RECOMBINANT HIRUDIN IN PATIENTS WITH CHRONIC, STABLE CORONARY-ARTERY DISEASE - SAFETY, HALF-LIFE, AND EFFECT ON COAGULATION PARAMETERS

Background. Because the specific antithrombin hirudin prevents platele t-rich arterial thrombus and accelerates thrombolysis in a variety of animal models, it has promise as antithrombotic therapy. We therefore studied the half-life, effect on anticoagulant parameters, and safety of hirudin in patients with coronary artery disease. Methods and Resul ts. Thirty-eight men and 1 woman (age [mean+/-SD], 60.4+/-6.9 years) w ith angiographic coronary disease were allocated in a single-blind asc ending dosage study to a 6-hour IV infusion of recombinant hirudin (CG P 39 393) or matching placebo. The median terminal half-life for hirud in, measured by ELISA, was 2.7, 2.3, 2.9, 3.1, and 2.0 hours for the 0 .02, 0.05, 0.1, 0.2, and 0.3 mg . kg-1 . h-1 groups, respectively. Act ivated partial thromboplastin times (aPTT) at 3, 4, and 6 hours were a veraged into a plateau value. The aPTT plateau-to-baseline ratios were 1.5+/-0.1, 2.0+/-0.1, 2.3+/-0.1, 2.7+/-0.1, and 2.9+/-0.1, respective ly, with hirudin infused at 0.02, 0.05, 0.1, 0.2, and 0.3 mg . kg-1 . h-1. From 62% to 77% of the aPTT plateau value was seen within 30 minu tes of starting the infusions and was directly related to dose. The aP TT-to-baseline ratios correlated well with plasma hirudin levels (r=.8 8), whereas poor correlation and sensitivity were observed between pla sma hirudin levels and activated coagulation time (ACT)-to-baseline ra tios (r=.44). Plasma levels of hirudin and ACT in seconds correlated o verall well (r=.80), but considerable overlap occurred between baselin e ACT and ACT at plasma hirudin concentrations <1000 ng/mL. Prothrombi n times were significantly prolonged only at a dosage of greater-than- or-equal-to 0.05 mg . kg-1 . h-1 and were 11.8+/-0.5 (INR=1.0), 12.3+/ -0.7 (INR=1.1), 13.3+/-1.2 (INR=1.4), 14.2+/-0.4 (INR=1.7), and 15.8+/ -0.9 (INR=2.3) seconds for each respective hirudin dosage. Thrombin ti mes were beyond range (>600 seconds) at 6 hours in all except 2 patien ts who received the lowest dosage. All parameters returned to baseline between 8 and 18 hours after the infusion. Bleeding times were not si gnificantly prolonged. No side effects occurred. No antibodies to hiru din were detected 2 weeks after the infusion. Conclusions. Recombinant hirudin has a terminal half-life of 2 to 3 hours. The aPTT correlates well with plasma levels of hirudin and allows close titration over a wide range of anticoagulation, while ACT and prothrombin time are rela tively insensitive for monitoring hirudin administration. At anticoagu lant levels effective in experimental thrombosis, a 6-hour infusion of hirudin is well tolerated and safe in a predominantly male group of p atients with stable coronary atherosclerosis.