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 anticoagulants for Asian patients with atrial fibrillation

Nature Reviews Cardiology volume 11, pages 290–303 (2014)Cite this article

Subjects

A Correction to this article was published on 02 September 2014

This article has been updated

Key Points

  • Although few prospective studies of atrial fibrillation (AF) epidemiology in Asian countries have been conducted, AF prevalence is thought to be lower in Asians than in white populations

  • However, Asian individuals seem to be at a higher risk of stroke, and have greater stroke-related morbidity and mortality, than white individuals

  • Asian individuals seem to be at particularly high risk of haemorrhagic stroke and intracranial haemorrhage, which has discouraged the widespread uptake of warfarin in Asian patients with AF

  • Antiplatelet agents have been overused for primary stroke prevention in Asian patients with AF, in whom these drugs are neither safe nor effective

  • Non-vitamin K antagonist anticoagulants are noninferior to warfarin for stroke prevention in AF, and are associated with a reduced incidence of haemorrhagic stroke and intracranial haemorrhage compared with warfarin

  • The efficacy and safety profile of non-vitamin K antagonist anticoagulants in randomized, controlled trials suggest these drugs have great potential as anticoagulants in Asian individuals with AF

Abstract

Anticoagulation is the most-important intervention to prevent stroke in patients with atrial fibrillation (AF). Despite a lower point prevalence of AF in Asian communities and Asian countries than in other populations, individuals of Asian ethnicity are at a disproportionately high risk of stroke and have greater consequent mortality. Warfarin and other vitamin K antagonists are conventionally used for anticoagulation, and demonstrably reduce the risk of stroke and all-cause mortality in patients with AF. The use of warfarin in Asian countries is suboptimal, primarily owing to the universal challenge of achieving controlled anticoagulation with an unpredictable drug as well as concerns about the particularly high-risk of haemorrhage in Asian patients. Instead, antiplatelet therapy has been favoured in Asian communities, this strategy is neither safe nor effective for stroke prevention in these individuals. The non-vitamin K antagonist, oral anticoagulant drugs offer a solution to this challenge. The direct thrombin inhibitor dabigatran, and the direct factor Xa inhibitors apixaban, edoxaban, and rivaroxaban, have demonstrated noninferiority to warfarin in the prevention of stroke and systemic embolism in international, randomized, controlled trials. Importantly, some of these drugs are also associated with a significantly lower incidence of major haemorrhage, and all result in lower rates of intracranial haemorrhage and haemorrhagic stroke than warfarin. In this article, we review the use of the non-vitamin K antagonist anticoagulants in the management of AF in Asian populations.

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: Interaction between anticoagulant drugs and the coagulation cascade.

Similar content being viewed by others

Change history

  • 02 September 2014

    In the version of this article initially published online and in print, 'thrombin' was misspelled in Figure 1. The error has been corrected for the HTML and PDF versions of the article.

References

  1. Lip, G. Y., Brechin, C. M. & Lane, D. A. The global burden of atrial fibrillation and stroke: a systematic review of the epidemiology of atrial fibrillation in regions outside North America and Europe. Chest 142, 1489–1498 (2012).

    PubMed  Google Scholar 

  2. Wolf, P. A., Abbott, R. D. & Kannel, W. B. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke 22, 983–988 (1991).

    CAS  PubMed  Google Scholar 

  3. Wang, T. J. et al. Temporal relations of atrial fibrillation and congestive heart failure and their joint influence on mortality: the Framingham Heart Study. Circulation 107, 2920–2925 (2003).

    PubMed  Google Scholar 

  4. Benjamin, E. J. et al. Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. Circulation 98, 946–952 (1998).

    CAS  PubMed  Google Scholar 

  5. Santangeli, P. et al. Atrial fibrillation and the risk of incident dementia: a meta-analysis. Heart Rhythm 9, 1761–1768 (2012).

    PubMed  Google Scholar 

  6. Iwasaki, Y. K., Nishida, K., Kato, T. & Nattel, S. Atrial fibrillation pathophysiology: implications for management. Circulation 124, 2264–2274 (2011).

    CAS  PubMed  Google Scholar 

  7. Benjamin, E. J. et al. Independent risk factors for atrial fibrillation in a population-based cohort. The Framingham Heart Study. JAMA 271, 840–844 (1994).

    CAS  PubMed  Google Scholar 

  8. Krahn, A. D., Manfreda, J., Tate, R. B., Mathewson, F. A. & Cuddy, T. E. The natural history of atrial fibrillation: incidence, risk factors, and prognosis in the Manitoba Follow-Up Study. Am. J. Med. 98, 476–484 (1995).

    CAS  PubMed  Google Scholar 

  9. Gami, A. S. et al. Association of atrial fibrillation and obstructive sleep apnea. Circulation 110, 364–367 (2004).

    PubMed  Google Scholar 

  10. Watanabe, H. et al. Metabolic syndrome and risk of development of atrial fibrillation: the Niigata preventive medicine study. Circulation 117, 1255–1260 (2008).

    PubMed  PubMed Central  Google Scholar 

  11. Fox, C. S. et al. Parental atrial fibrillation as a risk factor for atrial fibrillation in offspring. JAMA 291, 2851–2855 (2004).

    CAS  PubMed  Google Scholar 

  12. Lubitz, S. A. et al. Genetics of atrial fibrillation: implications for future research directions and personalized medicine. Circ. Arrhythm. Electrophysiol. 3, 291–299 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  13. Lloyd-Jones, D. et al. Heart disease and stroke statistics—2010 update: a report from the American Heart Association. Circulation 121, e46–e215 (2010).

    PubMed  Google Scholar 

  14. Stewart, S., Hart, C. L., Hole, D. J. & McMurray, J. J. A population-based study of the long-term risks associated with atrial fibrillation: 20-year follow-up of the Renfrew/Paisley study. Am. J. Med. 113, 359–364 (2002).

    PubMed  Google Scholar 

  15. Kim, M. H., Johnston, S. S., Chu, B. C., Dalal, M. R. & Schulman, K. L. Estimation of total incremental health care costs in patients with atrial fibrillation in the United States. Circ. Cardiovasc. Qual. Outcomes 4, 313–320 (2011).

    PubMed  Google Scholar 

  16. Feinberg, W. M., Blackshear, J. L., Laupacis, A., Kronmal, R. & Hart, R. G. Prevalence, age distribution, and gender of patients with atrial fibrillation. Analysis and implications. Arch. Intern. Med. 155, 469–473 (1995).

    CAS  PubMed  Google Scholar 

  17. Heeringa, J. et al. Prevalence, incidence and lifetime risk of atrial fibrillation: the Rotterdam study. Eur. Heart J. 27, 949–953 (2006).

    PubMed  Google Scholar 

  18. Go, A. S. et al. 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, 2370–2375 (2001).

    CAS  PubMed  Google Scholar 

  19. Chugh, S. S., Blackshear, J. L., Shen, W. K., Hammill, S. C. & Gersh, B. J. Epidemiology and natural history of atrial fibrillation: clinical implications. J. Am. Coll. Cardiol. 37, 371–378 (2001).

    CAS  PubMed  Google Scholar 

  20. Lloyd-Jones, D. M. et al. Lifetime risk for development of atrial fibrillation: the Framingham Heart Study. Circulation 110, 1042–1046 (2004).

    PubMed  Google Scholar 

  21. Kakkar, A. K. et al. Risk profiles and antithrombotic treatment of patients newly diagnosed with atrial fibrillation at risk of stroke: perspectives from the international, observational, prospective GARFIELD registry. PLoS ONE 8, e63479 (2013).

    PubMed  PubMed Central  Google Scholar 

  22. Mathur, R. et al. Ethnicity and stroke risk in patients with atrial fibrillation. Heart 99, 1087–1092 (2013).

    PubMed  Google Scholar 

  23. Lip, G. Y. et al. Atrial fibrillation amongst the Indo-Asian general practice population. The West Birmingham Atrial Fibrillation Project. Int. J. Cardiol. 65, 187–192 (1998).

    CAS  PubMed  Google Scholar 

  24. Zhou, Z. & Hu, D. An epidemiological study on the prevalence of atrial fibrillation in the Chinese population of mainland China. J. Epidemiol. 18, 209–216 (2008).

    PubMed  PubMed Central  Google Scholar 

  25. Inoue, H. et al. Prevalence of atrial fibrillation in the general population of Japan: an analysis based on periodic health examination. Int. J. Cardiol. 137, 102–107 (2009).

    Article  PubMed  Google Scholar 

  26. Lau, C. P. et al. Ethnic differences in atrial fibrillation identified using implanted cardiac devices. J. Cardiovasc. Electrophysiol. 24, 381–387 (2013).

    PubMed  Google Scholar 

  27. Tsai, C. F., Thomas, B. & Sudlow, C. L. Epidemiology of stroke and its subtypes in Chinese vs white populations: a systematic review. Neurology 81, 264–272 (2013).

    PubMed  PubMed Central  Google Scholar 

  28. Kim, A. S. & Johnston, S. C. Global variation in the relative burden of stroke and ischemic heart disease. Circulation 124, 314–323 (2011).

    PubMed  Google Scholar 

  29. Gunarathne, A. et al. Ischemic stroke in South Asians: a review of the epidemiology, pathophysiology, and ethnicity-related clinical features. Stroke 40, e415–e423 (2009).

    PubMed  Google Scholar 

  30. Steg, P. G. et al. One-year cardiovascular event rates in outpatients with atherothrombosis. JAMA 297, 1197–1206 (2007).

    CAS  PubMed  Google Scholar 

  31. Ducrocq, G. et al. Geographic differences in outcomes in outpatients with established atherothrombotic disease: results from the REACH Registry. Eur. J. Prev. Cardiol. http://dx.doi.org/10.1177/2047487313501278.

  32. Khan, N. A. et al. Risk factors, quality of care and prognosis in South Asian, East Asian and White patients with stroke. BMC Neurol. 13, 74 (2013).

    PubMed  PubMed Central  Google Scholar 

  33. Sen, S. et al. Racial-ethnic differences in stroke risk factors and subtypes: results of a prospective hospital-based registry. Int. J. Neurosci. 123, 568–574 (2013).

    PubMed  Google Scholar 

  34. Goto, S. et al. One-year cardiovascular event rates in Japanese outpatients with myocardial infarction, stroke, and atrial fibrillation. Results from the Japan Thrombosis Registry for Atrial Fibrillation, Coronary, or Cerebrovascular Events (J-TRACE). Circ. J. 75, 2598–2604 (2011).

    PubMed  Google Scholar 

  35. Li, S. Y. et al. One-year clinical prediction in Chinese ischemic stroke patients using the CHADS2 and CHA2DS2-VASc scores: the China National Stroke Registry. CNS Neurosci. Ther. 18, 988–993 (2012).

    PubMed  PubMed Central  Google Scholar 

  36. Toda, E. et al. Use of the CHADS2 and CHA2DS2-VASC score in Japanese patients with atrial fibrillation, coronary or cerebrovascular events (J-TRACE). J. Am. Coll. Cardiol. 59, E674 (2012).

    Google Scholar 

  37. Yap, K. B., Ng, T. P. & Ong, H. Y. Low prevalence of atrial fibrillation in community-dwelling Chinese aged 55 years or older in Singapore: a population-based study. J. Electrocardiol. 41, 94–98 (2008).

    PubMed  Google Scholar 

  38. Tanizaki, Y. et al. Incidence and risk factors for subtypes of cerebral infarction in a general population: the Hisayama study. Stroke 31, 2616–2622 (2000).

    CAS  PubMed  Google Scholar 

  39. Chien, K. L. et al. Atrial fibrillation prevalence, incidence and risk of stroke and all-cause death among Chinese. Int. J. Cardiol. 139, 173–180 (2010).

    PubMed  Google Scholar 

  40. Lip, G. Y., Kamath, S., Jafri, M., Mohammed, A. & Bareford, D. Ethnic differences in patient perceptions of atrial fibrillation and anticoagulation therapy: the West Birmingham Atrial Fibrillation Project. Stroke 33, 238–242 (2002).

    PubMed  Google Scholar 

  41. Zhao, D. et al. Epidemiological transition of stroke in China: twenty-one-year observational study from the Sino-MONICA-Beijing Project. Stroke 39, 1668–1674 (2008).

    PubMed  Google Scholar 

  42. Kubo, M. et al. Decreasing incidence of lacunar vs other types of cerebral infarction in a Japanese population. Neurology 66, 1539–1544 (2006).

    CAS  PubMed  Google Scholar 

  43. Greenberg, S. M. et al. Cerebral microbleeds: a guide to detection and interpretation. Lancet Neurol. 8, 165–174 (2009).

    PubMed  PubMed Central  Google Scholar 

  44. Koennecke, H. C. Cerebral microbleeds on MRI: prevalence, associations, and potential clinical implications. Neurology 66, 165–171 (2006).

    PubMed  Google Scholar 

  45. Bokura, H. et al. Microbleeds are associated with subsequent hemorrhagic and ischemic stroke in healthy elderly individuals. Stroke 42, 1867–1871 (2011).

    CAS  PubMed  Google Scholar 

  46. Lee, S. H., Ryu, W. S. & Roh, J. K. Cerebral microbleeds are a risk factor for warfarin-related intracerebral hemorrhage. Neurology 72, 171–176 (2009).

    CAS  PubMed  Google Scholar 

  47. Suzuki, S. et al. Incidence of major bleeding complication of warfarin therapy in Japanese patients with atrial fibrillation. Circ. J. 71, 761–765 (2007).

    CAS  PubMed  Google Scholar 

  48. Veenstra, D. L. et al. Association of Vitamin K epoxide reductase complex 1 (VKORC1) variants with warfarin dose in a Hong Kong Chinese patient population. Pharmacogenet. Genomics 15, 687–691 (2005).

    CAS  PubMed  Google Scholar 

  49. Hyun, K. K. et al. A comparative analysis of risk factors and stroke risk for Asian and non-Asian men: the Asia Pacific cohort studies collaboration. Int. J. Stroke 8, 606–611 (2013).

    PubMed  Google Scholar 

  50. Investigators, A. F. Risk factors for stroke and efficacy of antithrombotic therapy in atrial fibrillation. Analysis of pooled data from five randomized controlled trials. Arch. Intern. Med. 154, 1449–1457 (1994).

    Google Scholar 

  51. van Walraven, C. et al. Oral anticoagulants vs aspirin in nonvalvular atrial fibrillation: an individual patient meta-analysis. JAMA 288, 2441–2448 (2002).

    CAS  PubMed  Google Scholar 

  52. Holbrook, A. M. et al. Systematic overview of warfarin and its drug and food interactions. Arch. Intern. Med. 165, 1095–1106 (2005).

    CAS  PubMed  Google Scholar 

  53. Aithal, G. P., Day, C. P., Kesteven, P. J. & Daly, A. K. Association of polymorphisms in the cytochrome P450 CYP2C9 with warfarin dose requirement and risk of bleeding complications. Lancet 353, 717–719 (1999).

    CAS  PubMed  Google Scholar 

  54. D'Andrea, G. et al. A polymorphism in the VKORC1 gene is associated with an interindividual variability in the dose-anticoagulant effect of warfarin. Blood 105, 645–649 (2005).

    CAS  PubMed  Google Scholar 

  55. Kimmel, S. E. et al. A pharmacogenetic versus a clinical algorithm for warfarin dosing. N. Engl. J. Med. 369, 2283–2293 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  56. Verhoef, T. I. et al. A randomized trial of genotype-guided dosing of acenocoumarol and phenprocoumon. N. Engl. J. Med. 369, 2304–2312 (2013).

    CAS  PubMed  Google Scholar 

  57. Pirmohamed, M. et al. A randomized trial of genotype-guided dosing of warfarin. N. Engl. J. Med. 369, 2294–2303 (2013).

    CAS  PubMed  Google Scholar 

  58. Connolly, S. J. et al. Dabigatran versus warfarin in patients with atrial fibrillation. N. Engl. J. Med. 361, 1139–1151 (2009).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  60. Albertsen, I. E. et al. Risk of stroke or systemic embolism in atrial fibrillation patients treated with warfarin: a systematic review and meta-analysis. Stroke 44, 1329–1336 (2013).

    CAS  PubMed  Google Scholar 

  61. Guo, Y. et al. Stroke risk and suboptimal thromboprophylaxis in Chinese patients with atrial fibrillation: would the novel oral anticoagulants have an impact? Int. J. Cardiol. 168, 515–522 (2012).

    PubMed  Google Scholar 

  62. Hori, M. et al. Dabigatran versus warfarin: effects on ischemic and hemorrhagic strokes and bleeding in Asians and non-Asians with atrial fibrillation. Stroke 44, 1891–1896 (2013).

    CAS  PubMed  Google Scholar 

  63. Goto, S. et al. Efficacy and safety of apixaban compared with warfarin for stroke prevention in atrial fibrillation in East Asia. Eur. Heart J. 34, 1039 (2013).

    Google Scholar 

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

    CAS  PubMed  Google Scholar 

  65. Goto, S. et al. Regional differences in use of antithrombotic therapy for stroke prevention in atrial fibrillation and associated outcomes: European and Asian insights. Eur. Heart J. 34, 790–791 (2013).

    Google Scholar 

  66. Sato, H. et al. Low-dose aspirin for prevention of stroke in low-risk patients with atrial fibrillation: Japan Atrial Fibrillation Stroke Trial. Stroke 37, 447–451 (2006).

    CAS  PubMed  Google Scholar 

  67. Shinohara, Y. et al. Cilostazol for prevention of secondary stroke (CSPS 2): an aspirin-controlled, double-blind, randomised non-inferiority trial. Lancet Neurol. 9, 959–968 (2010).

    CAS  PubMed  Google Scholar 

  68. Kamal, A. K., Naqvi, I., Husain, M. R. & Khealani, B. A. Cilostazol versus aspirin for secondary prevention of vascular events after stroke of arterial origin. Cochrane Database of Systematic Reviews, Issue 1. Art. No.: CD008076. http://dx.doi.org/10.1002/14651858.CD008076.pub2.

  69. Wan, Y. et al. Anticoagulation control and prediction of adverse events in patients with atrial fibrillation: a systematic review. Circ. Cardiovasc. Qual. Outcomes 1, 84–91 (2008).

    PubMed  Google Scholar 

  70. Rose, A. J., Ozonoff, A., Grant, R. W., Henault, L. E. & Hylek, E. M. Epidemiology of subtherapeutic anticoagulation in the United States. Circ. Cardiovasc. Qual. Outcomes 2, 591–597 (2009).

    PubMed  Google Scholar 

  71. Bode, W. et al. The refined 1.9 A crystal structure of human alpha-thrombin: interaction with D-Phe-Pro-Arg chloromethylketone and significance of the Tyr-Pro-Pro-Trp insertion segment. EMBO J. 8, 3467–3475 (1989).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Di Nisio, M., Middeldorp, S. & Buller, H. R. Direct thrombin inhibitors. N. Engl. J. Med. 353, 1028–1040 (2005).

    CAS  PubMed  Google Scholar 

  73. Lee, C. J. & Ansell, J. E. Direct thrombin inhibitors. Br. J. Clin. Pharmacol. 72, 581–592 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Ho, S. J. & Brighton, T. A. Ximelagatran: direct thrombin inhibitor. Vasc. Health Risk Manag. 2, 49–58 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Albers, G. W. et al. Ximelagatran vs warfarin for stroke prevention in patients with nonvalvular atrial fibrillation: a randomized trial. JAMA 293, 690–698 (2005).

    PubMed  Google Scholar 

  76. AstraZeneca. AstraZeneca Decides to Withdraw Exanta™[online], (2006).

  77. Olsson, S. B. 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 (2003).

    CAS  PubMed  Google Scholar 

  78. Deinum, J., Mattsson, C., Inghardt, T. & Elg, M. Biochemical and pharmacological effects of the direct thrombin inhibitor AR-H067637. Thromb. Haemost. 101, 1051–1059 (2009).

    CAS  PubMed  Google Scholar 

  79. Lip, G. Y. et al. Oral direct thrombin inhibitor AZD0837 for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation: a randomized dose-guiding, safety, and tolerability study of four doses of AZD0837 vs. vitamin K antagonists. Eur. Heart J. 30, 2897–2907 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Olsson, S. B. et al. Safety and tolerability of an immediate-release formulation of theoral direct thrombin inhibitor AZD0837 in the prevention of stroke and systemic embolism in patients with atrial fibrillation. Thromb. Haemost. 103, 604–612 (2010).

    CAS  PubMed  Google Scholar 

  81. Lip, G. Y. et al. Oral direct thrombin inhibitor AZD0837 for the prevention of stroke and systemic embolism in patients with non-valvular atrial fibrillation: a phase II study of AZD0837 in patients who are appropriate for but unable or unwilling to take vitamin K antagonist therapy. Thromb. Res. 127, 91–99 (2011).

    CAS  PubMed  Google Scholar 

  82. Blech, S., Ebner, T., Ludwig-Schwellinger, E., Stangier, J. & Roth, W. The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans. Drug Metab. Dispos. 36, 386–399 (2008).

    CAS  PubMed  Google Scholar 

  83. Ezekowitz, M. D. et al. Dabigatran with or without concomitant aspirin compared with warfarin alone in patients with nonvalvular atrial fibrillation (PETRO Study). Am. J. Cardiol. 100, 1419–1426 (2007).

    CAS  PubMed  Google Scholar 

  84. Hori, M. et al. Efficacy and safety of dabigatran vs. warfarin in patients with atrial fibrillation-sub-analysis in Japanese population in RE-LY trial. Circ. J. 75, 800–805 (2011).

    CAS  PubMed  Google Scholar 

  85. Hartter, S., Yamamura, N., Stangier, J., Reilly, P. A. & Clemens, A. Pharmacokinetics and pharmacodynamics in Japanese and Caucasian subjects after oral administration of dabigatran etexilate. Thromb. Haemost. 107, 260–269 (2012).

    PubMed  Google Scholar 

  86. Yeh, C. H., Fredenburgh, J. C. & Weitz, J. I. Oral direct factor Xa inhibitors. Circ. Res. 111, 1069–1078 (2012).

    CAS  PubMed  Google Scholar 

  87. Buller, H. R. et al. Subcutaneous fondaparinux versus intravenous unfractionated heparin in the initial treatment of pulmonary embolism. N. Engl. J. Med. 349, 1695–1702 (2003).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  89. Padmanabhan, K. et al. Structure of human des(1–45) factor Xa at 2.2 A resolution. J. Mol. Biol. 232, 947–966 (1993).

    CAS  PubMed  Google Scholar 

  90. Perzborn, E., Roehrig, S., Straub, A., Kubitza, D. & Misselwitz, F. The discovery and development of rivaroxaban, an oral, direct factor Xa inhibitor. Nat. Rev. Drug Discov. 10, 61–75 (2011).

    CAS  PubMed  Google Scholar 

  91. 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).

    CAS  PubMed  Google Scholar 

  92. Depasse, F. et al. Effect of BAY 59-7939—a novel, oral, direct Factor Xa inhibitor—on clot-bound Factor Xa activity in vitro [abstract]. J. Thromb. Haemost. 3 (Suppl. 1), P1104 (2005).

    Google Scholar 

  93. 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).

    CAS  PubMed  Google Scholar 

  94. Kubitza, D., Becka, M., Wensing, G., Voith, B. & Zuehlsdorf, M. 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, 873–880 (2005).

    CAS  PubMed  Google Scholar 

  95. Jiang, J. et al. Safety, pharmacokinetics and pharmacodynamics of single doses of rivaroxaban—an oral, direct factor Xa inhibitor—in elderly Chinese subjects. Thromb. Haemost. 103, 234–241 (2010).

    CAS  PubMed  Google Scholar 

  96. Zhao, X. et al. Safety, pharmacokinetics and pharmacodynamics of single/multiple doses of the oral, direct factor Xa inhibitor rivaroxaban in healthy Chinese subjects. Br. J. Clin. Pharmacol. 68, 77–88 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  97. Stampfuss, J., Kubitza, D., Becka, M. & Mueck, W. The effect of food on the absorption and pharmacokinetics of rivaroxaban. Int. J. Clin. Pharmacol. Ther. 51, 549–561 (2013).

    CAS  PubMed  Google Scholar 

  98. Hori, M. et al. Rivaroxaban vs. warfarin in Japanese patients with atrial fibrillation—the J-ROCKET AF study. Circ. J. 76, 2104–2111 (2012).

    CAS  PubMed  Google Scholar 

  99. Hori, M. et al. Safety and efficacy of adjusted dose of rivaroxaban in Japanese patients with non-valvular atrial fibrillation: subanalysis of J-ROCKET AF for patients with moderate renal impairment. Circ. J. 77, 632–638 (2013).

    CAS  PubMed  Google Scholar 

  100. Lee, M. et al. Low glomerular filtration rate and risk of stroke: meta-analysis. BMJ 341, c4249 (2010).

    PubMed  PubMed Central  Google Scholar 

  101. Alonso, A. et al. Chronic kidney disease is associated with the incidence of atrial fibrillation: the Atherosclerosis Risk in Communities (ARIC) study. Circulation 123, 2946–2953 (2011).

    PubMed  PubMed Central  Google Scholar 

  102. Olesen, J. B. et al. Stroke and bleeding in atrial fibrillation with chronic kidney disease. N. Engl. J. Med. 367, 625–635 (2012).

    CAS  PubMed  Google Scholar 

  103. Lassen, M. R. et al. A phase II randomized, double-blind, five-arm, parallel-group, dose-response study of a new oral directly acting factor Xa inhibitor, razaxaban, for the prevention of deep vein thrombosis in knee replacement surgery (ASH Annual Meeting Abstracts) [abstract 41]. Blood 102, 41 (2003).

    Google Scholar 

  104. Wong, P. C. et al. Razaxaban, a direct factor Xa inhibitor, in combination with aspirin and/or clopidogrel improves low-dose antithrombotic activity without enhancing bleeding liability in rabbits. J. Thromb. Thrombolysis 24, 43–51 (2007).

    CAS  PubMed  Google Scholar 

  105. Wong, P. C. et al. Apixaban, an oral, direct and highly selective factor Xa inhibitor: in vitro, antithrombotic and antihemostatic studies. J. Thromb. Haemost. 6, 820–829 (2008).

    CAS  PubMed  Google Scholar 

  106. Jiang, X., Crain, E. J., Luettgen, J. M., Schumacher, W. A. & Wong, P. C. Apixaban, an oral direct factor Xa inhibitor, inhibits human clot-bound factor Xa activity in vitro. Thromb. Haemost. 101, 780–782 (2009).

    CAS  PubMed  Google Scholar 

  107. Frost, C. et al. Apixaban, a direct factor Xa inhibitor: single-dose pharmacokinetics and pharmacodynamics of an intravenous formulation [abstract 142]. Br. J. Clin. Pharmacol. 48, 1132 (2008).

    Google Scholar 

  108. Frost, C. et al. Apixaban, an oral, direct factor Xa inhibitor: single dose safety, pharmacokinetics, pharmacodynamics and food effect in healthy subjects. Br. J. Clin. Pharmacol. 75, 476–487 (2013).

    CAS  PubMed  Google Scholar 

  109. Vakkalagadda, B. et al. Effect of rifampin on the pharmacokinetics of apixaban, an oral direct inhibitor of factor Xa [abstract 143]. J. Clin. Pharmacol. 49, 1124 (2009).

    Google Scholar 

  110. Easton, J. D. et al. Apixaban compared with warfarin in patients with atrial fibrillation and previous stroke or transient ischaemic attack: a subgroup analysis of the ARISTOTLE trial. Lancet Neurol. 11, 503–511 (2012).

    CAS  PubMed  Google Scholar 

  111. Pisters, R. et al. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest 138, 1093–1100 (2010).

    PubMed  Google Scholar 

  112. Lopes, R. D. et al. Efficacy and safety of apixaban compared with warfarin according to patient risk of stroke and of bleeding in atrial fibrillation: a secondary analysis of a randomised controlled trial. Lancet 380, 1749–1758 (2012).

    CAS  PubMed  Google Scholar 

  113. Ogawa, S., Shinohara, Y. & Kanmuri, K. Safety and efficacy of the oral direct factor xa inhibitor apixaban in Japanese patients with non-valvular atrial fibrillation. The ARISTOTLE-J study. Circ. J. 75, 1852–1859 (2011).

    CAS  PubMed  Google Scholar 

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

    CAS  PubMed  Google Scholar 

  115. Hara, T. et al. DX-9065a, a new synthetic, potent anticoagulant and selective inhibitor for factor Xa. Thromb. Haemost. 71, 314–319 (1994).

    CAS  PubMed  Google Scholar 

  116. Fujii, Y. et al. Characteristics of gastrointestinal absorption of DX-9065a, a new synthetic anticoagulant. Drug Metab. Pharmacokinet. 22, 26–32 (2007).

    CAS  PubMed  Google Scholar 

  117. Zafar, M. U. et al. 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. Thromb. Haemost. 98, 883–888 (2007).

    CAS  PubMed  Google Scholar 

  118. Furugohri, T. et al. DU-176b, a potent and orally active factor Xa inhibitor: in vitro and in vivo pharmacological profiles. J. Thromb. Haemost. 6, 1542–1549 (2008).

    CAS  PubMed  Google Scholar 

  119. Matsushima, N., Lee, F., Sato, T., Weiss, D. & Mendell, J. Bioavailability and safety of the factor xa inhibitor edoxaban and the effects of quinidine in healthy subjects. Clin. Pharm. Drug Dev. 2, 358 (2013).

    CAS  Google Scholar 

  120. Giugliano, R. P. et al. Edoxaban versus warfarin in patients with atrial fibrillation. N. Engl. J. Med. 369, 2093–2104 (2013).

    CAS  PubMed  Google Scholar 

  121. Yamashita, T. et al. Randomized, multicenter, warfarin-controlled phase II study of edoxaban in Japanese patients with non-valvular atrial fibrillation. Circ. J. 76, 1840–1847 (2012).

    CAS  PubMed  Google Scholar 

  122. Chung, N. et al. Safety of edoxaban, an oral factor Xa inhibitor, in Asian patients with non-valvular atrial fibrillation. Thromb. Haemost. 105, 535–544 (2011).

    CAS  PubMed  Google Scholar 

  123. Mendell, J., Tachibana, M., Shi, M. & Kunitada, S. Effects of food on the pharmacokinetics of edoxaban, an oral direct factor Xa inhibitor, in healthy volunteers. J. Clin. Pharmacol. 51, 687–694 (2011).

    CAS  PubMed  Google Scholar 

  124. Ahrens, I., Peter, K., Lip, G. Y. & Bode, C. Development and clinical applications of novel oral anticoagulants. Part II. Drugs under clinical investigation. Discov. Med. 13, 445–450 (2012).

    PubMed  Google Scholar 

  125. Palladino, M., Merli, G. & Thomson, L. Evaluation of the oral direct factor Xa inhibitor—betrixaban. Expert Opin. Investig. Drugs 22, 1465–1472 (2013).

    CAS  PubMed  Google Scholar 

  126. Connolly, S. J. et al. Betrixaban compared with warfarin in patients with atrial fibrillation: results of a phase 2, randomized, dose-ranging study (Explore-Xa). Eur. Heart J. 34, 1498–1505 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  127. Lu, G. et al. A specific antidote for reversal of anticoagulation by direct and indirect inhibitors of coagulation factor Xa. Nat. Med. 19, 446–451 (2013).

    CAS  PubMed  Google Scholar 

  128. Ansell, J. Blocking bleeding: reversing anticoagulant therapy. Nat. Med. 19, 402–404 (2013).

    CAS  PubMed  Google Scholar 

  129. Dentali, F. et al. Efficacy and safety of the novel oral anticoagulants in atrial fibrillation: a systematic review and meta-analysis of the literature. Circulation 126, 2381–2391 (2011).

    Google Scholar 

  130. Miller, C. S., Grandi, S. M., Shimony, A., Filion, K. B. & Eisenberg, M. J. Meta-analysis of efficacy and safety of new oral anticoagulants (dabigatran, rivaroxaban, apixaban) versus warfarin in patients with atrial fibrillation. Am. J. Cardiol. 110, 453–460 (2012).

    CAS  PubMed  Google Scholar 

  131. Sardar, P. et al. New oral anticoagulants are not superior to warfarin in secondary prevention of stroke or transient ischemic attacks, but lower the risk of intracranial bleeding: insights from a meta-analysis and indirect treatment comparisons. PLoS ONE 8, e77694 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Capodanno, D., Capranzano, P., Giacchi, G., Calvi, V. & Tamburino, C. Novel oral anticoagulants versus warfarin in non-valvular atrial fibrillation: a meta-analysis of 50,578 patients. Int. J. Cardiol. 167, 1237–1241 (2013).

    PubMed  Google Scholar 

  133. Bruins Slot, K. M. & Berge, E. Factor Xa inhibitors versus vitamin K antagonists for preventing cerebral or systemic embolism in patients with atrial fibrillation. Cochrane Database of Systematic Reviews 2013, Issue 8. Art. No.: CD008980. http://dx.doi.org/10.1002/14651858.CD008980.pub2.

  134. Rasmussen, L. H., Larsen, T. B., Graungaard, T., Skjoth, F. & Lip, G. Y. Primary and secondary prevention with new oral anticoagulant drugs for stroke prevention in atrial fibrillation: indirect comparison analysis. BMJ 345, e7097 (2012).

    PubMed  PubMed Central  Google Scholar 

  135. Lip, G. Y., Larsen, T. B., Skjoth, F. & Rasmussen, L. H. Indirect comparisons of new oral anticoagulant drugs for efficacy and safety when used for stroke prevention in atrial fibrillation. J. Am. Coll. Cardiol. 60, 738–746 (2012).

    CAS  PubMed  Google Scholar 

  136. Savelieva, I. & Camm, A. J. Practical considerations for using novel oral anticoagulants in patients with atrial fibrillation. Clin. Cardiol. 37, 32–47 (2014).

    PubMed  Google Scholar 

  137. Wallentin, L. et al. Efficacy and safety of dabigatran compared with warfarin at different levels of international normalised ratio control for stroke prevention in atrial fibrillation: an analysis of the RE-LY trial. Lancet 376, 975–983 (2010).

    CAS  PubMed  Google Scholar 

  138. FDA. FDA Draft Briefing Document for the Cardiovascular and Renal Drugs Advisory Committee (CRDAC) [online], (2011).

  139. Rosendaal, F. R., Cannegieter, S. C., van der Meer, F. J. & Briet, E. A method to determine the optimal intensity of oral anticoagulant therapy. Thromb. Haemost. 69, 236–239 (1993).

    CAS  PubMed  Google Scholar 

  140. You, J. H. Novel oral anticoagulants versus warfarin therapy at various levels of anticoagulation control in atrial fibrillation-a cost-effectiveness analysis. J. Gen. Intern. Med. http://dx.doi.org/10.1007/s11606-013-2639-2.

  141. Ogawa, S. et al. The APHRS's 2013 statement on antithrombotic therapy of patients with nonvalvular atrial fibrillation. J. Arryth. 29, 190–200 (2013).

    Google Scholar 

  142. Group, J. J. Guidelines for pharmacotherapy of atrial fibrillation (JCS2008): digest version. Circ. J. 74, 2479–2500 (2010).

    Google Scholar 

  143. Department of Health, Western Australia. Atrial Fibrillation Working Group. Quick Reference Guide: Atrial Fibrillation Information for the Health Practitioner. Perth: Health Networks Branch [online], (2011).

Download references

Author information

Authors and Affiliations

  1. Rayne Institute, St Thomas' Hospital, London, SE1 7EH, UK

    Ian Sabir & Kaivan Khavandi

  2. Division of Cardiovascular Sciences, St George's Vascular Institute, St George's University of London, Cranmer Terrace, London, SW17 0RE, UK

    Jack Brownrigg

  3. Cardiovascular Sciences Research Centre, St George's University of London, Cranmer Terrace, London, SW17 0RE, UK

    A. John Camm

Authors
  1. Ian Sabir
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Kaivan Khavandi
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Jack Brownrigg
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. A. John Camm
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

I.S., K.K. and J.B. researched data for the article. All authors contributed substantially to the discussion of content. I.S., K.K. and J.B. wrote the manuscript. A.J.C. reviewed/edited the article before submission.

Corresponding author

Correspondence to Ian Sabir.

Ethics declarations

Competing interests

A.J.C has acted as an advisor or consultant for Actelion Pharmaceuticals, ARYx Therapeutics, Bristol-Myers Squibb Company, Cardiome Pharma Corporation, CV Therapeutics, Daiichi Sankyo, Menarini Group, Pfizer, Sanofi, and Xention Limited. He has served as a speaker or a member of the speaker's bureau for Cardiome Pharma Corporation, Daiichi Sankyo, Menarini Group, Pfizer, and Sanofi. He has received grants for clinical research from Bristol-Myers Squibb Company, Daiichi Sankyo, Sanofi, and SERVIER. He has served as a member of the data safety monitoring boards for Bristol-Myers Squibb, Novartis Pharmaceuticals Corporation, SERVIER, and an expert witness for Johnson & Johnson Pharmaceutical Research & Development, Sanofi and SERVIER. The other authors declare no competing interests.

PowerPoint slides

Rights and permissions

Reprints and permissions

About this article

Cite this article

Sabir, I., Khavandi, K., Brownrigg, J. et al. Oral anticoagulants for Asian patients with atrial fibrillation. Nat Rev Cardiol 11, 290–303 (2014). https://doi.org/10.1038/nrcardio.2014.22

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrcardio.2014.22

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