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Oral Direct Factor Xa Inhibitors, with Special Emphasis on Rivaroxaban

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Anticoagulants, Antiplatelets, and Thrombolytics

Part of the book series: Methods in Molecular Biology ((MIMB,volume 663))

Abstract

Rivaroxaban is a small-molecule, direct factor Xa inhibitor that is under investigation for the prevention and treatment of venous and arterial thrombosis. To date, oral anticoagulants have been limited largely to vitamin K antagonists. Despite their remarkable benefits, vitamin K antagonists are limited by their narrow therapeutic window, the existence of multiple food and drug interactions, and the need for frequent monitoring and dose-adjustment. Rivaroxaban represents a potentially attractive alternative to warfarin, as it could enable simplified once-daily dosing, requires no therapeutic monitoring, and has a lower potential for drug interactions. At present, the safety and efficacy of rivaroxaban for the prophylaxis and treatment of venous thromboembolism has been evaluated in phase-II and phase-III trials involving over 24,000 patients. Rivaroxaban is also being evaluated for the treatment of pulmonary embolism, secondary prevention after acute coronary syndromes, and the prevention of stroke and non-central nervous system embolism in patients with non-valvular atrial fibrillation. The need for new oral anticoagulants, the development and pharmacology of rivaroxaban, results of completed studies of rivaroxaban, and details of ongoing phase-II and phase-III trials with rivaroxaban are the subjects of this chapter.

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References

  1. Rosamond, W., Flegal, K., Friday, G., Furie, K., Go, A., Greenlund, K., Haase, N., Ho, M., Howard, V., Kissela, B., Kittner, S., Lloyd-Jones, D., McDermott, M., Meigs, J., Moy, C., Nichol, G., O’Donnell, C.J., Roger, V., Rumsfeld, J., Sorlie, P., Steinberger, J., Thom, T., Wasserthiel-Smoller, S., Hong, Y., and for the American Heart Association Statistics Committee and Stroke Statistics, S. (2007) Heart disease and stroke statistics–2007 update: a report from the American Heart Association Statistics Committee and Stroke Statistics Subcommittee Circulation 115, e69–171.

    Google Scholar 

  2. Caprini, J.A., Botteman, M.F., Stephens, J.M., Nadipelli, V., Ewing, M.M., Brandt, S., Pashos, C.L., and Cohen, A.T. (2003) Economic burden of long-term complications of deep vein thrombosis after total hip replacement surgery in the United States Value Health 6, 59–74.

    Article  PubMed  Google Scholar 

  3. MacDougall, D.A., Feliu, A.L., Boccuzzi, S.J., and Lin, J. (2006) Economic burden of deep-vein thrombosis, pulmonary embolism, and post-thrombotic syndrome Am J Health Syst Pharm 63, S5–15.

    Article  PubMed  Google Scholar 

  4. Go, A.S., Hylek, E.M., Phillips, K.A., Chang, Y., Henault, L.E., Selby, J.V., and Singer, D.E. (2001) Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the anticoagulation and risk factors in atrial fibrillation (ATRIA) study JAMA 285, 2370–5.

    Article  PubMed  CAS  Google Scholar 

  5. Wolf, P.A., Abbott, R.D., and Kannel, W.B. (1991) Atrial fibrillation as an independent risk factor for stroke: the Framingham Study Stroke 22, 983–8.

    Article  PubMed  CAS  Google Scholar 

  6. Dulli, D.A., Stanko, H., and Levine, R.L. (2003) Atrial fibrillation is associated with severe acute ischemic stroke Neuroepidemiology 22, 118–23.

    Article  PubMed  Google Scholar 

  7. Link, K. (1959) The discovery of dicumarol and its sequels Circulation 19, 97–107.

    Article  PubMed  CAS  Google Scholar 

  8. Hart, R.G., Pearce, L.A., Aguilar, M.I. (2007) Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation Ann Intern Med 146, 857–67.

    PubMed  Google Scholar 

  9. The ACTIVE Writing Group on behalf of the ACTIVE investigators (2006) Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial Lancet 367, 1903–12.

    Google Scholar 

  10. Jones, M., McEwan, P., Morgan, C.L., Peters, J.R., Goodfellow, J., and Currie, C.J. (2005) Evaluation of the pattern of treatment, level of anticoagulation control, and outcome of treatment with warfarin in patients with non-valvar atrial fibrillation: a record linkage study in a large British population Heart 91, 472–7.

    Article  PubMed  CAS  Google Scholar 

  11. Hylek, E.M., Evans-Molina, C., Shea, C., Henault, L.E., and Regan, S. (2007) Major hemorrhage and tolerability of warfarin in the first year of therapy among elderly patients with atrial fibrillation Circulation 115, 2689–96.

    Article  PubMed  CAS  Google Scholar 

  12. Breckenridge, A., Orme, M., Wesseling, H., Lewis, R., and Gibbons, R. (1974) Pharmacokinetics and pharmacodynamics of the enantiomers of warfarin in man Clin Pharmacol Ther 15, 424–30.

    PubMed  CAS  Google Scholar 

  13. Aithal, G.P., Day, C.P., Kesteven, P.J.L., and Daly, A.K. (1999) Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications Lancet 353, 717–9.

    Article  PubMed  CAS  Google Scholar 

  14. Hirsh, J., Dalen, J.E., and Guyatt, G. (2001) The sixth (2000) ACCP guidelines for antithrombotic therapy for prevention and treatment of thrombosis Chest 119, 1S–2.

    Article  PubMed  CAS  Google Scholar 

  15. James, A.H., Britt, R.P., Raskino, C.L., and Thompson, S.G. (1992) Factors affecting the maintenance dose of warfarin J Clin Pathol 45, 704–6.

    Article  PubMed  CAS  Google Scholar 

  16. D’Andrea, G., D’Ambrosio, R.L., Di Perna, P., Chetta, M., Santacroce, R., Brancaccio, V., Grandone, E., and Margaglione, M. (2005) A polymorphism in the VKORC1 gene is associated with an interindividual variability in the dose-anticoagulant effect of warfarin Blood 105, 645–9.

    Article  PubMed  Google Scholar 

  17. Gage, B.F., Birman-Deych, E., Radford, M.J., Nilasena, D.S., and Binder, E.F. (2006) Risk of osteoporotic fracture in elderly patients taking warfarin: results from the National Registry of Atrial Fibrillation 2 Arch Intern Med 166, 241–6.

    Article  PubMed  CAS  Google Scholar 

  18. Stroke Prevention in Atrial Fibrillation Investigators (1994) Warfarin versus aspirin for prevention of thromboembolism in atrial fibrillation: stroke prevention in Atrial Fibrillation II Study Lancet 343, 687–91.

    Google Scholar 

  19. Fang, M.C., Go, A.S., Hylek, E.M., Chang, Y., Henault, L.E., Jensvold, N.G., and Singer, D.E. (2006) Age and the risk of warfarin-associated hemorrhage: the anticoagulation and risk factors in atrial fibrillation study J Am Geriatrics Soc 54, 1231–6.

    Article  Google Scholar 

  20. McCormick, D., Gurwitz, J.H., Goldberg, R.J., Becker, R., Tate, J.P., Elwell, A., and Radford, M.J. (2001) Prevalence and quality of warfarin use for patients with atrial fibrillation in the long-term care setting Arch Intern Med 161, 2458–63.

    Article  PubMed  CAS  Google Scholar 

  21. Fang, M.C., Stafford, R.S., Ruskin, J.N., and Singer, D.E. (2004) National trends in antiarrhythmic and antithrombotic medication use in atrial fibrillation Arch Intern Med 164, 55–60.

    Article  PubMed  Google Scholar 

  22. Olsson, S.B. (2003) Stroke prevention with the oral direct thrombin inhibitor ximelagatran compared with warfarin in patients with non-valvular atrial fibrillation (SPORTIF III): randomised controlled trial Lancet 362, 1691–8.

    Article  PubMed  CAS  Google Scholar 

  23. Albers, G.W., Diener, H.C., Frison, L., Grind, M., Nevinson, M., Partridge, S., Halperin, J.L., Horrow, J., Olsson, S.B., Petersen, P., and Vahanian, A. (2005) Ximelagatran vs warfarin for stroke prevention in patients with nonvalvular atrial fibrillation: a randomized trial Jama 293, 690–8.

    Article  PubMed  Google Scholar 

  24. Lee, W.M., Larrey, D., Olsson, R., Lewis, J.H., Keisu, M., Auclert, L., and Sheth, S. (2005) Hepatic findings in long-term clinical trials of ximelagatran Drug Safety 28, 351–70.

    Article  PubMed  CAS  Google Scholar 

  25. Boos, C.J., and Lip, G.Y.H. (2006) Ximelagatran: an eulogy Thromb Res 118, 301–4.

    Article  PubMed  CAS  Google Scholar 

  26. van Walraven, C., Hart, R.G., Singer, D.E., Laupacis, A., Connolly, S., Petersen, P., Koudstaal, P.J., Chang, Y., and Hellemons, B. (2002) Oral anticoagulants vs aspirin in nonvalvular atrial fibrillation: an individual patient meta-analysis JAMA 288, 2441–8.

    Article  PubMed  Google Scholar 

  27. Rosenberg, R.D., and Aird, W.C. (1999) Vascular-bed – specific hemostasis and hypercoagulable states N Engl J Med 340, 1555–64.

    Article  PubMed  CAS  Google Scholar 

  28. Bauer, K.A. (2006) New anticoagulants: anti IIa vs anti Xa – is one better? J Thromb Thrombolysis 21, 67–72.

    Article  PubMed  CAS  Google Scholar 

  29. Mann, K.G., Brummel, K., and Butenas, S. (2003) What is all that thrombin for? J Thromb Haemost 1, 1504–14.

    Article  PubMed  CAS  Google Scholar 

  30. Suzuki, K., Dahlback, B., and Stenflo, J. (1982) Thrombin-catalyzed activation of human coagulation factor V J Biol Chem 257, 6556–64.

    PubMed  CAS  Google Scholar 

  31. Walsh, P.M.D. (2004) Platelet coagulation-protein interactions Sem Thromb Hemost 461–71.

    Google Scholar 

  32. Roehrig, S., Straub, A., Pohlmann, J., Lampe, T., Pernerstorfer, J., Schlemmer, K.H., Reinemer, P., and Perzborn, E. (2005) Discovery of the novel antithrombotic agent 5-chloro-N-({(5S)-2-oxo-3- [4-(3-oxomorpholin-4-yl)phenyl]-1,3-oxazolidin-5-yl}methyl)thiophene- 2-carboxamide (BAY 59-7939): an Oral, Direct Factor Xa Inhibitor J Med Chem 48, 5900–8.

    Article  PubMed  CAS  Google Scholar 

  33. Biemond, B.J., Perzborn, E., Friederich, P.W., Levi, M., Buetehorn, U., and Buller, H.R. (2007) Prevention and treatment of experimental thrombosis in rabbits with rivaroxaban (BAY 597939) – an Oral, Direct Factor Xa Inhibitor Thromb Haemost 97, 471–7.

    PubMed  CAS  Google Scholar 

  34. Perzborn, E., Strassburger, J., Wilmen, A., Pohlmann, J., Roehrig, S., Schlemmer, K.H., and Straub, A. (2005) In vitro and in vivo studies of the novel antithrombotic agent BAY 59-7939 – an Oral, Direct Factor Xa Inhibitor J Thromb Haemost 3, 514–21.

    Article  PubMed  CAS  Google Scholar 

  35. Kubitza, D., Becka, M., Mueck, W., and Zuehlsdorf, M. (2007) Rivaroxaban (BAY 59-7939) – an Oral, Direct Factor Xa Inhibitor – has no clinically relevant interaction with naproxen Br J Clin Pharmacol 63, 469–76.

    Article  PubMed  CAS  Google Scholar 

  36. Kubitza, D., Becka, M., Voith, B., Zuehlsdorf, M., and Wensing, G. (2005) Safety, pharmacodynamics, and pharmacokinetics of single doses of BAY 59-7939, an Oral, Direct Factor Xa Inhibitor Clin Pharmacol Ther 78, 412–21.

    Article  PubMed  CAS  Google Scholar 

  37. Mueck, W., Becka, M., Kubitza, D., Voith, B., and Zuehlsdorf, M. (2007) Population model of the pharmacokinetics and pharmacodynamics of rivaroxaban – an Oral, Direct Factor Xa Inhibitor – in healthy subjects Int J Clin Pharmacol Ther 45, 335–44.

    PubMed  CAS  Google Scholar 

  38. Hader, S., Graff, J., Hentig, N., Misselwitz, F., Kubitza, D., Zuelsdorf, M., Wensing, G., Mueck, W., Becka, M., and Breddin, H.-K. (2003) Effects of BAY 59-7939, an Oral, Direct Factor Xa Inhibitor, on thrombin generation in healthy volunteers Blood 102.

    Google Scholar 

  39. Kubitza, D., Becka, M., Wensing, G., Voith, B., and Zuehlsdorf, M. (2005) 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 61, 873–80.

    Article  PubMed  CAS  Google Scholar 

  40. Halabi, A., Maatouk, H., Klause, N., Lufft, V., Kubitza, D., Zuehlsdorf, M., Becka, M., Mueck, W., Schafers, R., Wand, D., Philipp, T., and Bruck, H. (2006) Effects of renal impairment on the pharmacology of rivaroxaban (BAY 59-7939) – An oral, direct, factor Xa inhibitor ASH Annu Meet Abs 108, Abs 913.

    Google Scholar 

  41. Kubitza, D., Becka, M., Zuehlsdorf, M., and Mueck, W. (2007) Body weight has limited influence on the safety, tolerability, pharmacokinetics, or pharmacodynamics of rivaroxaban (BAY 59-7939) in healthy subjects J Clin Pharmacol 47, 218–26.

    Article  PubMed  CAS  Google Scholar 

  42. Kubitza, D., Becka, M., Zuehlsdorf, M., and Mueck, W. (2006) 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 46, 549–58.

    Article  PubMed  CAS  Google Scholar 

  43. Kubitza, D., Becka, M., Mueck, W., and Zuehlsdorf, M. (2006) Safety, tolerability, pharmacodynamics, and pharmacokinetics of rivaroxaban – an Oral, Direct Factor Xa Inhibitor – are not affected by aspirin J Clin Pharmacol 46, 981–90.

    Article  PubMed  CAS  Google Scholar 

  44. Kubitza, D., Becka, M., Zuelsdorf, M., and Mueck, W. (2006) No interaction between the novel, Oral Direct Factor XA Inhibitor BAY 59-7939 and digoxin. J Clin Pharmacol 46, 11.

    Google Scholar 

  45. Kubitza, D., Becka, M., Voith, B., and Zuehlsdorf, M. (2005) Effect of enoxaparin on the safety, tolerability, pharmacodynamics and pharmacokinetics of BAY 59-7939-an Oral, Direct Factor Xa Inhibitor J Thromb Haemost 3, 1704.

    Google Scholar 

  46. Tinel, H., Huetter, J., and Perzborn, E. (2006) Partial reversal of the anticoagulant effect of high-dose rivaroxaban – an Oral, Direct Factor Xa Inhibitor – by recombinant Factor VIIa in rats Blood 108, 915.

    Article  Google Scholar 

  47. Fisher, W.D., Eriksson, B.I., Bauer, K.A., Borris, L., Dahl, O.E., Gent, M., Haas, S., Homering, M., Huisman, M.V., Kakkar, A.K., Kalebo, P., Kwong, L.M., Misselwitz, F., and Turpie, A.G. (2007) Rivaroxaban for thromboprophylaxis after orthopaedic surgery: pooled analysis of two studies Thromb Haemost 97, 931–7.

    PubMed  CAS  Google Scholar 

  48. Agnelli, G., Gallus, A., Goldhaber, S.Z., Haas, S., Huisman, M.V., Hull, R.D., Kakkar, A.K., Misselwitz, F., and Schellong, S. (2007) Treatment of proximal deep-vein thrombosis with the oral direct factor Xa inhibitor rivaroxaban (BAY 59-7939): the ODIXa-DVT (Oral Direct Factor Xa Inhibitor BAY 59-7939 in patients with acute smptomatic deep-vein thrombosis) study Circulation 116, 180–7.

    Article  PubMed  CAS  Google Scholar 

  49. Eriksson, B.I., Borris, L.C., Dahl, O.E., Haas, S., Huisman, M.V., Kakkar, A.K., Misselwitz, F., Muehlhofer, E., and Kalebo, P. (2007) Dose-escalation study of rivaroxaban (BAY 59-7939) – an Oral, Direct Factor Xa Inhibitor – for the prevention of venous thromboembolism in patients undergoing total hip replacement Thromb Res.

    Google Scholar 

  50. Turpie, A.G., Fisher, W.D., Bauer, K.A., Kwong, L.M., Irwin, M.W., Kalebo, P., Misselwitz, F., and Gent, M. (2005) BAY 59-7939: an Oral, Direct Factor Xa Inhibitor for the prevention of venous thromboembolism in patients after total knee replacement. A phase II dose-ranging study J Thromb Haemost 3, 2479–86.

    Article  PubMed  CAS  Google Scholar 

  51. Eriksson, B.I., Borris, L.C., Dahl, O.E., Haas, S., Huisman, M.V., Kakkar, A.K., Muehlhofer, E., Dierig, C., Misselwitz, F., and Kalebo, P. (2006) A once-daily, Oral, Direct Factor Xa Inhibitor, rivaroxaban (BAY 59-7939), for thromboprophylaxis after total hip replacement Circulation 114, 2374–81.

    Article  PubMed  CAS  Google Scholar 

  52. Lassen, M., Turpie, A.G., Rosencher, N., Borris, L., Ageno, W., Lieberman, J., Bandel, T., and Misselwitz, F. Rivaroxaban: an Oral, Direct Factor Xa Inhibitor for the prevention of venous thromboembolism in total knee replacement surgery – results of the RECORD3 study. In: XXIst Congress of the International Society on Thrombosis and Haemostasis; 2007; Geneva, Switzerland; 2007.

    Google Scholar 

  53. Büller, H., and Agnelli, G. (2006) Once- or twice-daily rivaroxaban for the treatment of proximal deep vein thrombosis: similar efficacy and safety to standard therapy in dose-ranging studies Blood 108, 572.

    Google Scholar 

  54. Connolly, S.J., Eikelboom, J., O’Donnell, M., Pogue, J., and Yusuf, S. (2007) Challenges of establishing new antithrombotic therapies in atrial fibrillation Circulation 116, 449–55.

    Article  PubMed  Google Scholar 

  55. Kaul, S., Diamond, G.A., and Weintraub, W.S. (2005) Trials and tribulations of non-inferiority: the ximelagatran experience J Am Coll Cardiol 46, 1986–95.

    Article  PubMed  Google Scholar 

  56. Claxton, A.J., Cramer, J., and Pierce, C. (2001) A systematic review of the associations between dose regimens and medication compliance Clin Ther 23, 1296–310.

    Article  PubMed  CAS  Google Scholar 

  57. Richter, A., Anton, S.E., Koch, P., and Dennett, S.L. (2003) The impact of reducing dose frequency on health outcomes Clin Ther 25, 2307–35; discussion 6.

    Article  PubMed  Google Scholar 

  58. Jacobson, B.C., Ferris, T.G., Shea, T.L., Mahlis, E.M., Lee, T.H., and Wang, T.C. (2003) Who is using chronic acid suppression therapy and why? Am J Gastroenterol 98, 51–8.

    Article  PubMed  Google Scholar 

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Mousa, S.A. (2010). Oral Direct Factor Xa Inhibitors, with Special Emphasis on Rivaroxaban. In: Mousa, S. (eds) Anticoagulants, Antiplatelets, and Thrombolytics. Methods in Molecular Biology, vol 663. Humana Press, Totowa, NJ. https://doi.org/10.1007/978-1-60761-803-4_6

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  • DOI: https://doi.org/10.1007/978-1-60761-803-4_6

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