New versus Established Drugs in Venous Thromboprophylaxis
Rent the article at a discountRent now
* Final gross prices may vary according to local VAT.Get Access
European surgeons generally administer thromboprophylaxis with low-molecular-weight heparins (LMWHs) at high doses 12 hours preoperatively in response to findings that surgery-related deep-vein thrombosis typically originates at the time of major orthopedic surgery or shortly afterwards. North American surgeons, in contrast, generally administer LMWHs at an almost 50% higher dose than that given in Europe 12–24 hours postoperatively, even though both pre- and postoperative administration are considered suitable in current guidelines. This review therefore examines how close to major orthopedic surgery thromboprophylaxis is administered, and the subsequent effect of timing on clinically relevant efficacy and safety parameters. The trials examined involve fondaparinux sodium (fondaparinux) and (xi)melagatran, in comparison with the established LMWHs enoxaparin sodium (enoxaparin) and dalteparin.
In key trials, fondaparinux reduced the risk of asymptomatic and clinical venous thromboembolism (VTE) by 55% compared with enoxaparin, at the expense of a 1.6-fold higher risk of bleeding. While the studies were not designed to compare efficacy endpoints based on clinical outcomes, no significant difference was demonstrated for symptomatic VTE. The fact that the enoxaparin regimen was started at the upper limits of its recommended initiation timeframe may have significantly influenced the results of comparative studies, given that several meta-analyses found that the timing of LMWH initiation significantly influenced its effectiveness on asymptomatic VTE and major bleedings.
Compared with once-daily LMWH in European trials, early postoperative doses/regimens of twice-daily (xi)melagatran did not increase severe bleeding and was significantly less effective at preventing asymptomatic total VTE in patients who had undergone total hip-replacement surgery. When used according to the ‘knife-to-skin’ protocol, the melagatran regimen was superior to enoxaparin in preventing major asymptomatic VTE, but at the cost of a higher rate of major bleeding. In North America, the delayed postoperative administration of (xi)melagatran (oral only) was less effective than the postoperative twice-daily enoxaparin regimen with regard to asymptomatic total and major VTE.
Our analysis highlights the fact that differences in efficacy and safety data in clinical trials of thromboprophylaxis might also be linked to differences in the timing of initiation. However, it is not possible to assess the importance of this ‘time effect’ among other factors considered as drug-specific properties (pharmacokinetics, mode of action, dosage) and evaluate their respective contribution in the observed differences. To avoid unbiased comparison in further studies, the possible effect of timing should be taken into account and, when feasible, both therapies started at the same time. For instance, harmonizing the initiation of thromboprophylaxis 6–8 or 12 hours postoperatively could be two acceptable harmonized options for scheduling in clinical trials.
- Prevention of fatal postoperative pulmonary embolism by low doses of heparin. An international multicentre trial. Lancet 1975; 2: 45–51.
- Gallus AS, Hirsh J, Tutle RJ, et al. Small subcutaneous doses of heparin in prevention of venous thrombosis. N Engl J Med 1973; 288: 545–51. CrossRef
- Bergqvist D, Burmark US, Frisell J, et al. Low molecular weight heparin once daily compared with conventional low-dose heparin twice daily: a prospective double-blind multicentre trial on prevention of postoperative thrombosis. Br J Surg 1986; 73: 204–8. CrossRef
- Raskob GE, Hirsh J. Controversies in timing of the first dose of anticoagulant prophylaxis against venous thromboembolism after major orthopedic surgery. Chest 2003; 124: 379S–85S. CrossRef
- Geerts WH, Pineo GF, Heit JA, et al. Prevention of venous thromboembolism. Chest 2004; 126: 338S–400S. CrossRef
- Dahl OE, Aspelin T, Lyberg T. The role of bone traumatization in the initiation of proximal deep vein thrombosis during cemented hip replacement surgery in pigs. Blood Coagul Fibrinolysis 1995; 6: 709–17. CrossRef
- Sharnoff JG, DeBlasio G. Prevention of fatal postoperative thromboembolism by heparin prophylaxis. Lancet 1970; 2: 1006–7. CrossRef
- Hull R, Pineo G. A synthetic pentasaccharide for the prevention of deep-vein thrombosis [letter]. N Engl J Med 2001; 345: 619–25. CrossRef
- Mismetti P. Prevention of venous thromboembolism after major orthopedic surgery: ‘new’ clinical trials for new antithrombotic agents. J Thromb Haemost 2003; 1: 2474–6. CrossRef
- Turpie AG, Bauer KA, Eriksson BI, et al. Postoperative fondaparinux versus postoperative enoxaparin for prevention of venous thromboembolism after elective hip-replacement surgery: a randomised double-blind trial. Lancet 2002; 359: 1721–6. CrossRef
- Lassen MR, Bauer KA, Eriksson BI, et al. Postoperative fondaparinux versus preoperative enoxaparin for prevention of venous thromboembolism in elective hip-replacement surgery: a randomised double-blind comparison. Lancet 2002; 359: 1715–20. CrossRef
- Bauer KA, Eriksson BI, Lassen MR, et al. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after elective major knee surgery. N Engl J Med 2001; 345: 1305–10. CrossRef
- Eriksson BI, Bauer KA, Lassen MR, et al. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after hip-fracture surgery. N Engl J Med 2001; 345: 1298–304. CrossRef
- Turpie AG, Bauer KA, Eriksson BI, et al. 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: 1833–40. CrossRef
- Reynolds NA, Perry CM, Scott LJ. Fondaparinux sodium: a review of its use in the prevention of venous thromboembolism following major orthopaedic surgery. Drugs 2004; 64: 1575–96. CrossRef
- EMEA. European Medicines Agency: Arixtra®. European Public Assessment Report (EPAR): scientific discussion [online]. Available from URL: http://www.emea.eu.int/humandocs/Humans/EPAR/arixtra/arixtra.htm [Accessed 2006 Dec 15].
- FDA. Food And Drug Administration, Center for Drug Evaluation and Research (CDER): Arixtra® (fondaparinux). Application number 21–345, medical review [online]. Available from URL: http://www.fda.gov/cder/foi/nda/2001/21-345_Arixtra.htm [Accessed 2006 Dec 15].
- Marlovits S. Prevention of venous thromboembolism with fondaparinux. N Engl J Med 2002; 346: 940–2. CrossRef
- Agnelli G, Bergqvist D, Cohen AT, et al. Randomized clinical trial of postoperative fondaparinux versus perioperative dalteparin for prevention of venous thromboembolism in high-risk abdominal surgery. Br J Surg 2005; 92: 1212–20. CrossRef
- Hull RD, Pineo GF, Francis C, et al. Low-molecular-weight heparin prophylaxis using dalteparin in close proximity to surgery vs warfarin in hip arthroplasty patients: a double-blind, randomized comparison. The North American Fragmin Trial Investigators. Arch Intern Med 2000; 160: 2199–207. CrossRef
- Bauersachs RM. Fondaparinux: an update on new study results. Eur J Clin Invest 2005; 35 Suppl. 1: 27–32. CrossRef
- Lee AY. Management of thrombosis in cancer: primary prevention and secondary prophylaxis. Br J Haematol 2005; 128: 291–302. CrossRef
- Swedko PJ, Clark HD, Paramsothy K, et al. Serum creatinine is an inadequate screening test for renal failure in elderly patients. Arch Intern Med 2003; 163: 356–60. CrossRef
- EMEA. European Medicines Agency: Arixtra®. European Public Assessment Report (EPAR): summary of product characteristics [online]. Available from URL: http://www.emea.eu.int/humandocs/Humans/EPAR/arixtra/arixtra.htm [Accessed 2006 Dec 15].
- Sanderink GJ, Guimart CG, Ozoux ML, et al. Pharmacokinetics and pharmacodynamics of the prophylactic dose of enoxaparin once daily over 4 days in patients with renal impairment. Thromb Res 2002; 105: 225–31. CrossRef
- FDA. Food And Drug Administration, Center for Drug Evaluation and Research (CDER): Lovenox® (enoxaparin sodium). NDA 020164, label and aproval history [online]. Available from URL: http://www.accessdata.fda.gov/scripts/cder/drugsatfda/index.cfm?fuseaction=Search.Overview&DrugName=LOVE-NOX [Accessed 2006 Dec 15].
- Colwell Jr CW, Kwong LM, Turpie AG, et al. Flexibility in administration of fondaparinux for prevention of symptomatic venous thromboembolism in orthopaedic surgery. J Arthroplasty 2006; 21: 36–45. CrossRef
- Eriksson BI, Bergqvist D, Kalebo 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: 1441–7. CrossRef
- ColwellJr CW, Berkowitz SD, Davidson BL, 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: 2119–30. CrossRef
- Eriksson BI, Agnelli G, Cohen AT, 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: 288–96.
- Eriksson BI, Agnelli G, Cohen AT, 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: 2490–6. CrossRef
- Eriksson BI, Wille-Jorgensen P, Kalebo P, et al. A comparison of recombinant hirudin with a low-molecular-weight heparin to prevent thromboembolic complications after total hip replacement. N Engl J Med 1997; 337: 1329–35. CrossRef
- Eriksson B. Ximelagatran in orthopedic surgery. Pathophysiol Haemost Thromb 2005; 34 Suppl. 1: 10–7. CrossRef
- Dahl OE, Eriksson BI, Agnelli G, 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. Clin Drug Investig 2005; 25: 65–77. CrossRef
- Geerts WH, Heit JA, Clagett GP, et al. Prevention of venous thromboembolism. Chest 2001; 119: 132–175S. CrossRef
- Eriksson UG, Johansson S, Attman PO, et al. Influence of severe renal impairment on the pharmacokinetics and pharmacodynamics of oral ximelagatran and subcutaneous melagatran. Clin Pharmacokinet 2003; 42: 743–53. CrossRef
- Francis CW, Berkowitz SD, Comp PC, et al. Comparison of ximelagatran with warfarin for the prevention of venous thromboembolism after total knee replacement. N Engl J Med 2003; 349: 1703–12. CrossRef
- Colwell Jr CW, Berkowitz SD, Lieberman JR, et al. Oral direct thrombin inhibitor ximelagatran compared with warfarin for the prevention of venous thromboembolism after total knee arthroplasty. J Bone Joint Surg Am 2005; 87: 2169–77. CrossRef
- Schulman S, Wahlander K, Lundstrom T, et al. Secondary prevention of venous thromboembolism with the oral direct thrombin inhibitor ximelagatran. N Engl J Med 2003; 349: 1713–21. CrossRef
- Olsson SB. Stroke prevention with the oral direct thrombin inhibitor ximelagatran compared with warfarin in patients with non-valvular atrial fibrillation (SPORTIF III): randomised controlled trial. Lancet 2003; 362: 1691–8. CrossRef
- Albers GW, Diener HC, Frison L, et al. Ximelagatran vs warfarin for stroke prevention in patients with nonvalvular atrial fibrillation: a randomized trial. JAMA 2005; 293: 690–8. CrossRef
- FDA. Food And Drug Administration Cardiovascular and Renal Drugs Advisory Committee: Exanta® (ximelagatran). NDA 21–686 briefing information September 10, 2004 [online]. Available from URL: http://www.fda.gov/ohrms/dockets/AC/04/briefing/2004-4069bl.htm [Accessed 2006 Dec 15].
- Vormfelde SV. Enoxaparin or fondaparinux for thrombosis prevention after orthopaedic surgery. Lancet 2002; 360: 1701. CrossRef
- Hull RD, Pineo GF, Stein PD, 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: 1952–60. CrossRef
- Strebel N, Prins M, Agnelli G, et al. Preoperative or postoperative start of prophylaxis for venous thromboembolism with low-molecular-weight heparin in elective hip surgery? Arch Intern Med 2002; 162: 1451–6. CrossRef
- Burnham KP, Anderson DR. Model selection and multi-model inference: a practical information-theoretic approach. New York: Springer-Verlag, 2002.
- Horlocker TT, Wedel DJ, Benzon H, et al. Regional anesthesia in the anticoagulated patient: defining the risks (the second ASRA Consensus Conference on Neuraxial Anesthesia and Anticoagulation). Reg Anesth Pain Med 2003; 28: 172–97.
- Korn EL, Albert PS, McShane LM. Assessing surrogates as trial endpoints using mixed models. Stat Med 2005; 24: 163–82. CrossRef
- ICH. ICH harmonised tripartite guidelines: International Conference on Harmonisation of technical requirements for registration of Pharmaceuticals for human use. Statistical principals for clinical trials [online]. Available from URL: http://www.emea.eu.int/pdfs/human/ich/036396en.pdf [Accessed 2006 Dec 16].
- Molenberghs G, Burzykowski T, Alonso A, et al. A perspective on surrogate endpoints in controlled clinical trials. Stat Methods Med Res 2004; 13: 177–206.
- Eikelboom JW, Quinlan DJ, Douketis JD. Extended-duration prophylaxis against venous thromboembolism after total hip or knee replacement: a meta-analysis of the randomised trials. Lancet 2001; 358: 9–15. CrossRef
- Hull RD, Burke N, Mah AF, et al. Timing of initial administration of prophylaxis against deep vein thrombosis in patients following hip or knee surgery [abstract]. Chest 2003; 124: 240S.
- New versus Established Drugs in Venous Thromboprophylaxis
American Journal of Cardiovascular Drugs
Volume 7, Issue 1 , pp 1-15
- Cover Date
- Print ISSN
- Online ISSN
- Springer International Publishing
- Additional Links