Once- or Twice-Daily Rivaroxaban for the Treatment of Proximal Deep Vein Thrombosis: Similar Efficacy and Safety to Standard Therapy in Dose-Ranging Studies.

Rivaroxaban (BAY 59–7939) is an oral, direct Factor Xa inhibitor in advanced clinical development for the prevention and treatment of venous and arterial thromboembolic disorders. Two phase IIb, randomized, dose-ranging studies were performed to investigate the efficacy and safety of rivaroxaban, relative to open-label standard therapy (LMWH/heparin+vitamin K antagonist), for the initial treatment and secondary prophylaxis of deep vein thrombosis (DVT). The EINSTEIN-DVT study included 543 patients with acute, symptomatic, objectively confirmed proximal DVT, without symptomatic pulmonary embolism (PE), who received rivaroxaban 20, 30, or 40 mg once daily (od) or standard therapy. The ODIXa-DVT study (n=613) included similar patients who received rivaroxaban 10, 20, 30 mg twice daily (bid), or 40 mg od, or standard therapy. Patients had a quantitative ultrasound (US) and a perfusion lung scan (PLS) at baseline, and after 3 weeks’ treatment in ODIXa-DVT and 3 months’ treatment in EINSTEIN-DVT. The efficacy outcome was the composite of venous thromboembolism (VTE) - objectively confirmed, symptomatic recurrent DVT or symptomatic, fatal or non-fatal PE - and asymptomatic deterioration on the repeat US or PLS at 3 weeks (ODIXa-DVT), or 3 months (EINSTEIN-DVT). Bleeding was classed as major; clinically relevant, non-major; or minor in EINSTEIN-DVT, and major or minor in ODIXa-DVT. EINSTEIN-DVT: Symptomatic, recurrent VTE or deterioration of US or PLS at 3 months occurred in 6.0%, 5.4%, and 6.6% of patients receiving rivaroxaban 20, 30, and 40 mg od, respectively, and in 9.9% of patients receiving standard therapy. ODIXa-DVT: Symptomatic, recurrent VTE or deterioration of US or PLS at 3 weeks occurred in 3.0%, 4.3%, 5.7%, and 4.8% of patients receiving rivaroxaban 10, 20, 30 mg bid, and 40 mg od, respectively, and in 2.9% of patients receiving standard therapy. Symptomatic, recurrent VTE at 3 months occurred in 1.0%, 1.0%, 0.9%, 1.8%, and 0.9% of patients receiving rivaroxaban 10, 20, 30 mg bid, 40 mg od, and standard therapy, respectively. Improvement in thrombotic burden by US or PLS at 3 weeks was observed in 71.7%, 69.1%, 67.9%, and 58.1% of patients receiving rivaroxaban 10, 20, 30 mg bid, and 40 mg od, respectively, and in 61.2% of patients receiving standard therapy. The incidence of major bleeding was low in both studies at 3 months (Table). In conclusion, rivaroxaban, given od or bid over a wide dose range, was as effective and safe as standard therapy for the treatment of acute, symptomatic DVT. At 3 weeks, the bid regimens were associated with greater improvement in the thrombotic burden than the od regimen, possibly because of higher rivaroxaban trough levels with bid dosing. At 3 months, the bid and od regimens performed similarly, compared with standard therapy. Therefore, rivaroxaban can be used for both the primary treatment and secondary prevention of VTE. For secondary prevention, these data support the use of long-term rivaroxaban 20 mg od for phase III studies.