Drugs

, Volume 74, Issue 4, pp 451–464

Rivaroxaban: A Review of Its Use in Acute Coronary Syndromes

Adis Drug Evaluation

Abstract

Rivaroxaban (Xarelto®) is an orally administered highly selective direct inhibitor of factor Xa that has been approved in many countries to reduce the risk of stroke in patients with atrial fibrillation and for the treatment and prevention of venous thromboembolism. More recently, rivaroxaban at a low dosage of 2.5 mg twice daily, co-administered with aspirin alone or aspirin plus either clopidogrel or ticlopidine, was approved for use in the EU for patients with a recent acute coronary syndrome (ACS). The approval of rivaroxaban in ACS was primarily based on findings of the phase III ATLAS ACS 2-TIMI 51 trial, which showed that after a median of 13.1 months of treatment with rivaroxaban 2.5 mg twice daily (combined with aspirin or aspirin plus either clopidogrel or ticlopidine) there was a statistically significant reduction in the rate of the primary composite endpoint, which was death from cardiovascular causes, myocardial infarction or stroke, compared with placebo. Rivaroxaban 2.5 mg twice daily was also associated with a reduction in all-cause and cardiovascular mortality. There was an increase in the risk of major bleeding and intracranial haemorrhage with rivaroxaban 2.5 mg twice daily compared with placebo; however, there was no increase in the risk of fatal bleeding. Aspirin plus either ticagrelor or prasugrel was not evaluated as background dual antiplatelet therapy in ATLAS ACS 2-TIMI 51 and the safety implications of rivaroxaban used in combination with such therapy are unknown. In conclusion, results of the ATLAS ACS 2-TIMI 51 trial suggest a potentially important role for rivaroxaban 2.5 mg twice daily co-administered with aspirin alone or aspirin plus either clopidogrel or ticlopidine in patients with a recent ACS.

References

  1. 1.
    Thygesen K, Alpert JS, White HD. Universal definition of myocardial infarction. J Am Coll Cardiol. 2007;50(22):2173–95.CrossRefPubMedGoogle Scholar
  2. 2.
    Gibson CM, Mega JL, Burton P, 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. 2011;161(5):815–821.e6.CrossRefPubMedGoogle Scholar
  3. 3.
    Jneid H, Alam M, Virani SS, et al. Redefining myocardial infarction: what is new in the ESC/ACCF/AHA/WHF third universal definition of myocardial infarction? Methodist Debakey Cardiovasc J. 2013;9(3):169–72.PubMedCentralPubMedGoogle Scholar
  4. 4.
    Patrick WL, Patel C, Guddeti R, et al. Is there a need for “triple therapy”? Role of anticoagulation with dual antiplatelet therapy in acute coronary syndromes (ATLAS study & TRAP study). Curr Cardiol Rep. 2013;15:411.CrossRefPubMedGoogle Scholar
  5. 5.
    Hamm CW, Bassand JP, Agewall S, et al. ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation: the task force for the management of acute coronary syndromes (ACS) in patients presenting without persistent ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J. 2011;32(23):2999–3054.CrossRefPubMedGoogle Scholar
  6. 6.
    Rothberg MB, Celestin C, Fiore LD, et al. Warfarin plus aspirin after myocardial infarction or the acute coronary syndrome: meta-analysis with estimates of risk and benefit. Ann Intern Med. 2005;143(4):241–50.CrossRefPubMedGoogle Scholar
  7. 7.
    Andreotti F, Testa L, Biondi-Zoccai GG, et al. Aspirin plus warfarin compared to aspirin alone after acute coronary syndromes: an updated and comprehensive meta-analysis of 25,307 patients. Eur Heart J. 2006;27(5):519–26.CrossRefPubMedGoogle Scholar
  8. 8.
    Wallentin L, Wilcox RG, Weaver WD, et al. Oral ximelagatran for secondary prophylaxis after myocardial infarction: the ESTEEM randomised controlled trial. Lancet. 2003;362(9386):789–97.CrossRefPubMedGoogle Scholar
  9. 9.
    Roe MT, Ohman EM. A new era in secondary prevention after acute coronary syndrome. N Engl J Med. 2012;366(1):85–7.CrossRefPubMedGoogle Scholar
  10. 10.
    Armstrong PW, Harrington RA. Road mapping ATLAS ACS 2: are we there yet? Eur Heart J. 2012;33(20):2510–2.CrossRefPubMedGoogle Scholar
  11. 11.
    Merlini PA, Bauer KA, Oltrona L, et al. Persistent activation of coagulation mechanism in unstable angina and myocardial infarction. Circulation. 1994;90(1):61–8.CrossRefPubMedGoogle Scholar
  12. 12.
    Skeppholm M, Kallner A, Malmqvist K, et al. Is fibrin formation and thrombin generation increased during and after an acute coronary syndrome? Thromb Res. 2011;128(5):483–9.CrossRefPubMedGoogle Scholar
  13. 13.
    Krantz MJ, Kaul S. The ATLAS ACS 2-TIMI 51 trial and the burden of missing data: (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects With Acute Coronary Syndrome ACS 2-Thrombolysis In Myocardial Infarction 51). J Am Coll Cardiol. 2013;62(9):777–81.CrossRefPubMedGoogle Scholar
  14. 14.
    Perzborn E, Strassburger J, Wilmen A, 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. 2005;3(3):514–21.CrossRefPubMedGoogle Scholar
  15. 15.
    Bayer Pharma AG. Xarelto (rivaroxaban) 2.5 mg film-coated tablets: EU summary of product characteristics. Berlin: Bayer Pharma AG; 2013.Google Scholar
  16. 16.
    Rupprecht HJ, Blank R. Clinical pharmacology of direct and indirect factor Xa inhibitors. Drugs. 2010;70:2153–70.PubMedGoogle Scholar
  17. 17.
    Sattari M, Lowenthal DT. Novel oral anticoagulants in development: dabigatran, rivaroxaban, and apixaban. Am J Ther. 2011;18(4):332–8.CrossRefPubMedGoogle Scholar
  18. 18.
    Oldgren J, Budaj A, Granger CB, et al. Dabigatran vs. placebo in patients with acute coronary syndromes on dual antiplatelet therapy: a randomized, double-blind, phase II trial. Eur Heart J. 2011;32(22):2781–9.CrossRefPubMedGoogle Scholar
  19. 19.
    Alexander JH, Lopes RD, James S, et al. Apixaban with antiplatelet therapy after acute coronary syndrome. N Engl J Med. 2011;365(8):699–708.CrossRefPubMedGoogle Scholar
  20. 20.
    Mega JL, Braunwald E, Wiviott SD, et al. Rivaroxaban in patients with a recent acute coronary syndrome. N Engl J Med. 2012;366(1):9-19 [plus supplementary appendix].Google Scholar
  21. 21.
    European Medicines Agency. Xarelto 10 mg film-coated tablets: summary of product characteristics; 2013. http://www.medicines.org.uk/emc/medicine/21265. Accessed 31 Oct 2013.
  22. 22.
    European Medicines Agency. Xarelto 20 mg film-coated tablets: summary of product characteristics; 2013. http://www.medicines.org.uk/emc/medicine/25586/SPC. Accessed 31 Oct 2013.
  23. 23.
    Xarelto (rivaroxaban) tablets for oral use: US prescribing information; 2013. http://www.janssenpharmaceuticalsinc.com/assets/xareltopi.pdf. Accessed 5 Nov 2013.
  24. 24.
    Kubitza D, Becka M, Voith B, et al. Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY 59-7939, an oral, direct factor Xa inhibitor. Clin Pharmacol Ther. 2005;78(4):412–21.CrossRefPubMedGoogle Scholar
  25. 25.
    Kubitza D, Becka M, Wensing G, et al. Safety, pharmacodynamics, and pharmacokinetics of BAY 59-7939—an oral, direct Factor Xa inhibitor—after multiple dosing in healthy male subjects. Eur J Clin Pharmacol. 2005;61(12):873–80.CrossRefPubMedGoogle Scholar
  26. 26.
    Mueck W, Becka M, Kubitza D, et al. Population model of the pharmacokinetics and pharmacodynamics of rivaroxaban - an oral, direct factor Xa inhibitor—in healthy subjects. Int J Clin Pharmacol Ther. 2007;45(6):335–44.CrossRefPubMedGoogle Scholar
  27. 27.
    Mueck W, Borris LC, Dahl OE, et al. Population pharmacokinetics and pharmacodynamics of once- and twice-daily rivaroxaban for the prevention of venous thromboembolism in patients undergoing total hip replacement. Thromb Haemost. 2008;100(3):453–61.PubMedGoogle Scholar
  28. 28.
    Mueck W, Eriksson BI, Bauer KA, et al. Population pharmacokinetics and pharmacodynamics of rivaroxaban—an oral, direct factor Xa inhibitor—in patients undergoing major orthopaedic surgery. Clin Pharmacokinet. 2008;47(3):203–16.CrossRefPubMedGoogle Scholar
  29. 29.
    Becker EM, Perzborn E, Klipp A, et al. Effects of rivaroxaban, acetylsalicylic acid and clopidogrel as monotherapy and in combination in a porcine model of stent thrombosis. J Thromb Haemost. 2012;10:2470–80.CrossRefPubMedGoogle Scholar
  30. 30.
    Wolzt M, Gouya G, Kapiotis S, et al. Open-label randomized study of the effect of rivaroxaban with or without acetylsalicylic acid on thrombus formation in a perfusion chamber. Thromb Res. 2013;132(2):240–7.CrossRefPubMedGoogle Scholar
  31. 31.
    Tripodi A, Chantarangkul V, Guinet C, et al. The International Normalized Ratio calibrated for rivaroxaban has the potential to normalize prothrombin time results for rivaroxaban-treated patients: results of an in vitro study. J Thromb Haemost. 2011;9(1):226–8.CrossRefPubMedGoogle Scholar
  32. 32.
    Kubitza D, Becka M, Mueck W, et al. Rivaroxaban (BAY 59-7939)—an oral, direct factor Xa inhibitor—has no clinically relevant interaction with naproxen. Br J Clin Pharmacol. 2007;63(4):469–76.CrossRefPubMedCentralPubMedGoogle Scholar
  33. 33.
    Kubitza D, Becka M, Mueck W, et al. Safety, tolerability, pharmacodynamics, and pharmacokinetics of rivaroxaban—an oral, direct factor Xa inhibitor—are not affected by aspirin. J Clin Pharmacol. 2006;46(9):981–90.CrossRefPubMedGoogle Scholar
  34. 34.
    Kubitza D, Becka M, Mueck W, et al. Co-administration of rivaroxaban—a novel, oral, direct factor Xa inhibitor—and clopidogrel in healthy subjects [abstract no. 1272]. Eur Heart J. 2007;28(Suppl. 1):189.Google Scholar
  35. 35.
    Gopalakrishnan L, Kumar V, Kohli P, et al. Pharmacokinetic evaluation of rivaroxaban for the treatment of acute coronary syndromes. Expert Opin Drug Metab Toxicol. 2012;8(7):889–900.CrossRefPubMedGoogle Scholar
  36. 36.
    Kreutz R. Pharmacodynamic and pharmacokinetic basics of rivaroxaban. Fundam Clin Pharmacol. 2012;26(1):27–32.CrossRefPubMedGoogle Scholar
  37. 37.
    Duggan ST. Rivaroxaban: a review of its use for the prophylaxis of venous thromboembolism after total hip or knee replacement surgery. Am J Cardiovasc Drugs. 2012;12(1):57–72.CrossRefPubMedGoogle Scholar
  38. 38.
    Kubitza D, Becka M, Zuehlsdorf M, et al. Effect of food, an antacid, and the H2 antagonist ranitidine on the absorption of BAY 59-7939 (rivaroxaban), an oral, direct factor Xa inhibitor, in healthy subjects. J Clin Pharmacol. 2006;46(5):549–58.CrossRefPubMedGoogle Scholar
  39. 39.
    Weinz C, Schwarz T, Kubitza D, et al. Metabolism and excretion of rivaroxaban, an oral, direct factor Xa inhibitor, in rats, dogs, and humans. Drug Metab Dispos. 2009;37(5):1056–64.CrossRefPubMedGoogle Scholar
  40. 40.
    Gnoth MJ, Buetehorn U, Muenster U, et al. In vitro and in vivo P-glycoprotein transport characteristics of rivaroxaban. J Pharmacol Exp Ther. 2011;338(1):372–80.CrossRefPubMedGoogle Scholar
  41. 41.
    Kubitza D, Becka M, Roth A, et al. Dose-escalation study of the pharmacokinetics and pharmacodynamics of rivaroxaban in healthy elderly subjects. Curr Med Res Opin. 2008;24(10):2757–65.CrossRefPubMedGoogle Scholar
  42. 42.
    Xu XS, Moore K, Burton P, et al. Population pharmacokinetics and pharmacodynamics of rivaroxaban in patients with acute coronary syndromes. Br J Clin Pharmacol. 2012;74(1):86–97.CrossRefPubMedCentralPubMedGoogle Scholar
  43. 43.
    Mega JL, Braunwald E, Mohanavelu S, et al. Rivaroxaban versus placebo in patients with acute coronary syndromes (ATLAS ACS-TIMI 46): a randomised, double-blind, phase II trial. Lancet. 2009;374(9683):29–38.CrossRefPubMedGoogle Scholar
  44. 44.
    Kubitza D, Becka M, Mueck W, et al. Effects of renal impairment on the pharmacokinetics, pharmacodynamics and safety of rivaroxaban, an oral, direct factor Xa inhibitor. Br J Clin Pharmacol. 2010;70(5):703–12.CrossRefPubMedCentralPubMedGoogle Scholar
  45. 45.
    Halabi A, Kubitza D, Zuehlsdorf M, et al. Effect of hepatic impairment on the pharmacokinetics, pharmacodynamics and tolerability of rivaroxaban an oral, direct factor Xa inhibitor [abstract]. J Thromb Haemost. 2007;5(Suppl. 2):P-M-635.Google Scholar
  46. 46.
    Kubitza D, Becka M, Schwers S, et al. Investigation of pharmacodynamic and pharmacokinetic interactions between rivaroxaban and enoxaparin in healthy male subjects. Clin Pharm Drug Dev. 2013;2(3):270–7.CrossRefGoogle Scholar
  47. 47.
    Moore KT, Plotnikov AN, Thyssen A. Effect of multiple doses of omeprazole on the pharmacokinetics, pharmacodynamics, and safety of a single dose of rivaroxaban. J Cardiovasc Pharmacol. 2011;58(6):581–8.CrossRefPubMedGoogle Scholar
  48. 48.
    Janssen Research & Development, LLC Advisory Committee Briefing Document: Rivaroxaban for Reducing the Risk of Cardiovascular Events (Cardiovascular Death, Myocardial Infarction and Stroke) After Acute Coronary Syndrome (ACS); 2012. http://www.fda.gov/downloads/advisorycommittees/committeesmeetingmaterials/drugs/cardiovascularandrenaldrugsadvisorycommittee/ucm304757.pdf. Accessed 5 Dec 2013.
  49. 49.
    Mega JL, Braunwald E, Wiviott S, et al. Comparison of the efficacy and safety of two rivaroxaban doses in acute coronary syndrome (from ATLAS ACS 2-TIMI 51). Am J Cardiol. 2013;112:472–8.CrossRefPubMedGoogle Scholar
  50. 50.
    Arora R, Lang C, Quddus A. Bayesian net-clinical benefit analysis of rivaroxaban in patients with acute coronary syndromes [abstract]. J Am Coll Cardiol. 2013;61(10):E1534.CrossRefGoogle Scholar
  51. 51.
    Mega JL, Braunwald E, Murphy S, et al. Rivaroxaban in the setting of continued dual antiplatelet therapy: findings from the ATLAS ACS 2-TIMI 51 trial [abstract]. J Am Coll Cardiol. 2013;61(10):E4.CrossRefGoogle Scholar
  52. 52.
    Mega JL, Braunwald E, Murphy SA, et al. Rivaroxaban in patients stabilized after a ST-segment elevation myocardial infarction: results from the ATLAS ACS-2-TIMI-51 trial (Anti-Xa Therapy to Lower Cardiovascular Events in Addition to Standard Therapy in Subjects with Acute Coronary Syndrome-Thrombolysis In Myocardial Infarction-51). J Am Coll Cardiol. 2013;61(18):1853–9.CrossRefPubMedGoogle Scholar
  53. 53.
    Gibson CM, Chakrabarti AK, Mega J, et al. Reduction of stent thrombosis in patients with acute coronary syndrome treated with rivaroxaban in ATLAS ACS 2-TIMI 51. J Am Coll Cardiol. 2013;62:286–90.CrossRefPubMedGoogle Scholar
  54. 54.
    Cavender M, Braunwald E, Michael Gibson CC, et al. Rivaroxaban reduces spontaneous and large myocardial infarctions: Findings from the ATLAS ACS 2 - TIMI 51 trial [abstract]. J Am Coll Cardiol. 2013;61(10):E3.CrossRefGoogle Scholar
  55. 55.
    O’Donoghue ML, Mega JL, Braunwald E, et al. The efficacy and safety of low-dose rivaroxaban with or without a proton pump inhibitor: insights from the ATLAS ACS 2-TIMI 51 trial [abstract plus poster]. Annual meeting and scientific sessions of the American Heart Association, Dallas; 16–20 Nov 2013.Google Scholar
  56. 56.
    Tricoci P, Huang Z, Held C, et al. Thrombin-receptor antagonist vorapaxar in acute coronary syndromes. N Engl J Med. 2012;366(1):20–33.CrossRefPubMedGoogle Scholar
  57. 57.
    Morrow DA, Braunwald E, Bonaca MP, et al. Vorapaxar in the secondary prevention of atherothrombotic events. N Engl J Med. 2012;366(15):1404–13.CrossRefPubMedGoogle Scholar
  58. 58.
    Oldgren J, Wallentin L, Alexander JH, et al. New oral anticoagulants in addition to single or dual antiplatelet therapy after an acute coronary syndrome: a systematic review and meta-analysis. Eur Heart J. 2013;34(22):1670–80.CrossRefPubMedCentralPubMedGoogle Scholar
  59. 59.
    Neale T. Third strike for Xarelto for ACS; 2014. http://www.medpagetoday.com/Cardiology/AcuteCoronarySyndrome/43845. Accessed 20 Jan 2014.
  60. 60.
    Steg G, James SK, Atar D, et al. ESC guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: the task force for the management of ST-segment elevation acute myocardial infarction of the European Society of Cardiology (ESC). Eur Heart J. 2012;33:2569–619.CrossRefPubMedGoogle Scholar
  61. 61.
    Dewilde WJ, Oirbans T, Verheugt FW, et al. Use of clopidogrel with or without aspirin in patients taking oral anticoagulant therapy and undergoing percutaneous coronary intervention: an open-label, randomised, controlled trial. Lancet. 2013;381(9872):1107–15.CrossRefPubMedGoogle Scholar
  62. 62.
    Verheugt FWA. Low-dose anticoagulation for secondary prevention in acute coronary syndrome. Am J Cardiol. 2013;111:618–26.CrossRefPubMedGoogle Scholar

Copyright information

© Springer International Publishing Switzerland 2014

Authors and Affiliations

  1. 1.AdisNorth ShoreNew Zealand

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