Pivotal phase III studies with edoxaban, a rapid, selective, once-daily, oral factor Xa inhibitor have recently been completed. |
The ENGAGE AF-TIMI 48 study in patients with non-valvular atrial fibrillation at moderate-to-high risk of stroke (N = 21,105; mean CHADS2 score 2.8), found that both high-dose edoxaban 60 mg once daily and low-dose edoxaban 30 mg once daily were non-inferior to well-controlled warfarin in the prevention of stroke or systemic embolism, and were also associated with significantly less bleeding and death from a cardiovascular cause than warfarin. |
The Hokusai-VTE study in patients with acute symptomatic venous thromboembolism (VTE) [N = 8,292] had a flexible treatment duration of 3–12 months and found that initial heparin/edoxaban 60 mg once daily was non-inferior to heparin/well-controlled warfarin for the treatment and prevention of recurrent VTE, with a significantly reduced risk of bleeding. |
1 Introduction
2 Pharmacokinetic Properties
Dabigatran [62] | Apixaban [63] | |||
---|---|---|---|---|
Predictable pharmacokinetics | Yes | Yes | Fed: yes Fasted: up to 15 mg | Yes |
T
max (h) | 0.5–2.0 | 3–4 | 2–4 | 1–2 |
T
½ (h) | 12–14 | 12 | 5–9 (young) 11–13 (elderly) | 10–14 |
Bioavailability (%) | 6.5 | 50 | Fed: ≥80 | 62 |
Plasma protein binding (%) | 35 | 87 | 92–95 | 55 |
Renal elimination (% of administered dose) | 85 | 27 | 66 (half as inactive metabolite) | 35 |
CYP metabolism (%) | None | 25 | ~66 | <4 |
Transport proteins | P-gp | P-gp, BCRP | P-gp, BCRP | P-gp |
Interactions | ||||
Drugs | Strong P-gp inhibitors and inducers | Strong inhibitors and inducers of P-gp and CYP3A4 | Strong inhibitors and inducers of P-gp and CYP3A4 | Strong P-gp inhibitors |
Weight |
C
min decrease of 20 % in patients >100 kg | Exposure increase of 30 % in patients <50 kg and decrease by 30 % in patients >120 kg | Exposure increase of 25 % in patients <50 kg and decrease by 25 % in patients >120 kg | Exposure increase in patients ≤60 kg |
Age |
C
min increase of 31 % in patients ≥75 y | AUC increase of 32 % in patients >65 years | AUC increase of 50 % in patients >65 years | None |
Food | Prolongs T
max to 2 h | None | Food increases mean AUC of rivaroxaban 20 mg by 39 %; 15 mg and 20 mg doses taken with food | None |
Gender | None | Exposure in females higher by 18 % | None | None |
Pregnancy | Contraindicated | Contraindicated | Contraindicated | Contraindicated |
3 Pharmacodynamic Properties
4 Clinical Trials
4.1 Phase I Clinical Trials
4.2 Phase II Clinical Trials
4.2.1 Stroke Prevention in Atrial Fibrillation (AF)
4.2.2 Prevention of Venous Thromboembolism (VTE) After Orthopedic Surgery
4.2.3 Patients with Renal Impairment
4.3 Phase III Clinical Trials
NOAC/trial | Interventions | Design |
N
| Mean CHADS2
| TTR (%) | Follow-up | Stroke and SEE (% per years; HR [95 % CI]; p vs. comparator) | Major bleeding (% per years; HR [95 % CI]; p vs. comparator) |
---|---|---|---|---|---|---|---|---|
Edoxaban
| ||||||||
ENGAGE AF-TIMI 48 [30] | Edoxaban 60 mg QD (or reduction to 30 mg QD) or edoxaban 30 mg QD (or reduction to 15 mg QD) vs. Warfarin (INR 2.0–3.0) | R, DB, DD, NI | 21,105 | 2.8 | Median: 68.4 Mean: 64.9 | Median: 2.8 y Mean: NR | Edoxaban 60 mg: 1.18 vs. 1.50; 0.79 [97.5 % CI 0.63–0.99]; p < 0.001 for NI Edoxaban 30 mg: 1.61 vs. 1.50; 1.07 [97.5 % CI 0.87–1.31]; p = 0.005 for NI | Edoxaban 60 mg: 2.75 vs. 3.43; 0.80 [0.71–0.91]; p < 0.001 Edoxaban 30 mg: 1.61 vs. 3.43; 0.47 [0.41–0.55]; p < 0.001 |
Rivaroxaban
| ||||||||
ROCKET AF [66] | Rivaroxaban 20 mg QD (or reduction to 15 mg QD) vs. Warfarin (INR 2.0–3.0) | R, DB, DD, NI | 14,264 | 3.5 | Median: 58 Mean: 55 | Median: 707 days Mean: NR | Rivaroxaban 20 mg: 1.7 vs. 2.2; 0.79 [0.66–0.96]; p < 0.001 for NI | Major and CRNM bleeding Rivaroxaban 20 mg: 14.9 vs. 14.5; 1.03 [0.96–1.11]; p < 0.44 |
J-ROCKET AF [67] | Rivaroxaban 15 mg QD vs. Warfarin (INR 2.0–3.0) | R, DB, NI | 1,280 | 3.25 | Median: NR Mean: 65.0 | 30 days | Rivaroxaban 20 mg: 1.26 vs. 2.61; 0.49 [0.24–1.00]; p = 0.05 for NI | Major and CRNM bleeding Rivaroxaban 20 mg: 18.04 vs. 16.42; 1.11 [0.87–1.42]; p < 0.001 for NI; p = 0.050 for Sup |
Apixaban
| ||||||||
ARISTOTLE [68] | Apixaban 5 mg BID (or reduction to 2.5 mg BID) vs. Warfarin (INR 2.0–3.0) | R, DB, DD, NI | 18,201 | 2.1 | Median: 66.0 Mean: 62.2 | Median: 1.8 y Mean: NR | Apixaban 5 mg: 1.27 vs. 1.60; 0.79 [0.66–0.95]; p < 0.001 for NI; p = 0.01 for Sup | Apixaban 5 mg: 2.13 vs. 3.09; 0.69 [0.60–0.80]; p < 0.001 |
AVERROES [69] | Apixaban 5 mg BID (or reduction to 2.5 mg BID) vs. Aspirin 84–324 mg/day | R, DB, Sup | 5,599 | 2.1 | NA | Median: NR Mean: 1.1 y (early termination) | Apixaban 5 mg: 1.6 vs. 3.7; 0.45 [0.32–0.62]; p < 0.001 | Apixaban 5 mg: 1.4 vs. 1.2; 1.13 [0.74–1.75]; p = 0.57 |
Dabigatran
| ||||||||
Dabigatran 110 mg BID or dabigatran 150 mg BID vs. Warfarin (INR 2.0–3.0) | R, SB, OL warfarin, NI | 18,113 | 2.1 | Median: 67 Mean: 64 | Median: 2.0 y Mean: NR | Dabigatran 150 mg: 1.11 vs. 1.69; RR 0.66 [0.53–0.82]; p < 0.001 for NI; p < 0.001 for Sup Dabigatran 110 mg: 1.53 vs. 1.69; RR 0.91 [0.74–1.11]; p < 0.001 for NI | Dabigatran 150 mg: 3.11 vs. 3.36; RR 0.93 [0.81–1.07]; p = 0.31 Dabigatran 110 mg: 2.71 vs. 3.36; RR 1.16 [1.00–1.34]; p = 0.052 | |
RELY-ABLE [71] | Dabigatran 150 mg BID vs. Dabigatran 110 mg BID | R, DB | 5,851 | 2.1 | NA | Median: 2.3 y Mean: 4.3 y including RE-LY | Dabigatran 150 mg: 1.46 vs. 1.60; 0.91 [0.69–1.20] | Dabigatran 150 mg: 3.74 vs. 2.99; 1.26 [1.04–1.53] |
NOAC/trial/setting | Interventions | Design | Treatment duration (months) |
N
| Mean TTR (%) | Primary efficacy outcome (% per years; HR [95 % CI]; p vs. comparator) | Primary safety outcome (% per years; HR [95 % CI]; p vs. comparator) |
---|---|---|---|---|---|---|---|
Edoxaban
| |||||||
Hokusai-VTE Treatment of symptomatic VTE [33] | Enoxaparin or UFH/edoxaban 60 mg QD (or reduction to 30 mg QD) vs. Enoxaparin or UFH/warfarin (INR 2.0–3.0) | R, DB, DD, NI | 3–12 | 8,292 | 63.5 | Recurrent VTE Edoxaban 60 mg: 3.2 vs. 3.5; 0.89 [0.70–1.13]; p < 0.001 for NI | Major or CRNM bleeding Edoxaban 60 mg: 8.5 vs. 10.3; 0.81 [0.71–0.94]; p = 0.004 for Sup |
Rivaroxaban
| |||||||
EINSTEIN-DVT Secondary prevention of VTE [72] | Rivaroxaban 15 mg BID (3 weeks), then 20 mg QD vs. Enoxaparin 1.0 mg/kg BID/VKA (INR 2.0–3.0) | R, SB, OL, NI | 3, 6, 12 | 3,449 | 57.7 | Recurrent VTE Rivaroxaban 20 mg: 2.1 vs. 3.0; 0.68 [0.44–1.04]; p < 0.001 for NI | Major or CRNM bleeding Rivaroxaban 20 mg: 8.1 vs. 8.1; 0.87 [0.76–1.22]; p = 0.77 |
EINSTEIN-PE Secondary prevention of VTE [73] | Rivaroxaban 15 mg BID (3 weeks), then 20 mg QD vs. Enoxaparin 1.0 mg/kg BID/VKA (INR 2.0–3.0) | R, SB, OL, NI | 3, 6, 12 | 4,832 | 62.7 | Recurrent VTE Rivaroxaban 20 mg: 2.1 vs. 1.8; 1.12 [0.75–1.68]; p = 0.003 for NI | Major or CRNM bleeding Rivaroxaban 20 mg: 10.3 vs. 11.4; 0.90 [0.76–1.07]; p = 0.23 |
EINSTEIN-Extension Extended secondary prevention of VTE [72] | Rivaroxaban 15 mg BID (3 weeks), then 20 mg QD vs. Placebo | R, DB, Sup | 6–12 + 6–12 | 1,196 | NA | Recurrent VTE Rivaroxaban 20 mg: 1.3 vs. 7.1; 0.18 [0.09–0.39]; p < 0.001 | Major bleeding Rivaroxaban 20 mg: 0.7 vs. 0; HR not estimable; p = 0.11 |
MAGELLAN Primary prevention of VTE in hospitalized, medically ill patients [74] | Rivaroxaban 10 mg QD (31–39 days) vs. Enoxaparin 40 mg QD (6–14 days) | R, DB | 35 | 8,101 | NA | VTE and death (day 10) Rivaroxaban 10 mg: 2.7 vs. 2.7; 0.97 [0.71–1.31]; p = 0.003 for NI VTE and death (day 35) Rivaroxaban 10 mg: 4.4 vs. 5.7; 0.77 [0.62–0.96]; p = 0.02 for Sup | Major or CRNM bleeding (day 10) Rivaroxaban 10 mg: 2.8 vs. 1.2; 2.3 [1.63–3.17]; p < 0.001 Major or CRNM bleeding (day 35) Rivaroxaban 10 mg: 4.1 vs. 1.7; 2.5 [1.85–3.25]; p < 0.001 |
ATLAS ACS 2–TIMI 51 Secondary prevention of CV events in ACS [75] | Rivaroxaban 5 mg BID or rivaroxaban 2.5 mg BID vs. Placebo | R, DB | <31 | 15,526 | NA | CV death, MI or stroke Rivaroxaban 2.5 + 5 mg combined: 8.9 vs. 10.7; 0.84 [0.74–0.96]; p = 0.008 Rivaroxaban 5 mg: 8.8 vs. 10.7; 0.85 [0.73–0.98]; p = 0.03 Rivaroxaban 2.5 mg: 9.1 vs. 10.7; 0.84 [0.72–0.97]; p = 0.02 | TIMI major bleeding not related to CABG Rivaroxaban 2.5 + 5 mg combined: 2.1 vs. 0.6; 3.96 [2.46–6.38]; p < 0.001 Rivaroxaban 5 mg: 2.4 vs. 0.6; p < 0.001 Rivaroxaban 2.5 mg: 1.8 vs. 0.6; p < 0.001 |
Apixaban
| |||||||
AMPLIFY Prevention of recurrent VTE or death [76] | Apixaban 10 mg BID (7 days), then 5 mg BID vs. Enoxaparin 1.0 mg/kg Q12H SC/warfarin (INR 2.0–3.0) | R, DB, NI | 6 | 5,400 | 61 | Recurrent VTE or VTE-related death Apixaban 10 mg: 2.3 vs. 2.7; RR 0.84 [0.60–1.18]; p < 0.001 for NI | Major bleeding Apixaban 10 mg: 0.6 vs. 1.8; RR 0.31 [0.17–0.55]; p < 0.001 for Sup |
AMPLIFY-Extension Extended prevention of recurrent VTE or death [77] | Apixaban 5 mg BID or apixaban 2.5 mg BID vs. Placebo | R, DB, Sup | 6–12 + 12 | 2,486 | NR | Recurrent VTE or VTE-related death Apixaban 5 mg BID: 1.7 vs. 8.8; ARR 7.0 % [4.9–9.1]; p < 0.001 for Sup Apixaban 2.5 mg BID: 1.7 vs. 8.8; ARR 7.2 % [5.0–9.3]; p < 0.001 for Sup | Major bleeding Apixaban 5 mg BID: 0.1 vs. 0.5; RR 0.25 [0.03–2.24] Apixaban 2.5 mg BID: 0.2 vs. 0.5; RR 0.49 [0.09–2.64] |
APPRAISE-2 Prevention of acute ischaemic events after recent ACS [78] | Apixaban 5 mg BID vs. Placebo | R, DB, Sup | 241 days (early termination) | 7,392 | NA | CV death, MI or ischaemic stroke Apixaban 5 mg: 7.5 vs. 7.9; 0.95; [0.80–1.11]; p = 0.51 | Major bleeding Apixaban 5 mg: 1.3 vs. 0.5; 2.59 [1.50–4.46]; p = 0.001 |
ADOPT Primary prevention of VTE in hospitalised, medically ill patients [79] | Apixaban 2.5 mg BID (30 days) vs. Enoxaparin 40 mg QD (6–14 days) | R, DB, DD, Sup | 30 days | 6,528 | NA | VTE-related death, PE, symptomatic DVT or asymptomatic DVT Apixaban 2.5 mg: 2.71 vs. 3.06; RR 0.87 [0.62–1.23]; p = 0.44 | Major bleeding Apixaban 2.5 mg: 0.47 vs. 0.19; RR 2.58 [1.02–7.24]; p = 0.04 |
Dabigatran
| |||||||
RE-COVER Prevention of recurrent VTE or death [80] | Heparin/dabigatran 150 mg BID vs. Heparin/warfarin (INR 2.0–3.0) | R, DB, DD, NI | 6 | 2,564 | 60 | Recurrent VTE or VTE-related death Dabigatran 150 mg: 2.4 vs. 2.1; 1.10 [0.65–1.84]; p < 0.001 for NI | Major bleeding Dabigatran 150 mg: 1.6 vs. 1.9; 0.82 [0.45–1.48] |
RE-COVER II Prevention of recurrent VTE or death [81] | Heparin/dabigatran 150 mg BID vs. Heparin/warfarin (INR 2.0–3.0) | R, DB, DD, NI | 6 | 2,589 | 57 | Recurrent VTE or VTE-related death Dabigatran 150 mg: 2.3 vs. 2.2; 1.08 [0.64–1.80]; p < 0.001 for NI | Major bleeding Dabigatran 150 mg: 1.2 vs. 1.7; 0.69 [0.36–1.32] |
RE-MEDY Extended secondary prevention of VTE [82] | Dabigatran 150 mg BID vs. Warfarin (INR 2.0–3.0) | R, DB, NI | 3–12 + 6–36 | 2,866 | 65.3a
| Recurrent VTE Dabigatran 150 mg: 1.8 vs. 1.3; 1.44 [0.78–2.64]; p = 0.01 for NI | Major bleeding Dabigatran 150 mg: 0.9 vs. 1.8; 0.52 [0.27–1.02]; p = 0.06 |
RE-SONATE Extended secondary prevention of recurrent VTE [82] | Dabigatran 150 mg BID vs. Placebo | R, DB, Sup | 6–18 + 6–18 | 1,343 | NA | Recurrent or fatal VTE or unexplained death Dabigatran 150 mg: 0.4 vs. 5.6; 0.08 [0.02–0.25]; p < 0.001 for Sup | Major bleeding Dabigatran 150 mg: 0.3 vs. 0; HR not estimable, p = 1.0 |
Betrixaban
| |||||||
APEX (NCT01583218) Extended prevention of VTE in acute medically ill patients [83] | Betrixaban 80 mg QD vs. Enoxaparin 40 mg QD (6–14 days) | R, DB, | 35–42 | ~6,850 | NA | VTE and VTE-related death | NR |
NOAC/trial/setting | Interventions | Design | Treatment duration (days) |
N
| Primary efficacy outcome (%; [95 % CI]; p vs. comparator) | Primary safety outcome (%; [95 % CI]; p vs. comparator) |
---|---|---|---|---|---|---|
Edoxaban
| ||||||
STARS E-3 Thromboprophylaxis after total knee replacement surgery [50] | Edoxaban 30 mg QD vs. Enoxaparin 20 mg BID | R, DB, DD, NI | 11–14 | 716 | Symptomatic PE, and symptomatic and asymptomatic DVT Edoxaban 30 mg: 7.4 vs. 13.9; RRR 46.8 %; p < 0.001 for NI; p = 0.010 for Sup | Major and CRNM bleeding Edoxaban 30 mg: 6.2 vs. 3.7; p = 0.129 |
STARS J-4 Thromboprophylaxis after hip-fracture surgery [52] | Edoxaban 30 mg QD vs. Enoxaparin 20 mg BID | R, OL | 11–14 | 92 | Thromboembolic events Enoxaparin: 3.7 Edoxaban 30 mg: 6.5 | Major and CRNM bleeding (primary study endpoint) Enoxaparin: 6.9 Edoxaban 30 mg: 3.4 |
STARS J-5 Thromboprophylaxis after total hip replacement surgery [51] | Edoxaban 30 mg QD vs. Enoxaparin 20 mg BID | R, DB, DD, NI | 11–14 | 610 | Symptomatic and asymptomatic DVT and PE Edoxaban 30 mg: 2.4 vs. 6.9; RRR 65.7 %; ARD −4.5 % [−8.6 to −0.9]; p < 0.001 for NI; p = 0.0157 for Sup | Major and CRNM bleeding Edoxaban 30 mg: 2.6 vs. 3.7; p = 0.465 |
Rivaroxaban
| ||||||
RECORD 1 Thromboprophylaxis after total hip replacement surgery [84] | Rivaroxaban 10 mg QD vs. Enoxaparin 40 mg QD SC | R, DB, DD | 35 | 4,541 | DVT, non-fatal PE or all-cause mortality up to days 30–42 Rivaroxaban 10 mg: 1.1 vs. 3.7; ARR 2.6 % [1.5–3.7]; p < 0.001 | Major bleeding Rivaroxaban 10 mg: 0.3 vs. 0.1; p = 0.18 |
RECORD 2 Thromboprophylaxis after total hip replacement surgery [85] | Rivaroxaban 10 mg QD (31–39 days) vs. Enoxaparin 40 mg QD SC (10–14 days) | R, DB, DD | 31–39 | 2,509 | DVT, non-fatal PE or all-cause mortality up to days 30–42 Rivaroxaban 10 mg: 2.0 vs. 9.3; ARR 7.3 % [5.2–9.4]; p < 0.001 | Any bleeding on-treatment Rivaroxaban 10 mg: 6.6 vs. 5.5; p = 0.25 |
RECORD 3 Thromboprophylaxis after total knee replacement surgery [86] | Rivaroxaban 10 mg QD vs. Enoxaparin 40 mg QD SC | R, DB, DD | 10–14 | 2,531 | DVT, non-fatal PE or all-cause mortality up to days 13–17 Rivaroxaban 10 mg: 9.6 vs. 18.9; ARR 9.2 % [5.9–12.4]; p < 0.001 | Major bleeding on-treatment Rivaroxaban 10 mg: 0.6 vs. 0.5; p = 0.77 |
RECORD 4 Thromboprophylaxis after total hip replacement surgery [87] | Rivaroxaban 10 mg QD vs. Enoxaparin 30 mg Q12H SC | R, DB, NI | 10–14 | 3,148 | DVT, non-fatal PE or all-cause mortality up to day 17 Rivaroxaban 10 mg: 6.9 vs. 10.1; ARR 3.19 % [0.71–5.67]; p = 0.0118 | Major bleeding on-treatment Rivaroxaban 10 mg: 0.7 vs. 0.3 |
Apixaban
| ||||||
ADVANCE-1 Thromboprophylaxis after total knee replacement surgery [88] | Apixaban 2.5 mg BID vs. Enoxaparin 30 mg BID SC | R, DB, DD, NI | 10–14 | 3,195 | DVT, non-fatal PE or all-cause mortality Apixaban 2.5 mg: 9.0 vs. 8.8; RR 1.02 [0.78–1.32]; p = 0.06 for NI | Major bleeding on-treatment Apixaban 2.5 mg: 0.7 vs. 1.4; ARD −0.81 % [−1.49 to 0.14]; p = 0.05 |
ADVANCE-2 Thromboprophylaxis after total knee replacement surgery [89] | Apixaban 2.5 mg BID vs. Enoxaparin 40 mg QD SC | R, DB, NI | 10–14 | 3,057 | DVT, non-fatal PE or all-cause mortality Apixaban 2.5 mg: 15.1 vs. 24.4; RR 0.62 [0.51–0.74]; p < 0.0001 | Major bleeding on-treatment Apixaban 2.5 mg: 0.6 vs. 0.9; p = 0.314 |
ADVANCE-3 Thromboprophylaxis after total hip replacement surgery [90] | Apixaban 2.5 mg BID vs. Enoxaparin 40 mg QD SC | R, DB, DD, NI | 35 | 5,407 | DVT, non-fatal PE or all-cause mortality Apixaban 2.5 mg: 1.4 vs. 3.9; RR 0.36 [0.22 – 0.54]; p < 0.001 for NI; p < 0.001 for Sup | Major bleeding on-treatment Apixaban 2.5 mg: 0.8 vs. 0.7; ARD 0.1 % [−0.3 to 0.6]; p = 0.54 |
Dabigatran
| ||||||
RE-NOVATE Thromboprophylaxis after total hip replacement surgery [91] | Dabigatran 220 mg QD or dabigatran 150 mg QD vs. Enoxaparin 40 mg QD | R, DB, DD, NI | 28–35 | 3,494 | Total VTE and all-cause mortality Dabigatran 220 mg: 6.0 vs. 6.7; ARD −0.7 % [−2.9 to 1.6]; p < 0.0001 for NI Dabigatran 150 mg: 8.6 vs. 6.7; ARD 1.9 % [−0.6 to 4.4]; p < 0.0001 for NI | Major bleeding Dabigatran 220 mg: 2.0 vs. 1.6; p = 0.44 Dabigatran 150 mg: 1.3 vs. 1.6; p = 0.60 |
RE-NOVATE II Thromboprophylaxis after total hip replacement surgery [92] | Dabigatran 220 mg QD vs. Enoxaparin 40 mg QD | R, DB, DD, NI | 28–35 | 2,055 | Total VTE and all-cause mortality Dabigatran 220 mg: 7.7 vs. 8.8; ARD −1.1 % [−3.8 to 1.6]; p < 0.0001 for NI | Major bleeding on-treatment Dabigatran 220 mg:1.4 [0.8–2.3] vs. 0.9 [0.4–0.7]; p = 0.40 |
RE-MODEL Thromboprophylaxis after total knee replacement surgery [93] | Dabigatran 220 mg QD or dabigatran 150 mg QD vs. Enoxaparin 40 mg QD | R, DB, NI | 6–10 | 2,076 | Total VTE and all-cause mortality Dabigatran 220 mg: 36.4 vs. 37.7; ARD −1.3 % [−7.3 to 4.6]; p = 0.0003 for NI Dabigatran 150 mg: 40.5 vs. 37.7; ARD 2.8 % [−3.1 to 8.7]; p = 0.017 for NI | Major bleeding on-treatment Dabigatran 220 mg: 1.5 [0.7–2.7] vs. 1.3 [0.6–2.4]; p = 0.28 Dabigatran 150 mg: 1.3 [0.6–2.4] vs. 1.3 [0.6–2.4]; p = 1.0 |
RE-MOBILIZE Thromboprophylaxis after total knee replacement surgery [94] | Dabigatran 220 mg QD or dabigatran 150 mg QD vs. Enoxaparin 30 mg BID | R, DB, DD, NI | 12–15 | 1896 | Total VTE and all-cause mortality Dabigatran 220 mg: 31.1 vs. 25.3; ARD 5.8 % [0.8–10.8]; p = 0.0234 Dabigatran 150 mg: 33.7 vs. 25.3; ARD 8.4 % [3.4–13.3]; p = 0.0009 | Major bleeding on-treatment Dabigatran 220 mg: 0.6 vs. 1.4 Dabigatran 150 mg: 0.6 vs. 1.4 |