Dose escalating safety study of a new oral direct thrombin inhibitor, dabigatran etexilate, in patients undergoing total hip replacement: BISTRO I

Abstract

USATo cite this article: Eriksson BI, Dahl OE, Ahnfelt L, Kä lebo P, Stangier J, Nehmiz G, Hermansson K, Kohlbrenner V. Dose escalating safety study of a new oral direct thrombin inhibitor, dabigatran etexilate, in patients undergoing total hip replacement: BISTRO I. (12.5, 25, 50, 100, 150, 200 and 300 mg twice daily or 150 and 300 mg once daily) administered 4-8 h after surgery, for 6-10 days. Dose escalation was based on clinical and pharmacokinetic data. The primary safety outcome was major bleeding. The primary efficacy outcome included venographic deep vein thrombosis (DVT), symptomatic DVT and pulmonary embolism, during the treatment period. Results: No major bleeding event was observed in any group, but two patients at the highest dose (300 mg twice daily) suffered bleeding from multiple sites associated with reduced renal clearance and prolonged pharmacodynamic (PD) parameters. A dose-response was demonstrated for minor bleeding events. Of the 289 treated patients, 225 patients had evaluable venograms. The overall incidence of DVT was 12.4% (28/225 patients). There was no consistent relationship between the dose and incidence of DVT, the highest incidence in any group being 20.8% (5/24 patients). The lowest dose (12.5 mg twice daily) showed a high rate of proximal DVT [12.5% (3/24)] and no increase in PD parameters. Peak and trough plasma concentrations, area under the dabigatran plasma concentration-time curve and PD parameters also increased in proportion with the dose. Higher dabigatran plasma concentrations were associated with lower DVT rates. Approximately 20% of the patients had low plasma concentrations after the first dose suggesting further optimization of the preliminary tablet formulation is required. Conclusions: Dabigatran etexilate demonstrates an acceptable safety profile, with a therapeutic window above 12.5 mg and below 300 mg twice daily. The low number of VTE events within each treatment group indicates a satisfactory antithrombotic potential, although the study was not powered for an efficacy analysis. Additional studies are ongoing to optimize oral absorption and the efficacy/safety balance.

Dabigatran for prophylaxis of thromboembolic events in patients with atrial fibrillation

“…46 This study could prove dabigatran to be superior at doses of 150 and 225 mg bid. 47 Subsequently, three larger Phase III studies for the treatment of deep venous thrombosis compared dabigatran (150 mg or 220 mg once daily) with enoxaparin.…”

Venous Thromboembolism in Orthopaedic Surgery

“…Dabaigatran etexilate is a pro-drug of the direct thrombin inhibitor, dabigatran (Eriksson et al, 2004). There have been four phase III clinical trials comparing this drug to enoxaparin.…”

Direct Thrombin Inhibitors

“…The efficacy and safety of dabigatran for prevention of VTE in elective major orthopaedic surgeries was first demonstrated in the Boehringer Ingelheim Study in ThROmbosis (BISTRO) phase II trials [44,51,52]. The principle results from this set of studies showed that increasing doses of dabigatran etexilate decreased total VTE in a dosedependent manner, and the incidence of major VTE (proximal DVT and/or PE) was lower in groups with any dose of dabigatran etexilate (1.7%-5.0%) compared with enoxaparin (5.6%).…”