TABLE 2

Main results of the published phase III randomised trials on the use of direct oral anticoagulants in the prevention and treatment of venous thromboembolism (VTE)

Study [ref.]IndicationPatientsStudy drug versus comparatorPrimary outcome
EfficacySafety
APX
 ADVANCE-1 [16]VTE prophylaxis after TKR3195APX 2.5 mg twice daily, 10–14 days versus ENX 30 mg twice daily, 10–14 daysVTE and all-cause cause death: APX 9.0%  versus ENX 8.8% (p=0.06, noninferiority)Major bleeding: APX 0.7%  versus ENX 1.4% (p=0.03)
 ADVANCE-2 [17]VTE prophylaxis after TKR3057APX 2.5 mg twice daily, 10–14 days versus ENX 40 mg once daily, 10–14 daysVTE and all-cause cause death: APX 15.0% versus ENX 24.0% (p<0.0001, superiority)Major bleeding: APX 0.6% versus ENX 0.9% (ns)
 ADVANCE-3 [18]VTE prophylaxis after THR5407APX 2.5 mg twice daily, 32–38 days versus ENX 40 mg once daily, 32–38 daysVTE and all-cause cause death: APX 1.4% versus ENX 3.9% (p<0.001, superiority)Major bleeding: APX 0.8% versus ENX 0.7% (ns)
 ADOPT [19]VTE prophylaxis in medically ill patients4495APX 2.5 mg twice daily, 30 days versus ENX 40 mg once daily, 6–14 daysVTE and VTE-related death: 2.7% versus 3.1 (ns, superiority)Major bleeding: APX 0.5% versus ENX 0.2% (p=0.04)
 Botticelli [20]DVT treatment520APX 5 mg twice daily or 10 mg twice daily or 20 mg once daily (3 months) versus ENX 1 mg·kg−1 twice daily (≥ days), WAR (3 months)Recurrent VTE: APX 4.7% versus ENX/WAR 4.2%Major bleeding and clinically relevant non-major bleeding: APX 7.3% versus ENX/WAR 7.9%
 AMPLIFY [21]VTE treatment5385APX 10 mg twice daily (7 days), 5 mg twice daily (6 months) versus ENX 1 mg·kg−1 twice daily (≥ days), WAR (6 months)Recurrent VTE: APX 2.3% versus ENX/WAR 2.7% (p<0.001, noninferiority)Major bleeding: APX 0.6% versus ENX/WAR 1.8% (p<0.001)
 AMPLIFY-EXT [22]VTE treatment2486APX 2.5 mg twice daily or 5 mg twice daily (12 months) versus placeboRecurrent VTE: APX 1.7% versus placebo 8.8% (p<0.001, superiority)Major bleeding: APX 2.5 mg 0.2%, APX 5 mg 0.1% versus placebo 0.5% (ns)
DAB
 RE-MODEL [23]VTE prophylaxis
after TKR
2076DAB 150 mg once daily or 220 mg once daily, 6–10 days versus ENX 40 mg once daily, 6–10 daysVTE: DAB 150 mg 40.5% (p=0.017, noninferiority) or DAB 220 mg 36.4% (p=0.0003, noninferiority) versus ENX 37.7%Major bleeding: DAB 150 mg 1.3% or DAB 220 mg 1.5% versus ENX 1.3% (ns)
 RE-NOVATE [24]VTE prophylaxis
after THR
3494DAB 150 mg once daily or 220 mg once daily, 28–35 days versus ENX 40 mg once daily, 28–35 daysVTE: DAB 150 mg 8.6% (p<0.0001, noninferiority) or DAB 220 mg 6.0% (p<0.0001, noninferiority) versus ENX 6.7%Major bleeding: DAB 150 mg 1.3% or DAB 220 mg 2.0% versus ENX 1.6% (ns)
 RE-MOBILIZE [25]VTE prophylaxis
after TKR
2715DAB 150 mg once daily or 220 mg once daily, 28–35 days versus ENX 30 mg twice daily, 12–15 daysVTE: DAB 150 mg 33.7% (p=0.0009, inferiority) or DAB 220 mg 31.7% (p=0.002, inferiority) versus ENX 25.3%Major bleeding: DAB 150 mg 0.6% or DAB 220 mg 0.6% versus ENX 1.4% (ns)
 RE-COVER I [26]VTE treatment2564DAB 150 mg twice daily, 6 months versus WAR, 6 monthsRecurrent VTE: DAB 2.4% versus WAR 2.1% (p<0.001 non-inferiority)Major bleeding: DAB 1.6% versus WAR 1.9% (ns)
 RE-COVER II [27]VTE treatment2568DAB 150 mg twice daily, 6 months versus WAR, 6 monthsRecurrent VTE: DAB 2.3% versus WAR 2.2% (p<0.001, noninferiority)Major bleeding: DAB 1.2% versus WAR 1.7% (ns)
 RE-MEDY [28]VTE treatment2856DAB 150 mg twice daily, 36 months versus WAR, 36 monthsRecurrent VTE: DAB 1.8% versus WAR 1.3%. (p=0.01, noninferiority)Major bleeding: DAB 0.9% versus WAR 1.8% (ns)
 RE-SONATE [28]VTE treatment1343DAB 150 mg twice daily, 6 months versus placebo, 6 monthsRecurrent VTE: DAB 0.4% versus placebo 5.6% (p<0.0001)Major bleeding: DAB 0.3% versus placebo 0% (ns)
EDX
 STARS-E3 [29]VTE prophylaxis after TKR716EDX 30 mg once daily, 11–14 days versus ENX 20 mg twice daily, 11–14 daysVTE: EDX 7.4% versus ENX 13.9% (p=0.010)Major bleeding: EDX 1.1% versus ENX 0.3% (ns)
 STARS-J5 [30]VTE prophylaxis after THR264EDX 15 mg once daily or 30 mg once daily, 11–14 days versus ENX 20 mg twice daily, 11–14 daysVTE: EDX 15 mg 3.8% or EDX 30 mg 2.8%
versus ENX 4.1% (p=1.000)
Major bleeding: EDX 15 mg 2.2% or EDX 30 mg 1.2% versus ENX 2.3% (ns)
 Hokusai-VTE [31]VTE treatment8292EDX 60 mg once daily or 30 mg once daily, 3–12 months versus WAR, 3–12 monthsRecurrent VTE: EDX 3.2% versus WAR 3.5% (p<0.001, noninferiority)Major bleeding: EDX 1.4% versus WAR 1.6% (ns)
RVX
 RECORD-1 [32]VTE prophylaxis after THR4541RVX 10 mg once daily, 35 days versus ENX 40 mg once daily, 35 daysVTE and all-cause death: RVX 1.1% versus ENX 3.7% (p<0.001, superiority)Major bleeding: RVX 0.3% versus ENX 0.1% (ns)
 RECORD-2 [33]VTE prophylaxis after THR2509RVX 10 mg once daily, 35 days versus ENX 40 mg once daily, 10–14 daysVTE and all-cause death: RVX 2.0% versus ENX 9.3% (p<0.001, superiority)Major bleeding: RVX 0.08% versus ENX 0.08% (ns)
 RECORD-3 [34]VTE prophylaxis after TKR2531RVX 10 mg once daily, 10–14 days versus ENX 40 mg once daily, 10–14 daysVTE and all-cause death: RVX 9.6% versus ENX 18.9% (p<0.001, superiority)Major bleeding: RVX 0.6% versus ENX 0.5% (ns)
 RECORD-4 [35]VTE prophylaxis after TKR3148RVX 10 mg once daily, 10–14 days versus ENX 30 mg twice daily, 10–14 daysVTE and all-cause death: RVX 6.9% versus ENX 10.1% (p=0.012, superiority)Major bleeding: RVX 0.7% versus ENX 0.3% (ns)
 EINSTEIN-DVT [36]VTE treatment3449RVX 15 mg twice daily (3 weeks), 20 mg once daily (3, 6 or 12 months) versus ENX 1 mg·kg−1 twice daily (≥ days),WAR (3, 6 or 12 months)Recurrent VTE: RVX 2.1% versus ENX/WAR 3.0% (p<0.001, noninferiority)Major bleeding: RVX 0.8% versus ENX/WAR 1.2% (ns)
 EINSTEIN-PE [37]VTE treatment4832RVX 15 mg twice daily (3 weeks), 20 mg once daily (3, 6 or 12 months) versus ENX 1 mg·kg−1 twice daily (≥ days),WAR (3, 6 or 12 months)Recurrent VTE: RVX 2.1% versus ENX/WAR 1.8% (p=0.003, noninferiority)Major bleeding: RVX 1.1% versus ENX/WAR 2.2% (p=0.003)
 EINSTEIN-Extension [36]VTE treatment1197RVX 20 mg once daily, 6–12 months versus placebo, 12 monthsRecurrent VTE: RVX 1.3% versus placebo 7.1% (p<0.001, superiority)Major bleeding: RVX 0.7% versus placebo 0% (ns)
  • APX: apixaban; ADVANCE: Apixaban Dosed Orally versus Anticoagulation with Enoxaparin; ADOPT: Apixaban Dosing to Optimize Protection from Thrombosis; AMPLIFY: Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line Therapy; EXT: Extended Treatment; DAB: dabigatran; EDX: edoxaban; STARS: Studying Thrombosis After Replacement Surgery; RVX: rivaroxaban; RECORD: Regulation of Coagulation in Orthopedic Surgery to Prevent Deep Venous Thrombosis and Pulmonary Embolism; DVT: deep vein thrombosis; PE: pulmonary embolism; TKR: total knee replacement; THR: total hip replacement; ENX: enoxaparin; WAR: warfarin; ns: nonsignificant.