Clinical experience with fondaparinux, a new synthetic selective factor Xa inhibitor

Abstract
Fondaparinux is the first of a new class of antithrombotic compounds, the synthetic selective factor Xa inhibitors. Administered subcutaneously, the absorption of fondaparinux is complete and rapid. Its half-life of approximately 17 hours allows for once-daily dosing. In four randomized, double-blind trials in 7344 patients undergoing major orthopedic surgery, compared to enoxaparin, 2.5 mg once-daily fondaparinux, starting postoperatively, reduced the overall incidence of venous thromboembolism up to day 11 by 55.2% (p<0.001). The incidence of clinically relevant bleeding was low and did not differ between the two groups. Overall, fondaparinux achieved optimal efficacy and safety when initiated six hours or more after the surgical procedure. Extending fondaparinux prophylaxis from one to four weeks after hip fracture surgery was well tolerated and, compared with one-week fondaparinux, reduced dramatically delayed venous thromboembolism events from 35.0% to 1.4% (p<0.001). Two large phase III trials have demonstrated the benefit of fondaparinux in the management of established venous thromboembolism. Other phase III trials in the prevention of venous thromboembolism in various surgical and medical settings and in the management of acute coronary syndromes are just completed or ongoing. In conclusion, fondaparinux may substantially improve and simplify the prevention and treatment of thrombosis.

Key words
Fondaparinux, heparinas de bajo peso molecular, trombosis venosa, profilaxis de la trombosis, síndromes coronarios agudos, tromboembolismo, cirugía mayor, reposo prolongado, coagulación

Bibliografía del artículo

1. Hirsh J, Warkentin TE, Shaughnessy SG, et al. Heparin and low-molecular-weight heparin: mechanisms of action, pharmacokinetics, dosing, monitoring, efficacy, and safety. Chest 2001; 119(suppl 1): 64S–94S
2. Hirsh J, Dalen JE, Anderson DR, et al. Oral anticoagulants: mechanism of action, clinical effectiveness, and optimal therapeutic range. Sixth ACCP Consensus Conference on antithrombotic therapy. Chest 119(Suppl):8S-21S, 2001
3. Herbert JM, Petitou M, Lormeau JC, et al. SR 90107/Org 31540, a novel anti-factor Xa antithrombotic agent. Cardiovasc Drug Rev 1997; 15: 1-26
4. Hara T, Yokoyama A, Tanabe K, Ishihara H, Iwamoto M. DX-9065a, an orally active, specific inhibitor of factor Xa, inhibits thrombosis without affecting bleeding time in rats. Thromb. Haemost 1995; 74: 635-639
5. Taniuchi Y, Sakai Y, Hisamichi N, et al. Biochemical and pharmacological characterization of YM-60828, a newly synthesized and orally active inhibitor of human factor Xa. Thromb. Haemost 1998; 79: 543-554
6. Petitou M, Duchaussoy P, Lederman I, et al. Synthesis of heparin fragments: a alpha-methyl pentaoside with high affinity for antithrombin III. Carbohydr Res 1987; 167: 67-75
7. Paolucci F, Clavies M, Donat F, et al. Fondaparinux sodium mechanism of action: identification of specific binding to purified and human plasma-derived proteins. Clin Pharmacokinet 2002; 41(suppl): 11-18
8. Boneu B, Necciari J, Cariou R, et al. Pharmacokinetics and tolerance of the natural pentasaccharide (SR90107/ORG31540) with high affinity to antithrombin III in man. Thromb Haemost 1995; 74: 1468-1473
9. Béguin S, Choay J, Hemker HC. The action of a synthetic pentasaccharide on thrombin generation in whole plasma. Thromb Haemost 1989; 61: 397-401
10. Donat F, Duret JP, Santoni A, et al. The pharmacokinetics of fondaparinux sodium in healthy volunteers. Clin Pharmacokinet 2002; 41(suppl): 1-9
11. Geerts WH, Heit JA, Clagett GP, et al. Prevention of venous thromboembolism. Chest 2001; 119(suppl 1): 132S–175S
12. Turpie AGG, Gallus AS, Hoek JA. A synthetic pentasaccharide for the prevention of deep-vein thrombosis after total hip replacement. N Engl J Med 2001; 344: 619-625
13. Bauer KA, Eriksson BI, Lassen MR, Turpie AGG. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after elective major knee surgery. N Engl J Med 2001; 345: 1305-1310
14. Eriksson BI, Bauer KA, Lassen MR, Turpie AGG. Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after hip-fracture surgery. N Engl J Med 2001; 345: 1298-1304
15. Lassen MR, Bauer KA, Eriksson BI, Turpie AGG. 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
16. Turpie AGG, Bauer KA, Eriksson BI, Lassen MR. 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
17. Eriksson BI, Lassen MR. Duration of prophylaxis against venous thromboembolism with fondaparinux after hip fracture surgery. A multicenter, randomized, placebo-controlled, double-blind study. Arch Intern Med 2003; 163: 1337-1342
18. Turpie AGG, Bauer KA, Eriksson BI, Lassen MR. Fondaparinux versus enoxaparin for the prevention of venous thromboembolism in major orthopedic surgery. A meta-analysis of 4 randomized studies. Arch Intern Med 2002; 162: 1833-1840
19. Committee for Proprietary Medicinal Products. Points to consider on clinical investigation of medicinal products for prophylaxis of intra- and postoperative venous thromboembolic risk. The European Agency for the Evaluation of Medicinal Products. London, 29 June 2000; CPMP/EWP/707/98.
20. Collins R, Scrimgeour A, Yusuf S, Peto R. Reduction in fatal pulmonary embolism and venous thrombosis by perioperative administration of subcutaneous heparin. Overview of results of randomized trials in general, orthopedic, and urologic surgery. N Engl J Med 1988; 318: 1162-1173.
21. Leizorovicz A, Haugh MC, Chapuis F-R, Samama MM, Boissel JP. Low molecular weight heparin in prevention of postoperative thrombosis. BMJ 1992;305:913-920.
22. Nurmohamed MT, Rosendaal FR, Büller HR, et al. Low-molecular-weight heparin versus standard heparin in general and orthopaedic surgery. Lancet 1992;340:152-156.
23. Eikelboom JW, Quinlan DJ, Douketis JD. Extended-duration prophylaxis against venous thromboembolism after total hip or knee replacement: a meta-analysis of the randomized trials. Lancet 2001;358:9-15.
24. Bauer KA, Eriksson BI, Lassen MR, Turpie AGG. Consistency of fondaparinux superiority over enoxaparin in prevention of venous thromboembolism in orthopaedic surgery according to different composite efficacy endpoints. In: 7th Annual Meeting of the European Haematology Association, Monduzzi Editore (Bologna, Italy), 2002 (pp. 289-292).
25. Turpie AGG, Bauer KA, Eriksson BI, Lassen MR. Efficacy and safety of fondaparinux in major orthopedic surgery according to the timing of its first administration. Thromb Haemost (in press).
26. Wiig JN, Solhaug JH, Bilberg T, et al. Prophylaxis of venographically diagnosed deep vein thrombosis in gastrointestinal surgery. Multicentre trials 20 mg and 40 mg enoxaparin versus dextran. Eur J Surg 1995;161:663-8
27. Enoxacan Study Group. Efficacy and safety of enoxaparin versus unfractionated heparin for prevention of deep vein thrombosis in elective cancer surgery: a double-blind randomized multicentre trial with venographic assessment. Br J Surg 1997; 84:1099-103
28. McLeod RS, Geerts WH, Sniderman KW, et al. Subcutaneous heparin versus low-molecular-weight heparin as thromboprophylaxis in patients undergoing colorectal surgery. Results of the Canadian Colorectal DVT Prophylaxis Trial: a randomized, double-blind trial. Ann Surg 2001; 233:438-44.
29. Agnelli G, Bergqvist D, Cohen A, Gallus A, Gent M. A randomized double-blind study to compare the efficacy and safety of fondaparinux with dalteparin in the prevention of venous thromboembolism after high-risk abdominal surgery: the PEGASUS study. J Thromb Haemost 2003; 1 (Suppl 1): abstract OC006
30. Cohen AT, Gallus AS, Lassen MR, et al. Fondaparinux versus placebo for the prevention of venous thromboembolism in acutely ill medical patients (ARTEMIS). J Thromb Haemost 2003; 1 (Suppl 1): abstract P1915
31. Samama MM, Cohen AT, Darmon JY, et al. A comparison of enoxaparin with placebo for the prevention of venous thromboembolism in acutely ill medical patients. N Engl J Med 1999; 341:793-800
32. Büller HR, Cariou R, Gallus A, et al. Treatment of proximal deep vein thrombosis with a novel synthetic compound (SR90107A/ ORG31540) with pure anti-factor Xa activity. Circulation 2000, 102:2726–31
33. The MATISSE Investigators. The MATISSE-DVT trial, a randomized, double-blind study comparing once-daily fondaparinux (Arixtra®) with the low-molecular-weight heparin (LMWH) enoxaparin, twice daily, in the initial treatment of symptomatic deep-vein thrombosis (DVT). J Thromb Haemost 2003; 1 (Suppl 1): abstract OC332
34. The MATISSE Investigators. The MATISSE-PE trial, a multicenter, randomized , open study comparing once-daily fondaparinux (Arixtra®) with adjusted-dose intravenous unfractionated heparin (UFH) in the initial treatment of acute symptomatic pulmonary embolism (PE). J Thromb Haemost 2003; 1 (Suppl 1): abstract OC331
35. Vuillemenot A, Schiele F, Meneveau N, et al. Efficacy of a synthetic pentasaccharide, a pure factor Xa inhibitor, as an antithrombotic agent. A pilot study in the setting of coronary angioplasty. Thromb Haemost 1999; 81:214-20
36. Simmoons M. Oral presentation on the PENTUA clinical trial. 74th Annual Scientific Sessions of the American Heart Association, Anaheim CA, USA (November 14, 2001)
37. Coussement PK, Bassand J-P, Convens C, et al. A synthetic factor-Xa inhibitor (ORG31540/SR90107A) as an adjunct to fibrinolysis in acute myocardial infraction. The PENTALYSE study. Eur Heart J 2001, 22:1716–24

Autoevaluación