Initial Experience With a Direct Antithrombin , Hirulog , in Unstable Angina

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. 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`', 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` h` 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` h` 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` h` dose and 14 the 0.5-mg. kg` h` dose before two failures occurred. Failure was observed in only one of21 patients at the dose of 1 mg * kg` h`. aPIT (±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` h`. 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. (Circulation. 1993;88[part 1]:1495-1501.)