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Hirudin for Improvement of Thrombolysis - HIT-III
Description:
The HIT-III trial was a prospective, randomized, double-blind multicenter trial designed to compare a recombinant hirudin (HBW 023) with heparin as adjuncts to thrombolysis in patients with acute myocardial infarction and to investigate the safety of hirudin therapy and its effects on mortality, reinfarction, and major bleeding.
Study Design
Study Design:
Patients Enrolled: 302
Mean Follow Up: 30 days
Patient Populations:
Male and female patients with acute MI and age >18 years with chest pain indicative of myocardial infarction with onset of symptoms within 6 hours
Exclusions:
Contraindications to thrombolysis and renal insufficiency.
Primary Endpoints:
Composite of 30-day mortality and in-hospital reinfarction rates.
Secondary Endpoints:
Incidence of stroke (hemorrhagic or ischemic), of other major bleeding and of cardiac morbidity.
Drug/Procedures Used:
Each patient was given a bolus of either hirudin (0.4 mg/kg body wt) or heparin (70 IU/kg body wt). Thrombolytic therapy with rTPA (Actilyse (alteplase) was given according to standard protocol (15 mg rTPA was given as IV bolus followed by 50 mg over 30 minutes and another 35 mg over the next 60 minutes). As soon as the thrombolytic infusion had been started, the blinded infusion of hirudin (0.15 mg x kg body wt sup -1 x h sup -1) or heparin (15 IU x kg body wt sup -1 x h sup -1) was started. The IV infusion of the trial medication was continued for at least 48 hours but could be prolonged up to 72 hours in patients with ongoing symptoms of cardiac ischemia.
Principal Findings:
On the recommendation of the Safety Committee, patient recruitment was terminated after inclusion of 302 patients (n=148 in the hirudin group, n=154 in the heparin group), due to an imbalance in the incidence of major bleeding events. Subsequently, results were focused on the incidence of major adverse cerebrovascular events and major bleeding (secondary end points). During the in-hospital/observation period, mortality was 8.8% in the hirudin group and 3.9% in the heparin group (P=0.1). There were nine cardiac deaths (6.1%) and four additional deaths due to hemorrhagic stroke (2.7%) in the hirudin group whereas in the heparin group, five deaths were due to cardiac causes (3.2%) (p=0.28). There were five strokes in the hirudin group, four of them hemorrhagic strokes. Four of these events were fatal. In the heparin group, two ischemic strokes occurred, one of which was fatal. The overall stroke rate was 3.4% in the hirudin group and 1.3% in the heparin group (P=0.27). All hemorrhagic strokes occurred within 24 hours whereas the ischemic strokes occurred on days 2 and 17. There were eight other major bleeding events, five of which occurred in the hirudin group (3.4%) and three in the heparin group (1.9%). Baseline median aPTT values in patients with bleeding events were comparable to those without bleeding.
Interpretation:
Among patients with acute MI, adjunctive treatment with hirudin was associated with a high rate of intracerebral bleeding. The study was terminated early secondary to the increased risk of adverse effects.
References:
Neuhaus KL, et al. Safety Observations From the Pilot Phase of the Randomized r-Hirudin for Improvement of Thrombolysis (HIT-III) Study. Circulation 1994; 90(4):1638-1642.
Keywords: Hirudin Therapy, Thrombolytic Therapy, Myocardial Infarction, Stroke, Chest Pain, Heparin, Recombinant Proteins, Fibrinolytic Agents, Tissue Plasminogen Activator, Hirudins
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