Recombinant Hirudin in Patients With Chronic, Stable Coronary Artery Disease Safety, Half-life, and Effect on Coagulation Parameters

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Abstract

Background.

Because the specific antithrombin hirudin prevents platelet-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 Results.

Thirty-eight men and 1 woman (age [mean±SD], 60.4±6.9 years) with angiographic coronary disease were allocated in a single-blind ascending dosage study to a 6-hour IV infusion of recombinant hirudin (CGP 39 393) or matching placebo. The median terminal half-life for hirudin, 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. Activated partial thromboplastin times (aPTT) at 3, 4, and 6 hours were averaged 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, respectively, 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 minutes of starting the infusions and was directly related to dose. The aPTT-to-baseline ratios correlated well with plasma hirudin levels (r=.88), whereas poor correlation and sensitivity were observed between plasma hirudin levels and activated coagulation time (ACT)-to-baseline ratios (r=.44). Plasma levels of hirudin and ACT in seconds correlated overall well (r=.80), but considerable overlap occurred between baseline ACT and ACT at plasma hirudin concen-trations <1000 ng/mL. Prothrombin times were significantly prolonged only at a dosage of 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 times were beyond range (>600 seconds) at 6 hours in all except 2 patients who received the lowest dosage. All parameters returned to baseline between 8 and 18 hours after the infusion. Bleeding times were not significantly prolonged. No side effects occurred. No antibodies to hirudin 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 relatively insensitive for monitoring hirudin administration. At anticoagulant levels effective in experimental thrombosis, a 6-hour infusion of hirudin is well tolerated and safe in a predominantly male group of patients with stable coronary atherosclerosis. (Circulation.1993;88[part 1]:2015–2022.)

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