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Oral factor Xa inhibitors for the long-term management of ACS

Abstract

Despite considerable reductions in cardiovascular events in patients with an acute coronary syndrome (ACS) receiving dual antiplatelet therapy (DAPT), substantial residual risk persists. This unmet need has stimulated the development of anticoagulant drugs that target specific coagulation factors involved in the pathogenesis of thrombosis after atheromatous plaque disruption. Factor Xa is an attractive target for inhibition because of both its integral role in coagulation and its recognized participation in cellular proliferation and inflammation. Several oral, direct factor Xa inhibitors are undergoing investigation and large, phase III clinical trials of two agents, apixaban and rivaroxaban, in patients with an ACS have been completed. On the basis of the known pathobiology of ACS, one might anticipate that drugs in this class of anticoagulant would beneficially reduce ischemic and thrombotic events; however, a strategy of combined anticoagulant therapy and DAPT is likely to increase concomitant bleeding complications. The balance of benefit and risk will ultimately determine uptake in clinical practice. We review the available data on factor Xa inhibitors in the long-term management of patients with an ACS.

Key Points

  • Factor Xa is an attractive target for inhibition in patients with an acute coronary syndrome (ACS) because of its roles in coagulation, cellular proliferation, apoptosis, matrix-metalloprotein stability, and inflammation

  • Four oral, competitive factor Xa inhibitors (apixaban, darexaban, letaxaban, and rivaroxaban) have been investigated in patients with an ACS; only apixaban and rivaroxaban have progressed to phase III clinical trials

  • In the APPRAISE-2 trial, addition of apixaban to standard therapy in patients with an ACS showed no clinical benefit, and increased the risk of major and intracranial bleeding

  • In ATLAS ACS 2–TIMI 51, addition of rivaroxaban to dual antiplatelet therapy (aspirin plus clopidogrel) reduced cardiovascular events and mortality, which outweighed the increased bleeding risk

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Figure 1: Cell-based model of coagulation, in which coagulation occurs in three overlapping phases.
Figure 2: Reduction in adverse cardiovascular events associated with rivaroxaban treatment.

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J. W. Wisler researched the data for this article. Both authors contributed substantially to discussion of its contents and to writing, reviewing, and editing the manuscript before submission.

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Correspondence to Richard C. Becker.

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R. C. Becker has received grants or research support from the following companies: AstraZeneca, Bayer Pharmaceuticals, Bristol–Myers Squibb, Daiichi Sankyo, Johnson & Johnson, The Medicines Company, Momenta, Regado Biosciences, and Schering–Plough. Additionally, he is, or has been, a consultant for Eli Lilly and Merck. J. W. Wisler declares no competing interests.

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Wisler, J., Becker, R. Oral factor Xa inhibitors for the long-term management of ACS. Nat Rev Cardiol 9, 392–401 (2012). https://doi.org/10.1038/nrcardio.2012.18

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