A new oral direct thrombin inhibitor, dabigatran etexilate, compared with enoxaparin for prevention of thromboembolic events following total hip or knee replacement: the BISTRO II randomized trial

Abstract

Reilly P for the BISTRO II Study Group. A new oral direct thrombin inhibitor, dabigatran etexilate, compared with enoxaparin for prevention of thromboembolic events following total hip or knee replacement: the BISTRO II randomized trial. J Thromb Haemost 2005; 3:Summary. Background: Dabigatran etexilate is an oral direct thrombin inhibitor undergoing evaluation for the prevention of venous thromboembolism (VTE) following orthopedic surgery. Methods: In a multicenter, parallel-group, double-blind study, 1973 patients undergoing total hip or knee replacement were randomized to 6-10 days of oral dabigatran etexilate (50, 150 mg twice daily, 300 mg once daily, 225 mg twice daily), starting 1-4 h after surgery, or subcutaneous enoxaparin (40 mg once daily) starting 12 h prior to surgery. The primary efficacy outcome was the incidence of VTE (detected by bilateral venography or symptomatic events) during treatment. Results: Of the 1949 treated patients, 1464 (75%) patients were evaluable for the efficacy analysis. VTE occurred in 28.5%, 17.4%, 16.6%, 13.1% and 24% of patients assigned to dabigatran etexilate 50, 150 mg twice daily, 300 mg once daily, 225 mg twice daily and enoxaparin, respectively. A significant dose-dependent decrease in VTE occurred with increasing doses of dabigatran etexilate (P < 0.0001). Compared with enoxaparin, VTE was significantly lower in patients receiving 150 mg twice daily [odds ratio (OR) 0.65, P ¼ 0.04], 300 mg once daily (OR 0.61, P ¼ 0.02) and 225 mg twice daily (OR 0.47, P ¼ 0.0007). Compared with enoxaparin, major bleeding was significantly lower with 50 mg twice daily (0.3% vs. 2.0%, P ¼ 0.047) but elevated with higher doses, nearly reaching statistical significance with the 300 mg once-daily dose (4.7%, P ¼ 0.051). Conclusions: Oral administration of dabigatran etexilate, commenced early in the postoperative period, was effective and safe across a range of doses. Further optimization of the efficacy/safety balance will be addressed in future studies.

Dabigatran: Review of Pharmacology and Management of Bleeding Complications of This Novel Oral Anticoagulant

“…Bleeding events tended to occur at the surgical sites. Increased daily doses of dabigatran of 300 mg or greater increased the bleeding rate to 3.8-4.7% without fatalities [35].…”

“…Five randomized trials have compared dabigatran with enoxaparin for the prevention of VTE in patients undergoing elective orthopedic surgery [31][32][33][34][35]. Between 100 and 450 mg total daily dose of dabigatran was compared to enoxaparin 30 mg twice daily or 40 mg daily.…”

“…Between 100 and 450 mg total daily dose of dabigatran was compared to enoxaparin 30 mg twice daily or 40 mg daily. Most studies demonstrated noninferiority, while in one study, dabigatran fared worse [34] and in another, better at doses 300 mg/day or greater [35]. Rates of major bleeding were similar in dabigatran (at daily doses of 220 mg or less) and enoxaparin arms, with a single fatal retroperitoneal hemorrhage occurring in a patient receiving dabigatran [33].…”

Thromboprophylaxis with dabigatran etexilate in patients over seventy-five years of age with moderate renal impairment undergoing or knee replacement

“…CRBE comprised the following: spontaneous skin haematoma greater than 25 cm 2 , wound haematomas greater than 100 cm 2 , spontaneous nose bleed lasting for over five minutes, macroscopic haematuria (spontaneous or lasting for more than 24 hours if associated with an intervention), spontaneous rectal bleeding, gingival bleeding for more than five minutes and any other bleeding event considered as clinically relevant by the investigator. All bleeding events were adjudicated by an independent expert committee blinded to treatment allocations and were categorised as a MBE, CRBE, minor bleeding event or no bleeding event [10,11,15,18]. In this study, we also present the composite of MBE and CRBE, as this was seen as the most informative and relevant bleeding definition for understanding the bleeding profile of drugs used in this investigational setting.…”

Pharmacological profile of non-vitamin K antagonist oral anticoagulants

“…This pro-drug was in phase II clinical trials for thromboembolism in 1999. It had shown excellent potential as an antithrombotic agent in preclinical studies and it demonstrated an acceptable safety profile for prevention deep vein thrombosis after total hip replacement (Mungall, 2002;Eriksson et al, 2005;Di Nisio et al, 2005). It was the first NOAC; U.S approved in many countries worldwide (in 2010 by the Food and Drug Administration -FDA -and in 2008 by European Medicines Agency -EMA) for the prevention of stroke and blood clots from AF based on the results of the RE-LY (Randomized Evaluation of Long-term Anticoagulant Therapy, Warfarin, compared with Dabigatran) trial (Connolly et al, 2009;Beasley et al, 2011).…”