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Meta-Analysis
. 2010 Apr 14;2010(4):CD005981.
doi: 10.1002/14651858.CD005981.pub2.

Direct thrombin inhibitors versus vitamin K antagonists or low molecular weight heparins for prevention of venous thromboembolism following total hip or knee replacement

Carlos A Salazar  1 , German Malaga, Giuliana Malasquez
Affiliations
Meta-Analysis

Direct thrombin inhibitors versus vitamin K antagonists or low molecular weight heparins for prevention of venous thromboembolism following total hip or knee replacement

Carlos A Salazar et al. Cochrane Database Syst Rev. .

Abstract

Background: Patients who have undergone total hip or knee replacement (THR, TKR) have a high risk of developing venous thromboembolism (VTE) following surgery, despite appropriate anticoagulation with warfarin or low molecular weight heparin (LMWH). New anticoagulants are under investigation.

Objectives: To examine the efficacy and safety of prophylactic anticoagulation with direct thrombin inhibitors (DTIs) versus LMWH or vitamin K antagonists in the prevention of VTE in patients undergoing THR or TKR.

Search strategy: The Cochrane Peripheral Vascular Disease Group searched their Specialized Register (last searched 12 March 2010) and CENTRAL (last searched 2010, Issue 2).

Selection criteria: Randomised controlled trials.

Data collection and analysis: Three reviewers independently assessed methodological quality and extracted data in pre-designed tables. The reported follow-up events were included

Main results: We included 14 studies included involving 21,642 patients evaluated for efficacy and 27,360 for safety. No difference was observed in major VTE in DTIs compared with LMWH in both types of operations (odds ratio (OR) 0.91; 95% confidence interval (CI) 0.69 to 1.19), with high heterogeneity (I(2) 71%). No difference was observed with warfarin (OR 0.85; 95% CI 0.63 to 1.15) in TKR, with no heterogeneity (I(2) 0%).More total bleeding events were observed in the DTI group (in ximelagatran and dabigatran but not in desirudin) in patients subjected to THR (OR 1.40; 95% CI 1.06, 1.85; I(2) 41%) compared with LMWH. No difference was observed with warfarin in TKR (OR 1.76; 95% CI 0.91 to 3.38; I(2) 0%). All-cause mortality was higher in the DTI group when the reported follow-up events were included (OR 2.06; 95% CI 1.10 to 3.87).Studies that initiated anticoagulation before surgery showed less VTE events; those that began anticoagulation after surgery showed more VTE events in comparison with LMWH. Therefore, the effect of the DTIs compared with LMWH appears to be influenced by the time of initiation of coagulation more than the effect of the drug itself.The results obtained from sensitivity analysis, did not differ from the analysed results; this strengthens the value of the results.

Authors' conclusions: Direct thrombin inhibitors are as effective in the prevention of major venous thromboembolism in THR or TKR as LMWH and vitamin K antagonists. However, they show higher mortality and cause more bleeding than LMWH. No severe hepatic complications were reported in the analysed studies. Use of ximelagatran is not recommended for VTE prevention in patients who have undergone orthopedic surgery. More studies are necessary regarding dabigatran.

PubMed Disclaimer

Conflict of interest statement

None of the authors has any working contact with pharmaceutical companies or companies that could influence the review results. The authors' interest and commitment was to apply without any intentional bias the techniques and methodology developed by The Cochrane Collaboration for the preparation of systematic reviews to obtain precise and objective results.

Figures

1
1
Methodological quality graph: review authors' judgements about each methodological quality item presented as percentages across all included studies. Note: data from EXTEND 2009a (an excluded study) is shown.
2
2
Methodological quality summary: review authors' judgements about each methodological quality item for each included study. Note: data from EXTEND 2009a study is shown to allow comparisons.
3
3
Sensitivity Analysis of Efficacy: DTI vs. LMWH in Major VTE in THR+TKR
4
4
Sensitivity Analysis of Safety: DTI vs. LMWH in Major Bleeding in THR+TKR
5
5
Funnel plot of comparison: Efficacy DTI (any dose) vs. LMWH + follow up events, outcome: Major VTE events in THR + TKR combined doses.
6
6
Funnel plot of comparison: Safety DTI (any dose) vs. LMWH + follow up events, outcome: Total Bleeding events in THR + TKR combined doses.
7
7
Funnel plot of comparison: Efficacy DTI (any dose) vs. VKA (Warfarin) + follow‐up events, outcome: Major VTE events in TKR combined doses.
8
8
Funnel plot of comparison: Safety DTI (any dose) vs. VKA (Warfarin) + follow‐up events, outcome: Major/ Significant Bleeding events in TKR combined doses.
1.1
1.1. Analysis
Comparison 1 Efficacy DTI (any dose) vs. LMWH + follow up events, Outcome 1 Major VTE events in THR + TKR combined doses.
1.2
1.2. Analysis
Comparison 1 Efficacy DTI (any dose) vs. LMWH + follow up events, Outcome 2 Total VTE events in THR + TKR combined doses.
1.3
1.3. Analysis
Comparison 1 Efficacy DTI (any dose) vs. LMWH + follow up events, Outcome 3 Symptomatic VTE.
2.1
2.1. Analysis
Comparison 2 Safety DTI (any dose) vs. LMWH + follow up events, Outcome 1 Major/Significant Bleeding events in THR + TKR combined doses.
2.2
2.2. Analysis
Comparison 2 Safety DTI (any dose) vs. LMWH + follow up events, Outcome 2 Total Bleeding events in THR + TKR combined doses.
2.3
2.3. Analysis
Comparison 2 Safety DTI (any dose) vs. LMWH + follow up events, Outcome 3 ALT >3 times the upper normal limit combined doses.
2.4
2.4. Analysis
Comparison 2 Safety DTI (any dose) vs. LMWH + follow up events, Outcome 4 All‐cause Mortality events combined doses in THR+TKR.
3.1
3.1. Analysis
Comparison 3 Sensitivity Analysis 1: Extended prophylactic anticoagulation vs. Standard prophylactic anticoagulation, Outcome 1 Major VTE events in TKR combined doses + follow‐up events.
3.2
3.2. Analysis
Comparison 3 Sensitivity Analysis 1: Extended prophylactic anticoagulation vs. Standard prophylactic anticoagulation, Outcome 2 Symptomatic VTE in TKR combined doses + follow‐up events.
3.3
3.3. Analysis
Comparison 3 Sensitivity Analysis 1: Extended prophylactic anticoagulation vs. Standard prophylactic anticoagulation, Outcome 3 Total Bleeding events in TKR combined doses + follow‐up events.
4.1
4.1. Analysis
Comparison 4 Sensitivity Analysis 2: Time of Initiation of Therapy in DTI vs. LMWH, Outcome 1 Major VTE events in THR + TKR combined doses.
4.2
4.2. Analysis
Comparison 4 Sensitivity Analysis 2: Time of Initiation of Therapy in DTI vs. LMWH, Outcome 2 Symptomatic VTE.
4.3
4.3. Analysis
Comparison 4 Sensitivity Analysis 2: Time of Initiation of Therapy in DTI vs. LMWH, Outcome 3 Total Bleeding events in THR + TKR combined doses.
4.4
4.4. Analysis
Comparison 4 Sensitivity Analysis 2: Time of Initiation of Therapy in DTI vs. LMWH, Outcome 4 All‐cause Mortality events combined doses in THR+TKR.
5.1
5.1. Analysis
Comparison 5 Efficacy DTI (any dose) vs. VKA (Warfarin) + follow‐up events, Outcome 1 Major VTE events in TKR combined doses.
5.2
5.2. Analysis
Comparison 5 Efficacy DTI (any dose) vs. VKA (Warfarin) + follow‐up events, Outcome 2 Total VTE events in TKR combined doses.
5.3
5.3. Analysis
Comparison 5 Efficacy DTI (any dose) vs. VKA (Warfarin) + follow‐up events, Outcome 3 Symptomatic VTE events in TKR combined doses.
6.1
6.1. Analysis
Comparison 6 Safety DTI (any dose) vs. VKA (Warfarin) + follow‐up events, Outcome 1 Major/ Significant Bleeding events in TKR combined doses.
6.2
6.2. Analysis
Comparison 6 Safety DTI (any dose) vs. VKA (Warfarin) + follow‐up events, Outcome 2 Total Bleeding events in TKR combined doses.
6.3
6.3. Analysis
Comparison 6 Safety DTI (any dose) vs. VKA (Warfarin) + follow‐up events, Outcome 3 All‐cause Mortality events in TKR combined doses.
6.4
6.4. Analysis
Comparison 6 Safety DTI (any dose) vs. VKA (Warfarin) + follow‐up events, Outcome 4 ALT >3 times the upper normal limit at the end of Treatment in TKR combined doses.
6.5
6.5. Analysis
Comparison 6 Safety DTI (any dose) vs. VKA (Warfarin) + follow‐up events, Outcome 5 ALT >3 times the upper normal limit at the end of Follow‐up in TKR combined doses.
See this image and copyright information in PMC

Comment in

References

References to studies included in this review

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Colwell 2003 {published data only (unpublished sought but not used)}
    1. Colwell CW Jr, Berkowitz SD, Davidson BL, Lotke PA, Ginsberg JS, Lieberman JR, et al. Comparison of ximelagatran, an oral direct thrombin inhibitor, with enoxaparin for the prevention of venous thromboembolism following total hip replacement. A randomized, double‐blind study. Journal of Thrombosis and Haemostasis 2003;1(10):2119‐30. - PubMed
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EXPRESS 2003 {published data only (unpublished sought but not used)}
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    1. Eriksson BI, Agnelli G, Cohen AT, Dahl OE, Lassen MR, Mouret P, et al. EXPRESS Study Group. The direct thrombin inhibitor melagatran followed by oral ximelagatran compared with enoxaparin for the prevention of venous thromboembolism after total hip or knee replacement: the EXPRESS study. Journal of Thrombosis and Haemostasis 2003;1(12):2490‐6. - PubMed
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EXULT B 2005 {published data only (unpublished sought but not used)}
    1. Colwell CW. EXULT B: More ximelagatran results in VTE prophylaxis after total knee replacement. Abstract of the Annual Meeting of the American Society of Hematology (http://www.theheart.org/article/231713.do). (accessed 10 May 2006).
    1. Colwell CW Jr, Berkowitz SD, Lieberman JR, Comp PC, Ginsberg JS, Paiement G, et al. Oral direct thrombin inhibitor ximelagatran compared with warfarin for the prevention of venous thromboembolism after total knee arthroplasty. Journal of Bone and Joint Surgery ‐ American Volume 2005;87(10):2169‐77. - PubMed
    1. Colwell CW, Berkowitz SD, Comp PC, Lieberman JR, Ginsberg JS, Paiement G, et al. Randomized, double‐blind comparison of ximelagatran, an oral direct thrombin inhibitor, and warfarin to prevent venous thromboembolism (VTE) after total knee replacement (TKR): EXULT B. Blood 2003;102(11):Abstract 39.
EXULT A 2003 {published data only (unpublished sought but not used)}
    1. Francis CW, Berkowitz SD, Comp PC, Lieberman JR, Ginsberg JS, Paiement G, et al. Randomized, double‐blind comparison of ximelagatran, an oral direct thrombin inhibitor, and warfarin to prevent venous thromboembolism (VTE) after total knee replacement (TKR). Journal of Thrombosis and Haemostasis 2003;1(Suppl 1):Abstract P1912. - PubMed
    1. Francis CW, Berkowitz SD, Comp PC, Lieberman JR, Ginsberg JS, Paiement G, et al. EXULT A Study Group. Comparison of ximelagatran with warfarin for the prevention of venous thromboembolism after total knee replacement. New England Journal of Medicine 2003;349(18):1703‐12. - PubMed
    1. Francis CW, Berkowitz SD, Comp PC, Lieberman JR, Ginsberg JS, Paiement GD, et al. Randomized, double‐blind, comparison of ximelagatran, an oral direct thrombin inhibitor, and warfarin to prevent venous thromboembolism (VTE) after total knee replacement (TKR). Blood 2002;100(11 pt 2):Abstract 300.
Francis 2002 {published data only (unpublished sought but not used)}
    1. Francis CW, Davidson BL, Berkowitz SD, Lotke PA, Ginsberg JS, Lieberman JR, et al. Randomized double‐blind, comparative study of ximelagatran (pINN, formerly H 376/95), an oral direct thrombin inhibitor, and warfarin to prevent venous thromboembolism (VTE) after total knee arthroplasty (TKA). Thrombosis and Haemostasis 2001;July Suppl:Abstract OC44.
    1. Francis CW, Davidson BL, Berkowitz SD, Lotke PA, Ginsberg JS, Lieberman JR, et al. Ximelagatran versus warfarin for the prevention of venous thromboembolism after total knee arthroplasty. A randomized, double‐blind trial. Annals of Internal Medicine 2002;137(8):648‐55. - PubMed
Heit 2001 {published data only (unpublished sought but not used)}
    1. Heit JA, Colwell CW, Francis CW, Ginsberg JS, Berkowitz SD, Whipple J, et al. Astrazeneca Arthroplasty Study Group. Comparison of the oral direct thrombin inhibitor ximelagatran with enoxaparin as prophylaxis against venous thromboembolism after total knee replacement: A phase 2 dose‐finding study. Archives of Internal Medicine 2001;161(18):2215‐21. - PubMed
METHRO I 2002 {published data only (unpublished sought but not used)}
    1. Eriksson BI, Arfwidsson AC, Frison L, Eriksson UG, Bylock A, Kalebo P, et al. A dose‐ranging study of the oral direct thrombin inhibitor, ximelagatran, and its subcutaneous form, melagatran, compared with dalteparin in the prophylaxis of thromboembolism after hip or knee replacement: METHRO I. MElagatran for THRombin inhibition in Orthopaedic surgery. Thrombosis & Haemostasis 2002;87(2):231‐37. - PubMed
METHRO II 2002 {published data only (unpublished sought but not used)}
    1. Eriksson BI, Bergqvist D, Kalebo P, Dahl OE, Lindbratt S, Bylock A, et al. Melagatran for Thrombin, inhibition in Orthopaedic Surgery. Ximelagatran and melagatran compared with dalteparin for prevention of venous thromboembolism after total hip or knee replacement: the METHRO II randomised trial. Lancet 2002;360(9344):1441‐47. - PubMed
    1. Eriksson BI, Lindbratt S, Kalebo P. Methro II: dose‐response study of the novel oral, direct thrombin inhibotor, H 376/95 and its subcutaneous formulation melagatran, compared with dalteparin as thromboembolic prophylaxis after total hip knee replacement. Haemostasis 2000;30(Suppl 1):20‐1.
METHRO III 2003 {published data only (unpublished sought but not used)}
    1. Dahl O, Eriksson B, Agnelli G, Cohen A, Mouret P, Rosencher N, et al. ASA and NSAIDs with Melagatran/Ximelagatran or Enoxaparin Do NOT Increase Bleeding in Patients Undergoing Joint Replacement Surgery. The METHRO III Study. Journal of Thrombosis and Haemostasis 2005;3(1):Abstract P 1627.
    1. Dahl OE, Eriksson BI, Agnelli G, Cohen AT, Mouret P, Rosencher N, et al. Postoperative melagatran/ximelagatran for the prevention of venous thromboembolism following major elective orthopaedic surgery: Effects of timing of first dose and risk factors for thromboembolism and bleeding complications on efficacy and safety. Clinical Drug Investigation 2005;25(1): 2005;25(1):65‐77. - PubMed
    1. Eriksson BI, Agnelli G, Cohen A, Dahl O, Mouret P, Rosencher N, et al. Significantly lower need for blood transfusions associated with post‐operatively initiated subcutaneous melagatran/oral ximelagatran compared with enoxaparin. Thrombosis and Haemostasis 2004;92(2):428‐30. - PubMed
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RE‐MOBILIZE 2009 {published data only}
    1. Ginsberg JS, Davidson BL, Comp PC, Francis CW, MD, Friedman RJ, Huo MH, et al. Oral thrombin inhibitor dabigatran etexilate vs North American enoxaparin regimen for prevention of venous thromboembolism after knee arthroplasty surgery. The Journal of Arthroplasty 2009;24(1):1‐9. - PubMed
RE‐MODEL 2007 {published data only (unpublished sought but not used)}
    1. Eriksson BI, Dahl OE, Rosencher N, Kurth AA, van Dijk, CN, Frostick SP, etal. 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. Journal of Thrombosis and Haemostasis 2007;5(11):2178‐85. - PubMed
    1. Eriksson BI, Dahl OE, Dijk CN, Frostick SP, Kurth AA, Rosencher N, et al. A new oral aniticoagulant, dabigatran etexilate, is effective and safe in preventing venous thromboembolism after total knee replacement surgery (The RE‐MODEL Trial). Blood 2006;108:173.
    1. Eriksson, et al. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, double‐blind, non‐inferiority trial. (Erratum). Lancet 2007;370:2003. - PubMed
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RE‐NOVATE 2007 {published data only (unpublished sought but not used)}
    1. Eriksson BI, Dahl OE, Rosencher N, Kurth AA, Dijk CN, Frostick SP, et al. Dabigatran etexilate versus enoxaparin for prevention of venous thromboembolism after total hip replacement: a randomised, doubleblind, non‐inferiority trial. Lancet 2007;370(9591):949‐56. - PubMed

References to studies excluded from this review

Cofrancesco 1996 {published data only}
    1. Cofrancesco E, Cortellaro M, Leonardi P, Corradi A, Ravasi F, Bertocchi F. Markers of hemostatic system activation during thromboprophylaxis with recombinant hirudin in total hip replacement. Thrombosis and Haemostasis 1996;75(3):407‐11. - PubMed
Ekman 1995 {published data only}
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Eriksson 1996 {published data only}
    1. Eriksson BI, Ekman S, Kälebo P, Zachrisson B, Bach D, Close P. Prevention of deep‐vein thrombosis after total hip replacement: direct thrombin inhibition with recombinant hirudin, CGP 39393. Lancet 1996;347(9002):635‐9. - PubMed
Eriksson 2002 {published data only}
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Eriksson 2003 {published data only}
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Eriksson 2003b {published data only}
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EXTEND 2009 {published data only}
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Harenberg 2006 {published data only}
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Mouret 2002 {published data only}
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ODIXa‐HIP 2006 {published data only}
    1. Eriksson BI, Borris L, Dahl OE, Haas S, Huisman MV, Kakkar AK, et al. Oral, direct Factor Xa inhibition with BAY 59‐7939 for the prevention of venous thromboembolism after total hip replacement. Journal of Thrombosis and Haemostasis 2006;4(1):121‐8. - PubMed
    1. Eriksson BI, Borris LC, Dahl OE, Haas S, Huisman MV, Kakkar AK, et al. A once‐daily, oral, direct Factor Xa inhibitor, rivaroxaban (BAY 59‐7939), for thromboprophylaxis after total hip replacement [see comment]. Circulation 2006;114(22):2374‐81. - PubMed
    1. Eriksson BI, Borris LC, Dahl OE, Haas SK, Huisman MV, Kakkar AK, et al. Prevention of venous thromboembolism with an oral, direct factor Xa inhibitor ‐ BAY 59‐7939 ‐ in elective hip replacement: A dose‐ranging study. Thrombosis and Haemostasis 2005;3:Abstract number: OR062.
ODIXa‐Knee 2005 {published data only}
    1. Turpie AG, Fisher WD, Bauer K, Kwong L, Gent M, Misselwitz F. An oral, direct factor Xa inhibitor ‐ BAY 59‐7939 ‐ for prophylaxis against venous thromboembolism after total knee replacement: A dose‐ranging study. Journal of Thrombosis and Haemostasis 2005;3(1):Abstract number: OR063. - PubMed
    1. Turpie AG, Fisher WD, Bauer KA, Kwong LM, Irwin MW, Kalebo P, et al. BAY 59‐7939: an oral, direct factor Xa inhibitor for the prevention of venous thromboembolism in patients after total knee replacement. A phase II dose‐ranging study. Journal of Thrombosis and Haemostasis 2005;3(11):2479‐86. - PubMed
ONYX 2007 {published data only}
    1. Eriksson BI, Turpie AG, Lassen MR, Prins MH, Agnelli G, Kalebo P, et al. A dose escalation study of YM150, an oral direct factor Xa inhibitor, in the prevention of venous thromboembolism in elective primary hip replacement surgery. Thrombosis and Haemostasis 2007;5(8):1660‐5. - PubMed
    1. Eriksson BI, Turpie AGG, Lassen MR, Prins MH, Agnelli G, Gaillard ML, et al. YM150, an oral direct factor Xa inhibitor, as prophylaxis for venous thromboembolism in patients with elective primary hip replacement surgery. A dose escalation study. Blood 2005;106(11):Abstract 1865.
RECORD 2007 {published data only}
    1. Lassen MR, Turpie AG, Rosencher N, Borris LC, Ageno W, Lieberman JR, et al. Rivaroxaban: An oral, direct factor Xa inhibitor for the prevention of venous thromboembolism in total knee replacement surgery ‐ Results of the RECORD 3 study. XXIst Congress of the International Society on Thrombosis and Haemostasis. 2007:Abstract.
Troc¢niz 2007 {published data only}
    1. Troc¢niz IF, Tillmann C, Liesenfeld KH, Sch"fer HG, Stangier J. Population pharmacokinetic analysis of the new oral thrombin inhibitor dabigatran etexilate (BIBR 1048) in patients undergoing primary elective total hip replacement surgery. Journal of Clinical Pharmacology 2007;47:371‐82. - PubMed
Turpie 2005 {published data only}
    1. Turpie AG, Fisher WD, Bauer KA, Kwong LM, Irwin MW, Kälebo P, et al. BAY 59‐7939: an oral, direct factor Xa inhibitor for the prevention of venous thromboembolism in patients after total knee replacement. A phase II dose‐ranging study. Journal of Thrombosis and Haemostasis 2005;11:2479‐86. - PubMed
Wahlander 2002 {published data only}
    1. Wahlander K, Larson G, Lindahl TL, Andersson C, Frison L, Gustafsson D, et al. Factor V Leiden (G1691A) and prothrombin gene G20210A mutations as potential risk factors for venous thromboembolism after total hip or total knee replacement surgery. Thrombosis and Haemostasis 2002;87(4):580‐5. - PubMed

References to ongoing studies

RE‐NOVATE II 2009 {published data only}
    1. Dabigatran Etexilate Compared With Enoxaparin in Prevention of VTE Following Total Hip Arthroplasty. Ongoing study March 2008. Estimated Enrollment:1920 patients.

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