anticoagulation and thrombosis management a review of non-vitamin k oral anticoagulants: venous...
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Anticoagulation and Thrombosis Management
Anticoagulation and Thrombosis Management
A Review of Non-Vitamin K Oral Anticoagulants: Venous Thromboembolism
Dabigatran Rivaroxaban Apixaban Edoxaban
Target IIa (thrombin) Xa Xa Xa
Hours to maximum concentration 1-3 2-4 3-4 1-2
Half-life, h 12-17 5-13 12 9-11
Renal clearance, % 80 33* 27 50
Transporters P-gp P-gp P-gp P-gp
Cytochrome P450 metabolism, % None 32 <32 <4
*33% renally cleared; 33% excreted unchanged in urine.
Comparative PK/PD of NOACsComparative PK/PD of NOACs
Heidbuchel H, et al. Europace. 2013;15:625-651[1]; Hellwig T, et al. Ann Pharmacother. 2013;47:1478-1487.[2]
Treatment and Secondary PreventionTreatment and Secondary Prevention
VKA or NOAC
Extended: ~3 months to indefinite
Parenteral: Heparin, LMWH,
fondaparinux
Long-term(subacute):
~7 days to ~3 months
Initial(acute):
0 to ~7 days
Kearon C, et al. Chest. 2012;141(2 Suppl):e419s-e494S.[3]
VKA: initiated concurrently with parenteral anticoagulant; parenteral anticoagulant is continued until the INR ≥ 2.0 for 24 hoursNOAC: initiated after parenteral anticoagulant (dabigatran/edoxaban) or initiated in place of parenteral anticoagulant (rivaroxaban/apixaban) and continued thereafter
Secondary Prevention
Acute VTE Treatment TrialsAcute VTE Treatment Trials
RE-COVER IIa EINSTEINb,c AMPLIFYd Hokusaie
Drug Dabigatran Rivaroxaban Apixaban Edoxaban
N 2589 8281 5395 8240
Design 2 x blind PROBE 2 x blind 2 x blind
Indication VTE DVT or PE VTE VTE
Heparin bridge Yes No No Yes
Duration, mo 6 3, 6, 12 6 3-12
a. Schulman S, et al. Circulation. 2014;129:764-772[4]; b. Bauersachs R, et al. N Engl J Med. 2010;363:2499-2510[5]; c. Büller HR, et al. N Engl J Med. 2012;366:1287-1297[6]; d. Agnelli G, et al. N Engl J Med. 2013;369:799-808[7]; e. Büller HR, et al. N Engl J Med. 2013;369:1406-1415.[8]
RE-COVER IIStudy DesignRE-COVER IIStudy Design
N = 2589
• Primary efficacy outcomes: Symptomatic recurrent VTE and related death
• Principal safety outcome: Major bleeding
Schulman S, et al. Circulation. 2014;129:764-772.[4]
Warfarin INR 2.0 to 3.0
Dabigatran 150 mg twice daily
R6 months
of treatment
Acute VTE
Treatment with LMWH or UFH for 5 to 11 days
0
0.5
1
1.5
2
2.52.3
1.2
2.2
1.7
Efficacy
% P < .001(for
noninferiority)
Dabigatran
Warfarin
Safety
RE-COVER IIResultsRE-COVER IIResults
Schulman S, et al. Circulation. 2014;129:764-772.[4]
EINSTEIN DVT/PEStudy DesignsEINSTEIN DVT/PEStudy Designs
• Open-label, noninferiority study• Predefined treatment period of 3, 6, or 12 months
• Primary efficacy outcome: Symptomatic recurrent VTE• Principal safety outcome: Major or nonmajor clinically relevant bleeding
Bauersachs R, et al. N Engl J Med. 2010;363:2499-2510[5]; Büller HR, et al. N Engl J Med. 2012;366:1287-1297.[6]
Rivaroxaban15 mg twice daily
Day 1
Day 21
Enoxaparin twice daily for 5 or more days, plus VKA INR 2.0 to 3.0
Rivaroxaban 20 mg once daily
N = 4832EINSTEIN-PE: Objectively
confirmed PE ± DVT
30-day poststudy treatment
period
EINSTEIN-DVT:Objectively
confirmed VTE without PE N = 3449
R
Prins MH, et al. Thromb J. 2013;11:21[9]; Büller HR, et al. ASH 2012. Abstract 20.[10]
EINSTEIN Pooled DataEfficacyEINSTEIN Pooled DataEfficacy
Overall <65 65-75 >75 ≤70 >70 to <90
>90 ≥80 50 to ≤80 <500
0.5
1
1.5
2
2.5
3
3.5
4
2.1 2.11.8
2.32.5
1.82
1.8
2.3
3.3
2.32 2.1
3.7
2.72.4
1.8 1.9
3
3.4
Rivaroxaban Enoxaparin/VKA
P < .001
Age, y Weight, kg Cr Cl, mL/min
%
Overall < 65 65-75 > 75 ≤70 >70 to <90
>90 ≥80 50 to ≤80
<500
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
10.7
1.51.2
1.5
0.8 0.7 0.8
1.4
0.9
1.7
0.9
2.2
4.5
2.21.8
1.31
3
4.1
Rivaroxaban Enoxaparin/VKA
P = .002
Age, y Weight, kg Cr Cl, mL/min
%
EINSTEIN Pooled DataMajor BleedingEINSTEIN Pooled DataMajor Bleeding
Prins MH et al. Thromb J. 2013;11:21[9]; Büller HR, et al. ASH 2012. Abstract 20.[10]
OutcomeRivaroxaban, %
(n = 791)Enoxaparin/VKA, %
(n = 782)HR
(95% CI)P
Value
Recurrence of thromboembolism 2.7 3.8 0.68 (0.39-1.18) --
Overall 2.1 2.3 0.89 (0.66-1.19) < .001
Major bleeding 1.3 4.5 0.27 (0.13-0.54) --
Overall 1.0 1.7 0.54 (0.37-0.79) .002
• Elderly (>75 years) • Body weight ≤ 50 kg • Renal failure (Cr Cl < 50 mL/min)
Büller HR, et al. ASH 2012. Abstract 20.[10]
EINSTEIN Pooled DataFragile PatientsEINSTEIN Pooled DataFragile Patients
AMPLIFYStudy DesignAMPLIFYStudy Design
Enoxaparin every 12 hours for 5 or more days and warfarin to INR 2.0 to 3.0N = 5395
Apixaban 10 mg twice daily for 7
days
Follow-up at 6 months
• Primary efficacy outcome: Symptomatic recurrent VTE or VTE-related death
• Principal safety outcome: Major bleeding
Patients with DVT or PE ±
DVT
Agnelli G, et al. N Engl J Med. 2013;369:799-808.[7]
Apixaban 5 mg twice daily
R
Major Bleeding CRNM Bleeding Major or CRNM Bleeding
0
2
4
6
8
10
12
0.8
3.84.3
1.8
8
9.7
Apixaban
Conventional therapy
Apixaban Conventional Therapy
2
2.1
2.2
2.3
2.4
2.5
2.6
2.7
2.8
2.3
2.7
Recu
rren
t VTE
, %
P < .001(noninferiority)
P < .001(superiority)
P < .001
Blee
ding
Rat
e, %
AMPLIFYResultsAMPLIFYResults
Efficacy Safety
Agnelli G, et al. N Engl J Med. 2013;369:799-808.[7]
Hokusai-VTE Study Design
Maximum treatment period of 12 months
• Primary efficacy outcome: – Symptomatic recurrent VTE or VTE-related death
• Principal safety outcome: – Major or CRNM bleeding during treatment
Raskob, G et al. J Thromb Haemost. 2013;11:1287-1294.[11]
Standard therapy
LMWH/UFH (at least 5 days) + warfarin (INR, 2.0-3.0)N = 8292
Symptomatic DVT and/or PE
Edoxaban
LMWH/UFH (at least 5 days) + edoxaban 60 mg once daily
R
Day 1
Efficacy Safety0
2
4
6
8
10
12
3.2
8.5
3.5
10.3
Edoxaban Warfarin
Hokusai-VTE ResultsHokusai-VTE Results
%
P < .001 (noninferiority)
Büller HR, et al. N Engl J Med. 2013;369:1406-1415.[8]
P = .004 (superiority)
Recurrent VTE in Extension VTE TrialsRecurrent VTE in Extension VTE TrialsIncidence of Recurrent VTE
Trial Agent NOAC, % Warfarin, % HR (95% CI)
RE-MEDYa Dabigatran 1.8 1.3 1.44 (0.78-2.64)
NOAC, % Placebo, % HR (95% CI)
RE-SONATEa Dabigatran 0.4 5.6 0.08 (0.02-0.25)
EINSTEIN-EXTb Rivaroxaban 1.3 7.1 0.18 (0.09-0.39)
AMPLIFY-EXTc
Apixaban 2.5 mg 1.7 8.8 0.19 (0.11-0.33)
Apixaban 5 mg 1.7 8.8 0.20 (0.11-0.34)
a. Schulman S, et al. N Engl J Med. 2013;368:709-718[12]; b. Bauersachs R, et al. N Engl J Med. 2010;363:2499-2510[5]; c. Agnelli G, et al. N Engl J Med. 2013;368:699-708.[13]
Major Bleeding in Extension VTE TrialsMajor Bleeding in Extension VTE Trials
Incidence of Major BleedingTrial Agent NOAC, % Warfarin, % HR (95% CI)
RE-MEDYa Dabigatran 0.9 1.8 0.52 (0.27-1.02)
NOAC, % Placebo, % HR (95% CI)RE-SONATEa Dabigatran 0.3 0 Not estimable
EINSTEIN-EXTb Rivaroxaban 0.7 0 Not estimable
AMPLIFY-EXTc
Apixaban 2.5 mg 0.2 0.5 0.49 (0.09-2.64)
Apixaban 5 mg 0.1 0.5 0.25 (0.03-2.24)
a. Schulman S, et al. N Engl J Med. 2013;368:709-718[12]; b. EINSTEIN Investigators. N Engl J Med. 2010;363:2499-2510[5]; c. Agnelli G, et al. N Engl J Med. 2013;368:699-708.[13]
Schulman S, et al. N Engl J Med. 2013;368:709-718.[12]
RE-MEDY Study Design
Warfarin (INR, 2.0-3.0)
Placebo
Confirmed VTE
Anticoagulant therapy
3 to 12 monthsand “increased
risk of recurrence”
Dabigatran etexilate 150 mg twice daily
PlaceboR
0 to 7 days
until INR ≤ 2.3
Follow-upevery 30 days to 6
months, then every 90
days to end of treatment
Up to 36 monthsEnd of treatmentScreening
Screening/baseline
Treatment period
Schulman S, et al. N Engl J Med. 2013;368:709-718.[12]
RE-SONATE Study Design
Placebo
Confirmed VTE
Anticoagulant (VKA) therapy
6 to 18 months
Dabigatran etexilate 150 mg twice daily
R
0 to 7 days
until INR ≤ 2.3
Follow-up30 days
6 monthsEnd of
treatment
Screening
Screening Treatment period
7 monthsEnd of study
follow-up
Extended follow-up 11 months
18 monthsEnd of
extension follow-up
RE-MEDY, RE-SONATEResultsRE-MEDY, RE-SONATEResults
Dabigatran Warfarin Dabigatran Placebo0
1
2
3
4
5
6
1.81.3
0.4
5.6
Prim
ary
Endp
oint
, %
Efficacy Safety
Major Bleed-ing
Major/CR Bleeding
0
2
4
6
8
10
12
0.9
5.6
1.8
10.2
RE-MEDY RE-SONATE
Major Bleed-ing
Major/CR Bleeding
0.3
5.3
0
1.8
Schulman S, et al. N Engl J Med. 2013;368:709-718.[12]
RE-MEDY RE-SONATE
Dabigatran
Warfarin
Dabigatran
Placebo
Placebo
Rivaroxaban 20 mg once daily
N = 1197
Additional 6 to 12
months of treatment
• Primary efficacy outcome: Symptomatic recurrent VTE
• Principal safety outcome: Major bleeding
Bauersachs R, et al. N Engl J Med. 2010;363:2499-2510.[5]
Patients in EINSTEIN-DVT
who had completed 6 to 12 months of
therapy
Equipoise: Should treatment be continued?
R
EINSTEIN-Extension Study Design
Rivaroxaban Placebo0
1
2
3
4
5
6
7
8
1.3
7.1
Recurrent VTE
Patie
nts,
%EINSTEIN-ExtensionResults
P < .001
P < .001
Major/CRNM Bleeding
Major Bleeding CRNM Bleeding0
1
2
3
4
5
6
76
0.7
5.4
1.2
0
1.2
Safety
Rivaroxaban Placebo
Patie
nts,
%
Bauersachs R, et al. N Engl J Med. 2010;363:2499-2510.[5]
AMPLIFY-EXT Study DesignAMPLIFY-EXT Study Design
• Primary endpoint: VTE recurrence or death• Secondary outcome measures: Major bleeding
Agnelli G, et al. N Engl J Med. 2013;368:699-708.[13]
PlaceboN = 2482
Clinical diagnosis of DVT or PE,
anticoagulation treatment 6 to 12
months, no recurrence
Follow-up at 12
months
Apixaban 2.5 mg twice daily
Apixaban 5 mg twice daily
Equipoise: Should treatment be continued?
R
Apixaban 2.5 mg
Apixaban 5 mg Placebo0
2
4
6
8
10
12
14
3.8 4.2
11.6
Efficacy
Recu
rren
t VTE
or D
eath
, %
Agnelli G, et al. N Engl J Med. 2013;368:699-708.[13]
P < .001 P < .001
AMPLIFY-EXTResultsAMPLIFY-EXTResults
Major Bleeding CRNM Bleeding Major/CRNM Bleeding
0
0.5
1
1.5
2
2.5
3
3.5
4
4.5
5
0.2
33.2
0.1
4.2 4.3
0.5
2.3
2.7
SafetyApixaban 2.5 mg
Apixaban 5 mg
Placebo
Blee
ding
Rat
e, %
• Dabigatran (not approved by the US Food and Drug Administration for this indication)
– RE-MODEL: Dabigatran 150/220 mg vs enoxaparin 40 mg daily, 6 to 10 days, TKRa
– RE-MOBILIZE: Dabigatran 150/220 mg daily vs enoxaparin 30 mg twice a day, 12 to 15 days, TKRb
– RE-NOVATE: Dabigatran 150/220 mg vs enoxaparin 40 mg daily, 28 to 35 days THRc
– RE-NOVATE II: Dabigatran 220 mg vs enoxaparin 40 mg daily, 28 to 35 days, THRd
a. Eriksson BI, et al. J Thromb Haemost. 2007;5:2178-2185[14] ; b. Ginsberg JS, et al. J Arthroplasty. 2009;24:1-9[15]; c. Eriksson BI, et al. Lancet. 2007;370:949-956[16]; d. Eriksson BI, et al. Thromb Haemost. 2011;105:721-729.[17]
DabigatranTrials in Major Orthopedic Surgery
DabigatranPooled AnalysisDabigatranPooled Analysis
EnoxaparinDabigatran
150 mg Dabigatran
220 mg
Efficacy P Value P Value
Major VTE and VTE-related mortality, %
3.3 3.8 .91 3.0 .20
Safety
Major bleeding, % 1.4 1.1 .16 1.4 .61
Major + CRNM 5.0 5.6 .58 5.6 .56
Friedman RJ, et al. Thromb Res. 2010;126:175-182.[18]
• Apixaban – ADVANCE-1: Apixaban 2.5 mg twice daily vs enoxaparin
30 mg every 12 hours for 10 to 14 days, TKRa
– ADVANCE-2: Apixaban 2.5 mg twice daily vs enoxaparin 40 mg daily for 10 to 14 days, TKRb
– ADVANCE-3: Apixaban 2.5 mg twice daily vs enoxaparin 40 mg daily every 24 hours for 5 weeks, THRc
a. Lassen MR, et al. N Engl J Med. 2009;361:594-604[19]; b. Lassen MR, et al. Lancet 2010;375:807-815[20]; c. Lassen MR, et al. N Engl J Med 2010;363:2487-2498. [21]
ApixabanTrials in Major Orthopedic Surgery
ApixabanPooled Results of ADVANCE-2 and ADVANCE-3
• N = 8464 patients undergoing TKR (ADVANCE-2) and THR (ADVANCE-3)
Raskob GE, et al. J Bone Joint Surg Br 2012;94:257-264.[22]
Efficacy Apixaban Enoxaparin Risk Difference (95% CI) P
Major VTE, % 0.7 1.5 −0.8 (−1.2 to −0.3) .001
Safety
Major bleeding, % 0.7 0.8 −0.02 (−0.4 to 0.4) --
CRNM bleeding, % 3.6 4.2 −0.6 (−1.4 to 0.3) --
• Rivaroxaban – RECORD1: Rivaroxaban 10 mg daily vs enoxaparin 40 mg
daily for 5 weeks, THRa
– RECORD2: Rivaroxaban 10 mg daily for 5 weeks vs enoxaparin 40 mg daily for 10 to 14 days, THRb
– RECORD3: Rivaroxaban 10 mg vs enoxaparin 40 mg daily for 13 to 17 days, TKRc
– RECORD4: Rivaroxaban 10 mg daily vs enoxaparin 30 mg every 12 hours for 17 days, TKRd
a. Eriksson BI, et al. N Engl J Med. 2008;358:2765-2775[23]; b. Kakkar AK, et al. Lancet. 2008;372:31-39[24] ; c. Lassen MR, et al. N Engl J Med. 2008;358:2776-2786[25]; d. Turpie AG, et al. Lancet. 2009;373:1673-1680.[26]
Rivaroxaban Trials in Major Orthopedic Surgery
N = 12,729 Rivaroxaban, % Enoxaparin, % HR (95% CI) P
Primary Efficacy End Point
Composite of symptomatic VTE + all-cause mortality
0.5 1.0 0.48 (0.30-0.76) .001
Symptomatic VTE 0.39 0.84 0.46 (0.27-0.76) --
PE 0.11 0.26 0.44 (0.15-1.12) --
All-cause mortality 0.10 0.16 0.60 (0.18-1.82) --
Bleeding Events
Major bleeding 0.3 0.2 1.62 (0.77-3.53) .23
Major + CRNM bleeding 2.8 2.5 1.17 (0.93-1.46) .19
Any bleeding 6.6 6.2 1.07 (0.92-1.24) .38
Rivaroxaban RECORD1-RECORD4: Pooled Analysis
Turpie AG. et al. Thromb Haemost. 2011;105:444-453.[27]
95% CI = 95% confidence intervalADVANCE-1 = Apixaban Dose Orally vs Anticoagulation with Enoxaparin ADVANCE-2 = Apixaban versus enoxaparin for thromboprophylaxis after knee replacementADVANCE-3 = Apixaban Dosed Orally Versus Anticoagulation with Injectable Enoxaparin to Prevent Venous Thromboembolism 3 AMPLIFY = Apixaban for the Initial Management of Pulmonary Embolism and Deep-Vein Thrombosis as First-Line TherapyCRNM = clinically relevant nonmajorDVT = deep vein thrombosisEXT = extensionHR = hazard ratioINR = international normalized ratioLMWH = low-molecular-weight heparinNOAC = non-vitamin K (novel) oral anticoagulantsPE = pulmonary embolism
AbbreviationsAbbreviations
P-gp = P-glycoproteinPK/PD = pharmacokinetics/pharmacodynamics PROBE = prospective, randomized, open-label, blinded end point evaluation RECORD = Regulation of Coagulation in Orthopedic Surgery to Prevent Deep Venous Thrombosis and Pulmonary Embolism RE-COVER = Efficacy and Safety of Dabigatran Compared to Warfarin for 6 Month Treatment of Acute Symptomatic Venous ThromboembolismRE-LY = Randomized Evaluation of Long-Term Anticoagulation Therapy RE-SONATE = Twice-daily Oral Direct Thrombin Inhibitor Dabigatran Etexilate in the Long Term Prevention of Recurrent Symptomatic VTEROCKET AF = Rivaroxaban Once Daily Oral Direct Factor Xa Inhibitor Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation THR = total hip replacementTKR = total knee replacementUFH = unfractionated heparinVKA = vitamin K antagonistVTE = venous thromboembolism
Abbreviations (cont)Abbreviations (cont)
ReferencesReferences1. Heidbuchel H, Verhamme P, Alings M, et al; European Heart Rhythm Association. European Heart Rhythm Association Practical Guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation. Europace. 2013;15:625-651.
2. Hellwig T, Gulseth M. Pharmacokinetic and pharmacodynamic drug interactions with new oral anticoagulants: what do they mean for patients with atrial fibrillation? Ann Pharmacother. 2013;47:1478-1487.
3. Kearon C, Akl EA, Comerota AJ, et al; American College of Chest Physicians. Antithrombotic therapy for VTE disease: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141:e419S-e494S.
4. Schulman S, Kakkar AK, Goldhaber SZ, et al; RE-COVER II Trial Investigators. Treatment of acute venous thromboembolism with dabigatran or warfarin and pooled analysis. Circulation. 2014;129:764-772.
5. Bauersachs R, Berkowitz SD, Brenner B, et al; EINSTEIN Investigators. Oral rivaroxaban for symptomatic venous thromboembolism. N Engl J Med. 2010;363:2499-2510.
6. Büller HR, Prins MH, Lensin AW, et al; EINSTEIN–PE Investigators. Oral rivaroxaban for the treatment of symptomatic pulmonary embolism. N Engl J Med. 2012;366:1287-1297.
7. Agnelli G, Büller HR, Cohen A, et al; AMPLIFY Investigators. Oral apixaban for the treatment of acute venous thromboembolism. N Engl J Med. 2013;369:799-808.
8. Büller HR, Décousus H, Grosso MA, et al; Hokusai-VTE Investigators. Edoxaban versus warfarin for the treatment of symptomatic venous thromboembolism. N Engl J Med. 2013;369:1406-1415.
9. Prins MH, Lensing AW, Bauersachs R, et al; EINSTEIN Investigators. Oral rivaroxaban versus standard therapy for the treatment of symptomatic venous thromboembolism: a pooled analysis of the EINSTEIN-DVT and PE randomized studies. Thromb J. 2013;11:21.
10. Büller HR, et al. Oral Rivaroxaban for the Treatment of Symptomatic Venous Thromboembolism: A Pooled Analysis of the EINSTEIN DVT and EINSTEIN PE Studies. ASH Annual Meeting Abstracts. 2012;120:Abstract 20.
11. Raskob G, Büller H, Prins M, et al; Hokusai-VTE Investigators. Edoxaban for the long-term treatment of venous thromboembolism: rationale and design of the Hokusai-venous thromboembolism study--methodological implications for clinical trials. J Thromb Haemost. 2013;11:1287-1294.
12. Schulman S, Kearon C, Kakkar AK, et al; RE-MEDY Trial Investigators; RE-SONATE Trial Investigators. Extended use of dabigatran, warfarin, or placebo in venous thromboembolism. N Engl J Med. 2013;368:709-718.
13. Agnelli G, Büller HR, Cohen A, et al; AMPLIFY-EXT Investigators. Apixaban for extended treatment of venous thromboembolism. N Engl J Med. 2013;368:699-708.
References (cont)References (cont)
14. Eriksson BI, Dahl OE, Rosencher N, et al; RE-MODEL Study Group. Oral dabigatran etexilate vs. subcutaneous enoxaparin for the prevention of venous thromboembolism after total knee replacement: the RE-MODEL randomized trial. J Thromb Haemost. 2007;5:2178-2185.
15. Ginsberg JS, Davidson BL, Comp PC, et al; RE-MOBILIZE Writing Committee. Oral thrombin inhibitor dabigatran etexilate vs North American enoxaparin regimen for prevention of venous thromboembolism after knee arthroplasty surgery. J Arthroplasty. 2009;24:1-9.
16. Eriksson BI, Dahl OE, Rosencher N, et al; RE-NOVATE Study Group. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double-blind, non-inferiority trial. Lancet. 2007;370:949-956.
17. Eriksson BI, Dahl OE, Huo MH, et al; RE-NOVATE II Study Group. Oral dabigatran versus enoxaparin for thromboprophylaxis after primary total hip arthroplasty (RE-NOVATE II). A randomised, double-blind, non-inferiority trial. Thromb Haemost. 2011;105:721-729. 18. Friedman RJ, Dahl OE, Rosencher N, et al; RE-MOBILIZE, RE-MODEL, RE-NOVATE Steering Committees. Dabigatran versus enoxaparin for prevention of venous thromboembolism after hip or knee arthroplasty: a pooled analysis of three trials. Thromb Res. 2010;126:175-182.
19. Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Portman RJ. Apixaban or enoxaparin for thromboprophylaxis after knee replacement. N Engl J Med. 2009;361:594-604.
References (cont)References (cont)
20. Lassen MR, Raskob GE, Gallus A, Pineo G, Chen D, Hornick P; ADVANCE-2 investigators. Apixaban versus enoxaparin for thromboprophylaxis after knee replacement (ADVANCE-2): a randomised double-blind trial. Lancet. 2010;375:807-815.
21. Lassen MR, Gallus A, Raskob GE, Pineo G, Chen D, Ramirez LM; ADVANCE-3 Investigators. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N Engl J Med 2010;363:2487-2498.
22. Raskob GE, Gallus AS, Pineo GF, et al. Apixaban versus enoxaparin for thromboprophylaxis after hip or knee replacement: pooled analysis of major venous thromboembolism and bleeding in 8464 patients from the ADVANCE-2 and ADVANCE-3 trials. J Bone Joint Surg Br. 2012;94:257-264.
23. Eriksson BI, Borris LC, Friedman RJ, et al; RECORD1 Study Group. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N Engl J Med. 2008;358:2765-2775.
24. Kakkar AK, Brenner B, Dahl OE, et al; RECORD2 Investigators. Extended duration rivaroxaban versus short-term enoxaparin for the prevention of venous thromboembolism after total hip arthroplasty: a double-blind, randomised controlled trial. Lancet. 2008;372:31-39.
25. Lassen MR, Ageno W, Borris LC, et al; RECORD3 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N Engl J Med. 2008;358:2776-2786.
References (cont)References (cont)
26. Turpie AG, Lassen MR, Davidson BL, et al; RECORD4 Investigators. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty (RECORD4): a randomised trial. Lancet. 2009;373:1673-1680.
27. Turpie AG, Lassen MR, Eriksson BI, et al. Rivaroxaban for the prevention of venous thromboembolism after hip or knee arthroplasty. Pooled analysis of four studies. Thromb Haemost. 2011;105:444-453.
References (cont)References (cont)