Skip to main content

Advertisement

SpringerLink
Log in

Advancement in antithrombotics for stroke prevention in atrial fibrillation

  • REVIEW
  • Published:
Journal of Interventional Cardiac Electrophysiology Aims and scope Submit manuscript

Abstract

The focus of this review is the evolving field of antithrombotic drug therapy for stroke prevention in patients with atrial fibrillation (AF). The current standard of therapy includes warfarin, acenocoumarol and phenprocoumon which have proven efficacy by reducing stroke by 68% against placebo. However, a narrow therapeutic index, wide variation in metabolism, and numerous food and drug interactions have limited their clinical application to only 50% of the indicated population. Newer agents such as direct thrombin inhibitors, factor Xa inhibitors, factor IX inhibitors, tissue factor inhibitors and a novel vitamin K antagonist are being developed to overcome the limitations of current agents. The direct thrombin inhibitor dabigatran is farthest along in development. Further clinical trial testing, and eventual incorporation into clinical practice will depend on safety, efficacy and cost. Development of a novel vitamin K antagonist with better INR control will challenge the newer mechanistic agents in their quest to replace the existing vitamin K antagonists. Till then, the large unfilled gap to replace conventional agents remains open. This review will assess all these agents, and compare their mechanism of action, stage of development and pharmacologic profile.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Mueller, R. L., & Scheidt, S. (1994). History of drugs for thrombotic disease. Discovery, development, and directions for the future. Circulation, 89, 432–449.

    PubMed  CAS  Google Scholar 

  2. Shapiro, S. S. (2003). Treating thrombosis in the 21st century. New England Journal of Medicine, 349, 1762–1764.

    Article  PubMed  CAS  Google Scholar 

  3. Fasco, M. J., & Principe, L. M. (1982). R- and S- Warfarin inhibition of vitamin K and vitamin K 2,3-epoxide reductase activities in the rat. Journal of Biological Chemistry, 257, 4894–4901.

    PubMed  CAS  Google Scholar 

  4. Hirsh, J., Dalen, J. E., Anderson, D. R., Poller, L., Bussey, H., Ansell, J., et al. (2001). Oral anticoagulants: Mechanism of action, clinical effectiveness, and optimal therapeutic range. Chest, 119(1 Suppl), 8S–21S (Jan).

    Article  PubMed  CAS  Google Scholar 

  5. Ansell, J., Hirsh, J., Poller, L., Bussey, H., Jacobson, A., & Hylek, E. (2004). The pharmacology and management of the vitamin K antagonists: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest, 126(Suppl), 204S–233S.

    Article  PubMed  CAS  Google Scholar 

  6. Ufer, M. (2005). Comparative pharmacokinetics of vitamin K antagonists: warfarin, phenprocoumon and acenocoumarol. Clinical Pharmacokinetics, 44, 1227–1246 Review.

    Article  PubMed  CAS  Google Scholar 

  7. Petersen, P., Boysen, G., Godtfredsen, J., Andersen, E. D., & Andersen, B. (1989). Placebo controlled, randomised trial of warfarin and aspirin for prevention of thromboembolic complications in chronic atrial fibrillation. The Copenhagen AFASAK study. Lancet, 1, 175–179.

    Article  PubMed  CAS  Google Scholar 

  8. Petersen, P., & Boysen, G. (1990). Stroke prevention in atrial fibrillation study. New England Journal of Medicine, 323, 482.

    Google Scholar 

  9. The Boston Area Anticoagulation Trial for Atrial Fibrillation Investigators (1990). The effect of low-dose warfarin on the risk of stroke in patients with nonrheumatic atrial fibrillation.. New England Journal of Medicine, 323, 1505–1511.

    Google Scholar 

  10. Stroke Prevention in Atrial Fibrillation Study Group (1991). Final results. Circulation, 84, 527–539.

    Google Scholar 

  11. Connolly, S. J., Laupacis, A., Gent, M., Roberts, R. S., Cairns, J. A., & Joyner, C. (1991). Canadian Atrial Fibrillation Anticoagulation (CAFA) Study. Journal of the American College of Cardiology, 18, 349–355.

    Article  PubMed  CAS  Google Scholar 

  12. Ezekowitz, M. D., Bridgers, S. L., James, K. E., et al. (1992). Warfarin in the prevention of stroke associated with nonrheumatic atrial fibrillation. Veterans Affairs Stroke Prevention in Nonrheumatic Atrial Fibrillation Investigators. New England Journal of Medicine, 327, 1406–1412.

    PubMed  CAS  Google Scholar 

  13. EAFT (European Atrial Fibrillation Trial) Study Group (1993). Secondary prevention in non-rheumatic atrial fibrillation after transient ischaemic attack or minor stroke.. Lancet, 342, 1255–1262.

    Google Scholar 

  14. Stroke Prevention in Atrial Fibrillation II Study Group (1994). Warfarin versus aspirin for prevention of thromboembolism in atrial fibrillation: Stroke Prevention in Atrial Fibrillation II Study. Lancet, 343, 687–691.

    Google Scholar 

  15. Morocutti, C., Amabile, G., Fattapposta, F., et al. (1997). Indobufen versus warfarin in the secondary prevention of major vascular events in nonrheumatic atrial fibrillation. SIFA (Studio Italiano Fibrillazione Atriale) Investigators. Stroke, 28, 1015–1021.

    PubMed  CAS  Google Scholar 

  16. Gulløv, A. L., Koefoed, B. G., Petersen, P., et al. (1998). Fixed minidose warfarin and aspirin alone and in combination vs adjusted-dose warfarin for stroke prevention in atrial fibrillation: Second Copenhagen Atrial Fibrillation, Aspirin, and Anticoagulation Study. Archives of Internal Medicine, 158, 1513–1521.

    Article  PubMed  Google Scholar 

  17. Hellemons, B. S., Langenberg, M., Lodder, J., et al. (1999). Primary prevention of arterial thromboembolism in non-rheumatic atrial fibrillation in primary care: randomised controlled trial comparing two intensities of coumarin with aspirin. British Medical Journal, 319, 958–964.

    PubMed  CAS  Google Scholar 

  18. Pérez-Gómez, F, Alegría, E, Berjón, J., Iriarte, J. A., Zumalde, J., Salvador, A, Mataix, L., & NASPEAF Investigators (2004). Comparative effects of antiplatelet, anticoagulant, or combined therapy in patients with valvular and nonvalvular atrial fibrillation: a randomized multicenter study. Journal of the American College of Cardiology, 44, 1557–1566.

    Article  PubMed  CAS  Google Scholar 

  19. Writing ACTIVE Group (2006). Group on behalf of the ACTIVE Investigators. 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, 1903–1912.

    Article  CAS  Google Scholar 

  20. Antithrombotic Therapy in Atrial Fibrillation Study Group (2006). [The randomized study of efficiency and safety of antithrombotic therapy in nonvalvular atrial fibrillation: warfarin compared with aspirin]. Zhonghua Xin Xue Guan Bing Za Zhi, 34, 295–298.

    Google Scholar 

  21. Mant, J., Hobbs, F. D., Fletcher, K., et al. (2007). BAFTA investigators; Midland Research Practices Network (MidReC). Warfarin versus aspirin for stroke prevention in an elderly community population with atrial fibrillation (the Birmingham Atrial Fibrillation Treatment of the Aged Study, BAFTA): a randomised controlled trial. Lancet, 370, 493–503.

    Article  PubMed  CAS  Google Scholar 

  22. Hart, R. G., Pearce, L. A., & Aguilar, M. I. (2007). Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Annals of Internal Medicine, 146, 857–867.

    PubMed  Google Scholar 

  23. Bungard, T. J., Ghali, W. A., Teo, K. K., McAlister, F. A., & Tsuyuki, R. T. (2000). Why do patients with atrial fibrillation not receive warfarin? Archives of Internal Medicine, 160, 41–46.

    Article  PubMed  CAS  Google Scholar 

  24. Bradley, B. C., Perdue, K. S., Tisdel, K. A., & Gilligan, D. M. (2000). Frequency of anticoagulation for atrial fibrillation and reasons for its non-use at a Veterans Affairs medical center. American Journal of Cardiology, 85, 568–572.

    Article  PubMed  CAS  Google Scholar 

  25. Siguret, V. (2007 ). Impact of pharmacogenetics on interindividual variability in the response to vitamin K antagonist therapy. Pathologie et Biologie (Paris), 55, 295–298 Article in French.

    Article  CAS  Google Scholar 

  26. Ansell, J., Hirsh, J., Poller, L., Bussey, H., Jacobson, A., & Hylek, E. (2004). The pharmacology and management of the vitamin K antagonists: the Seventh ACCP Conference on Antithrombotic and Thrombolytic Therapy. Chest, 126(Suppl), 204S–233S.

    Article  PubMed  CAS  Google Scholar 

  27. Carlquist, J. F., Horne, B. D., Muhlestein, J. B., et al. (2006). Genotypes of the cytochrome p450 isoform, CYP2C9, and the vitamin K epoxide reductase complex subunit 1 conjointly determine stable warfarin dose: a prospective study. Journal of Thrombosis and Thrombolysis, 22, 191–197.

    Article  PubMed  CAS  Google Scholar 

  28. Bauer, K. A. (2006). New anticoagulants. Hematology (Am Soc Hematol Educ Program), 450–456, DOI 10.1182/asheducation-2006.1.450.

  29. Gage, B. F., Eby, C., Milligan, P. E., Banet, G. A., Duncan, J. R., & McLeod, H. L. (2004). Use of pharmacogenetics and clinical factors to predict the maintenance dose of warfarin. Thrombosis and Haemostasis, 91, 87–94.

    PubMed  CAS  Google Scholar 

  30. Bates, S. M., & Weitz, J. I. (2000). The mechanism of action of thrombin inhibitors. Journal of Invasive Cardiology, 12(Suppl F), 27F–32F.

    PubMed  Google Scholar 

  31. Weitz, J. I., Leslie, B., & Hudoba, M. (1998). Thrombin binds to soluble fibrin degradation products where it is protected from inhibition by heparin-antithrombin but susceptible to inactivation by antithrombin-independent inhibitors. Circulation, 97, 544–552.

    PubMed  CAS  Google Scholar 

  32. 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, 1691–1698.

    Article  PubMed  CAS  Google Scholar 

  33. Albers, G. W., Diener, H. C., Frison, L., et al. (2005). SPORTIF Executive Steering Committee for the SPORTIF V Investigators. Ximelagatran vs warfarin for stroke prevention in patients with nonvalvular atrial fibrillation: a randomized trial. JAMA, 293, 690–698.

    Article  PubMed  Google Scholar 

  34. Akins, P. T., Feldman, H. A., Zoble, R. G., et al. (2007). Secondary stroke prevention with ximelagatran versus warfarin in patients with atrial fibrillation: pooled analysis of SPORTIF III and V clinical trials. Stroke, 38, 874–880.

    Article  PubMed  CAS  Google Scholar 

  35. Kaul, S., Diamond, G. A., & Weintraub, W. S. (2005). Trials and tribulations of non-inferiority: the ximelagatran experience. Journal of the American College of Cardiology, 46, 1986–1995.

    Article  PubMed  Google Scholar 

  36. Wallentin, L., Ezekowitz, M., Simmers, T. A., et al. (2005). PETRO-investigators. Safety and efficacy of a new oral direct thrombin inhibitor dabigatran in atrial fibrillation: a dose finding trial with comparison to warfarin. European Heart Journal, 26(suppl), 482 Abstract.

    Google Scholar 

  37. Gustafsson, D. (2003). Oral direct thrombin inhibitors in clinical development. Journal of Internal Medicine, 254, 322–334.

    Article  PubMed  CAS  Google Scholar 

  38. Mungall, D. (2002). BIBR-1048 Boehringer Ingelheim. Current Opinion in Investigational Drugs, 3, 905–907.

    PubMed  CAS  Google Scholar 

  39. Ezekowitz, M. D., Reilly, P. A., Nehmiz, G., Simmers, T. A., Nagarakanti, R., Parcham-Azad, K., et al. (2007). Dabigatran with or without concomitant aspirin compared with warfarin alone in patients with nonvalvular atrial fibrillation (PETRO Study). American Journal of Cardiology, 100(9), 1419–1426 (Nov 1).

    Article  PubMed  CAS  Google Scholar 

  40. The Petro-ex Investigators (2006). Safety and efficacy of extended exposure to several doses of a new oral direct thrombin inhibitor dabigatran etexilate in atrial fibrillation. Cerebrovascular Diseases, 21(suppl 4), 2 Abstract.

    Google Scholar 

  41. Bauer, K. A. (2006). New anticoagulants: anti IIa vs anti Xa—is one better? Journal of Thrombosis and Thrombolysis, 21, 67–72.

    Article  PubMed  CAS  Google Scholar 

  42. Perzborn, E., Strassburger, J., Wilmen, A., et al. (2005). In vitro and in vivo studies of the novel antithrombotic agent BAY 59-7939—an oral, direct Factor Xa inhibitor. Thrombosis and Haemostasis, 3, 514–521.

    Article  CAS  Google Scholar 

  43. Mueck, W., Becka, M., Kubitza, D., Voith, B., & Zuehlsdorf, M. (2007). Population model of the pharmacokinetics and pharmacodynamics of rivaroxaban—an oral, direct factor xa inhibitor—in healthy subjects. International Journal of Clinical Pharmacology and Therapeutics, 45, 335–344.

    PubMed  CAS  Google Scholar 

  44. Kubitza, D., Becka, M., Wensing, G., Voith, B., & Zuehlsdorf, M. (2005). Safety, pharmacodynamics, and pharmacokinetics of BAY 59-7939—an oral, direct Factor Xa inhibitor—after multiple dosing in healthy male subjects. European Journal of Clinical Pharmacology, 61, 873–880.

    Article  PubMed  CAS  Google Scholar 

  45. Kubitza, D., Becka, M., Zuehlsdorf, M., & Mueck, W. (2007). Body weight has limited influence on the safety, tolerability, pharmacokinetics, or pharmacodynamics of rivaroxaban (BAY 59-7939) in healthy subjects. Journal of Clinical Pharmacology, 47, 218–226.

    Article  PubMed  CAS  Google Scholar 

  46. Kubitza, D., Becka, M., Zuehlsdorf, M., & 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. Journal of Clinical Pharmacology, 46, 549–558.

    Article  PubMed  CAS  Google Scholar 

  47. Pinto, D. J., Orwat, M. J., Koch, S., et al. (2007). 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. Journal of Medicinal Chemistry, 50, 5339–5356.

    Article  PubMed  CAS  Google Scholar 

  48. Lassen, M. R., Davidson, B. L., Gallus, A., Pineo, G., Ansell, J., & Deitchman, D. (2007). The efficacy and safety of apixaban, an oral, direct factor Xa inhibitor, as thromboprophylaxis in patients following total knee replacement. Thrombosis and Haemostasis, 5, 2368–2375.

    Article  CAS  Google Scholar 

  49. Koopman, M. M. W., & Buller, H. R. (2003). Short- and long-acting synthetic pentasaccharides (minisymposium). Journal of Internal Medicine, 254, 335–342.

    Article  PubMed  CAS  Google Scholar 

  50. Sanofi-aventis Press Release (2007). en.sanofi-aventis.com/Images/070711_idraparinux_en_tcm24-18621.pdf.

  51. Agnelli, G., Haas, S., Ginsberg, J. S., Krueger, K. A., Dmitrienko, A., & Brandt, J. T. (2007). A phase II study of the oral factor Xa inhibitor LY517717 for the prevention of venous thromboembolism after hip or knee replacement. Thrombosis and Haemostasis, 5, 746–753.

    Article  CAS  Google Scholar 

  52. Iwatsuki, Y., Shigenaga, T., Moritani, Y., et al. (2006) Biochemical and pharmacological profiles of YM150, an oral direct Factor Xa inhibitor. Blood, 108, Abstract 911.

    Google Scholar 

  53. Overvie R&D. (2003). Yamanouchi Pharmaceutical Co Ltd. Company Presentation.

  54. Eriksson, B. I., Turpie, A. G., Lassen, M. R., et al. (2007). ONYX study group.A dose escalation study of YM150, an oral direct factor Xa inhibitor, in the prevention of venous thromboembolism in elective primary hip replacement surgery. Thrombosis and Haemostasis, 5, 1660–1665.

    Article  CAS  Google Scholar 

  55. Zafar, M. U., Vorchheimer, D. A., Gaztanaga, J., et al. (2007). Antithrombotic effects of factor Xa inhibition with DU-176b: Phase-I study of an oral, direct factor Xa inhibitor using an ex-vivo flow chamber. Thrombosis and Haemostasis, 98, 883–888.

    PubMed  CAS  Google Scholar 

  56. Furugohri, T., Honda, Y., Matsumoto, C., et al. (2004). Antithrombotic and hemorrhagic effects of DU-176b, a novel, potent and orally active direct Factor Xa inhibitor: a wider safety margin compared to heparins and warfarin. American Society of Hematology Annual Meeting Abstract, 104, 1851.

    Google Scholar 

  57. Fukuda, T., Matsumoto, C., Honda, Y., Sugiyama, N., Morishima, Y., & Shibano, T. (2004). Antithrombotic properties of DU-176b, a novel, potent and orally active direct Factor Xa inhibitor in rat models of arterial and venous thrombosis: comparison with fondaparinux, an antithrombin dependent Factor Xa inhibitor. American Society of Hematology Annual Meeting Abstract, 104, 1852.

    Google Scholar 

  58. Neels, J. G., van Den Berg, B. M., Mertens, K., et al. (2000). Activation of factor IX zymogen results in exposure of a binding site for low-density lipoprotein receptor-related protein. Blood, 96, 3459–3465.

    PubMed  CAS  Google Scholar 

  59. Lawson, J. H., & Mann, K. G. (1991). Cooperative activation of human factor IX by the human extrinsic pathway of blood coagulation. Journal of Biological Chemistry, 266, 11317–11327.

    PubMed  CAS  Google Scholar 

  60. Ahmad, S. S., Rawala-Sheikh, R., & Walsh, P. N. (1989). Platelet receptor occupancy with factor IXa promotes factor X activation. Journal of Biological Chemistry, 264, 20012–20016.

    PubMed  CAS  Google Scholar 

  61. Chow, F. S., Benincosa, L. J., Sheth, S. B., et al. (2002). Pharmacokinetic and pharmacodynamic modeling of humanized anti-factor IX antibody (SB 249417) in humans. Clinical Pharmacology and Therapeutics, 71, 235–245.

    Article  PubMed  CAS  Google Scholar 

  62. Dyke, C. K., Steinhubl, S. R., Kleiman, N. S., et al. (2006). First-in-human experience of an antidote-controlled anticoagulant using RNA aptamer technology: a phase 1a pharmacodynamic evaluation of a drug-antidote pair for the controlled regulation of factor IXa activity. Circulation, 114, 2490–2497.

    Article  PubMed  CAS  Google Scholar 

  63. Rothlein, R., Shen, J. M., Naser, N., et al. (2005). TTP889, a Novel Orally Active Partial Inhibitor of FIXa Inhibits Clotting in Two A/V Shunt Models without Prolonging Bleeding Times. Blood, 106, Abstract 1886.

    Google Scholar 

  64. Steffel, J., Lüscher, T. F., & Tanner, F. C. (2006). Tissue factor in cardiovascular disease. Molecular mechanisms and clinical implications. Circulation, 113, 722–731.

    Article  PubMed  CAS  Google Scholar 

  65. Ragni, M., Cirillo, P., Pascucci, I., et al. (1996). Monoclonal antibody against tissue factor shortens tissue plasminogen activator lysis time and prevents reocclusion in a rabbit model of carotid artery thrombosis. Circulation, 93, 1913–1918.

    PubMed  CAS  Google Scholar 

  66. Harker, L. A., Hanson, S. R., Wilcox, J. N., & Kelly, A. B. (1996). Antithrombotic and antilesion benefits without hemorrhagic risks by inhibiting tissue factor pathway. Haemostasis, 26(Suppl 1), 76–82 Review.

    PubMed  CAS  Google Scholar 

  67. Himber, J., Kirchhofer, D., Riederer, M., Tschopp, T. B., Steiner, B., & Roux, S. P. (1997). Dissociation of antithrombotic effect and bleeding time prolongation in rabbits by inhibiting tissue factor function. Thrombosis and Haemostasis, 78, 1142–1149.

    PubMed  CAS  Google Scholar 

  68. Pawashe, A., Golino, P., Ambrosio, G., et al. (1994). A monoclonal antibody against rabbit tissue factor inhibits thrombus formation in stenotic injured rabbit carotid arteries. Circulation Research, 74, 56–63.

    PubMed  CAS  Google Scholar 

  69. Golino, P., Ragni, M., Cirillo, P., et al. (1998). Antithrombotic effects of recombinant human, active site-blocked factor VIIa in a rabbit model of recurrent arterial thrombosis. Circulation Research, 82, 39–46.

    PubMed  CAS  Google Scholar 

  70. Riggs, J. R., Kolesnikov, A., Hendrix, J., et al. (2006). FVIIa inhibitors: A prodrug strategy to improve oral bioavailability. Bioorganic & Medicinal Chemistry Letters, 16, 2224–2228.

    Article  CAS  Google Scholar 

  71. Zbinden, K. G., Obst-Sander, U., Hilpert, K., et al. (2005). Selective and orally bioavailable phenylglycine tissue factor/factor VIIa inhibitors. Bioorganic & Medicinal Chemistry Letters, 15, 5344–5352.

    Article  CAS  Google Scholar 

  72. Himber, J., Refino, C. J., Burcklen, L., Roux, S., & Kirchhofer, D. (2001). Inhibition of arterial thrombosis by a soluble tissue factor mutant and active site-blocked factors IXa and Xa in the guinea pig. Thrombosis and Haemostasis, 85, 475–481.

    PubMed  CAS  Google Scholar 

  73. Fingerle, J., Himber, J., Tschopp, T., Bunting, S., Steiner, B., & Riederer, M. A. (2001). Minimal bleeding risk after chronic application of factor VIIa inhibitor in a guinea pig model. Thrombosis and Haemostasis, Supplement:abstract #OC1766.

  74. Szalony, J. A., Suleymanov, O. D., Salyers, A. K., et al. (2003). Administration of a small molecule tissue factor/factor VIIa inhibitor in a non-human primate thrombosis model of venous thrombosis: effects on thrombus formation and bleeding time. Thrombosis Research, 112, 167–174.

    Article  PubMed  CAS  Google Scholar 

  75. Lee, A., Agnelli, G., Buller, H., et al. (2001). Dose-response study of recombinant factor VIIa/tissue factor inhibitor recombinant nematode anticoagulant protein c2 in prevention of postoperative venous thromboembolism in patients undergoing total knee replacement. Circulation, 104, 74–78.

    Article  PubMed  CAS  Google Scholar 

  76. Giugliano, R. P., Wiviott, S. D., Stone, P. H., et al. (2007). ANTHEM-TIMI-32 Investigators. Recombinant nematode anticoagulant protein c2 in patients with non-ST-segment elevation acute coronary syndrome: the ANTHEM-TIMI-32 trial. Journal of the American College of Cardiology, 49, 2398–2407.

    Article  PubMed  CAS  Google Scholar 

  77. Shirk, R. A., & Vlasuk, G. P. (2007). Inhibitors of Factor VIIa/tissue factor. Arteriosclerosis, Thrombosis, and Vascular Biology, 27, 1895–1900.

    Article  PubMed  CAS  Google Scholar 

  78. Shirk, R. A., & Vlasuk, G. P. (2007). Inhibitors of Factor VIIa/tissue factor. Arteriosclerosis, Thrombosis, and Vascular Biology, 27, 1895–1900.

    Article  PubMed  CAS  Google Scholar 

Download references

Author information

Authors and Affiliations

  1. Lankenau Institute for Medical Research, Wynnewood, PA, USA

    Mohammed Haris Umer Usman, Sabreen Raza, Shariq Raza & Michael Ezekowitz

  2. Mercy Catholic Medical Center, Drexel University College of Medicine, Darby, PA, USA

    Mohammed Haris Umer Usman

  3. Lankenau Institute for Medical Research, 100 Lancaster Avenue, Wynnewood, PA, 19096-3425, USA

    Michael Ezekowitz

Authors
  1. Mohammed Haris Umer Usman
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Sabreen Raza
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Shariq Raza
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Michael Ezekowitz
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Michael Ezekowitz.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Umer Usman, M.H., Raza, S., Raza, S. et al. Advancement in antithrombotics for stroke prevention in atrial fibrillation. J Interv Card Electrophysiol 22, 129–137 (2008). https://doi.org/10.1007/s10840-008-9210-9

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10840-008-9210-9

Keywords

Search

Navigation