title: Direct thrombin inhibitors versus vitamin K antagonists or low molecular weight heparins for prevention of venous thromboembolism following total hip or knee replacement.
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.
  
  
  OBJECTIVE
  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.
  
  
  METHODS
  The Cochrane Peripheral Vascular Disease Group searched their Specialized Register (last searched 12 March 2010) and CENTRAL (last searched 2010, Issue 2).
  
  
  METHODS
  Randomised controlled trials.
  
  
  METHODS
  Three reviewers independently assessed methodological quality and extracted data in pre-designed tables. The reported follow-up events were included
  
  
  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.
  
  
  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.
authors.affiliation: Universidad Peruana Cayetano Heredia, Avenida Honorio Delgado 430, San Martin de Porres, Lima, Peru.
authors.forename: Carlos A
authors.initials: CA
authors.lastname: Salazar
authors.forename: German
authors.initials: G
authors.lastname: Malaga
authors.forename: Giuliana
authors.initials: G
authors.lastname: Malasquez
mesh_terms: D000925:Anticoagulants / Q000627:therapeutic use*; D000933:Antifibrinolytic Agents / Q000627:therapeutic use; D019644:Arthroplasty, Replacement, Hip / Q000009:adverse effects*; D019645:Arthroplasty, Replacement, Knee / Q000009:adverse effects*; D001384:Azetidines; D001562:Benzimidazoles / Q000627:therapeutic use; D001596:Benzylamines; D000075202:Contraindications; D000069604:Dabigatran; D006495:Heparin, Low-Molecular-Weight / Q000627:therapeutic use*; D006801:Humans; D011725:Pyridines / Q000627:therapeutic use; D016032:Randomized Controlled Trials as Topic; D013917:Thrombin / Q000037:antagonists & inhibitors*; D054556:Venous Thromboembolism / Q000209:etiology / Q000517:prevention & control*; D014812:Vitamin K / Q000037:antagonists & inhibitors*; D014859:Warfarin / Q000627:therapeutic use
chemical_list: D000925:Anticoagulants; D000933:Antifibrinolytic Agents; D001384:Azetidines; D001562:Benzimidazoles; D001596:Benzylamines; D006495:Heparin, Low-Molecular-Weight; D011725:Pyridines; D014812:Vitamin K; C426686:ximelagatran; D014859:Warfarin; D013917:Thrombin; D000069604:Dabigatran
references.citation: JAMA. 1994 Jan 5;271(1):59-63
references.pmid: 8258890
references.citation: Control Clin Trials. 1995 Feb;16(1):62-73
references.pmid: 7743790
references.citation: Cochrane Database Syst Rev. 2002;(4):CD000305
references.pmid: 12519540
references.citation: Lancet. 2002 Aug 10;360(9331):491-2; author reply 492
references.pmid: 12241752
references.citation: Circulation. 2002 Feb 26;105(8):1004-11
references.pmid: 11864933
references.citation: Thromb Haemost. 1995 Dec;74(6):1428-31
references.pmid: 8772214
references.citation: J Bone Joint Surg Am. 2001 Jun;83(6):900-6
references.pmid: 11407799
references.citation: Thromb Haemost. 2003 Feb;89(2):288-96
references.pmid: 12574809
references.citation: Anesth Analg. 2007 Dec;105(6):1540-7, table of contents
references.pmid: 18042845
references.citation: Int J Clin Pract. 2003 Jan-Feb;57(1):57-9
references.pmid: 12587945
references.citation: J Natl Cancer Inst. 1959 Apr;22(4):719-48
references.pmid: 13655060
references.citation: N Engl J Med. 2003 Oct 30;349(18):1703-12
references.pmid: 14585938
references.citation: Control Clin Trials. 1986 Sep;7(3):177-88
references.pmid: 3802833
references.citation: Arch Intern Med. 2002 Jul 8;162(13):1465-71
references.pmid: 12090882
references.citation: JAMA. 1993 Dec 1;270(21):2598-601
references.pmid: 8230645
references.citation: Ann Intern Med. 2002 Oct 15;137(8):648-55
references.pmid: 12379064
references.citation: J Bone Joint Surg Am. 1991 Apr;73(4):484-93
references.pmid: 2013587
references.citation: Chest. 2001 Jan;119(1 Suppl):132S-175S
references.pmid: 11157647
references.citation: Thromb Haemost. 1992 Apr 2;67(4):417-23
references.pmid: 1321509
references.citation: Thromb Haemost. 1996 Mar;75(3):407-11
references.pmid: 8701398
references.citation: Thromb Res. 2003 Jul 15;109 Suppl 1:S23-9
references.pmid: 12818631
references.citation: Arch Intern Med. 2001 Oct 8;161(18):2215-21
references.pmid: 11575978
references.citation: Isr Med Assoc J. 2004 Aug;6(8):479-81
references.pmid: 15326828
references.citation: J Bone Joint Surg Br. 1989 May;71(3):492-7
references.pmid: 2785998
references.citation: J Thromb Haemost. 2005 Jan;3(1):103-11
references.pmid: 15634273
references.citation: J Bone Joint Surg Am. 2005 Oct;87(10):2169-77
references.pmid: 16203879
references.citation: Eur J Clin Pharmacol. 2006 Mar;62(3):173-7
references.pmid: 16416154
references.citation: Ann Intern Med. 1996 Apr 1;124(7):619-26
references.pmid: 8607589
references.citation: Control Clin Trials. 1996 Feb;17(1):1-12
references.pmid: 8721797
references.citation: Thromb Haemost. 1997 Jan;77(1):32-8
references.pmid: 9031445
references.citation: J Arthroplasty. 2001 Sep;16(6):679-88
references.pmid: 11547365
references.citation: J Thromb Haemost. 2003 Oct;1(10):2119-30
references.pmid: 14521593
references.citation: Lancet. 2007 Sep 15;370(9591):949-56
references.pmid: 17869635
references.citation: Thromb Haemost. 2002 Feb;87(2):231-7
references.pmid: 11858482
references.citation: Can J Surg. 1999 Dec;42(6):457-61
references.pmid: 10593248
references.citation: J Thromb Haemost. 2007 Aug;5(8):1660-5
references.pmid: 17663737
references.citation: Curr Opin Gastroenterol. 2005 May;21(3):283-92
references.pmid: 15818148
references.citation: Chest. 2004 Sep;126(3 Suppl):338S-400S
references.pmid: 15383478
references.citation: N Engl J Med. 1997 Nov 6;337(19):1329-35
references.pmid: 9358126
references.citation: Thromb Haemost. 1996 May;75(5):706-11
references.pmid: 8725709
references.citation: Ann Intern Med. 2001 Nov 20;135(10):858-69
references.pmid: 11712876
references.citation: Lancet. 2003 Nov 22;362(9397):1691-8
references.pmid: 14643116
references.citation: J Thromb Haemost. 2006 Jan;4(1):121-8
references.pmid: 16409461
references.citation: J Clin Pharmacol. 2007 Mar;47(3):371-82
references.pmid: 17322149
references.citation: Thromb Haemost. 2004 Aug;92(2):428-30
references.pmid: 15269843
references.citation: J Arthroplasty. 1997 Sep;12(6):599-602
references.pmid: 9306209
references.citation: Chest. 2001 Jan;119(1 Suppl):22S-38S
references.pmid: 11157641
references.citation: Thromb Haemost. 2002 Apr;87(4):580-5
references.pmid: 12008938
references.citation: J Thromb Haemost. 2007 Nov;5(11):2178-85
references.pmid: 17764540
references.citation: N Engl J Med. 1993 Nov 4;329(19):1370-6
references.pmid: 8413432
references.citation: Clin Drug Investig. 2005;25(1):65-77
references.pmid: 17523747
references.citation: Arch Intern Med. 1998 Jul 27;158(14):1525-31
references.pmid: 9679793
references.citation: Arch Intern Med. 2001 Sep 10;161(16):1952-60
references.pmid: 11525697
references.citation: J Thromb Haemost. 2003 Dec;1(12):2490-6
references.pmid: 14675083
references.citation: Arch Intern Med. 1998 Apr 27;158(8):873-8
references.pmid: 9570173
references.citation: Arch Intern Med. 2003 Aug 11-25;163(15):1849-56
references.pmid: 12912723
references.citation: Clin Pharmacokinet. 2003;42(7):687-701
references.pmid: 12844328
references.citation: J Thromb Haemost. 2005 Nov;3(11):2479-86
references.pmid: 16241946
references.citation: BMJ. 1991 Dec 7;303(6815):1431-5
references.pmid: 1773147
references.citation: Hamostaseologie. 2002 Aug;22(3):21-4
references.pmid: 12215757
references.citation: Lancet. 2002 Jan 26;359(9303):294-302
references.pmid: 11830196
references.citation: Arch Intern Med. 2003 Jun 9;163(11):1362-6
references.pmid: 12796074
references.citation: JAMA. 2005 Feb 9;293(6):690-8
references.pmid: 15701910
references.citation: Thromb Res. 2002 Mar 1;105(5):371-8
references.pmid: 12062537
references.citation: JAMA. 2005 Feb 9;293(6):699-706
references.pmid: 15701911
references.citation: Thromb Res. 2002 May 1;106(3):V275-84
references.pmid: 12356489
references.citation: Chest. 2004 Sep;126(3 Suppl):265S-286S
references.pmid: 15383475
references.citation: N Engl J Med. 2003 Oct 30;349(18):1713-21
references.pmid: 14585939
references.citation: Thromb Res. 2009;123(3):488-97
references.pmid: 18485453
references.citation: Health Technol Assess. 2009 Sep;13 Suppl 2:55-62
references.pmid: 19804690
references.citation: J Arthroplasty. 2009 Jan;24(1):1-9
references.pmid: 18534438
references.citation: Chest. 1998 Nov;114(5 Suppl):531S-560S
references.pmid: 9822062
references.citation: J Am Coll Cardiol. 2003 May 7;41(9):1445-51
references.pmid: 12742279
references.citation: Lancet. 1996 Mar 9;347(9002):635-9
references.pmid: 8596376
references.citation: Lancet. 2002 Nov 9;360(9344):1441-7
references.pmid: 12433510
references.citation: Clin Orthop Relat Res. 1996 Dec;(333):27-40
references.pmid: 8981880
references.citation: Circulation. 2006 Nov 28;114(22):2374-81
references.pmid: 17116766
references.citation: BMJ. 2007 May 19;334(7602):1053-4
references.pmid: 17510154
references.citation: BMJ. 2003 Sep 6;327(7414):557-60
references.pmid: 12958120
references.citation: Chest. 2001 Jan;119(1 Suppl):8S-21S
references.pmid: 11157640