INITIAL EXPERIENCE WITH A DIRECT ANTITHROMBIN, HIRULOG, IN UNSTABLE ANGINA - ANTICOAGULANT, ANTITHROMBOTIC, AND CLINICAL EFFECTS

Background. Currently available antithrombotic therapy for unstable angina is unwieldy and occasion-ally ineffective. This study was designed to investigate the potential of Hirulog, a new synthetic specific antithrombin agent, for the management of this condition. Methods and 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 . 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 . 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 . 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 . h-1 dose and 14 the 0.5-mg . kg-1 . h-1 dose before two failures occurred. Failure was observed in only one of 21 patients at the dose of 1 mg . kg-1 . 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 . 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.