Recombinant hirudin in patients with chronic, stable coronary artery disease. Safety, half-life, and effect on coagulation parameters
Phase I trial published in Circulation (1993)
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 i.v. 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 x 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 x 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 concentrations < 1000 ng/mL. Prothrombin times were significantly prolonged only at a dosage of > or = 0.05 mg.kg-1 x 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.
Abstract sourced from PubMed (NCBI) for the cited record. See the original publication for the authoritative version.
Summary
Phase I single-blind ascending-dose study of recombinant hirudin (CGP 39,393) in 39 CAD patients showed median terminal half-life of 2.0–3.1 h across doses 0.02–0.3 mg/kg/h, aPTT correlated well with plasma hirudin levels (r=0.88), no antibodies at 2 weeks.
Why This Matters for Hirudotherapy
This single-blind ascending-dose study in 39 patients (38 men, 1 woman) with angiographic coronary artery disease evaluated recombinant hirudin (CGP 39,393) for half-life, coagulation parameter effects, and safety over a 6-hour IV infusion. Hirudin exhibited a terminal half-life of approximately 2–3 hours, with aPTT-to-baseline ratios correlating well with plasma hirudin levels (r=0.88), while ACT and prothrombin time were relatively insensitive for monitoring. At anticoagulant levels, the 6-hour infusion was well tolerated with no side effects, no bleeding time prolongation, and no detectable antibodies at two weeks. This study provides valuable human pharmacokinetic and safety data directly relevant to hirudotherapy. Limitations include the small, predominantly male sample and short-term exposure; clinical antithrombotic efficacy was not assessed.
Citation
Recombinant hirudin in patients with chronic, stable coronary artery disease. Safety, half-life, and effect on coagulation parameters.
Zoldhelyi P et al. · Circulation, 1993
Added to ASH library: May 27, 2026 · Site last updated: June 18, 2026