title: Initial experience with a direct antithrombin, Hirulog, in unstable angina. Anticoagulant, antithrombotic, and clinical effects.
abstract: BACKGROUND
  Currently available antithrombotic therapy for unstable angina is unwieldy and occasionally ineffective. This study was designed to investigate the potential of Hirulog, a new synthetic specific antithrombin agent, for the management of this condition.
  
  
  RESULTS
  A total of 55 patients in the acute phase of unstable angina received intravenous Hirulog according to one of two protocols. In an acute dose-escalating study, 0.02, 0.05, 0.1, 0.25, and 0.5 mg.kg-1 x h-1, each for 30 minutes, were infused in 15 patients. Prolongation of activated partial thromboplastin time (aPTT) (r = .95), fibrinopeptide A inhibition (r = .96), and Hirulog plasma levels (r = .91) correlated closely with the dose infused, with significant changes compared with baseline appearing at doses of 0.25 mg.kg-1 x h-1 and higher. The purposes of the second protocol were to determine whether the anticoagulant and antithrombotic effects of the drug were sustained during a 72-hour infusion and to assess whether such treatment prevented the complications of unstable angina. Based on the initial study, we planned to give a dose of 0.25 mg.kg-1 x h-1 to each patient until 2 patients failed therapy, then successively higher doses until a 95% success rate was achieved or adverse effects intervened, increasing the dose after two failures had occurred at each level. Five patients received the 0.25-mg.kg-1 x h-1 dose and 14 the 0.5-mg.kg-1 x h-1 dose before two failures occurred. Failure was observed in only one of 21 patients at the dose of 1 mg.kg-1 x h-1. aPTT (+/- SEM) levels increased to 62 +/- 5, 76 +/- 2, and 98 +/- 3 seconds at the three doses, with minimal intraindividual variation, and Hirulog plasma levels to 1050, 2100, and 4200 mg/mL, respectively. Fibrinopeptide A plasma levels decreased at all doses but more consistently at the dose of 1 mg.kg-1 x h-1. The overall clinical success rate was 87.5%: 60% (3/5) at the low dose, 86% (12/14) at the intermediate dose, and 95% (20/21) at the high dose. No deaths, myocardial infarctions, or bleeding complications occurred.
  
  
  CONCLUSIONS
  In unstable angina patients, Hirulog infusions quickly and reproducibly yield stable, dose-dependent anticoagulant and antithrombotic effects with a favorable clinical efficacy profile.
authors.affiliation: Department of Medicine, Montreal Heart Institute, Quebec, Canada.
authors.forename: R M
authors.initials: RM
authors.lastname: Lidón
authors.forename: P
authors.initials: P
authors.lastname: Théroux
authors.forename: M
authors.initials: M
authors.lastname: Juneau
authors.forename: B
authors.initials: B
authors.lastname: Adelman
authors.forename: J
authors.initials: J
authors.lastname: Maraganore
mesh_terms: D000789:Angina, Unstable / Q000097:blood / Q000188:drug therapy*; D004305:Dose-Response Relationship, Drug; D005260:Female; D005344:Fibrinopeptide A / Q000032:analysis; D024764:Hirudin Therapy; D006629:Hirudins / Q000008:administration & dosage / Q000031:analogs & derivatives*; D006801:Humans; D008297:Male; D008875:Middle Aged; D010314:Partial Thromboplastin Time; D010446:Peptide Fragments / Q000008:administration & dosage / Q000627:therapeutic use*; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000627:therapeutic use; D013917:Thrombin / Q000037:antagonists & inhibitors*
chemical_list: D006629:Hirudins; D010446:Peptide Fragments; D011994:Recombinant Proteins; D005344:Fibrinopeptide A; D013917:Thrombin; C074619:bivalirudin