Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

  • Review Article
  • Published:

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

Nature Reviews Cardiology volume 9, pages 392–401 (2012)Cite this article

Subjects

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

This is a preview of subscription content, access via your institution

Access options

Buy this article

  • Purchase on Springer Link
  • Instant access to full article PDF
Buy now

Prices may be subject to local taxes which are calculated during checkout

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.

Similar content being viewed by others

References

  1. Wallentin, L. et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N. Engl. J. Med. 361, 1045–1057 (2009).

    Article  CAS  PubMed  Google Scholar 

  2. Wiviott, S. D. et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N. Engl. J. Med. 357, 2001–2015 (2007).

    Article  CAS  PubMed  Google Scholar 

  3. Yusuf, S. et al. Effects of clopidogrel in addition to aspirin in patients with acute coronary syndromes without ST-segment elevation. N. Engl. J. Med. 345, 494–502 (2001).

    CAS  PubMed  Google Scholar 

  4. Rothberg, M. B., Celestin, C., Fiore, L. D., Lawler, E. & Cook, J. R. Warfarin plus aspirin after myocardial infarction or the acute coronary syndrome: meta-analysis with estimates of risk and benefit. Ann. Intern. Med. 143, 241–250 (2005).

    Article  CAS  PubMed  Google Scholar 

  5. Bertrand, M. E. et al. Randomized multicenter comparison of conventional anticoagulation versus antiplatelet therapy in unplanned and elective coronary stenting. The full anticoagulation versus aspirin and ticlopidine (FANTASTIC) study. Circulation 98, 1597–1603 (1998).

    Article  CAS  PubMed  Google Scholar 

  6. Hurlen, M., Abdelnoor, M., Smith, P., Erikssen, J. & Arnesen, H. Warfarin, aspirin, or both after myocardial infarction. N. Engl. J. Med. 347, 969–974 (2002).

    Article  CAS  PubMed  Google Scholar 

  7. Khurram, Z. et al. Combination therapy with aspirin, clopidogrel and warfarin following coronary stenting is associated with a significant risk of bleeding. J. Inv. Cardiol. 18, 162–164 (2006).

    Google Scholar 

  8. Rossini, R. et al. Long-term outcomes in patients undergoing coronary stenting on dual oral antiplatelet treatment requiring oral anticoagulant therapy. Am. J. Cardiol. 102, 1618–1623 (2008).

    Article  PubMed  Google Scholar 

  9. Anand, S. S. & Yusuf, S. Oral anticoagulants in patients with coronary artery disease. J. Am. Coll. Cardiol. 41 (Suppl. S), 62S–69S (2003).

    Article  CAS  PubMed  Google Scholar 

  10. Hoffman, M. & Monroe, D. M. 3rd. A cell-based model of hemostasis. Thromb. Haemost. 85, 958–965 (2001).

    Article  CAS  PubMed  Google Scholar 

  11. Herbert, J. et al. Effector protease receptor 1 mediates the mitogenic activity of factor Xa for vascular smooth muscle cells in vitro and in vivo. J. Clin. Invest. 101, 993–1000 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  12. Versteeg, H. H., Spek, C. A., Richel, D. J. & Peppelenbosch, M. P. Coagulation factors VIIa and Xa inhibit apoptosis and anoikis. Oncogene 23, 410–417 (2004).

    Article  CAS  PubMed  Google Scholar 

  13. Rauch, B. H., Bretschneider, E., Braun, M. & Schror, K. Factor Xa releases matrix metalloproteinase-2 (MMP-2) from human vascular smooth muscle cells and stimulates the conversion of pro-MMP-2 to MMP-2: role of MMP-2 in factor Xa-induced DNA synthesis and matrix invasion. Circ. Res. 90, 1122–1127 (2002).

    Article  CAS  PubMed  Google Scholar 

  14. Cirino, G. et al. Factor Xa as an interface between coagulation and inflammation. Molecular mimicry of factor Xa association with effector cell protease receptor-1 induces acute inflammation in vivo. J. Clin. Invest. 99, 2446–2451 (1997).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Eriksson, B. I., Quinlan, D. J. & Weitz, J. I. Comparative pharmacodynamics and pharmacokinetics of oral direct thrombin and factor Xa inhibitors in development. Clin. Pharmacokinet. 48, 1–22 (2009).

    Article  CAS  PubMed  Google Scholar 

  16. Eriksson, B. I. et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after hip arthroplasty. N. Engl. J. Med. 358, 2765–2775 (2008).

    Article  CAS  PubMed  Google Scholar 

  17. Lassen, M. R. et al. The efficacy and safety of apixaban, an oral, direct factor Xa inhibitor, as thromboprophylaxis in patients following total knee replacement. J. Thromb. Haemost. 5, 2368–2375 (2007).

    Article  CAS  PubMed  Google Scholar 

  18. Lassen, M. R. et al. Rivaroxaban versus enoxaparin for thromboprophylaxis after total knee arthroplasty. N. Engl. J. Med. 358, 2776–2786 (2008).

    Article  CAS  PubMed  Google Scholar 

  19. Lassen, M. R. et al. Apixaban versus enoxaparin for thromboprophylaxis after hip replacement. N. Engl. J. Med. 363, 2487–2498 (2010).

    Article  CAS  PubMed  Google Scholar 

  20. Connolly, S. J. et al. Apixaban in patients with atrial fibrillation. N. Engl. J. Med. 364, 806–817 (2011).

    Article  CAS  PubMed  Google Scholar 

  21. Granger, C. B. et al. Apixaban versus warfarin in patients with atrial fibrillation. N. Engl. J. Med. 365, 981–992 (2011).

    Article  CAS  PubMed  Google Scholar 

  22. Patel, M. R. et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N. Engl. J. Med. 365, 883–891 (2011).

    Article  CAS  PubMed  Google Scholar 

  23. Cabral, K. P. & Ansell, J. Oral direct factor Xa inhibitors for stroke prevention in atrial fibrillation. Nat. Rev. Cardiol. http://dx.doi.org/10.1038/nrcardio.2012.19

  24. Furie, B. & Furie, B. C. Mechanisms of thrombus formation. N. Engl. J. Med. 359, 938–949 (2008).

    Article  CAS  PubMed  Google Scholar 

  25. Morrissey, J. H., Macik, B. G., Neuenschwander, P. F. & Comp, P. C. Quantitation of activated factor VII levels in plasma using a tissue factor mutant selectively deficient in promoting factor VII activation. Blood 81, 734–744 (1993).

    CAS  PubMed  Google Scholar 

  26. Monroe, D. M., Hoffman, M. & Roberts, H. R. Transmission of a procoagulant signal from tissue factor-bearing cell to platelets. Blood Coagul. Fibrinolysis 7, 459–464 (1996).

    Article  CAS  PubMed  Google Scholar 

  27. Diaz-Ricart, M. et al. Thrombin facilitates primary platelet adhesion onto vascular surfaces in the absence of plasma adhesive proteins: studies under flow conditions. Haematologica 85, 280–288 (2000).

    CAS  PubMed  Google Scholar 

  28. Monkovic, D. D. & Tracy, P. B. Functional characterization of human platelet-released factor V and its activation by factor Xa and thrombin. J. Biol. Chem. 265, 17132–17140 (1990).

    CAS  PubMed  Google Scholar 

  29. Monkovic, D. D. & Tracy, P. B. Activation of human factor V by factor Xa and thrombin. Biochemistry 29, 1118–1128 (1990).

    Article  CAS  PubMed  Google Scholar 

  30. Hultin, M. B. Modulation of thrombin-mediated activation of factor VIII:C by calcium ions, phospholipid, and platelets. Blood 66, 53–58 (1985).

    CAS  PubMed  Google Scholar 

  31. Bono, F. et al. Human umbilical vein endothelial cells express high affinity receptors for factor Xa. J. Cell. Physiol. 172, 36–43 (1997).

    Article  CAS  PubMed  Google Scholar 

  32. Pejler, G., Lunderius, C. & Tomasini-Johansson, B. Macrophages synthesize factor X and secrete factor X/Xa-containing prothrombinase activity into the surrounding medium. Thromb. Haemost. 84, 429–435 (2000).

    Article  CAS  PubMed  Google Scholar 

  33. Altieri, D. C. & Edgington, T. S. Identification of effector cell protease receptor-1. A leukocyte-distributed receptor for the serine protease factor Xa. J. Immunol. 145, 246–253 (1990).

    CAS  PubMed  Google Scholar 

  34. Macfarlane, R. G. An enzyme cascade in the blood clotting mechanism, and its function as a biochemical amplifier. Nature 202, 498–499 (1964).

    Article  CAS  PubMed  Google Scholar 

  35. Yin, E. T. & Wessler, S. Investigation of the apparent thrombogenicity of thrombin. Thromb. Diath. Haemorrh. 20, 465–468 (1968).

    Article  CAS  PubMed  Google Scholar 

  36. Ieko, M. et al. Synthetic selective inhibitors of coagulation factor Xa strongly inhibit thrombin generation without affecting initial thrombin forming time necessary for platelet activation in hemostasis. J. Thromb. Haemost. 2, 612–618 (2004).

    Article  CAS  PubMed  Google Scholar 

  37. Petros, S., Siegemund, T., Siegemund, A. & Engelmann, L. The effect of different anticoagulants on thrombin generation. Blood Coagul. Fibrinolysis 17, 131–137 (2006).

    Article  CAS  PubMed  Google Scholar 

  38. Furugohri, T., Sugiyama, N., Morishima, Y. & Shibano, T. Antithrombin-independent thrombin inhibitors, but not direct factor Xa inhibitors, enhance thrombin generation in plasma through inhibition of thrombin–thrombomodulin–protein C system. Thromb. Haemost. 106, 1076–1083 (2011).

    Article  CAS  PubMed  Google Scholar 

  39. Morishima, Y., Furugohri, T., Shiozaki, Y., Sugiyama, N. & Shibano, T. Antithrombin-independent thrombin inhibitors, but not factor Xa inhibitors, enhance thrombin generation in human plasma via inhibition of thrombin-thrombomodulin–protein C system [abstract]. Blood 108, a914 (2006).

    Google Scholar 

  40. Food and Drug Administration, Cardiovascular and Renal Drugs Advisory Committee. Briefing information [online] (2004).

  41. Ansell, J. Factor Xa or thrombin: is factor Xa a better target? J. Thromb. Haemost. 5 (Suppl. 1), 60–64 (2007).

    Article  CAS  PubMed  Google Scholar 

  42. Yusuf, S. et al. Comparison of fondaparinux and enoxaparin in acute coronary syndromes. N. Engl. J. Med. 354, 1464–1476 (2006).

    Article  CAS  PubMed  Google Scholar 

  43. Yusuf, S. et al. Effects of fondaparinux on mortality and reinfarction in patients with acute ST-segment elevation myocardial infarction: the OASIS-6 randomized trial. JAMA 295, 1519–1530 (2006).

    Article  CAS  PubMed  Google Scholar 

  44. Alexander, J. H. et al. Apixaban, an oral, direct, selective factor Xa inhibitor, in combination with antiplatelet therapy after acute coronary syndrome: results of the Apixaban for Prevention of Acute Ischemic and Safety Events (APPRAISE) trial. Circulation 119, 2877–2885 (2009).

    Article  CAS  PubMed  Google Scholar 

  45. Turpie, A. G. et al. A randomized evaluation of betrixaban, an oral factor Xa inhibitor, for prevention of thromboembolic events after total knee replacement (EXPERT). Thromb. Haemost. 101, 68–76 (2009).

    Article  CAS  PubMed  Google Scholar 

  46. Steg, P. G. et al. RUBY-1: a randomized, double-blind, placebo-controlled trial of the safety and tolerability of the novel oral factor Xa inhibitor darexaban (YM150) following acute coronary syndrome. Eur. Heart J. 32, 2541–2554 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  47. Ogata, K. et al. Clinical safety, tolerability, pharmacokinetics, and pharmacodynamics of the novel factor Xa inhibitor edoxaban in healthy volunteers. J. Clin. Pharmacol. 50, 743–753 (2010).

    Article  CAS  PubMed  Google Scholar 

  48. Kohrt, J. T. et al. The discovery of (2R,4R)-N-(4-chlorophenyl)-N-(2-fluoro-4-(2-oxopyridin-1(2H)-yl)phenyl)-4-methoxypyrrolidine-1,2-dicarboxamide (PD 0348292), an orally efficacious factor Xa inhibitor. Chem. Biol. Drug Des. 70, 100–112 (2007).

    Article  CAS  PubMed  Google Scholar 

  49. Goldstein, S. et al. Safety evaluation of the factor Xa inhibitor TAK-442 in subjects with acute coronary syndromes: phase 2 AXIOM-ACS trial results [abstract]. Eur. Heart J. 32 (Abstract Suppl.), 414 (2011).

    Google Scholar 

  50. Agnelli, G. et al. A phase II study of the oral factor Xa inhibitor LY517717 for the prevention of venous thromboembolism after hip or knee replacement. J. Thromb. Haemost. 5, 746–753 (2007).

    Article  CAS  PubMed  Google Scholar 

  51. Mega, J. L. et al. Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS–TIMI 46): a randomised, double-blind, phase II trial. Lancet 374, 29–38 (2009).

    Article  CAS  PubMed  Google Scholar 

  52. Pinto, D. J. et al. Discovery of 1-(4-methoxyphenyl)-7-oxo-6-(4-(2-oxopiperidin-1-yl)phenyl)-4,5,6,7-tetrahydro-1H-pyrazolo[3,4-c]pyridine-3-carboxamide (apixaban, BMS-562247), a highly potent, selective, efficacious, and orally bioavailable inhibitor of blood coagulation factor Xa. J. Med. Chem. 50, 5339–5356 (2007).

    Article  CAS  PubMed  Google Scholar 

  53. Raghavan, N. et al. Apixaban metabolism and pharmacokinetics after oral administration to humans. Drug Metab. Dispos. 37, 74–81 (2009).

    Article  CAS  PubMed  Google Scholar 

  54. Karthikeyan, G. & Eikelboom, J. W. Apixaban in acute coronary syndromes. Cardiovasc. Ther. 29, 285–290 (2011).

    Article  CAS  PubMed  Google Scholar 

  55. Wang, L. et al. In vitro assessment of metabolic drug–drug interaction potential of apixaban through cytochrome P450 phenotyping, inhibition, and induction studies. Drug Metab. Dispos. 38, 448–458 (2010).

    Article  CAS  PubMed  Google Scholar 

  56. Schulman, S. & Kearon, C. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J. Thromb. Haemost. 3, 692–694 (2005).

    Article  CAS  PubMed  Google Scholar 

  57. Alexander, J. H. et al. Apixaban with antiplatelet therapy after acute coronary syndrome. N. Engl. J. Med. 365, 699–708 (2011).

    Article  CAS  PubMed  Google Scholar 

  58. Chesebro, J. H. et al. Thrombolysis in Myocardial Infarction (TIMI) Trial, phase I: a comparison between intravenous tissue plasminogen activator and intravenous streptokinase. Clinical findings through hospital discharge. Circulation 76, 142–154 (1987).

    Article  CAS  PubMed  Google Scholar 

  59. Davis, E. M., Packard, K. A., Knezevich, J. T. & Campbell, J. A. New and emerging anticoagulant therapy for atrial fibrillation and acute coronary syndrome. Pharmacotherapy 31, 975–1016 (2011).

    Article  CAS  PubMed  Google Scholar 

  60. Weinz, C., Radtke, M., Schmeer, K., Kern, A. & Pleiss, U. In vitro metabolism of BAY 59-7939—an oral, direct factor Xa inhibitor. Drug Metab. Rev. 36, 98–98 (2004).

    Google Scholar 

  61. Weinz, C. et al. Metabolism and distribution of [C14]BAY 59-7939—an oral, direct factor Xa inhibitor—in rat, dog and human. Drug Metab. Rev. 36, 98–98 (2004).

    Google Scholar 

  62. Mega, J. L. et al. Rivaroxaban in patients with a recent acute coronary syndrome. N. Engl. J. Med. 366, 9–19 (2012).

    Article  CAS  PubMed  Google Scholar 

  63. Mehta, R. S. Novel oral anticoagulants for prophylaxis and treatment of venous thromboembolism: part I (factor Xa inhibitors). Expert Rev. Hematol. 3, 227–241 (2010).

    Article  CAS  PubMed  Google Scholar 

  64. Astellas Pharma. Astellas Pharma Inc. discontinues development of darexaban (YM150), an oral direct factor Xa inhibitor[online], (2011).

  65. Fujimoto, T. et al. Discovery of a tetrahydropyrimidin-2(1H)-one derivative (TAK-442) as a potent, selective, and orally active factor Xa inhibitor. J. Med. Chem. 53, 3517–3531 (2010).

    Article  CAS  PubMed  Google Scholar 

  66. Weitz, J. I. New oral anticoagulants in development. Thromb. Haemost. 103, 62–70 (2010).

    Article  CAS  PubMed  Google Scholar 

  67. Weitz, J. I. et al. A dose-finding study with TAK-442, an oral factor Xa inhibitor, in patients undergoing elective total knee replacement surgery. Thromb. Haemost. 104, 1150–1157 (2010).

    Article  CAS  PubMed  Google Scholar 

  68. Lee, C. W. et al. Comparison of ruptured coronary plaques in patients with unstable and stable clinical presentation. J. Thromb. Thrombolysis 32, 150–157 (2011).

    Article  PubMed  Google Scholar 

  69. Undas, A., Brummel, K., Musial, J., Mann, K. G. & Szczeklik, A. Blood coagulation at the site of microvascular injury: effects of low-dose aspirin. Blood 98, 2423–2431 (2001).

    Article  CAS  PubMed  Google Scholar 

  70. Brummel, K. E., Paradis, S. G., Butenas, S. & Mann, K. G. Thrombin functions during tissue factor-induced blood coagulation. Blood 100, 148–152 (2002).

    Article  CAS  PubMed  Google Scholar 

  71. Mann, K. G. Thrombin generation in hemorrhage control and vascular occlusion. Circulation 124, 225–235 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  72. Haynes, L. M., Dubief, Y. C., Orfeo, T. & Mann, K. G. Dilutional control of prothrombin activation at physiologically relevant shear rates. Biophys. J. 100, 765–773 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  73. Diener, H. C. et al. Aspirin and clopidogrel compared with clopidogrel alone after recent ischaemic stroke or transient ischaemic attack in high-risk patients (MATCH): randomised, double-blind, placebo-controlled trial. Lancet 364, 331–337 (2004).

    Article  CAS  PubMed  Google Scholar 

  74. Bauersachs, R. et al. Oral rivaroxaban for symptomatic venous thromboembolism. N. Engl. J. Med. 363, 2499–2510 (2010).

    Article  CAS  PubMed  Google Scholar 

  75. Kubitza, D., Becka, M., Voith, B., Zuehlsdorf, M. & Wensing, G. Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY 59-7939, an oral, direct factor Xa inhibitor. Clin. Pharmacol. Ther. 78, 412–421 (2005).

    Article  CAS  PubMed  Google Scholar 

  76. Roe, M. T. & Ohman, E. M. A new era in secondary prevention after acute coronary syndrome. N. Engl. J. Med. 366, 85–87 (2011).

    Article  PubMed  CAS  Google Scholar 

  77. Tricoci, P. et al. Thrombin-receptor antagonist vorapaxar in acute coronary syndromes. N. Engl. J. Med. 366, 20–33 (2011).

    Article  PubMed  CAS  Google Scholar 

  78. Lu, G. et al. Recombinant antidote for reversal of anticoagulation by factor Xa inhibitors [abstract]. Blood 112, a983 (2008).

    Google Scholar 

  79. Turpie, A. G. Oral, direct factor Xa inhibitors in development for the prevention and treatment of thromboembolic diseases. Arterioscler. Thromb. Vasc. Biol. 27, 1238–1247 (2007).

    Article  CAS  PubMed  Google Scholar 

  80. Iwatsuki, Y. et al. Biochemical and pharmacological profiles of YM150, an oral direct factor Xa inhibitor [abstract]. Blood 108, a273 (2006).

    Google Scholar 

  81. Groenendaal-van de Meent, D. et al. YM150, an oral direct inhibitor of factor Xa, demonstrated a predictable and dose-proportional pharmacokinetic/pharmacodynamic profile after single and multiple dosing: results from three studies [abstract]. Blood 116, a3323 (2010).

    Google Scholar 

  82. Saiah, E. & Soares, C. Small molecule coagulation cascade inhibitors in the clinic. Curr. Top. Med. Chem. 5, 1677–1695 (2005).

    Article  CAS  PubMed  Google Scholar 

  83. Perzborn, E. et al. In vitro and in vivo studies of the novel antithrombotic agent BAY 59-7939—an oral, direct factor Xa inhibitor. J. Thromb. Haemost. 3, 514–521 (2005).

    Article  CAS  PubMed  Google Scholar 

  84. Lu, G. et al. Reversal of rivaroxaban mediated anticoagulation in animal models by a recombinant antidote protein (r-Antidote, PRT064445) [abstract]. Eur. Heart J. 32 (Abstract Suppl.), 640–641 (2011).

    Google Scholar 

  85. Kawamura, M. et al. Antithrombotic and anticoagulant profiles of TAK-442, a novel factor Xa inhibitor, in a rabbit model of venous thrombosis. J. Cardiovasc. Pharmacol. 56, 156–161 (2010).

    Article  CAS  PubMed  Google Scholar 

  86. Nakamura, K. et al. Comparison of the pharmacokinetics and pharmacodynamics of TAK-442, a novel factor Xa inhibitor, between Japanese acute coronary syndrome patients and healthy Japanese males. J. Thromb. Haemost. 9, 107–107 (2011).

    Google Scholar 

  87. Gibson, C. M. et al. Rationale and design of the Anti-Xa therapy to lower cardiovascular events in addition to standard therapy in subjects with acute coronary syndrome—thrombolysis in myocardial infarction 51 (ATLAS ACS 2–TIMI 51) trial: a randomized, double-blind, placebo-controlled study to evaluate the efficacy and safety of rivaroxaban in subjects with acute coronary syndrome. Am. Heart J. 161, 815–821e6 (2011).

    Article  CAS  PubMed  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Division of Cardiology, Duke University Medical Center, Box 3850, 2400 Pratt Street, Durham, 27705, NC, USA

    James W. Wisler

  2. Duke Clinical Research Institute, Duke University Medical Center, Box 3850, 2400 Pratt Street, Durham, 27705, NC, USA

    Richard C. Becker

Authors
  1. James W. Wisler
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Richard C. Becker
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

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.

Corresponding author

Correspondence to Richard C. Becker.

Ethics declarations

Competing interests

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.

Rights and permissions

Reprints and permissions

About this article

Cite this article

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

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrcardio.2012.18

This article is cited by

Search

Advanced search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing