METHODS AND RESULTS: At 275 participating hospitals in 12 countries, patients within 12 hours from the onset of ischemic chest discomfort with an abnormal ECG were randomly assigned to receive a 72- to 120-hour infusion of
heparin (5000-U bolus and 1000- to 1300-U/h infusion, adjusted to activated partial thromboplastin time (APTT) of 60 to 90 seconds or
hirudin (0.6-mg/kg bolus and 0.2-mg/kg per hour infusion without aPTT adjustment) on a double-blind basis. Although recruitment of 12,000 patients was planned, the trial was stopped earlier because of an excess of intracerebral hemorrhagic events after 2564 patients were enrolled. The overall incidence of
hemorrhagic stroke tended to be higher for patients receiving
hirudin (1.3%) compared with
heparin (0.7%),
P = .11, but the incidence was significantly higher in patients receiving
thrombolytic therapy (1264 patients, 1.8%) compared with those who did not (1168 patients, 0.3%), P < .001. The
hemorrhagic stroke rate varied by the thrombolytic and
antithrombin combination:
tissue-type plasminogen activator and
heparin, 0.9%; with
hirudin, 1.7%;
streptokinase with
heparin, 2.7%; with
hirudin, 3.2%. All these rates are higher than the overall incidence of
hemorrhagic stroke in the patients receiving
thrombolytic therapy and intravenous
heparin in the GUSTO I trial (30,892 patients with rate of 0.7%, 95% CI of 0.6 to 0.8%). Among the 26 patients who had
intracerebral hemorrhages, the aPTT was significantly elevated compared with the event-free patients (110 +/- 46 versus 87 +/- 36 seconds at 12 hours of
therapy, respectively), P = .03.
CONCLUSIONS: