Society of Cardiovascular Anesthesiologists

Fondaparinux

James DiNardo, MD
Children's Hospital
Boston, MA

Fondaparinux is a new synthetic pentasaccharide which like the animal tissue derived mucopolysaccharides (glycosaminoglycans) unfractioned heparin (UFH), low-molecular weight heparin (LMWH), and danaparoid has a anticoagulant mechanism of action which is anti-thrombin (AT) III dependant.1 AT-III is responsible for binding to and inactivating the serine proteases thrombin (factor IIa), factor Xa, factor IXa, factor XIa, and factor XIIa. AT-III is 10-20 times more efficient in inactivating thrombin and factor Xa than it is in inactivating factors IXa, and XIa, and XIIa. Binding of AT-III to a specific pentasaccharide induces a conformation change in AT-III which enhances binding to and subsequent inhibition of these serine proteases by a factor of 1,000-10,000. This pentasaccharide is present in about a third of the 10-90 mucopolysaccharide units which comprise UFH, in about a third of the 3-30 mucopolysaccharide units which comprise LMWH, and in about 5% of the units which comprise danaparoid. In contrast, fondaparinux is comprised solely of this pentasaccharide.

The important clinical anticoagulant effects of these AT-III enhancing agents are mediated through factor IIa and factor Xa inhibition. In combination with AT-III, any mucopolysaccharide chain containing the specific pentasaccharide can inhibit factor Xa while only mucopolysaccharides with the specific pentasaccharide and a chain length 18 can inhibit factor IIa.3 This is due to the fact that a chain length of at least 18 monosaccharides is necessary to link factor IIa (thrombin) to AT-III. As a result, the anti-Xa/anti-IIa ratio of these mucopolysaccharides is solely dependent on their chain lengths. Essentially all the mucopolysaccharide chains in UFH contain > 18 monosaccharide units. Many chains in LMWH contain < 18 units while most chains in danaparoid contain < 18 units. All the chains in fondaparinux contain only the specific pentasaccharide. Thus, the anti-Xa/anti-IIa ratio of these agents is summarized as follows:

Agent	Anti-Xa/anti-IIa ratio
UFH	1:1
LMWH	2-4:1
Danaparoid	22:1
Fondaparinux	∞

Thus fondaparinux is a pure AT-III dependant factor Xa inhibitor. Factor Xa bound together with factor Va on a phosphotidylserine membrane such as that present on platelets forms the prothrombinase or IIase complex. This complex is responsible for the highly efficient conversion of prothrombin (factor II) to thrombin (factor IIa).

Fondaparinux is 100% bioavailable and has a highly predictable pharmacokinetic profile with linear dose dependent peak plasma levels reached in 2 hours. The dose independent half-life is 17 hours with the drug excreted unchanged in the urine. Unlike UFH and LMWH, fondaparinux has no effect on platelet function. It does not cross-react with antibodies to PF-4 making it potentially more useful than danaparoid (which has a 10-15% cross-reactivity rate) in HIT.2 Fondaparinux does not interfere with the anticoagulant effects of warfarin, ASA, or NSAIDs.1,3 Fondaparinux does not cross the placenta.4 Administration of fondaparinux produces slight increases in PTT (5 seconds) and PT (1 second) with the peak and duration of this effect mirroring the peak and steady state drug levels.5 There is no specific reversal agent for fondaparinux. Reversal of fondaparinux anticoagulation has been shown to be possible with administration of recombinant factor VIIa.5 Fondaparinux is not unique in this regard as rVIIa has been touted as the universal hemostatic agent.6 Whether protamine is an effective reversal agent remains to be determined.

Fondaparinux has been studied in clinical trials and shows promise as a safe and efficacious agent for prevention of DVT after major orthopedic surgery, treatment of DVT, and in treatment of acute coronary syndromes (ACS). These studies are summarized:

Prevention of DVT after major orthopedic surgery- The Pentamaks,7 Penthifra,8 Ephesus,9 and Pentathlon 2000,10 studies investigated the efficacy and safety of fondaparinux 2.5 mg sq qd starting 6 hours postoperatively and again 12 hours later compared to LMWH enoxaparin 30 mg sq bid (Penthifra, Pentamaks, and Pentathlon) or 40 mg (Ephesus) sq bid starting 12 hours postoperatively and again 12-24 hours later in prevention of DVT after hip fracture surgery (Penthifra), elective major knee surgery (Pentamaks), primary total hip replacement (Pentathlon), and primary or revision total hip replacement (Ephesus). A total of 5,385 patients were eligible for efficacy followup. The incidence of venous thromboembolism up to 11 days post surgery was significantly reduced from 13.7% in the enoxaparin group to 6.8% in the fondaparinux group (risk reduction of 55.2%). A total of 7,237 patients were eligible for safety followup. Although major bleeding defined as a bleeding index 2 (bleeding index = number of units of blood transfused + the prebleeding Hct - the post transfusion Hct)3 occurred more often in the fondaparinux group, there was no difference between groups in the incidence of clinically relevant bleeding defined as bleeding in a critical organ, or bleeding leading to death or reoperation.11,12
Treatment of DVT- the phase II Rembrandt trial determined that fondaparinux 5.0, 7.5, and 10.0 mg qd was as safe and effective as the LMWH dalteparin 100 IU/kg bid in treatment of DVT.13 The Matisse phase III trial is currently comparing fondaparinux 7.5 mg sq qd to enoxaparin 1mg/kg bid in treatment of DVT.1
Treatment of ACS- the Pentalyse trial demonstrated fondaparinux to be as safe and effective as UFH as an adjunct to alteplase and ASA in restoring patency of infarct related arteries.14 Fondaparinux appears to be as safe and effective as UFH in preventing acute vessel closure following PCTA.15 The Pentua trial demonstrated fondaparinux 2.5 mg qd to be more effective and as safe as enoxaparin 1 mg/kg bid in preventing ischemic complications in patients with ACS.16

The issue of bleeding complication related to fondaparinux administration in patients receiving regional anesthesia or peripheral nerve blocks has recently been addressed. ASA 2003 abstract A-1027 addressed the issue of fondaparinux administered in conjunction with regional anesthesia. In the 4 major orthopedic surgery trials described, approximately 50% patients received regional anesthesia, but the proportion varied from 1/3 to 2/3 depending on the particular trial. No bleeding complications related to regional anesthesia were reported. However, it must be noted that the first dose of fondaparinux was administered 6 hours postoperatively, indwelling intrathecal or epidural catheters were removed at least 2 hours before drug administration, and patients who required more than 2 attempts at spinal or epidural anesthesia were excluded from enrollment. ASA 2003 abstract A-1098 addressed the issue of peripheral nerve blocks administered to patients receiving fondapariunux and reported no complications.

Referemces:

1. Turpie AG: Pentasaccharides. Semin Hematol 2002; 39: 158-71
2. Amiral J, Lormeau JC, Marfaing-Koka A, Vissac AM, Wolf M, Boyer-Neumann C, Tardy B, Herbert JM, Meyer D: Absence of cross-reactivity of SR90107A / ORG31540 penta saccharide with antibodies to heparin-PF4 complexes developed in heparin-induced thrombocytopenia. Blood Coagul Fibrinolysis 1997; 8: 114-7
3. Ollier C, Faaij RA, Santoni A, Duvauchelle T, van Haard PM, Schoemaker RC, Cohen AF, de Greef R, Burggraaf J: Absence of interaction of fondaparinux sodium with aspirin and piroxicam in healthy male volunteers. Clin Pharmacokinet 2002; 41 Suppl 2: 31-7
4. Lagrange F, Brun JL, Vergnes MC, Paolucci F, Nadal T, Leng JJ, Saux MC, Bannwarth B: Fondaparinux sodium does not cross the placental barrier: study using the in-vitro human dually perfused cotyledon model. Clin Pharmacokinet 2002; 41 Suppl 2: 47-9
5. Bijsterveld NR, Moons AH, Boekholdt SM, van Aken BE, Fennema H, Peters RJ, Meijers JC, Buller HR, Levi M: Ability of recombinant factor VIIa to reverse the anticoagulant effect of the pentasaccharide fondaparinux in healthy volunteers. Circulation 2002; 106: 2550-4
6. Hedner U: Recombinant factor VIIa (Novoseven) as a hemostatic agent. Semin Hematol 2001; 38: 43-7
7. Bauer KA, Eriksson BI, Lassen MR, Turpie AG: Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after elective major knee surgery. N Engl J Med 2001; 345: 1305-10
8. Eriksson BI, Bauer KA, Lassen MR, Turpie AG: Fondaparinux compared with enoxaparin for the prevention of venous thromboembolism after hip-fracture surgery. N Engl J Med 2001; 345: 1298-304
9. Lassen MR, Bauer KA, Eriksson BI, Turpie AG: 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
10. Turpie AG, Bauer KA, Eriksson BI, Lassen MR: Postoperative fonda- parinux versus postoperative enoxaparin for prevention of venous thromboembolism after elective hip-replacement surgery: a randomised double-blind trial. Lancet 2002; 359: 1721-6
11. Turpie AG: Overview of the clinical results of pentasaccharide in major orthopedic surgery. Haematologica 2001; 86: 59-62
12. Turpie AG, Bauer KA, Eriksson BI, Lassen MR: 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
13. Treatment of proximal deep vein thrombosis with a novel synthetic compound (SR90107A/ORG31540) with pure anti-factor Xa activity: A phase II evaluation. The Rembrandt Investigators. Circulation 2000; 102: 2726-31
14. Coussement PK, Bassand JP, Convens C, Vrolix M, Boland J, Grollier G, Michels R, Vahanian A, Vanderheyden M, Rupprecht HJ, Van de Werf F: A synthetic factor-Xa inhibitor (ORG31540/SR9017A) as an adjunct to fibrinolysis in acute myocardial infarction. The PENTALYSE study. Eur Heart J 2001; 22: 1716-24
15. Vuillemenot A, Schiele F, Meneveau N, Claudel S, Donat F, Fontecave S, Cariou R, Samama MM, Bassand JP: 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
16. Van de Werf F: New data in treatment of acute coronary syndromes. Am Heart J 2001; 142: S16-21

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