Anticoagulant effects of hirulog, a novel thrombin inhibitor, in patients with coronary artery disease.
Selective thrombin inhibitors are a new class of antithrombotic drugs that, unlike heparin, can effectively inhibit clot-bound thrombin and escape neutralization by activated platelets. Hirulog is a 20 amino acid hirudin-based synthetic peptide that has shown promise in experimental models of thrombosis. Little information is available about the effects of hirulog in patients with coronary artery disease. Forty-five patients undergoing cardiac catheterization, who were taking aspirin, were randomized to receive either (1) hirulog, 0.05 mg/kg intravenous bolus followed by 0.2 mg/kg/hour intravenous infusion until the end of the catheterization; (2) hirulog, 0.15 mg/kg intravenous bolus followed by 0.6 mg/kg/hour intravenous infusion; or (3) heparin; 5,000 U intravenous bolus. Serial activated partial thromboplastin time (APTT), prothrombin time, activated clotting time and fibrinopeptide A were measured. Hirulog produced a dose-dependent prolongation of all coagulation parameters; the 0.6 mg/kg/hour dose prolonged the APTT to 218 +/- 50% of baseline after 2 minutes and 248 +/- 50% of baseline after 15 minutes. The half-life of the effect on APTT was 40 minutes. The hirulog blood level correlated well with the APTT, prothrombin time and activated clotting time (r = 0.77, 0.73, and 0.82 respectively, all p < 0.001). Both doses of hirulog potently suppressed the generation of fibrinopeptide A (p < 0.05). There were no major hemorrhagic, thrombotic or allergic complications in patients treated with hirulog or heparin. Thus, hirulog, a direct thrombin inhibitor, provides a predictable level of anticoagulation and appears to have a potent yet well-tolerated anticoagulant profile in patients with coronary artery disease.
Cannon
C P
CP
Department of Medicine, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts 02115.
Maraganore
J M
JM
Loscalzo
J
J
McAllister
A
A
Eddings
K
K
George
D
D
Selwyn
A P
AP
Adelman
B
B
Fox
I
I
Braunwald
E
E
D000595:Amino Acid Sequence; D001241:Aspirin / Q000627:therapeutic use; D001777:Blood Coagulation / Q000187:drug effects*; D001780:Blood Coagulation Tests; D006328:Cardiac Catheterization; D003327:Coronary Disease / Q000097:blood* / Q000188:drug therapy; D005260:Female; D006493:Heparin / Q000627:therapeutic use; D024764:Hirudin Therapy; D006629:Hirudins / Q000031:analogs & derivatives* / Q000737:chemistry; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D010446:Peptide Fragments / Q000737:chemistry / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000737:chemistry / Q000627:therapeutic use; D013917:Thrombin / Q000037:antagonists & inhibitors*
D006629:Hirudins; D010446:Peptide Fragments; D011994:Recombinant Proteins; D006493:Heparin; D013917:Thrombin; D001241:Aspirin; C074619:bivalirudin