Thrombolysis and Thrombin Inhibition in Myocardial Infarction 9A Trial - TIMI 9A
The TIMI 9A trial compared the efficacy and safety of intravenous hirudin, a direct-acting thrombin inhibitor, with heparin as adjunctive therapy to thrombolysis and aspirin in patients with acute myocardial infarction.
Patients Enrolled: 757
Mean Follow Up: 30 days
Mean Patient Age: >=21 years
acute MI with >=0.1 mV ST elevation in >=2 ECG leads; presentation within 12 hours of onset of ischemic discomfort; no contraindications to thrombolytic therapy (active bleeding, history of stroke, major surgery within 2 months, blood pressure >190/110 mm Hg despite medical therapy); age >=21 years
recent surgery recent trauma excess bleeding risk
Safety endpoint: major hemorrhage or anaphylaxis Efficacy endpoint: any of the following by 30 days: death, recurrent MI, development of CHF/cardiogenic shock, left ventricular ejection fraction <40%
All patients received 150-325 mg aspirin immediately and daily thereafter. Patients were treated with thrombolytic therapy (front loaded, weight-adjusted tPA or 1.5 million U SK at the treating physician's discretion). Patients were randomized to heparin or hirudin. Hirudin dosing was 0.6 mg/kg followed by a 96 hour infusion of 0.2 mg/kg/h. Heparin dosing was 5000 U bolus with infusion of 1000 U/h for patients <80 kg and 1300 U/h for patients >=80 kg with titration to a target activated partial thromboplastin time (aPTT) of 60 to 90 seconds..
Randomization in TIMI 9A was suspended after 757 patients had been enrolled due to higher than expected rates of hemorrhage in both treatment arms. ICH occurred in 1.7% of patients in the hirudin arm and 1.9% of those in the heparin arm (p=NS). Major hemorrhage occurred in 13.9% of hirudin treated patients and 10.1% of heparin patients (p=NS). This was higher than the major hemorrhage rate in other clinical trials with similar treatment strategies: TIMI 5 (tPA plus heparin/hirudin) and TIMI 6 (SK plus heparin/hirudin). The rate of major spontaneous hemorrhage at a nonintracranial site was more frequent in hirudin patients than in heparin patients (7.0% vs 3.0%, p=0.02). Patients who developed a major hemorrhage were older (mean 68 yrs vs 61 yrs, p<0.001), had lower body weight (p<0.001), were more often women (p=0.03) and had higher aPTT values in the first 12 hours after thrombolysis (100 sec vs 85 sec, p=0.001). The thrombolytic used in nearly 85% of patients was tPA. Permanent discontinuation of the study drug was required in 23% of patients.
Due to the higher than expected rate of hemorrhage and the need for discontinuation of the study drug in one-quarter of patients, it appears the dose of both heparin and hirudin used in this trial was too high when used as an adjunct to thrombolytic and aspirin. Since higher a aPTT was associated with a higher risk of hemorrhage in both arms, this study demonstrated the need for frequent monitoring of aPTT when using either heparin or hirudin to detect patients who require downward titration of the infusion. As a result of the TIMI 9A trial, TIMI 9B was designed to use a lower hirudin bolus (0.1 mg/kg) and infusion (0.1 mg/kg/h) and lower heparin infusion (1000 U/h without weight adjustment). Both antithrombotic agents were also titrated using a lower aPTT target range in TIMI 9B (55 to 85 seconds).
Keywords: Thrombolytic Therapy, Myocardial Infarction, Stroke, Thrombin, Platelet Aggregation Inhibitors, Body Weight, Heparin, Blood Pressure, Fibrinolytic Agents, Electrocardiography, Hirudins, Streptokinase, Partial Thromboplastin Time, Tissue Plasminogen Activator, Hemorrhage
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