0%, 7.1%, and 1.4% in the 40 mg arm).
TNK-tPA administered in 30 mg and 40 mg doses as a bolus intravenously for fibrinolysis has an adequate safety profile with low overall rates of intracerebral hemorrhage and major bleeding. In conjunction with the findings of the parallel TIMI-10B angiographic efficacy trial, these findings serve as the basis for further testing of TNK in the ASSENT-2 Phase III trial of TNK versus accelerated tPA.
Van de Werf F, Cannon CP, Luyten A, et al. Safety assessment of single-bolus administration of TNK tissue-plasminogen activator in acute myocardial infarction: the ASSENT-1 Trial. The ASSENT-1 Investigators. Am Heart J 1999;137:786-91.
Keywords: Myocardial Infarction, Stroke, Intracranial Hemorrhages, Fibrinolysis, Bundle-Branch Block, Fibrinolytic Agents, Tissue Plasminogen Activator, Cerebral Hemorrhage
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