TNK-Tissue Plasminogen Activator Compared With Front-Loaded Tissue Plasminogen Activator in Acute Myocardial Infarction - TIMI 10B

Description:

The Thrombolysis in Myocardial Infarction 10B (TIMI 10B) trial was a multicenter, randomized phase II dose-ranging trial in patients with acute ST-segment elevation myocardial infarction (MI) designed to compare prospectively the angiographic efficacy and safety of several doses of tumor necrosis factor-tissue plasminogen activator (TNK-tPA) with tPA.

Hypothesis:

The goal of the study was to identify a specific bolus dosing regimen of TNK-tPA that would achieve similar rates of TIMI-3 flow on 90-minute angiography as tPA, with a similar safety profile.

Study Design

Study Design:

Patients Enrolled: 886
Mean Patient Age: Mean 59.6
Female: 24

Patient Populations:

Presence of ischemic pain lasting ≥30 minutes, associated with ST-segment elevation ≥0.1 mV in ≥2 contiguous leads, and the ability to be randomized within 12 hours of symptom onset. An amendment during the trial added an upper age limit of 80 years.

Exclusions:

Prior stroke, transient ischemic attack, or central nervous system structural damage; 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 (including head trauma associated with the presenting MI) within three months; prolonged (>2 minutes) cardiopulmonary resuscitation within two weeks; recent noncompressible vascular puncture; previous coronary artery bypass graft; inability to undergo cardiac catheterization; therapeutic oral anticoagulation; pregnancy, lactation, or women of childbearing potential not using adequate birth control; allergy to heparin or history of multiple allergies; cocaine abuse; other serious illness; participation in another protocol; previous treatment with TNK-tPA; inability to follow the protocol; or any other condition that the investigator felt would pose a significant hazard to the patient. The use of abciximab within the preceding 96 hours was added in an amendment.

Primary Endpoints:

Rate of TIMI 3 grade flow at 90 minutes

Secondary Endpoints:

Rate of TIMI 3 grade flow at 60 and 75 minutes, TIMI 2 or 3 flow at all time points, pharmacokinetics, coagulation parameters, recurrent MI, and serious bleeding

Drug/Procedures Used:

At the start of the trial, there were three arms: TNK 30 mg bolus, TNK 50 mg bolus, and front-loaded tPA (0.75 mg/kg up to 50 mg over 30 minutes, followed by 0.5 mg/kg up to 35 mg over 60 minutes). The 50 mg dose of TNK was suspended during the course of the trial, and a TNK 40 mg bolus arm was added, due to the recommendation of the Data Safety and Monitoring Board.

Concomitant Medications:

Aspirin and Heparin. Beta-blockers were recommended.

Heparin dosing was initially at the physician’s discretion based on a nomogram, but an amendment to the protocol instituted after supratherapeutic heparin doses was found and specified a weight-based dosing (for >67 kg, 5000 U bolus and 1000 U/h infusion; for ≤67 kg, 4000 U bolus, and 800 U/h infusion). Patients undergoing rescue percutaneous coronary intervention had activated clotting times titrated to 300 seconds, with additional bolus heparin.

Principal Findings:

A total of 886 patients were randomized. The median time from onset of symptoms to treatment was 2.9 hours, and the groups were well-balanced overall. TNK 40 mg and 50 mg produced similar rates of TIMI 3 flow to tPA (62.8% for 40 mg dose and 65.8% for 50 mg dose vs. 62.7% for tPA, p=NS), but the 30 mg dose had a lower rate of TIMI 3 flow (54.3%, p=0.035 for comparison with tPA). Similar results were seen when the endpoint of combined TIMI 2 or 3 flow was compared, and there were no differences seen when the analyses were compared before and after the protocol amendment (lowering the dose of heparin) was made. The half-life of TNK was longer than that of TPA, and there was less fibrinogen depletion with TNK.

There was a dose-response relationship between TNK dosing and serious bleeding and intracranial hemorrhage (the 50 mg dose of TNK was suspended due to three intracranial hemorrhages in patients treated with that dose). Overall, rates of intracranial hemorrhage were 1.0% for 30 mg TNK, 1.9% for 40 mg TNK, 3.8% for 50 mg TNK, and 1.9% for tPA. There were no significant differences between TNK and tPA with regard to mortality or reinfarction.

Interpretation:

The Phase II dose-ranging trials TIMI 10B and ASSENT-1 were conducted in conjunction to test both the angiographic efficacy (TIMI 10B) and overall safety (ASSENT-1) of TNK-tPA. In TIMI 10B, there was a dose-response in the association of higher rates of TIMI 3 flow, as well as bleeding complications with increasing doses of TNK. The 40 mg dose of TNK demonstrated similar efficacy and safety to tPA, and overall bleeding was reduced with the institution of lower heparin dosing in all arms. Based on a prespecified weight-adjusted dosing analysis, an optimal dose of TNK of approximately 0.5 mg/kg was selected for further testing in the Phase III ASSENT-2 trial.

References:

Cannon CP, Gibson CM, McCabe CH, et al. TNK-tissue plasminogen activator compared with front-loaded alteplase in acute myocardial infarction: results of the TIMI 10B trial. Thrombolysis in Myocardial Infarction (TIMI) 10B Investigators. Circulation 1998;98:2805-14.

Clinical Topics: Anticoagulation Management, Dyslipidemia, Lipid Metabolism

Keywords: Myocardial Infarction, Intracranial Hemorrhages, Half-Life, Tumor Necrosis Factors, Heparin, Coronary Disease, Fibrinolytic Agents, Pain, Fibrinogen, Tissue Plasminogen Activator


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