Assessment of the Safety of a New Thrombolytic: TNK-tPA - ASSENT-1

Description:

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).

Hypothesis:

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.

Study Design

Study Design:

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
Female: 24

Patient Populations:

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

Exclusions:

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.

Primary Endpoints:

Rates of intracranial hemorrhage at 30 days

Secondary Endpoints:

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

Drug/Procedures Used:

Three arms, each with different doses of TNK-tPA (30 mg, 40 mg, and 50 mg) were given as a bolus intravenously.

Concomitant Medications:

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).

Principal Findings:

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).

Interpretation:

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.

References:

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.

Clinical Topics: Arrhythmias and Clinical EP, Dyslipidemia, EP Basic Science, Lipid Metabolism

Keywords: Myocardial Infarction, Stroke, Intracranial Hemorrhages, Fibrinolysis, Bundle-Branch Block, Fibrinolytic Agents, Tissue Plasminogen Activator, Cerebral Hemorrhage


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