WJNS  Vol.2 No.1 , February 2012
Clinical and pharmacological properties of new oral anticoagulants for the prevention of cerebral thromboembolism: Factor Xa and thrombin inhibitors
ABSTRACT
Vitamin K antagonists, such as warfarin and phen-procoumon, are the first-line oral anticoagulants for primary and secondary prevention of cerebral embo-lism in patients with atrial fibrillation. Although vitamin K antagonists can significantly decrease the risk of stroke, their use is limited by several important drawbacks, such as a narrow therapeutic window, the risk of intracranial and gastrointestinal bleeding, interactions with a number of drugs and nutrients, and the need for regular laboratory tests for therapy adjustment. Currently, new oral anticoagulants, such as direct thrombin inhibitors (e.g., dabigatran) and direct factor Xa inhibitors (e.g., apixaban, rivaroxaban), are being developed and tested in clinical trials. Dabigatran and rivaroxaban were recently approved for prevention of cerebral embolism in patients with atrial fibrillation. The ad-vantages of dabigatran in comparison to warfarin are a lower rate of major bleedings with dabigatran 110mg bid, a better efficacy with dabigatran 150mg bid, no clinically relevant interactions with other drugs and no need for routine coagulation monitoring. The disadvantages are the absence of antidote and the absence of routine laboratory tests for precise mea-surements of anticoagulant effect of direct thrombin/ factor Xa inhibitors. This review will focus on throm-bin and factor Xa inhibitors, which are new and promising oral anticoagulants for the prevention of cerebral embolism. We will discuss their pharmacol-ogical and clinical properties and provide the most recent updates on their clinical trials.

Cite this paper
Winter, Y. , Dodel, R. , Korchounov, A. , Grond, M. , Oertel, W. and Back, T. (2012) Clinical and pharmacological properties of new oral anticoagulants for the prevention of cerebral thromboembolism: Factor Xa and thrombin inhibitors. World Journal of Neuroscience, 2, 7-14. doi: 10.4236/wjns.2012.21002.
References
[1]   Wolf, P., Kannel, W. and D’Agostino, R. (1998) Epide-miology of stroke. In: Ginsberg, M. and Bogousslavsky, J., Eds., Cerebrovascular Disease: Pathophysiology, Di-agnosis and Management, Blackwell Science, Malden, 834-850.

[2]   Winter, Y., Wolfram, C., Schaeg, M. et al. (2009) Evalu- ation of costs and outcome in cardioembolic stroke or TIA. Journal of Neurology, 256, 954-963. doi:10.1007/s00415-009-5053-2

[3]   Gage, B.F., Waterman, A.D., Shannon, W., et al. (2001) Validation of clinical classification schemes for predicting stroke: Re-sults from the national registry of atrial fibrillation. Journal of the American Medical Association, 285, 2864-2870. doi:10.1001/jama.285.22.2864

[4]   Wolf, P.A., Mitchell, J.B., Baker, C.S., Kannel, W.B., and D’Agostino, R.B. (1998) Impact of atrial fibrillation on mortality, stroke, and medical costs. Archives of internal medicine, 158, 229-234. doi:10.1001/archinte.158.3.229

[5]   Lloyd-Jones, D.M., Wang, T.J., Leip, E.P., et al. (2004) Lifetime risk for de-velopment of atrial fibrillation: The Framingham heart study. Circulation, 110, 1042-1046. doi:10.1161/01.CIR.0000140263.20897.42

[6]   Fuster, V., Ryden, L.E., Cannom, D.S., et al. (2006) ACC/AHA/ESC 2006 guidelines for the management of patients with atrial fibrillation: A report of the American college of cardiology/American heart association task force on practice guidelines and the European society of cardiology committee for practice guidelines (writing committee to revise the 2001 guidelines for the manage-ment of patients with atrial fibrillation): Developed in col-laboration with the European heart rhythm association and the heart

[7]   DGN, DSG (Germany Neurological So-ciety and German Stroke Society). (2008) Primary and secondary pervention of cerebral ischemic events. In: Diener, H.C. and Putzki, N., Eds., Guidelines for Diag-nostics and Therapy in Neurology, 4th Edition, Georg Thieme Stuttgart, New York, 261-287.

[8]   Ansell, J., Hirsh, J., Hylek, E., et al. (2008) Pharmacology and management of the vitamin K antagonists: American col-lege of chest physicians evidence-based clinical practice guidelines (8th Edition). Chest, 133, 160S-198S. doi:10.1378/chest.08-0670

[9]   Singer, D.E., Albers, G.W., Dalen, J.E. et al. (2004) Antithrombotic therapy in atrial fibrillation: The seventh american college of clinical pharmacy conference on antithrombotic and thrombolytic therapy. Chest, 126, 429S-456S. doi:10.1378/chest.126.3_suppl.429S

[10]   Bye, A. and King, H.K. (1970) The biosynthesis of 4-hydroxycoumarin and dicoumarol by aspergillus fumi-gatus fresenius. Biochemical Journal, 117, 237-245.

[11]   Schimanski, C.C., Burg, J., Mohler, M., et al. (2004) Phenprocoumon-induced liver disease ranges from mild acute hepatitis to (sub-) acute liver failure. Journal of Hepatology, 41, 67-74. doi:10.1016/j.jhep.2004.03.010

[12]   Hirsh, J., Bauer, K.A., Donati, M.B., et al. (2008) Parenteral anticoagulants: American college of chest physicians evidence-based clinical practice guidelines (8th Edition). Chest, 133, 141S-159S.

[13]   Stangier, J. (2008) Clinical pharmacokinetics and pharmacodynamics of the oral direct thrombin inhibitor dabigatran etexilate. Clin Phar-macokinet, 47, 285-295.

[14]   Raghavan, N., Frost, C.E., Yu, Z., et al. (2009) Apixaban metabolism and pharma-cokinetics after oral administration to humans. Drug Me-tabolism and Disposition, 37, 74-81.

[15]   Shantsila, E. and Lip, G.Y. (2008) Apixaban, an oral, direct inhibitor of activated factor Xa. Current Opinion in Investigational Drugs, 9, 1020-1033.

[16]   Wong, P.C., Crain, E.J., Xin, B., et al. (2008) Apixaban, an oral, direct and highly se-lective factor Xa inhibitor: in vitro, antithrombotic and antihemostatic studies. Journal of Thrombosis and Haemostasis, 6, 820-829.

[17]   Harenberg, J. (2009) Development of idraparinux and idrabiotaparinux for an-ticoagulant therapy. Thrombosis and haemostasis, 102, 811-815.

[18]   Ansell, J. (2007) Factor Xa or thrombin: is factor Xa a better target? Journal of Thrombosis and Haemostasis, 5, 60-64.

[19]   Mann, K.G., Brummel, K. and Butenas, S. (2003) What is all that thrombin for? Journal of Thrombosis and Haemostasis, 1, 1504-1514. doi:10.1046/j.1538-7836.2003.00298.x

[20]   Kubitza, D. and Haas, S. (2006) Novel factor Xa inhibitors for pre-vention and treatment of thromboembolic diseases. Expert Opinion Investigational Drugs, 15, 843-855. doi:10.1517/13543784.15.8.843

[21]   Stangier, J., Rath-gen, K., Stahle, H., Gansser, D. and Roth, W. (2007) The pharmacokinetics, pharmacodynamics and tolerability of dabigatran etexilate, a new oral direct thrombin inhibitor, in healthy male subjects. British Journal of Clinical Pharmacology, 64, 292-303.

[22]   Stangier, J., Rathgen, K., Stahle, H., et al. (2009) Coadministration of dabigatran etexilate and atorvastatin: Assessment of potential impact on pharmacokinetics and pharmacodynamics. American Journal of Cardiovascular Drugs, 9, 59-68.

[23]   Connolly, S.J., Ezekowitz, M.D., Yusuf, S., et al. (2009) Dabigatran versus warfarin in patients with atrial fibrillation. The New England Journal of Medicine, 361, 1139-1151.

[24]   Wann, L.S., Curtis, A.B., Ellen-bogen, K.A., et al. (2011) 2011 ACCF/AHA/HRS fo-cused update on the management of patients with atrial fibrillation (update on Dabigatran): A report of the American college of cardiology foundation/American heart association task force on practice guidelines. Circulation, 123, 1144-1150.

[25]   Patel, M.R., Mahaffey, K.W., Garg, J. et al. (2011) Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. The New England journal of medicine, 365, 883-891.

[26]   Rocket, AF Study Investigators. (2010) Rivaroxaban-once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fib-rillation: Rationale and design of the Rocket AF Study. American Heart Journal, 159, 340-347.

[27]   Granger, C.B., Alexander, J.H., McMurray, J.J., et al. (2011) Apixaban versus warfarin in patients with atrial fibrillation. The New England journal of medicine, 365, 981-992.

[28]   Eikelboom, J.W., O'Donnell, M., Yusuf, S. et al. (2010) Rationale and design of AVERROES: Apixaban versus acetylsalicylic acid to prevent stroke in atrial fibrillation patients who have failed or are unsuitable for vitamin K antagonist treatment. American Heart Journal, 159, 348-353.

[29]   Connolly, S.J., Eikelboom, J., Joyner, C., et al. (2011) Apixaban in patients with atrial fibrillation. The New England Journal of Medicine, 364, 806-817. doi:10.1056/NEJMoa1007432

[30]   Lassen, M.R., Ras-kob, G.E., Gallus, A., et al. (2009) Apixaban or enoxa-parin for thromboprophylaxis after knee replacement. The New England Journal of Medicine, 361, 594-604.

[31]   Lassen, M.R., Raskob, G.E., Gallus, A., et al. (2010) Apixaban versus enoxaparin for thrombopro-phylaxis after knee replacement (ADVANCE-2): A ran-domised double-blind trial. Lancet, 375, 807-815.

[32]   Furugohri, T., Isobe, K., Honda, Y., et al. (2008) DU-176b, a potent and orally active factor Xa in-hibitor: In vitro and in vivo pharmacological profiles. Journal of Thrombosis and Haemostasis, 6, 1542-1549.

[33]   Ogata, K., Mendell-Harary, J., Tachi-bana, M., et al. (2010) Clinical safety, tolerability, phar-macokinetics, and pharmacodynamics of the novel factor Xa inhibitor edoxaban in healthy volunteers. The Journal of Clinical Pharmacology, 50, 743-753.

[34]   Ruff, C.T., Giugliano, R.P., Antman, E.M., et al. (2010) Evaluation of the novel factor Xa inhibitor edoxaban compared with warfarin in patients with atrial fibrillation: Design and ra-tionale for the Effective aNticoaGulation with factor Xa next generation in atrial fibrillation- thrombolysis in myo-cardial infarction study 48 (ENGAGE AF-TIMI 48). American Heart Journal, 160, 635-641.

[35]   Agnelli, G., Haas, S., Ginsberg, J.S., et al. (2007) A phase II study of the oral factor Xa inhibitor LY517717 for the prevention of venous thromboembolism after hip or knee replacement. Journal of Thrombosis and Haemostasis, 5, 746-753.

[36]   Eriksson, B.I., Quinlan, D.J., Weitz ,J.I. (2009) Comparative pharmacodynamics and pharma-cokinetics of oral direct thrombin and factor Xa inhibitors in development. Clinical Pharmacokinetics, 48, 1-22.

[37]   Turpie, A.G., Bauer, K.A., Davidson, B.L., et al. (2009) A randomized evaluation of betrixaban, an oral factor Xa inhibitor, for prevention of thromboembolic events after total knee replacement (EXPERT). Thrombo-sis and haemostasis, 101, 68-76.

[38]   Kawamura, M., Konishi, N., Hiroe, K., et al. (2010) Antithrombotic and anticoagulant profiles of TAK-442, a novel factor Xa in-hibitor, in a rabbit model of venous thrombosis. Journal of Cardiovascular Pharmacology, 56, 156-161.doi:10.1097/FJC.0b013e3181e2bfcf

[39]   Eriksson, B.I., Turpie, A.G., Lassen, M.R., et al. (2007) A dose escalation study of YM150, an oral direct factor Xa in-hibitor, in the prevention of venous thromboembolism in elective primary hip replacement surgery. Journal of Thrombosis and Haemostasis, 5, 1660-1665.

[40]   Weitz, J.I., Cao, C., Eriksson, B.I., et al. (2010) A dose- finding study with TAK-442, an oral factor Xa inhibitor, in pa-tients undergoing elective total knee replacement surgery. Thrombosis and haemostasis, 104, 1150-1157.

[41]   Bauer, K.A. (2001) Fondaparinux so-dium: A selective inhibitor of factor Xa. American Journal of HealthSystem Pharmacy, 58, S14-17.

[42]   Turpie, A.G., Bauer, K.A., Eriksson, B.I. and Lassen, M.R. (2002) Fondaparinux vs enoxaparin for the prevention of venous thromboembolism in major orthopedic surgery: A meta-analysis of 4 randomized double-blind studies. Ar-chives of internal medicine, 162, 1833-1840.

[43]   Strzelczyk, A., Haag, A., Raupach, H., et al. (2010) Prospective evaluation of a post-stroke epi-lepsy risk scale. Journal of Neurology, 257, 1322-1326. doi:10.1007/s00415-010-5520-9

[44]   Pendlebury, S.T. and Rothwell, P.M. (2009) Prevalence, incidence, and factors associated with pre-stroke and post-stroke dementia: A systematic review and meta- analysis. Lancet Neurology, 8, 1006-1018. doi:10.1016/S1474-4422(09)70236-4

 
 
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