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Table 2 Summary of phase III studies of direct oral anticoagulants for the acute treatment of VTE[49]

From: Pharmacokinetic and pharmacodynamic evaluation of rivaroxaban: considerations for the treatment of venous thromboembolism

Drug Study Indication Regimen Dose schedule Comparator Efficacy Safety
Rivaroxaban EINSTEIN DVT Patients with DVT without PE Single drug 15 mg bid for 3 weeks then 20 mg od for 3, 6 or 12 months Standard enoxaparin for ≥5 days overlapping with and transitioning to VKA once INR ≥2.0 on 2 consecutive days; thereafter VKA dose adjusted to maintain INR 2.0–3.0 Recurrent VTE: rivaroxaban non-inferior to standard therapy (2.1% vs. 3.0%; HR = 0.68; p < 0.001 for non-inferiority) Clinically relevant bleeding: similar incidence (8.1% vs. 8.1%; HR = 0.97; p = 0.77)
Major bleeding: similar incidence (0.8% vs. 1.2%; HR = 0.65; p = 0.21)
Rivaroxaban EINSTEIN PE Patients with PE with or without DVT Single drug 15 mg bid for 3 weeks then 20 mg od for 3, 6 or 12 months Standard enoxaparin for ≥5 days overlapping with and transitioning to VKA once INR ≥2.0 on 2 consecutive days; thereafter VKA dose adjusted to maintain INR 2.0–3.0 Recurrent VTE: rivaroxaban non-inferior to standard therapy (2.1% vs. 1.8%; HR = 1.12; p = 0.003 for non-inferiority) Clinically relevant bleeding: similar incidence (10.3% vs. 11.4%; HR = 0.90; p = 0.23)
Major bleeding: significant reduction with rivaroxaban vs. standard therapy (1.1% vs. 2.2%; HR = 0.49; p = 0.003)
Rivaroxaban EINSTEIN DVT and PE pooled Patients with DVT and/or PE Single drug 15 mg bid for 3 weeks then 20 mg od for 3, 6 or 12 months Standard enoxaparin for ≥5 days overlapping with and transitioning to VKA once INR ≥2.0 on 2 consecutive days; thereafter VKA dose adjusted to maintain INR 2.0–3.0 Recurrent VTE: rivaroxaban non-inferior to standard therapy (2.1% vs. 2.3%; HR = 0.89; p < 0.001 for non-inferiority) Clinically relevant bleeding: similar incidence (9.4% vs. 10.0%; HR = 0.93; p = 0.27)
Major bleeding: significant reduction with rivaroxaban vs. standard therapy (1.0% vs. 1.7%; HR = 0.54; p = 0.002)
Apixaban AMPLIFY Patients with DVT and/or PE Single drug 10 mg bid for 7 days then 5 mg bid for 6 months Standard enoxaparin for ≥5 days overlapping with and transitioning to warfarin once INR ≥2.0 on 2 consecutive days; thereafter VKA dose adjusted to maintain INR 2.0–3.0 Recurrent VTE: apixaban non-inferior to standard therapy (2.3% vs. 2.7%; RR = 0.84; p < 0.001 for non-inferiority) Clinically relevant bleeding: significant reduction with apixaban vs. standard therapy (4.3% vs. 9.7%; RR = 0.44; p < 0.001)
Major bleeding: significant reduction with apixaban vs. standard therapy (0.6% vs. 1.8%; RR = 0.31; p < 0.001)
Edoxaban Hokusai-VTE Patients with DVT and/or PE Dual drug 60 mga od for 3–12 months after standard heparin induction Standard heparin for ≥5 days overlapping with and transitioning to warfarin (INR 2.0–3.0) Recurrent VTE: edoxaban non-inferior to standard therapy (3.2% vs. 3.5%; HR = 0.89; p < 0.001 for non-inferiority) Clinically relevant bleeding: significant reduction with edoxaban vs. standard therapy (8.5% vs. 10.3%; HR = 0.81; p = 0.004)
Major bleeding: similar incidence (1.4% vs. 1.6%; HR = 0.84; p = 0.35)
Dabigatran RE-COVERb Patients with DVT and/or PE Dual drug 150 mg bid for 6 months after heparin induction Standard heparin for ≥5 days overlapping with and transitioning to warfarin once INR ≥2.0 on 2 consecutive days; thereafter VKA dose adjusted to maintain INR 2.0–3.0 Recurrent VTE: dabigatran non-inferior to standard therapy (2.4% vs. 2.1%; HR = 1.10; p < 0.001 for non-inferiority) Clinically relevant bleeding: significant reduction with dabigatran vs. standard therapy (5.6% vs. 8.8%; HR = 0.63; p = 0.002)
        Major bleeding: similar incidence (1.6% vs. 1.9%; HR = 0.82; p = N/S)
  1. Clinically relevant bleeding defined as the composite of major and non-major clinically relevant bleeding. a30 mg once daily in patients with creatinine clearance 30–50 ml/min or body weight ≤60 kg or in patients receiving concomitant potent P-glycoprotein inhibitors; bSimilar outcomes reported in RE-COVER II (data not shown).
  2. bid, twice daily; DVT, deep vein thrombosis; HR, hazard ratio; INR, international normalised ratio; N/S, not specified; od, once daily; PE, pulmonary embolism; RR, relative risk; VKA, vitamin K antagonist; VTE, venous thromboembolism.