Heparin pentasaccharide.
Fondaparinux (a synthetic heparin analogue) (Sanofi-Synthelabo; Paris, France and Organon Research; Oss, The Netherlands) is the subject of intense recent clinical evaluation for the prevention and treatment of venous and arterial thromboembolism. The drug replicates the sulphated antithrombin-binding pentasaccharide sequence in heparin and induces potent and specific antithrombin-mediated anti-Xa activity with excellent bioavailability and a long circulating half-life of 18 hours that makes it ideal for once-daily subcutaneous dosing. Its very short chain length ensures this heparin pentasaccharide (PS) is devoid of anti-factor IIa activity. No need for laboratory monitoring is anticipated. Fondaparinux does not cross-react ex vivo with the anti-platelet antibodies responsible for heparin-induced thrombocytopenia. Fondaparinux was evaluated in four large, randomized, placebo-controlled, double-blind phase III trials of deep vein thrombosis prevention after major joint surgery where the PS given after surgery was compared with a low molecular weight heparin (LMWH). LMWH was started before surgery in two comparisons and soon after surgery in the others. The trials shared the same blindly adjudicated efficacy and safety endpoints: efficacy was measured by recording subclinical deep vein thrombosis detected by screening with bilateral venography, plus clinically suspected and confirmed symptomatic thrombosis and embolism; safety was indicated by the rate of major bleeding. Bleeding was considered major if it caused death or reoperation, affected an internal organ, or was overt and associated with a bleeding index of 2 or more. By comparison with LMWH, 2.5 mg/d of the PS beginning 4 to 8 hours after wound closure reduced venous thromboembolism rates by 56% and 26% after elective hip replacement, 63% after knee replacement, and 62% after hip fracture surgery. In three studies and overall, the effect was statistically very significant and included similarly reduced rates of proximal deep vein thrombosis. In absolute terms, the DVT rates with PS are the lowest yet seen after major joint surgery. Trends toward more major bleeding with PS in three studies were statistically significant in one trial. PS did not increase risks from reoperation, internal bleeding, or death because of bleeding, because between-group differences were caused entirely by an excess of patients with a raised bleeding index. Post hoc analysis suggests this excess can be explained by too-early postoperative drug administration and may be avoided without loss of efficacy by giving the first PS injection 6 to 8 hours after surgery. Results of phase III treatment trials for DVT/PE will soon be available, but studies in coronary artery disease are less advanced.
Gallus
Alexander S
AS
Department of Haematology, Flinders Medical Centre, Belford Park, SA 5042, Adelaide, Australia. alexander.gallus@flinders.edu.au
Coghlan
Douglas W
DW
D000818:Animals; D002986:Clinical Trials as Topic; D000077425:Fondaparinux; D006493:Heparin / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use*; D006801:Humans; D009844:Oligosaccharides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D019637:Orthopedic Procedures / Q000009:adverse effects; D011134:Polysaccharides / Q000009:adverse effects / Q000493:pharmacokinetics / Q000627:therapeutic use; D013927:Thrombosis / Q000188:drug therapy / Q000209:etiology / Q000517:prevention & control
D009844:Oligosaccharides; D011134:Polysaccharides; C049714:IC 831423; D006493:Heparin; D000077425:Fondaparinux