RANDOMIZED TRIAL OF INTRAVENOUS HEPARIN VERSUS RECOMBINANT HIRUDIN FOR ACUTE CORONARY SYNDROMES

Background Although intravenous heparin is routinely used in the treat ment of patients with acute coronary syndromes, this anticoagulant req uires antithrombin III as a cofactor, has no affinity to clot-bound th rombin, and is bound or inactivated by several plasma proteins and pla telet factor 4. Recombinant hirudin, the prototypic direct thrombin in hibitor, has been demonstrated in pilot studies to yield improved angi ographic and clinical outcomes compared with heparin. We compared thes e two antithrombins in a large-scale randomized trial. Methods and Res ults At 275 participating hospitals in 12 countries, patients within 1 2 hours from the onset of ischemic chest discomfort with an abnormal E CG were randomly assigned to receive a 72- to 120-hour infusion of hep arin (5000-U bolus and 1000- to 1300-U/h infusion, adjusted to activat ed 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 adjustmen t) on a double-blind basis. Although recruitment of 12 000 patients wa s planned, the trial was stopped earlier because of an excess of intra cerebral hemorrhagic events after 2564 patients were enrolled. The ove rall incidence of hemorrhagic stroke tended to be higher for patients receiving hirudin (1.3%) compared with heparin (0.7%), P = .11, but th e incidence was significantly higher in patients receiving thrombolyti c therapy (1264 patients, 1.8%) compared with those who did not (1168 patients, 0.3%), P < .001. The hemorrhagic stroke rate varied by the t hrombolytic and antithrombin combination: tissue-type plasminogen acti vator and heparin, 0.9%; with hirudin, 1.7%; streptokinase with hepari n, 2.7%; with hirudin, 3.2%. All these rates are higher than the overa ll incidence of hemorrhagic stroke in the patients receiving thromboly tic therapy and intravenous heparin in the GUSTO I trial (30 892 patie nts with rate of 0.7%, 95% CI of 0.6 to 0.8%). Among the 26 patients w ho had intracerebral hemorrhages, the aPTT was significantly elevated compared with the event-free patients (110 +/- 46 versus 87 +/- 36 sec onds at 12 hours of therapy, respectively), P = .03. Conclusions At th e dose of hirudin tested, there was a trend of an excess of hemorrhagi c stroke compared with heparin. Heparin, at a slightly higher dose tha n previously used in a large-scale trial (approximately 20% increase) was accompanied by a twofold risk of hemorrhagic stroke in patients re ceiving thrombolytic therapy. With both thrombin inhibitors, the aPTT appears to be a useful index for predicting risk of hemorrhagic stroke in patients receiving thrombolytic therapy.