Evidence for a rebound coagulation phenomenon after cessation of a 4-hour infusion of a specific thrombin inhibitor in patients with unstable angina pectoris

Abstract

Objectives. In a Phase I clinical trial, we studied the antithrombotic and clinical effects of the synthetic competitive thrombin inhibitor, argatroban, in 43 patients with unstable angina pectoris.Background. Thrombin has a pivotal rote in platelet-mediated thrombosis associated with atheromatous plaque rupture in patients with an acute ischemic coronary syndrome. However, the efficacy of conventional heparin therapy to prevent ischemic events is limited and has been surpassed by that of specific thrombin inhibitors in experimental models of arterial thrombosis.Methods. Intravenous infusion of the drug (0.5 to 5.0 μg/kg per min) for 4 h was monitored by sequential measurements of coagulation times and of indexes of thrombin activity in vivo followed by a 24-h clinical observation period.Results. Significant dose-related increases in plasma drug concentrations and activated partial thromboplastin times (aPTT), but no bleeding time prolongation or spontaneous bleeding, was observed. Myocardial ischemia did not occur during therapy but, surprisingly, 9 of the 43 patients experienced an episode of unstable angina 5.8 ± 2.6 h (mean ± SD) after infusion. This early recurrent angina was correlated significantly with a higher argatroban dose and with greater prolongation of aPTT but not with other demographic, clinical, laboratory and angiographic characteristics. Pretreatment plasma concentrations of thrombin-antithrombin III complex and fibrinopeptide A were elevated two to three times above normal values. During infusion, thrombin-antithrombin III complex levels remained unchanged, whereas a significant 2.3-fold decrease in fibrinopeptide A concentrations was observed. By contrast, 2 h after infusion, thrombin-antithrombin III complex concentrations increased 3.9-fold over basetine measurements together with return of fibrinopeptide A levels to values before treatment with argatroban.Conclusions. In patients with unstable angina, argatroban inhibits clotting (aPTT prolongation) and thrombin activity toward fibrinogen (fibrinopeptide A decrease), but in vivo thrombin (thrombin-antithrombin III complex) formation is not suppressed. However, cessation of infusion is associated with rebound thrombin (thrombin-antithrombin III complex) generation and with an early dose-related recurrence of unstable angina. Although the mechanism of this clinical and biochemical rebound phenomenon remains to be determined, its implication for the clinical use of specific thrombin inhibitors in the management of ischemic coronary syndromes may be significant.