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Table 2 Phase III trials of direct oral anticoagulants in the treatment of venous thromboembolism[32]-[38]

From: Treatment options for venous thromboembolism: lessons learnt from clinical trials

Drug Indication Study name Treatments Main findings
Rivaroxaban Acute treatment of DVT without PE EINSTEIN DVT [32] Rivaroxaban 15 mg bid for 3 weeks, then 20 mg od for 3–12 months or Enoxaparin for ≥5 days with VKA (target INR 2.0–3.0) for 3–12 months VTE recurrence for rivaroxaban vs LMWH/VKA 2.1% vs 3.0% (HR 0.68; 95% CI 0.44–1.04; p < 0.001 for non-inferiority; p = 0.08 for superiority). Major or non-major clinically relevant bleeding for rivaroxaban vs LMWH/VKA 8.1% vs 8.1% (HR 0.97; 95% CI 0.76–1.22; p = NS)
  Acute treatment of PE with or without DVT EINSTEIN PE [33] Rivaroxaban 15 mg bid for 3 weeks, then 20 mg od for 3–12 months or Enoxaparin for ≥5 days with VKA (target INR 2.0–3.0) for 3–12 months VTE recurrence for rivaroxaban vs LMWH/VKA 2.1% vs 1.8% (HR 1.12; 95% CI 0.75–1.68; p = 0.003 for non-inferiority). Major or non-major clinically relevant bleeding for rivaroxaban vs LMWH/VKA 10.3% vs 11.4%; p = NS
  Secondary prevention of VTE EINSTEIN EXT [32] After completion of 6–12 months’ treatment: Rivaroxaban 20 mg od for 6 or 12 months or Placebo for 6 or 12 months VTE recurrence for rivaroxaban vs placebo 1.3% vs 7.1% (HR 0.18; 95% CI 0.09–0.39; p < 0.001 for superiority). Major bleeding for rivaroxaban vs placebo 0.7% vs 0% (HR not available; p = 0.11)
Apixaban Acute treatment of VTE AMPLIFY Apixaban 10 mg bid for 7 days then 5 mg bid for 6 months or Enoxaparin 1 mg/kg (s.c.) bid until INR ≥2, warfarin (target INR 2.0–3.0) VTE recurrence or VTE-related death for apixaban vs LMWH/warfarin 2.3% vs 2.7% (RR 0.84; 95% CI 0.60–1.18; p < 0.001 for non-inferiority for apixaban). Major bleeding for apixaban vs LMWH/warfarin 0.6% vs 1.8% (RR 0.31; 95% CI 0.17–0.55; p < 0.001 for superiority for apixaban)
  Secondary prevention of VTE AMPLIFY-EXT [37] After 6–12 months of apixaban or warfarin: Apixaban 2.5 mg or 5 mg bid for 12 months or Placebo for 12 months VTE recurrence or any-cause death for apixaban 2.5 mg or 5.0 mg vs placebo, 3.8% or 4.2% vs 11.6% (2.5 mg RR 0.33; 95% CI 0.22–0.48; 5 mg RR 0.36; 95% CI 0.25–0.53; p < 0.001 for superiority for both apixaban doses). Major bleeding for apixaban 2.5 mg or 5.0 mg vs placebo, 0.2% (RR 0.49; 95% CI 0.09–2.64) or 0.1% (RR 0.25; 95% CI 0.03–2.24) vs 0.5% (p values not available)
Edoxaban Acute treatment of VTE Hokusai-VTE [39] LMWH or UFH for ≥5 days then edoxaban 60 mg od for 3–12 months or LMWH or UFH for ≥5 days then warfarin (target INR 2.0–3.0) for 3–12 months VTE recurrence or VTE-related death for edoxaban vs warfarin 3.2% vs 3.5% (HR 0.89; 95% CI 0.70–1.13; p < 0.001 for non-inferiority for edoxaban). First major or non-major clinically relevant bleeding event 8.5% vs 10.3% (HR 0.81; 95% CI 0.71–0.94; p = 0.004 for superiority for edoxaban)
  Acute treatment of VTE eTRIS (NCT01662908) Edoxaban 90 mg od for 10 days then 60 mg od (total 90 days) or Warfarin (target INR 2.0–3.0) for 90 days, with enoxaparin or UFH for ≥5 days until target INR reached Ongoing
Dabigatran Acute treatment of VTE RE-COVER [35] LMWH or UFH for ≥5 days; dabigatran 150 mg bid for 6 months or LMWH or UFH for ≥5 days; warfarin (target INR 2.0–3.0) for 6 months VTE recurrence for dabigatran vs warfarin 2.4% vs 2.1% (HR 1.10; 95% CI 0.65–1.84; p < 0.001 for non-inferiority). Major bleeding for dabigatran vs warfarin 1.6% vs 1.9% (HR 0.82; 95% CI 0.45–1.48; p = 0.38)
  Acute treatment of VTE RE-COVER II [36] LMWH or UFH for 5–11 days; dabigatran 150 mg bid for 6 months or LMWH or UFH for 5–11 days; warfarin (target INR 2.0–3.0) for 6 months VTE recurrence or VTE-related death for dabigatran vs warfarin 2.3% vs 2.2% (HR 1.08; 95% CI 0.64–1.80; p < 0.001 for non-inferiority)*. Major bleeding for dabigatran vs warfarin 1.2% vs 1.7% (HR 0.69; 95% CI 0.36–1.32; p value not available)
  Secondary prevention of VTE RE-MEDY [38] After 3–12 months of anticoagulant therapy: Dabigatran 150 mg bid for 6–36 months or Warfarin (target INR 2.0–3.0) for 6–36 months VTE recurrence for dabigatran vs warfarin 1.8% vs 1.3% (HR 1.44; 95% CI 0.78–2.64; p = 0.01 for non-inferiority). Major bleeding for dabigatran vs warfarin 0.9% vs 1.8% (HR 0.52; 95% CI 0.27–1.02; p = 0.06)
  Secondary prevention of VTE RE-SONATE [38] After 6–18 months of anticoagulant therapy: Dabigatran 150 mg bid for 6 months or Placebo for 6 months VTE recurrence for dabigatran vs placebo 0.4% vs 5.6% (HR 0.08; 95% CI 0.02–0.25; p < 0.001). Major bleeding for dabigatran vs placebo 0.39% vs 0% (HR not available; 95% CI 0.04–1.05; p = 0.5)
  1. *During 6 months of treatment, excluding the additional 30-day follow-up.
  2. Abbreviations: bid twice daily, CI confidence interval, DVT deep vein thrombosis, HR hazard ratio, INR international normalized ratio, LMWH low molecular weight heparin, NS not significant, od once daily, PE pulmonary embolism, RR relative risk, s.c. subcutaneous, UFH unfractionated heparin, VKA vitamin K antagonist, VTE venous thromboembolism.