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- Blick, S.K.A., Orman, J.S., Wagstaff, A.J. et al. Am J Cardiovasc Drugs (2008) 8: 113. doi:10.1007/BF03256588
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Fondaparinux sodium (Arixtra®) is a synthetic, sulfated pentasaccharide, selective factor Xa inhibitor that is indicated in Europe for preventing thrombus formation in patients with acute coronary syndromes (ACS; the focus of this review), including those with ST-segment elevation myocardial infarction (STEMI), non-STEMI (NSTEMI), or unstable angina.
The large (n = 20 078), well designed OASIS-5 trial showed that subcutaneous fondaparinux 2.5 mg/day for ≤8 days was noninferior to subcutaneous enoxaparin 1 mg/kg twice daily (once daily in those with renal dysfunction) in reducing death or ischemic events at 9 days and the efficacy was maintained for up to 6 months (study end) in patients with unstable angina or NSTEMI. During this time, major bleeding occurred in fewer fondaparinux than enoxaparin recipients, resulting in a benefit: risk balance favoring fondaparinux. The incidence of death or reinfarction at 30 days was significantly lower in recipients of subcutaneous fondaparinux 2.5 mg/day than in those who received usual care (including unfractionated heparin [UFH] treatment as indicated) in patients with STEMI in the large (n > 12 000) OASIS-6 trial. There were no differences in the incidence of major bleeding between these groups, resulting in a benefit: risk balance favoring fondaparinux.
The specificity and selectivity of fondaparinux, combined with its long half-life and 100% bioavailability, allows once-daily anticoagulation without the need for monitoring activated clotting time. Subcutaneous fondaparinux was noninferior to enoxaparin treatment in patients with unstable angina or NSTEMI, and was more effective than usual care in those with STEMI. Fondaparinux has a favorable tolerability profile, particularly with regard to the risk of major bleeding, and limited data suggest that it is more cost effective than enoxaparin in the short term. Thus, overall, clinical evidence suggests that fondaparinux has a valuable place in the treatment of patients with ACS.
Fondaparinux inhibits thrombus formation by binding strongly to antithrombin III, enhancing its inhibitory activity, and thus indirectly inhibiting free factor Xa and interrupting the blood coagulation cascade. Coagulation parameters, such as activated partial thromboplastin time, are not affected. Activated factor VII has been shown to partially reverse the anticoagulant effects of fondaparinux in humans.
Fondaparinux is rapidly and completely absorbed following subcutaneous administration, demonstrating 100% bioavailability. The pharmacokinetic profile is linear over a 2–8 mg dose range. Peak plasma fondaparinux concentrations are obtained ≈2 hours following single or multiple subcutaneous doses. Steady-state fondaparinux concentrations are reached after 3–4 days of repeat once-daily administration. Distribution of fondaparinux may be limited to the vascular compartment; the volume of distribution is 8.2–10.2 L.
Fondaparinux does not appear to be metabolized and, in vitro, does not inhibit cytochrome P450 isoenzymes. Elimination is primarily by renal excretion. Fondaparinux clearance is reduced in patients with renal impairment, and clearance is lower in patients weighing <50 kg.
Subcutaneous fondaparinux 2.5 mg/day for ≤8 days was noninferior to subcutaneous enoxaparin 1 mg/kg twice daily in patients with ACS involving unstable angina or NSTEMI. The primary composite endpoint comprising death, myocardial infarction (MI) or refractory ischemia had occurred in 5.8% and 5.7% of patients in the respective groups at day 9 in the OASIS-5 trial and the incidence remained similar between treatment groups to trial end at 180 days.
In patients with ACS presenting as STEMI who received subcutaneous fondaparinux 2.5 mg/day for ≤8 days (given intravenously on day 1), the incidence of death or reinfarction was significantly less than in those who received usual care (placebo or UFH therapy) in the OASIS-6 trial. The primary composite endpoint comprising death or reinfarction at 30 days occurred in 9.7% and 11.2% of patients in the respective groups (p < 0.001) and the between-group difference remained statistically significant from day 9 to study end (3–6 months).
When subcutaneous fondaparinux 2.5 mg/day was given during percutaneous coronary intervention (PCI) to subgroups in these two trials, therapeutic outcomes were similar to those seen with enoxaparin (in patients with unstable angina or NSTEMI) or UFH (in patients with STEMI).
The tolerability profile of subcutaneous fondaparinux in patients with ACS is similar to that in patients undergoing orthopedic or abdominal surgery, or in medical patients at risk of thromboembolic complications.
The main adverse effect of fondaparinux is bleeding. In the OASIS-5 trial, major bleeding occurred in significantly fewer patients with unstable angina or NSTEMI receiving subcutaneous fondaparinux 2.5 mg/day than those receiving subcutaneous enoxaparin 1 mg/kg twice daily for ≤8 days (2.2% vs 4.1% at 9 days; p < 0.001). The difference became apparent at day 5 and remained significant for up to 180 days. In patients with STEMI in the OASIS-6 trial, there were no differences in the incidence of major bleeding between the fondaparinux and usual care groups (1.8% vs 2.1%).
Benefit: risk calculations using multiple endpoints comprising death/MI/refractory ischemia/major bleeding (OASIS-5) or death/MI/severe bleeding (OASIS-6) indicated that these endpoints occurred in significantly fewer fondaparinux recipients than enoxaparin recipients with unstable angina or NSTEMI (7.3% vs 9.0% at 9 days; p < 0.001), and in usual care recipients with STEMI (7.7% vs 9.2% at 9 days; p < 0.01).
In patients undergoing PCI in the OASIS-5 trial, the incidence of catheter-related thrombosis was higher in fondaparinux recipients than in those who received enoxaparin alone (0.9% vs 0.4%; p < 0.001); however, when UFH was administered at the time of PCI, this complication was virtually eliminated.