Real-world comparisons of reduced-dose non-vitamin K antagonist oral anticoagulants versus warfarin in atrial fibrillation: a systematic review and meta-analysis

  • Xiaoping Wang
  • Lili Fang
  • Bin Liu
  • Yongliang Zheng
  • Junquan ZengEmail author


We performed this meta-analysis to compare the efficacy and safety of reduced-dose non-vitamin K antagonist oral anticoagulants (NOACs) versus warfarin in patients with atrial fibrillation (AF). The PubMed and Embase databases were systematically searched until July 2019 for eligible studies that comparing the effect between any reduced-dose NOAC and warfarin in patients with AF. Risk ratios (RRs) and 95% confidence intervals (CIs) were pooled by using a random-effects model. A total of 14 observational cohorts were included. Compared with warfarin use, the use of reduced-dose NOACs was associated with decreased risks of stroke or systemic embolism (RR, 0.83; 95% CI 0.74–0.93), ischemic stroke (RR, 0.87; 95% CI 0.77–0.98), major bleeding (RR, 0.71; 95% CI 0.60–0.84), intracranial hemorrhage (RR, 0.51; 95% CI 0.44–0.60), and gastrointestinal bleeding (RR, 0.72; 95% CI 0.54–0.94), but not all cause death (RR, 0.84; 95% CI 0.67–1.06). In the subgroup analyses, all NOAC users had lower or similar rates of thromboembolic and bleeding events; and the reductions in stroke or systemic embolism, all-cause death, major bleeding, and gastrointestinal bleeding were more prominent in Asians than non-Asians. In conclusion, current published data suggest that the use of reduced-dose NOACs is non-inferior to warfarin in patients with AF (in particular Asians).


Atrial fibrillation Anticoagulants Outcomes Stroke prevention 


Author contributions

Xiaoping Wang, and Junquan Zeng contributed to the whole process of this meta-analysis including study design, literature search, data curation, methodology, data analysis, and data interpretation and drafted the manuscript. Lili Fang, Bin Liu, and Yongliang Zheng help revised the original draft.

Funding information

This study was supported by Jiangxi Educational Department Foundation of China(NO.GJJ170628, 170656, 160761, GL1569).

Compliance with ethical standards

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical approval

Not required.

Supplementary material

10741_2019_9887_MOESM1_ESM.pdf (1.1 mb)
ESM 1 (PDF 1150 kb)


  1. 1.
    January CT, Wann LS, Calkins H, Chen LY, Cigarroa JE, Cleveland JC, Ellinor PT, Ezekowitz MD, Field ME, Furie KL, Heidenreich PA, Murray KT, Shea JB, Tracy CM, Yancy CW (2019) AHA/ACC/HRS focused update of the 2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation. Circulation 2019:R665Google Scholar
  2. 2.
    Kirchhof P, Benussi S, Kotecha D, Ahlsson A, Atar D, Casadei B, Castella M, Diener H, Heidbuchel H, Hendriks J, Hindricks G, Manolis AS, Oldgren J, Popescu BA, Schotten U, Van Putte B, Vardas P, Agewall S, Camm J, Baron Esquivias G, Budts W, Carerj S, Casselman F, Coca A, De Caterina R, Deftereos S, Dobrev D, Ferro JM, Filippatos G, Fitzsimons D, Gorenek B, Guenoun M, Hohnloser SH, Kolh P, Lip GYH, Manolis A, McMurray J, Ponikowski P, Rosenhek R, Ruschitzka F, Savelieva I, Sharma S, Suwalski P, Tamargo JL, Taylor CJ, Van Gelder IC, Voors AA, Windecker S, Zamorano JL, Zeppenfeld K (2016) 2016 ESC guidelines for the management of atrial fibrillation developed in collaboration with EACTS. Eur Heart J 37(38):2893–2962CrossRefGoogle Scholar
  3. 3.
    Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, Waldo AL, Ezekowitz MD, Weitz JI, Špinar J, Ruzyllo W, Ruda M, Koretsune Y, Betcher J, Shi M, Grip LT, Patel SP, Patel I, Hanyok JJ, Mercuri M, Antman EM (2013) Edoxaban versus warfarin in patients with atrial fibrillation. New Engl J Med 369(22):2093–2104CrossRefGoogle Scholar
  4. 4.
    Granger CB, Alexander JH, McMurray JJV, Lopes RD, Hylek EM, Hanna M, Al-Khalidi HR, Ansell J, Atar D, Avezum A, Bahit MC, Diaz R, Easton JD, Ezekowitz JA, Flaker G, Garcia D, Geraldes M, Gersh BJ, Golitsyn S, Goto S, Hermosillo AG, Hohnloser SH, Horowitz J, Mohan P, Jansky P, Lewis BS, Lopez-Sendon JL, Pais P, Parkhomenko A, Verheugt FWA, Zhu J, Wallentin L (2011) Apixaban versus warfarin in patients with atrial fibrillation. New Engl J Med 365(11):981–992CrossRefGoogle Scholar
  5. 5.
    Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W, Breithardt G, Halperin JL, Hankey GJ, Piccini JP, Becker RC, Nessel CC, Paolini JF, Berkowitz SD, Fox KAA, Califf RM (2011) Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. New Engl J Med 365(10):883–891CrossRefGoogle Scholar
  6. 6.
    Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, Pogue J, Reilly PA, Themeles E, Varrone J, Wang S, Alings M, Xavier D, Zhu J, Diaz R, Lewis BS, Darius H, Diener H, Joyner CD, Wallentin L (2009) Dabigatran versus warfarin in patients with atrial fibrillation. New Engl J Med 361(12):1139–1151CrossRefGoogle Scholar
  7. 7.
    Wang K, Lopes RD, Patel MR, Büller HR, Tan DS, Chiang C, Giugliano RP (2019) Efficacy and safety of reduced-dose non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation: a meta-analysis of randomized controlled trials. Eur Heart J 40(19):1492–1500CrossRefGoogle Scholar
  8. 8.
    Lip GYH, Clemens A, Noack H, Ferreira J, Connolly SJ, Yusuf S (2017) Patient outcomes using the European label for dabigatran. Thromb Haemost 111(05):933–942Google Scholar
  9. 9.
    Ruff CT, Giugliano RP, Braunwald E, Morrow DA, Murphy SA, Kuder JF, Deenadayalu N, Jarolim P, Betcher J, Shi M, Brown K, Patel I, Mercuri M, Antman EM (2015) Association between edoxaban dose, concentration, anti-factor Xa activity, and outcomes: an analysis of data from the randomised, double-blind ENGAGE AF-TIMI 48 trial. Lancet 385(9984):2288–2295CrossRefGoogle Scholar
  10. 10.
    Halvorsen S, Atar D, Yang H, De Caterina R, Erol C, Garcia D, Granger CB, Hanna M, Held C, Husted S, Hylek EM, Jansky P, Lopes RD, Ruzyllo W, Thomas L, Wallentin L (2014) Efficacy and safety of apixaban compared with warfarin according to age for stroke prevention in atrial fibrillation: Observations from the ARISTOTLE trial. Eur Heart J 35(28):1864–1872CrossRefGoogle Scholar
  11. 11.
    Hohnloser SH, Oldgren J, Yang S, Wallentin L, Ezekowitz M, Reilly P, Eikelboom J, Brueckmann M, Yusuf S, Connolly SJ (2012) Myocardial ischemic events in patients with atrial fibrillation treated with dabigatran or warfarin in the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial. Circulation. 125(5):669–676CrossRefGoogle Scholar
  12. 12.
    Fox KAA, Piccini JP, Wojdyla D, Becker RC, Halperin JL, Nessel CC, Paolini JF, Hankey GJ, Mahaffey KW, Patel MR, Singer DE, Califf RM (2011) Prevention of stroke and systemic embolism with rivaroxaban compared with warfarin in patients with non-valvular atrial fibrillation and moderate renal impairment. Eur Heart J 32(19):2387–2394CrossRefGoogle Scholar
  13. 13.
    Barra ME, Fanikos J, Connors JM, Sylvester KW, Piazza G, Goldhaber SZ (2016) Evaluation of dose-reduced direct oral anticoagulant therapy. Am J Med 129(11):1198–1204CrossRefGoogle Scholar
  14. 14.
    Chan Y, Yen K, See L, Chang S, Wu L, Lee H, Tu H, Yeh Y, Kuo C (2016) Cardiovascular, bleeding, and mortality risks of dabigatran in asians with nonvalvular atrial fibrillation. Stroke. 47(2):441–449CrossRefGoogle Scholar
  15. 15.
    Sato T, Aizawa Y, Fuse K, Fujita S, Ikeda Y, Kitazawa H, Takahashi M, Okabe M (2018) The comparison of inappropriate-low-doses use among 4 direct oral anticoagulants in patients with atrial fibrillation: from the database of a single-center registry. J Stroke Cerebrovasc Dis 27(11):3280–3288CrossRefGoogle Scholar
  16. 16.
    Higgins J, Green S. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0[updated March 2011]. Available at: Accessed July 28, 2019.
  17. 17.
    Moher D, Liberati A, Tetzlaff J, Altman DG (2009) Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. PLoS Med 6(7):e1000097CrossRefGoogle Scholar
  18. 18.
    Zhu W, Wan R, Liu F, Hu J, Huang L, Li J, Hong K (2016) Relation of body mass index with adverse outcomes among patients with atrial fibrillation: a meta-analysis and systematic review. J Am Heart Assoc 5(9):e4006CrossRefGoogle Scholar
  19. 19.
    Doi SA, Barendregt JJ, Khan S, Thalib L, Williams GM (2015) Advances in the meta-analysis of heterogeneous clinical trials II: the quality effects model. Contemp Clin Trials 45(Pt A):123–129CrossRefGoogle Scholar
  20. 20.
    Kim HM, Choi E, Park CS, Cha M, Lee S, Kwon J, Oh S (2019) Effectiveness and safety of non-vitamin K antagonist oral anticoagulants in octogenarian patients with non-valvular atrial fibrillation. PLoS One 14(3):e211766Google Scholar
  21. 21.
    Lee KH, Park HW, Lee N, Hyun DY, Won J, Oh SS, Park HJ, Kim Y, Cho JY, Kim MC, Sim DS, Yoon HJ, Yoon NS, Kim KH, Hong YJ, Kim JH, Ahn Y, Jeong MH, Park JC, Cho JG (2017) Optimal dose of dabigatran for the prevention of thromboembolism with minimal bleeding risk in Korean patients with atrial fibrillation. EP Europace 19(suppl_4):v1–v9CrossRefGoogle Scholar
  22. 22.
    Lee SR, Choi EK, Han KD, Jung JH, Oh S, Lip GYH (2018) Edoxaban in Asian patients with atrial fibrillation: effectiveness and safety. J Am Coll Cardiol 72(8):838–853CrossRefGoogle Scholar
  23. 23.
    Cho MS, Yun JE, Park JJ, Kim YJ, Lee J, Kim H, Park DW, Nam GB (2018) Outcomes after use of standard- and low-dose non-vitamin K oral anticoagulants in Asian patients with atrial fibrillation. Stroke:a118023093Google Scholar
  24. 24.
    Chan Y, Lee H, See L, Tu H, Chao T, Yeh Y, Wu L, Kuo C, Chang S (2019. [Epub ahead of print]) Lip GYH. Effectiveness and safety of four direct oral anticoagulants in asian patients with nonvalvular atrial fibrillation, CHEST. CrossRefGoogle Scholar
  25. 25.
    Chan YH, See LC, Tu HT, Yeh YH, Chang SH, Wu LS, Lee HF, Wang CL, Kuo CF, Kuo CT. Efficacy and safety of apixaban, dabigatran, rivaroxaban, and warfarin in asians with nonvalvular atrial fibrillation. J AM HEART ASSOC. 2018;7(8).Google Scholar
  26. 26.
    Kohsaka S, Murata T, Izumi N, Katada J, Wang F, Terayama Y (2017) 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 33(11):1955–1963CrossRefGoogle Scholar
  27. 27.
    Lip G, Keshishian A, Li X, Hamilton M, Masseria C, Gupta K, Luo X, Mardekian J, Friend K, Nadkarni A, Pan X, Baser O, Deitelzweig S (2018) Effectiveness and safety of oral anticoagulants among nonvalvular atrial fibrillation patients. Stroke. 49(12):2933–2944CrossRefGoogle Scholar
  28. 28.
    Li X, Keshishian A, Hamilton M, Horblyuk R, Gupta K, Luo X, Mardekian J, Friend K, Nadkarni A, Pan X, Lip GYH, Deitelzweig S (2018) Apixaban 5 and 2.5 mg twice-daily versus warfarin for stroke prevention in nonvalvular atrial fibrillation patients: comparative effectiveness and safety evaluated using a propensity-score-matched approach. PLoS One 13(1):e191722Google Scholar
  29. 29.
    Nielsen PB, Skjoth F, Sogaard M, Kjaeldgaard JN, Lip GY, Larsen TB (2017) Effectiveness and safety of reduced dose non-vitamin K antagonist oral anticoagulants and warfarin in patients with atrial fibrillation: propensity weighted nationwide cohort study. BMJ. 356:j510CrossRefGoogle Scholar
  30. 30.
    Avgil-Tsadok M, Jackevicius CA, Essebag V, Eisenberg MJ, Rahme E, Behlouli H, Pilote L (2016) Dabigatran use in elderly patients with atrial fibrillation. Thromb Haemost 115(1):152–160CrossRefGoogle Scholar
  31. 31.
    Nishtala PS, Gnjidic D, Jamieson HA, Hanger HC, Kaluarachchi C, Hilmer SN (2016) ‘Real-world’ haemorrhagic rates for warfarin and dabigatran using population-level data in New Zealand. Int J Cardiol 203:746–752CrossRefGoogle Scholar
  32. 32.
    Graham DJ, Reichman ME, Wernecke M, Zhang R, Southworth MR, Levenson M, Sheu T, Mott K, Goulding MR, Houstoun M, MaCurdy TE, Worrall C, Kelman JA (2015) Cardiovascular, bleeding, and mortality risks in elderly medicare patients treated with dabigatran or warfarin for nonvalvular atrial fibrillation. Circulation. 131(2):157–164CrossRefGoogle Scholar
  33. 33.
    Larsen TB, Gorst-Rasmussen A, Rasmussen LH, Skjøth F, Rosenzweig M, Lip GYH (2014) Bleeding events among new starters and switchers to dabigatran compared with warfarin in atrial fibrillation. Am J Med 127(7):650–656CrossRefGoogle Scholar
  34. 34.
    Arbel R, Sergienko R, Hammerman A, Greenberg-Dotan S, Batat E, Avnery O, Ellis MH (2019) Effectiveness and safety of off-label dose-reduced direct oral anticoagulants in atrial fibrillation. Am J Med. [Epub ahead of print]CrossRefGoogle Scholar
  35. 35.
    Cheng WH, Chao TF, Lin YJ, Chang SL, Lo LW, Hu YF, Tuan TC, Liao JN, Chung FP, Lip G, Chen SA. Low-dose rivaroxaban and risks of adverse events in patients with atrial fibrillation. Stroke. 2019:A119025623.Google Scholar
  36. 36.
    Yao X, Shah ND, Sangaralingham LR, Gersh BJ, Noseworthy PA. Non–vitamin K antagonist oral anticoagulant dosing in patients with atrial fibrillation and renal dysfunction. J Am Coll Cardiol 2017;69(23):2779-2790, Non-Vitamin K Antagonist Oral Anticoagulant Dosing in Patients With Atrial Fibrillation and Renal Dysfunction.CrossRefGoogle Scholar
  37. 37.
    Steinberg BA, Shrader P, Thomas L, Ansell J, Fonarow GC, Gersh BJ, Kowey PR, Mahaffey KW, Naccarelli G, Reiffel J, Singer DE, Peterson ED, Piccini JP (2016) Off-label dosing of non-vitamin k antagonist oral anticoagulants and adverse outcomes: the ORBIT-AF II Registry. J Am Coll Cardiol 68(24):2597–2604CrossRefGoogle Scholar
  38. 38.
    Wang KL, Lip GY, Lin SJ, Chiang CE (2015) Non-vitamin K antagonist oral anticoagulants for stroke prevention in asian patients with nonvalvular atrial fibrillation: meta-analysis. Stroke. 46(9):2555–2561CrossRefGoogle Scholar
  39. 39.
    Chiang C, Okumura K, Zhang S, Chao T, Siu C, Wei Lim T, Saxena A, Takahashi Y, Siong TW (2017) 2017 consensus of the Asia Pacific Heart Rhythm Society on stroke prevention in atrial fibrillation. J Arrhythmia 33(4):345–367CrossRefGoogle Scholar
  40. 40.
    Lip GY, Wang KL, Chiang CE (2015) Non-vitamin K antagonist oral anticoagulants (NOACs) for stroke prevention in Asian patients with atrial fibrillation: time for a reappraisal. Int J Cardiol 180:246–254CrossRefGoogle Scholar

Copyright information

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

Authors and Affiliations

  • Xiaoping Wang
    • 1
  • Lili Fang
    • 2
  • Bin Liu
    • 2
  • Yongliang Zheng
    • 2
  • Junquan Zeng
    • 3
    Email author
  1. 1.Comprehensive Teaching and Research OfficeJi’an CollegeJi’anChina
  2. 2.Department of HematologyThe Affiliated Hospital of Jinggangshan UniversityJi’anChina
  3. 3.Department of Internal MedicineJinggangshan UniversityJi’anChina

Personalised recommendations