Real-world Comparisons of Direct Oral Anticoagulants for Stroke Prevention in Asian Patients with Non-valvular Atrial Fibrillation: a Systematic Review and Meta-analysis

  • Yi-Hsin Chan
  • Hsin-Fu Lee
  • Tze-Fan Chao
  • Chia-Tung Wu
  • Shang-Hung Chang
  • Yung-Hsin Yeh
  • Lai-Chu See
  • Chi-Tai Kuo
  • Pao-Hsien Chu
  • Chun-Li WangEmail author
  • Gregory Y. H. LipEmail author



Whether four direct oral anticoagulants (DOACs) are superior to warfarin among Asians with non-valvular atrial fibrillation (NVAF) remains unclear in the real-world setting.


We searched PubMed and Medline + Journals@Ovid + EMBASE from September 17, 2009 to May 4, 2019 to perform a systematic review and meta-analysis of all observational real-world studies comparing four DOACs with warfarin specifically focused on Asian patients with NVAF.


From the original 212 results retrieved, 18 studies were included in the meta-analysis. Overall, DOACs were associated with lower risks of thromboembolism (hazard ratio; [95% confidence interval], 0.70; [0.63–0.78]), acute myocardial infarction (0.67; [0.57–0.79]), all-cause mortality (0.62; [0.56–0.69]), major bleeding (0.59; [0.50–0.69]), intracranial hemorrhage (0.50; [0.40–0.62]), gastrointestinal bleeding (0.66; [0.46–0.95]), and any bleeding (0.82; [0.73–0.92]) than warfarin. There was statistic heterogeneity between DOACs for the risks of thromboembolism (P interaction = 0.03) and acute myocardial infarction (P interaction = 0.007) when compared to warfarin. However, all DOACs showed lower risks of thromboembolism and acute myocardial infarction than warfarin when pooling studies that compared individual DOAC with warfarin. With regard to the other outcomes when compared to warfarin, there was no statistical heterogeneity between DOACs. In addition, the effectiveness and safety of four DOACs versus warfarin persisted in the subgroups of either standard-dose or low-dose DOACs.


The meta-analysis shows that the DOACs had greater effectiveness and safety compared to warfarin in real-world practice for stroke prevention, among Asian patients with NVAF.


Atrial fibrillation Direct thrombin inhibitor Factor Xa inhibitor Ischemic stroke Hemorrhage Mortality Warfarin 



This study was supported by grants 105-2628-B-182A-003-MY3 from the Ministry of Science and Technology and CMRPG3E0291 from the Chang Gung Memorial Hospital, Linkou, Taiwan.

Compliance with Ethical Standards


GYHL: Consultant for Bayer/Janssen, BMS/Pfizer, Medtronic, Boehringer Ingelheim, Novartis, Verseon and Daiichi-Sankyo. Speaker for Bayer, BMS/Pfizer, Medtronic, Boehringer Ingelheim, and Daiichi-Sankyo. No fees are directly received personally. The remaining authors have nothing to disclose.

Supplementary material

10557_2019_6910_MOESM1_ESM.doc (5.2 mb)
ESM 1 (DOC 5.21 MB)


  1. 1.
    Lip GYH, Freedman B, De Caterina R, Potpara TS. Stroke prevention in atrial fibrillation: past, present and future. Thromb Haemost. 2017;117(7):1230–9.CrossRefGoogle Scholar
  2. 2.
    Ruff CT, Giugliano RP, Braunwald E, Hoffman EB, Deenadayalu N, Ezekowitz MD, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet. 2014;383(9921):955–62.CrossRefGoogle Scholar
  3. 3.
    Shen AY, Yao JF, Brar SS, Jorgensen MB, Chen W. Racial/ethnic differences in the risk of intracranial hemorrhage among patients with atrial fibrillation. J Am Coll Cardiol. 2007;50(4):309–15.CrossRefGoogle Scholar
  4. 4.
    Lip GY, Wang KL, Chiang CE. Non-vitamin K antagonist oral anticoagulants (NOACs) for stroke prevention in Asian patients with atrial fibrillation: time for a reappraisal. Int J Cardiol. 2015;180:246–54.CrossRefGoogle Scholar
  5. 5.
    Wang KL, Lip GY, Lin SJ, Chiang CE. Non-vitamin K antagonist oral anticoagulants for stroke prevention in Asian patients with nonvalvular atrial fibrillation: meta-analysis. Stroke. 2015;46(9):2555–61.CrossRefGoogle Scholar
  6. 6.
    Freedman B, Potpara TS, Lip GY. Stroke prevention in atrial fibrillation. Lancet. 2016;388(10046):806–17.CrossRefGoogle Scholar
  7. 7.
    Cho MS, Yun JE, Park JJ, Kim YJ, Lee J, Kim H et al. Outcomes after use of standard- and low-dose non-vitamin K oral anticoagulants in Asian patients with atrial fibrillation. Stroke. 2018:STROKEAHA118023093.Google Scholar
  8. 8.
    Chan YH, See LC, Tu HT, Yeh YH, Chang SH, Wu LS et al. Efficacy and safety of apixaban, dabigatran, rivaroxaban, and warfarin in Asians with nonvalvular atrial fibrillation. J Am Heart Assoc. 2018;7(8).Google Scholar
  9. 9.
    Kohsaka S, Katada J, Saito K, Terayama Y. Safety and effectiveness of apixaban in comparison to warfarin in patients with nonvalvular atrial fibrillation: a propensity-matched analysis from Japanese administrative claims data. Curr Med Res Opin. 2018;34(9):1627–34.CrossRefGoogle Scholar
  10. 10.
    Kohsaka S, Murata T, Izumi N, Katada J, Wang F, Terayama Y. Bleeding risk of apixaban, dabigatran, and low-dose rivaroxaban compared with warfarin in Japanese patients with non-valvular atrial fibrillation: a propensity matched analysis of administrative claims data. Curr Med Res Opin. 2017;33(11):1955–63.CrossRefGoogle Scholar
  11. 11.
    Chan YH, Lee HF, See LC, Tu HT, Chao TF, Yeh YH, et al. Effectiveness and safety of four direct oral anticoagulants in Asians with non-valvular atrial fibrillation. Chest. 2019.Google Scholar
  12. 12.
    Moher D, Liberati A, Tetzlaff J, Altman DG, Group P. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. Int J Surg. 2010;8(5):336–41.CrossRefGoogle Scholar
  13. 13.
    Stroup DF, Berlin JA, Morton SC, Olkin I, Williamson GD, Rennie D, et al. Meta-analysis of observational studies in epidemiology: a proposal for reporting. Meta-analysis Of Observational Studies in Epidemiology (MOOSE) group. JAMA. 2000;283(15):2008–12.CrossRefGoogle Scholar
  14. 14.
    Bai Y, Deng H, Shantsila A, Lip GY. Rivaroxaban versus dabigatran or warfarin in real-world studies of stroke prevention in atrial fibrillation: systematic review and meta-analysis. Stroke. 2017;48(4):970–6.CrossRefGoogle Scholar
  15. 15.
    Cha MJ, Choi EK, Han KD, Lee SR, Lim WH, Oh S, et al. Effectiveness and safety of non-vitamin K antagonist oral anticoagulants in Asian patients with atrial fibrillation. Stroke. 2017;48(11):3040–8.CrossRefGoogle Scholar
  16. 16.
    Ho JC, Chang AM, Yan BP, Yu CM, Lam YY, Lee VW. Dabigatran compared with warfarin for stroke prevention with atrial fibrillation: experience in Hong Kong. Clin Cardiol. 2012;35(12):E40–5.CrossRefGoogle Scholar
  17. 17.
    Li WH, Huang D, Chiang CE, Lau CP, Tse HF, Chan EW, et al. Efficacy and safety of dabigatran, rivaroxaban, and warfarin for stroke prevention in Chinese patients with atrial fibrillation: the Hong Kong Atrial Fibrillation Project. Clin Cardiol. 2017;40(4):222–9.CrossRefGoogle Scholar
  18. 18.
    Chan PH, Huang D, Hai JJ, Li WH, Yin LX, Chan EW, et al. Stroke prevention using dabigatran in elderly Chinese patients with atrial fibrillation. Heart Rhythm. 2016;13(2):366–73.CrossRefGoogle Scholar
  19. 19.
    Lau WCY, Li X, Wong ICK, Man KKC, Lip GYH, Leung WK, et al. Bleeding-related hospital admissions and 30-day readmissions in patients with non-valvular atrial fibrillation treated with dabigatran versus warfarin. J Thromb Haemost. 2017;15(10):1923–33.CrossRefGoogle Scholar
  20. 20.
    Lee KH, Park HW, Lee N, Hyun DY, Won J, Oh SS, et al. Optimal dose of dabigatran for the prevention of thromboembolism with minimal bleeding risk in Korean patients with atrial fibrillation. Europace. 2017;19(suppl_4):iv1–9.CrossRefGoogle Scholar
  21. 21.
    Naganuma M, Shiga T, Nagao T, Suzuki A, Murasaki K, Hagiwara N. Effectiveness and safety of dabigatran versus warfarin in “real-world” Japanese patients with atrial fibrillation: a single-center observational study. J Arrhythm. 2017;33(2):107–10.CrossRefGoogle Scholar
  22. 22.
    Chan LXWY, Chia PL, Kek ZL. A single institution’s experience with using dabigatran, rivaroxaban and warfarin for prevention of thromboembolism in atrial fibrillation. PoSH. 2018;27(1):20–5.CrossRefGoogle Scholar
  23. 23.
    Wee XT, Ho LM, Ho HK, Lee JY, Yap CW, William H, et al. Incidence of thromboembolic and bleeding events in patients with newly diagnosed nonvalvular atrial fibrillation: an Asian multicenter retrospective cohort study in Singapore. Clin Cardiol. 2017;40(12):1218–26.CrossRefGoogle Scholar
  24. 24.
    Lau WCY, Chan EW, Wong ICK. Dabigatran versus warfarin in patients with non-valvular atrial fibrillation: a population-wide cohort study in chinese patients. Pharmacoepidemiol Drug Saf. 2016;25(Supplement 3):282.Google Scholar
  25. 25.
    Koretsune Y, Yamashita T, Yasaka M, Ono Y, Hirakawa T, Ishida K, et al. Comparative effectiveness and safety of warfarin and dabigatran in patients with non-valvular atrial fibrillation in Japan: a claims database analysis. J Cardiol. 2019;73(3):204–9.CrossRefGoogle Scholar
  26. 26.
    Mao L, Li C, Li T, Yuan K. Prevention of stroke and systemic embolism with rivaroxaban compared with warfarin in Chinese patients with atrial fibrillation. Vascular. 2014;22(4):252–8.CrossRefGoogle Scholar
  27. 27.
    Jeong HK, Lee KH, Park HW, Yoon NS, Kim MC, Lee N, et al. Real world comparison of rivaroxaban and warfarin in Korean patients with atrial fibrillation: propensity matching cohort analysis. Chonnam Med J. 2019;55(1):54–61.CrossRefGoogle Scholar
  28. 28.
    Yu HT, Yang PS, Kim TH, Jang E, Kim D, Uhm JS, et al. Impact of renal function on outcomes with edoxaban in real-world patients with atrial fibrillation. Stroke. 2018;49(10):2421–9.CrossRefGoogle Scholar
  29. 29.
    Lee CJ, Gerds TA, Carlson N, Bonde AN, Gislason GH, Lamberts M, et al. Risk of myocardial infarction in anticoagulated patients with atrial fibrillation. J Am Coll Cardiol. 2018;72(1):17–26.CrossRefGoogle Scholar
  30. 30.
    Weijs B, Blaauw Y, Rennenberg RJ, Schurgers LJ, Timmermans CC, Pison L, et al. Patients using vitamin K antagonists show increased levels of coronary calcification: an observational study in low-risk atrial fibrillation patients. Eur Heart J. 2011;32(20):2555–62.CrossRefGoogle Scholar
  31. 31.
    Schurgers LJ, Cranenburg EC, Vermeer C. Matrix Gla-protein: the calcification inhibitor in need of vitamin K. Thromb Haemost. 2008;100(4):593–603.PubMedGoogle Scholar
  32. 32.
    Ntaios G, Papavasileiou V, Makaritsis K, Vemmos K, Michel P, Lip GYH. Real-world setting comparison of nonvitamin-K antagonist oral anticoagulants versus vitamin-K antagonists for stroke prevention in atrial fibrillation: a systematic review and meta-analysis. Stroke. 2017;48(9):2494–503.CrossRefGoogle Scholar
  33. 33.
    Wallentin L, Yusuf S, Ezekowitz MD, Alings M, Flather M, Franzosi MG, 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. 2010;376(9745):975–83.CrossRefGoogle Scholar
  34. 34.
    Singer DE, Hellkamp AS, Piccini JP, Mahaffey KW, Lokhnygina Y, Pan G, et al. Impact of global geographic region on time in therapeutic range on warfarin anticoagulant therapy: data from the ROCKET AF clinical trial. J Am Heart Assoc. 2013;2(1):e000067.Google Scholar
  35. 35.
    Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883–91.CrossRefGoogle Scholar
  36. 36.
    Hori M, Matsumoto M, Tanahashi N, Momomura S, Uchiyama S, Goto S, et al. Rivaroxaban vs. warfarin in Japanese patients with atrial fibrillation - the J-ROCKET AF study. Circ J. 2012;76(9):2104–11.CrossRefGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2019

Authors and Affiliations

  • Yi-Hsin Chan
    • 1
    • 2
    • 3
  • Hsin-Fu Lee
    • 1
    • 2
    • 4
  • Tze-Fan Chao
    • 5
    • 6
  • Chia-Tung Wu
    • 1
    • 2
  • Shang-Hung Chang
    • 1
    • 2
  • Yung-Hsin Yeh
    • 1
    • 2
  • Lai-Chu See
    • 7
    • 8
    • 9
  • Chi-Tai Kuo
    • 1
    • 2
  • Pao-Hsien Chu
    • 1
    • 2
  • Chun-Li Wang
    • 1
    • 2
    Email author
  • Gregory Y. H. Lip
    • 10
    Email author
  1. 1.The Cardiovascular Department, Chang Gung Memorial HospitalTaoyuan CityTaiwan
  2. 2.College of MedicineChang Gung UniversityTaoyuanTaiwan
  3. 3.Microscopy Core Laboratory, Chang Gung Memorial HospitalTaoyuanTaiwan
  4. 4.Graduate Institute of Clinical Medical Sciences, College of MedicineChang Gung UniversityTaoyuanTaiwan
  5. 5.Division of Cardiology, Department of MedicineTaipei Veterans General HospitalTaipeiTaiwan
  6. 6.Institute of Clinical Medicine, Cardiovascular Research CenterNational Yang-Ming UniversityTaipeiTaiwan
  7. 7.Department of Public Health, College of MedicineChang Gung UniversityTaoyuanTaiwan
  8. 8.Biostatistics Core Laboratory, Molecular Medicine Research CenterChang Gung UniversityTaoyuanTaiwan
  9. 9.Division of Rheumatology, Allergy and Immunology, Department of Internal Medicine, Chang Gung Memorial HospitalTaoyuanTaiwan
  10. 10.Liverpool Centre for Cardiovascular ScienceUniversity of Liverpool and Liverpool Heart & Chest HospitalLiverpoolUK

Personalised recommendations