Background Coronary artery thrombosis plays an important pathophysiological role in unstable angina and non-Q-wave myocardial infarction. To date, heparin and thrombolytic therapy has not provided complete or consistent benefit. We hypothesized that recombinant hirudin, a direct thrombin inhibitor, would prevent accumulation of coronary artery thrombus in a manner superior to heparin.=60% stenosis of a culprit coronary artery or saphenous vein graft with visual appearance of thrombus were randomized to one of two different doses of heparin (either a target activated partial thromboplastin time (aPTT) of 65 to 90 or 90 to 110 seconds) or one of four doses of hirudin (0.05, 0.10, 0.20, or 0.30 mg x kg sup -1 x h sup -1 infusion) in a dose-escalating protocol. After 72 to 120 hours of study drug, a repeat coronary angiogram was obtained, and the paired studies underwent quantitative analysis. The primary end point was change in the average cross-sectional area of the culprit lesion. Other efficacy end points also involved changes in culprit lesion dimensions and TIMI flow grade. Recombinant hirudin led to a dose-dependent elevation of aPTT that appeared to plateau at the 0.2-mg/kg dose. A higher proportion of hirudin-treated patients had their aPTT within a 40-second range (16% heparin versus 71% hirudin, P<.001). Overall, the 116 patients treated with hirudin tended to show more improvement than the 50 patients receiving heparin relative to the primary efficacy variable--the average cross-sectional area (P=.08)--as well as minimal cross-sectional area (P=.028), minimal luminal diameter (P=.029), and percent diameter stenosis (P=.07).Conclusions Recombinant hirudin appears to be a promising antithrombotic intervention compared with heparin for inhibition of coronary artery thrombus. Large-scale comparative trials are warranted. (Circulation. 1994;89:1557-1566.)