Ximelagatran for the Prevention of Venous Thromboembolism Following Elective Hip or Knee Replacement Surgery

ABSTRACT

Patients undergoing major lower-extremity orthopedic surgery such as total hip replacement (THR) and total knee replacement (TKR) are at an increased risk of venous thromboembolism (VTE). Routine prophylaxis is necessary to reduce the risk of deep vein thrombosis (DVT), which may progress to potentially fatal pulmonary embolism and secondary complications such as postthrombotic syndrome, recurrent DVT, and chronic pulmonary hypertension. Prophylaxis in patients undergoing TKR, THR, and hip fracture surgery is now standard practice and generally involves anticoagulant treatment with either low-molecular-weight heparin (LMWH) or warfarin for a period of 7 to 10 days, with extended prophylaxis in those with ongoing risk factors such as obesity, cancer, or previous VTE. Data from clinical practice suggest that there is a general trend toward longer postsurgical prophylaxis and shorter hospital stays, making practicality of treatment an important consideration. LMWH is effective for the prophylaxis of VTE, but the parenteral route of administration is not convenient for use in the outpatient setting. Warfarin, on the other hand, can be administered orally but requires the infrastructure for careful patient monitoring and dose adjustments because of its unpredictable dose-response relationship. The development of new anticoagulants has been pursued with the aim of improving efficacy, predictability, consistency of response, safety, and convenience. A recently approved anticoagulant, fondaparinux, has been proven to provide superior efficacy for the prevention of VTE compared with LMWH, but this agent requires parenteral administration and does not overcome the convenience issue. Ximelagatran is the oral form of the direct thrombin inhibitor melagatran, which is available for subcutaneous administration. Ximelagatran has a consistent anticoagulant response allowing fixed oral dosing without the need for coagulation monitoring. The efficacy and safety profile of melagatran/ximelagatran prophylaxis for VTE following THR and TKR has compared favorably with standard LMWH prophylaxis, as seen in the European METHRO II and III trials and EXPRESS trial, and with warfarin prophylaxis, as seen in the North American EXULT A and B trials. Several prophylactic treatment regimens have been evaluated in the European trials to determine the optimal dosing and timing of first dose of melagatran to achieve the best balance of efficacy and safety. Preoperative initiation of melagatran was more effective than when prophylactic treatment was initiated postoperatively, and the lowest rates of bleeding were associated with a postoperative initiation of prophylaxis. Early administration of the first postoperative melagatran dose (4 to 8 hours) was also associated with better prophylactic efficacy relative to a later postoperative start (8 to 12 hours). The results of the comprehensive international clinical trial program and in particular the optimal balance of efficacy/safety data provided by the METHRO III study have led to approval of melagatran/ximelagatran in 2004 in the European Union for the prevention of VTE in patients undergoing elective hip or knee replacement surgery. Ximelagatran has the potential to maximize the use of anticoagulation in patients discharged following major lower-extremity orthopedic surgery.

KEYWORDS

Venous thromboembolism - orthopedic surgery - oral direct thrombin inhibitors - ximelagatran - METHRO

REFERENCES

• 1 Dahl O E, Pedersen T, Kierulf P et al.. Sequential intrapulmonary and systemic activation of coagulation and fibrinolysis during and after total hip replacement surgery.  Thromb Res. 1993;  70 451-458
• 2 Dahl O E, Aspelin T, Arnesen H et al.. Increased activation of coagulation and formation of late deep venous thrombosis following discontinuation of thromboprophylaxis after hip replacement surgery.  Thromb Res. 1995;  80 299-306
• 3 McNally M A, Mollan R A. Total hip replacement, lower limb blood flow and venous thrombogenesis.  J Bone Joint Surg Br. 1993;  75 640-644
• 4 Geerts W H, Pineo G F, Heit J A et al.. Prevention of venous thromboembolism: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy.  Chest. 2004;  126 338S-400S
• 5 Brookenthal K R, Freedman K B, Lotke P A, Fitzgerald R H, Lonner J H. A meta-analysis of thromboembolic prophylaxis in total knee arthroplasty.  J Arthroplasty. 2001;  16 293-300
• 6 Geerts W H, Heit J A, Clagett G P et al.. Prevention of venous thromboembolism.  Chest. 2001;  119 132S-175S
• 7 Colwell Jr C W. Managing thromboembolic risk in hip and knee arthroplasty: state of the art.  Orthopedics. 2003;  26 s231-s236
• 8 Dahl O E, Andreassen G, Aspelin T et al.. Prolonged thromboprophylaxis following hip replacement surgery-results of a double-blind, prospective, randomised, placebo-controlled study with dalteparin (Fragmin).  Thromb Haemost. 1997;  77 26-31
• 9 Planes A, Vochelle N, Darmon J Y, Fagola M, Bellaud M, Huet Y. Risk of deep-venous thrombosis after hospital discharge in patients having undergone total hip replacement: double-blind randomised comparison of enoxaparin versus placebo.  Lancet. 1996;  348 224-228
• 10 Hull R D, Pineo G F, Francis C et al.. Low-molecular-weight heparin prophylaxis using dalteparin extended out-of-hospital vs in-hospital warfarin/out-of-hospital placebo in hip arthroplasty patients: a double-blind, randomized comparison. North American Fragmin Trial Investigators.  Arch Intern Med. 2000;  160 2208-2215
• 11 Agnelli G, Mancini G B, Biagini D. The rationale for long-term prophylaxis of venous thromboembolism.  Orthopedics. 2000;  23 s643-s646
• 12 Cohen A T, Bailey C S, Alikhan R, Cooper D J. Extended thromboprophylaxis with low molecular weight heparin reduces symptomatic venous thromboembolism following lower limb arthroplasty-a meta-analysis.  Thromb Haemost. 2001;  85 940-941
• 13 Anderson Jr F A, Hirsh J, White K, Fitzgerald Jr R H. Temporal trends in prevention of venous thromboembolism following primary total hip or knee arthroplasty 1996-2001: findings from the Hip and Knee Registry.  Chest. 2003;  124 349S-356S
• 14 Turpie A G, Chin B S, Lip G Y. ABC of antithrombotic therapy: venous thromboembolism: treatment strategies.  BMJ. 2002;  325 948-950
• 15 Hirsh J, Fuster V, Ansell J, Halperin J L. American Heart Association/American College of Cardiology Foundation guide to warfarin therapy.  Circulation. 2003;  107 1692-1711
• 16 Giangrande P L. Fondaparinux (Arixtra): a new anticoagulant.  Int J Clin Pract. 2002;  56 615-617
• 17 Hirsh J, Anand S S, Halperin J L, Fuster V. AHA Scientific Statement: guide to anticoagulant therapy: heparin: a statement for healthcare professionals from the American Heart Association.  Arterioscler Thromb Vasc Biol. 2001;  21 9-13
• 18 Eriksson B I, Bauer K A, Lassen M R, Turpie A G. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after hip-fracture surgery.  N Engl J Med. 2001;  345 1298-1304
• 19 Bauer K A, Eriksson B I, Lassen M R, Turpie A G. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after elective major knee surgery.  N Engl J Med. 2001;  345 1305-1310
• 20 Lassen M R, Bauer K A, Eriksson B I, Turpie A G. Postoperative fondaparinux versus preoperative enoxaparin for prevention of venous thromboembolism in elective hip-replacement surgery: a randomised double-blind comparison.  Lancet. 2002;  359 1715-1720
• 21 Turpie A G, Bauer K A, Eriksson B I, Lassen M R. Postoperative fondaparinux versus postoperative enoxaparin for prevention of venous thromboembolism after elective hip-replacement surgery: a randomised double-blind trial.  Lancet. 2002;  359 1721-1726
• 22 Turpie A G, Bauer K A, Eriksson B I, Lassen M R. Fondaparinux vs enoxaparin for the prevention of venous thromboembolism in major orthopedic surgery: a meta-analysis of 4 randomized double-blind studies.  Arch Intern Med. 2002;  162 1833-1840
• 23 Weitz J I. New anticoagulants for treatment of venous thromboembolism.  Circulation. 2004;  110 I19-I26
• 24 Phillips C B, Barrett J A, Losina E et al.. Incidence rates of dislocation, pulmonary embolism, and deep infection during the first six months after elective total hip replacement.  J Bone Joint Surg Am. 2003;  85 20-26
• 25 Hauptmann J. Pharmacokinetics of an emerging new class of anticoagulant/antithrombotic drugs. A review of small-molecule thrombin inhibitors.  Eur J Clin Pharmacol. 2002;  57 751-758
• 26 Wolzt M, Wollbratt M, Svensson M, Wåhlander K, Grind M, Eriksson U G. Consistent pharmacokinetics of the oral direct thrombin inhibitor ximelagatran in patients with nonvalvular atrial fibrillation and in healthy subjects.  Eur J Clin Pharmacol. 2003;  59 537-543
• 27 Eriksson U G, Bergqvist D, Kalebo P, Dahl O E, Lindbratt S, Bylock A. Predictable pharmacokinetics of ximelagatran, an oral direct thrombin inhibitor, in non-valvular atrial fibrillation patients receiving long-term treatment.  Pathophysiol Haemost Thromb. 2002;  32 56
• 28 Johansson L C, Andersson M, Fager G, Gustafsson D, Eriksson U G. No influence of ethnic origin on the pharmacokinetics and pharmacodynamics of melagatran following oral administration of ximelagatran, a novel oral direct thrombin inhibitor, to healthy male volunteers.  Clin Pharmacokinet. 2003;  42 475-484
• 29 Johansson L C, Frison L, Logren U, Fager G, Gustafsson D, Eriksson U G. Influence of age on the pharmacokinetics and pharmacodynamics of ximelagatran, an oral direct thrombin inhibitor.  Clin Pharmacokinet. 2003;  42 381-392
• 30 Johansson S, Wåhlander K, Larson G, Ohlsson L, Larsson M, Eriksson U G. Pharmacokinetics and anticoagulant effect of the direct thrombin inhibitor melagatran following subcutaneous administration to healthy young men.  Blood Coagul Fibrinolysis. 2003;  14 677-684
• 31 Sarich T C, Teng R, Peters G R et al.. No influence of obesity on the pharmacokinetics and pharmacodynamics of melagatran, the active form of the oral direct thrombin inhibitor ximelagatran.  Clin Pharmacokinet. 2003;  42 485-492
• 32 Wåhlander K, Eriksson-Lepkowska M, Frison L, Fager G, Eriksson U G. No influence of mild-to-moderate hepatic impairment on the pharmacokinetics and pharmacodynamics of ximelagatran, an oral direct thrombin inhibitor.  Clin Pharmacokinet. 2003;  42 755-764
• 33 Wolzt M, Eriksson U G. Pharmacokinetics and pharmacodynamics of ximelagatran.  Semin Vasc Med. 2005;  5 245-253
• 34 Hull R D, Pineo G F, Stein P D et al.. Timing of initial administration of low-molecular-weight heparin prophylaxis against deep vein thrombosis in patients following elective hip arthroplasty: a systematic review.  Arch Intern Med. 2001;  161 1952-1960
• 35 Eriksson B I, Bergqvist D, Kälebo P et al.. 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 1441-1447
• 36 Eriksson B I, Agnelli G, Cohen A T et al.. Direct thrombin inhibitor melagatran followed by oral ximelagatran in comparison with enoxaparin for prevention of venous thromboembolism after total hip or knee replacement.  Thromb Haemost. 2003;  89 288-296
• 37 Dahl O E, Erikkson B I, Agnelli G et al.. Postoperative melagatran/ximelagatran for the prevention of venous thromboembolism following major elective orthopaedic surgery: effect of timing of first dose and risk factors for thromboembolism and bleeding complications on efficacy and safety.  Clinical Drug Investigation. 2005;  25 65-77
• 38 Eriksson B I, Agnelli G, Cohen A T et al.. 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.  J Thromb Haemost. 2003;  1 2490-2496
• 39 Cohen A T, Agnelli G, Dahl O E et al.. Efficacy and safety of the treatment regimen of melagatran and ximelagatran for the prevention of thromboembolic events after total hip and knee replacement: a meta-analysis of 3 randomized, double-blind studies to evaluate the influence of time and dose. Thromb Haemost. 2003 1 (suppl 1) Abstract P1915
• 40 Colwell C W, Berkowitz S D, Davidson B L 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.  J Thromb Haemost. 2003;  1 2119-2130
• 41 Heit J A, Colwell C W, Francis C W et al.. 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.  Arch Intern Med. 2001;  161 2215-2221
• 42 Francis C W, Davidson B L, Berkowitz S D et al.. Ximelagatran versus warfarin for the prevention of venous thromboembolism after total knee arthroplasty. A randomized, double-blind trial.  Ann Intern Med. 2002;  137 648-655
• 43 Francis C W, Berkowitz S D, Comp P C et al.. Comparison of ximelagatran with warfarin for the prevention of venous thromboembolism after total knee replacement.  N Engl J Med. 2003;  349 1703-1712
• 44 Colwell C W, Berkowitz S D, Comp P C 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 14 , Abstract
• 45 Rosencher N. Ximelagatran, a new oral direct thrombin inhibitor, for the prevention of venous thromboembolic events in major elective orthopaedic surgery. Efficacy, safety and anaesthetic considerations.  Anaesthesia. 2004;  59 803-810
• 46 Lee W M, Larrey D, Olsson R et al.. Hepatic findings in long-term clinical trials of ximelagatran.  Drug Saf. 2005;  28 351-370