Treatment of ACS

Recent clinical studies have explored the use of fondaparinux in the treatment of ACS, based on the rationale that antithrombotic therapy with UFH and LMWH is beneficial in this clinical context, as well as percutaneous coronary intervention (PCI). A pilot study was performed in patients undergoing elective or urgent PCI (Mehta et al., 2005). Fondaparinux was administered at either 2.5 or 5.0 mg, by intravenous (iv) infusion, and compared to iv UFH. Comparable efficacy was observed using a composite endpoint (all-cause mortality, infarction, revasculariza-tion, or need for glycoprotein IIb/IIIa antagonist therapy). However, a reduced incidence of hemorrhage in patients receiving 2.5 mg (3.4%) versus 5.0 mg (9.6%) prompted further evaluation of the 2.5 mg dose of fondaparinux in registration studies.

The OASIS-5 study compared the efficacy of fondaparinux (2.5 mg o.d.) versus enoxaparin (1 mg/kg twice-daily) in patients with ACS (Yusuf et al., 2006a). In this large (n = 20,078) international study, patients were randomized and treated for 6-8 days. The primary endpoint of death, infarction or ischemia was examined at day 9, without a significant difference noted between the groups. However, significant differences in mortality were noted at 30 days and at 180 days, favoring treatment with fondaparinux. Major bleeding was also markedly reduced by the use of fondaparinux (2.2% vs. 4.1%; p < 0.001) and most of the excess deaths in the enoxaparin group occurred in patients who experienced bleeding.

With an interest in establishing the efficacy of fondaparinux in the treatment of ST-segment myocardial infarction (MI), fondaparinux was studied in another large (n = 12,092) randomized control trial (RCT) (Yusuf et al., 2006b). Patients were randomized to fondaparinux (2.5 mg o.d.) administered for an average of 8 days or usual care, either UFH or no anticoagulation (placebo). The primary endpoint of this study, the composite of death or recurrent infarction at 30 days, was reduced by treatment with fondaparinux (9.7% vs. 11.2%; p = 0.008). The benefit of therapy was durable through the study to final follow-up at 3-6 mo, including a significant reduction in mortality. This large study allows for speculative examination of clinically meaningful subpopulations. Of note, there was no efficacy benefit among those patients undergoing primary therapy with PCI, whereas patients receiving thrombolytic therapy as well as those who received no reperfusion therapy derived a significant benefit from fondaparinux.

Together, these studies have defined a striking activity and tolerability of fondaparinux in the cardiac patient. Fondaparinux is currently undergoing expedited FDA review for the treatment of ACS (as of March 2007).

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