Skip to main content
SpringerLink
Log in

Comparison of treatment effect estimates of non-vitamin K antagonist oral anticoagulants versus warfarin between observational studies using propensity score methods and randomized controlled trials

  • META-ANALYSIS
  • Published:
European Journal of Epidemiology Aims and scope Submit manuscript

Abstract

Emerging observational studies using propensity score (PS) methods assessed real-world comparative effectiveness of non-vitamin K antagonist oral anticoagulants (NOACs) versus warfarin in patients with non-valvular atrial fibrillation (AF). We aimed to compare treatment effect estimates of NOACs between PS studies and randomized controlled trials (RCTs). Electronic databases and conference proceedings were searched systematically. Primary outcomes included stroke or systemic embolism (SE) and major bleeding. A random-effects meta-analysis was performed to synthesize the data by pooling the PS- and RCT-derived hazard ratios (HRs) separately. The ratio of HRs (RHR) from the ratio of PS-derived HRs relative to RCT-derived HRs was used to determine whether there was a difference between estimates from PS studies and RCTs. There were 10 PS studies and 5 RCTs included for analysis. No significant difference of treatment effect estimates between the PS studies and RCTs was observed: RHR 1.11, 95 % CI 0.98–1.23 for stroke or SE; RHR 1.07, 95 % CI 0.87–1.34 for major bleeding. A significant association between NOACs and risk of stroke or SE was observed: HR 0.88, 95 % CI 0.83–0.94 for the PS studies; HR 0.79, 95 % CI 0.72–0.87 for the RCTs. However, no relationship between NOACs and risk of major bleeding was found: HR 0.91, 95 % CI 0.79–1.05 for the PS studies; HR 0.85, 95 % CI 0.73–1.00 for the RCTs. In this study, treatment effect estimates of NOACs versus warfarin in patients with non-valvular AF from PS studies are found to be in agreement with those from RCTs.

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
Fig. 4
Fig. 5

Similar content being viewed by others

References

  1. Chugh SS, Havmoeller R, Narayanan K, Singh D, Rienstra M, Benjamin EJ, et al. Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study. Circulation. 2014;129(8):837–47.

    Article  PubMed  Google Scholar 

  2. Rockson SG, Albers GW. Comparing the guidelines: anticoagulation therapy to optimize stroke prevention in patients with atrial fibrillation. J Am Coll Cardiol. 2004;43(6):929–35.

    Article  PubMed  Google Scholar 

  3. Cairns JA, Connolly S, McMurtry S, Stephenson M, Talajic M. Canadian Cardiovascular Society atrial fibrillation guidelines 2010: prevention of stroke and systemic thromboembolism in atrial fibrillation and flutter. Can J Cardiol. 2011;27(1):74–90.

    Article  PubMed  Google Scholar 

  4. Camm AJ, Kirchhof P, Lip GY, Schotten U, Savelieva I, Ernst S, et al. Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Eur Heart J. 2010;31(19):2369–429.

    Article  PubMed  Google Scholar 

  5. Ageno W, Gallus AS, Wittkowsky A, Crowther M, Hylek EM, Palareti G. Oral anticoagulant therapy: antithrombotic therapy and prevention of thrombosis, 9th ed: American college of chest physicians evidence-based clinical practice guidelines. Chest. 2012;141(2 Suppl):e44S–88S.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Verheugt FW, Granger CB. Oral anticoagulants for stroke prevention in atrial fibrillation: current status, special situations, and unmet needs. Lancet. 2015;386(9990):303–10.

    Article  CAS  PubMed  Google Scholar 

  7. Dentali F, Riva N, Crowther M, Turpie AG, Lip GY, Ageno W. Efficacy and safety of the novel oral anticoagulants in atrial fibrillation: a systematic review and meta-analysis of the literature. Circulation. 2012;126(20):2381–91.

    Article  CAS  PubMed  Google Scholar 

  8. Adam SS, McDuffie JR, Ortel TL, Williams JW Jr. Comparative effectiveness of warfarin and new oral anticoagulants for the management of atrial fibrillation and venous thromboembolism: a systematic review. Ann Intern Med. 2012;157(11):796–807.

    Article  PubMed  Google Scholar 

  9. Miller CS, Grandi SM, Shimony A, Filion KB, Eisenberg MJ. Meta-analysis of efficacy and safety of new oral anticoagulants (dabigatran, rivaroxaban, apixaban) versus warfarin in patients with atrial fibrillation. Am J Cardiol. 2012;110(3):453–60.

    Article  CAS  PubMed  Google Scholar 

  10. Cameron C, Coyle D, Richter T, Kelly S, Gauthier K, Steiner S, et al. Systematic review and network meta-analysis comparing antithrombotic agents for the prevention of stroke and major bleeding in patients with atrial fibrillation. BMJ Open. 2014;4(6):e004301.

    Article  PubMed  PubMed Central  Google Scholar 

  11. Fox BD, Kahn SR, Langleben D, Eisenberg MJ, Shimony A. Efficacy and safety of novel oral anticoagulants for treatment of acute venous thromboembolism: direct and adjusted indirect meta-analysis of randomised controlled trials. BMJ (Clinical research ed). 2012;345:e7498.

    Google Scholar 

  12. Jia B, Lynn HS, Rong F, Zhang W. Meta-analysis of efficacy and safety of the new anticoagulants versus warfarin in patients with atrial fibrillation. J Cardiovasc Pharmacol. 2014;64(4):368–74.

    Article  CAS  PubMed  Google Scholar 

  13. 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.

    Article  CAS  PubMed  Google Scholar 

  14. Gomez-Outes A, Terleira-Fernandez AI, Calvo-Rojas G, Suarez-Gea ML, Vargas-Castrillon E. Dabigatran, rivaroxaban, or apixaban versus warfarin in patients with nonvalvular atrial fibrillation: a systematic review and meta-analysis of subgroups. Thrombosis. 2013;2013:640723.

    Article  PubMed  PubMed Central  Google Scholar 

  15. Liu GJ, Wang YF, Chen PY, Chang W, Tu ML, Chang LY, et al. The efficacy and safety of novel oral anticoagulants for the preventive treatment in atrial fibrillation patients: a systematic review and meta-analysis. Drug Deliv. 2014;21(6):436–52.

    Article  CAS  PubMed  Google Scholar 

  16. Sibbald B, Roland M. Understanding controlled trials. Why are randomised controlled trials important? BMJ (Clinical research ed). 1998;316(7126):201.

    Article  CAS  PubMed Central  Google Scholar 

  17. Rothwell PM. External validity of randomised controlled trials: “to whom do the results of this trial apply?”. Lancet. 2005;365(9453):82–93.

    Article  PubMed  Google Scholar 

  18. Byar DP. Why data bases should not replace randomized clinical trials. Biometrics. 1980;36(2):337–42.

  19. Austin PC. An introduction to propensity score methods for reducing the effects of confounding in observational studies. Multivar Behav Res. 2011;46(3):399–424.

    Article  Google Scholar 

  20. Heinze G, Juni P. An overview of the objectives of and the approaches to propensity score analyses. Eur Heart J. 2011;32(14):1704–8.

    Article  PubMed  Google Scholar 

  21. Guo S, Fraser MW. Propensity score analysis: statistical methods and applications: statistical methods and applications. Thousand Oaks: Sage Publications; 2014.

    Google Scholar 

  22. Rubin DB. The design versus the analysis of observational studies for causal effects: parallels with the design of randomized trials. Stat Med. 2007;26(1):20–36.

    Article  PubMed  Google Scholar 

  23. Heinze G, Jüni P. An overview of the objectives of and the approaches to propensity score analyses. Eur Heart J. 2011;32(14):1704–8.

  24. Dahabreh IJ, Sheldrick RC, Paulus JK, Chung M, Varvarigou V, Jafri H, et al. Do observational studies using propensity score methods agree with randomized trials? A systematic comparison of studies on acute coronary syndromes. Eur Heart J. 2012;33(15):1893–901.

    Article  PubMed  PubMed Central  Google Scholar 

  25. Lonjon G, Boutron I, Trinquart L, Ahmad N, Aim F, Nizard R, et al. Comparison of treatment effect estimates from prospective nonrandomized studies with propensity score analysis and randomized controlled trials of surgical procedures. Ann Surg. 2014;259(1):18–25.

    Article  PubMed  Google Scholar 

  26. Zhang Z, Ni H, Xu X. Do the observational studies using propensity score analysis agree with randomized controlled trials in the area of sepsis? J Crit Care. 2014;29(5):886.e9–15. doi:10.1016/j.jcrc.2014.05.023.

    Article  Google Scholar 

  27. Zhang Z, Ni H, Xu X. Observational studies using propensity score analysis underestimated the effect sizes in critical care medicine. J Clin Epidemiol. 2014;67(8):932–9.

    Article  PubMed  Google Scholar 

  28. Kuss O, Legler T, Borgermann J. Treatments effects from randomized trials and propensity score analyses were similar in similar populations in an example from cardiac surgery. J Clin Epidemiol. 2011;64(10):1076–84.

    Article  CAS  PubMed  Google Scholar 

  29. Kitsios GD, Dahabreh IJ, Callahan S, Paulus JK, Campagna AC, Dargin JM. Can we trust observational studies using propensity scores in the critical care literature? A systematic comparison with randomized clinical trials. Crit Care Med. 2015;43(9):1870–9.

  30. Higgins JPT, Green S. Cochrane handbook for systematic reviews of interventions 5.1.0. [updated March 2011] http://handbook.cochrane.org. Accessed October, 2015.

  31. Moher D, Liberati A, Tetzlaff J, Altman DG. Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement. BMJ (Clinical research ed). 2009;339:b2535.

    Article  PubMed Central  Google Scholar 

  32. Providencia R, Albenque JP, Combes S, Bouzeman A, Casteigt B, Combes N, et al. Safety and efficacy of dabigatran versus warfarin in patients undergoing catheter ablation of atrial fibrillation: a systematic review and meta-analysis. Heart (British Cardiac Society). 2014;100(4):324–35.

    CAS  Google Scholar 

  33. Lip GY, Merino J, Ezekowitz M, Ellenbogen K, Zamoryakhin D, Lanz H, et al. A prospective evaluation of edoxaban compared to warfarin in subjects undergoing cardioversion of atrial fibrillation: the EdoxabaN vs. warfarin in subjectS UndeRgoing cardiovErsion of Atrial Fibrillation (ENSURE-AF) study. Am Heart J. 2015;169(5):597–604.e5. doi:10.1016/j.ahj.2015.02.009.

    Article  CAS  PubMed  Google Scholar 

  34. Nairooz R, Sardar P, Pino M, Aronow WS, Sewani A, Mukherjee D, et al. Meta-analysis of risk of stroke and thrombo-embolism with rivaroxaban versus vitamin K antagonists in ablation and cardioversion of atrial fibrillation. Int J Cardiol. 2015;6(187):345–53.

    Article  Google Scholar 

  35. Viera AJ, Garrett JM. Understanding interobserver agreement: the kappa statistic. Fam Med. 2005;37(5):360–3.

    PubMed  Google Scholar 

  36. The ROBINS-I tool (Risk Of Bias In Non-randomized Studies—of Interventions). https://sites.google.com/site/riskofbiastool/. Accessed June, 2016.

  37. Altman DG, Bland JM. Interaction revisited: the difference between two estimates. BMJ (Clinical research ed). 2003;326(7382):219.

    Article  PubMed Central  Google Scholar 

  38. Guyatt G, Oxman AD, Akl EA, Kunz R, Vist G, Brozek J, et al. GRADE guidelines: 1. Introduction-GRADE evidence profiles and summary of findings tables. J Clin Epidemiol. 2011;64(4):383–94.

    Article  PubMed  Google Scholar 

  39. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139–51.

  40. Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369(22):2093–104.

  41. Granger CB, Alexander JH, McMurray JJ, Lopes RD, Hylek EM, Hanna M, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11):981–92.

    Article  CAS  PubMed  Google Scholar 

  42. 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.

    Article  CAS  PubMed  Google Scholar 

  43. 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.

    Article  CAS  PubMed  Google Scholar 

  44. Abraham NS, Singh S, Alexander GC, Heien H, Haas LR, Crown W, et al. Comparative risk of gastrointestinal bleeding with dabigatran, rivaroxaban, and warfarin: population based cohort study. BMJ (Clinical research ed). 2015;350:h1857.

    PubMed Central  Google Scholar 

  45. Hernandez I, Baik SH, Pinera A, Zhang Y. Risk of bleeding with dabigatran in atrial fibrillation. JAMA Intern Med. 2015;175(1):18–24.

    Article  PubMed  Google Scholar 

  46. Laliberte F, Cloutier M, Nelson WW, Coleman CI, Pilon D, Olson WH, et al. Real-world comparative effectiveness and safety of rivaroxaban and warfarin in nonvalvular atrial fibrillation patients. Curr Med Res Opin. 2014;30(7):1317–25.

    Article  CAS  PubMed  Google Scholar 

  47. Larsen TB, Rasmussen LH, Skjoth F, Due KM, Callreus T, Rosenzweig M, et al. Efficacy and safety of dabigatran etexilate and warfarin in “real-world” patients with atrial fibrillation: a prospective nationwide cohort study. J Am Coll Cardiol. 2013;61(22):2264–73.

    Article  CAS  PubMed  Google Scholar 

  48. Lauffenburger JC, Farley JF, Gehi AK, Rhoney DH, Brookhart MA, Fang G. Effectiveness and safety of dabigatran and warfarin in real-world US patients with non-valvular atrial fibrillation: a retrospective cohort study. J Am Heart Assoc. 2015;4(4):e001798.

  49. Graham DJ, Reichman ME, Wernecke M, Zhang R, Southworth MR, Levenson M, et al. Cardiovascular, bleeding, and mortality risks in elderly medicare patients treated with dabigatran or warfarin for nonvalvular atrial fibrillation. Circulation. 2014;131(2):157–64.

    Article  PubMed  Google Scholar 

  50. Leef G, Qin D, Althouse A, Alam MB, Rattan R, Munir MB, et al. Risk of stroke and death in atrial fibrillation by type of anticoagulation: a propensity-matched analysis. Pacing Clin Electrophysiol. 2015;38(11):1310–6.

    Article  PubMed  Google Scholar 

  51. Bengtson L, Chen L, MacLehose R, Lutsey P, Alonso A. Comparative effectiveness of dabigatran and rivaroxaban versus warfarin in patients with non-valvular atrial fibrillation. Circulation. 2014;130(Suppl 2):A20218.

  52. Seeger JD, Bartels DB, Huybrechts K, Bykov K, Shash D, Zint K, et al. Safety and effectiveness of dabigatran relative to warfarin in routine care. Circulation. 2014;130(Suppl 2):A16227.

  53. Tsadok MA, Jackevicius CA, Essebag V, Eisenberg MJ, Rahme E, Humphries KH, et al. Comparative effectiveness and safety of dabigatran vs. Warfarin in patients with atrial fibrillation-evidence from real world practice. Circulation. 2013;128(Suppl 22):A13884.

  54. Connolly SJ, Ezekowitz MD, Yusuf S, Reilly PA, Wallentin L. Newly identified events in the RE-LY trial. N Engl J Med. 2010;363(19):1875–6.

    Article  CAS  PubMed  Google Scholar 

  55. Brookhart MA, Schneeweiss S, Rothman KJ, Glynn RJ, Avorn J, Sturmer T. Variable selection for propensity score models. Am J Epidemiol. 2006;163(12):1149–56.

    Article  PubMed  PubMed Central  Google Scholar 

  56. Chai-Adisaksopha C, Crowther M, Isayama T, Lim W. The impact of bleeding complications in patients receiving target-specific oral anticoagulants: a systematic review and meta-analysis. Blood. 2014;124(15):2450–8.

    Article  CAS  PubMed  Google Scholar 

  57. Robins JM. Correction for non-compliance in equivalence trials. Stat Med. 1998;17(3):269–302 (discussion 387–269).

    Article  CAS  PubMed  Google Scholar 

  58. Swanson SA, Robins JM, Miller M, Hernan MA. Selecting on treatment: a pervasive form of bias in instrumental variable analyses. Am J Epidemiol. 2015;181(3):191–7.

    Article  PubMed  PubMed Central  Google Scholar 

Download references

Acknowledgments

GL. receives a Father Sean O’Sullivan Research Award, the Research Institute of St. Joseph’s Healthcare Hamilton, and a doctoral award from the CSC. M.C. sat on advisory boards for Janssen, Leo Pharma, Portola, and AKP America; his institution has received funding for research projects from Leo Pharma; and he received funding for presentations from Leo Pharma, Bayer, Celgene, Shire, and CSL Behring. S.C. received consulting fees, lecture fees, and grant support from Boehringer Ingelheim.

Author information

Authors and Affiliations

  1. Department of Clinical Epidemiology and Biostatistics, McMaster University, Hamilton, ON, Canada

    Guowei Li, Anne Holbrook, Yanling Jin, Mitchell A. H. Levine, Lawrence Mbuagbaw, Mark Crowther, Chatree Chai-Adisaksopha, Ji Cheng & Lehana Thabane

  2. St. Joseph’s Healthcare Hamilton, 50 Charlton Avenue East, Hamilton, ON, L8N 4A6, Canada

    Guowei Li, Anne Holbrook, Mitchell A. H. Levine, Lawrence Mbuagbaw, Mark Crowther, Ji Cheng & Lehana Thabane

  3. Department of Medicine, McMaster University, Hamilton, ON, Canada

    Anne Holbrook, Mitchell A. H. Levine, Mark Crowther & Stuart Connolly

  4. Department of Epidemiology, School of Public Health, Soochow University, Suzhou, China

    Yonghong Zhang

  5. Department of Pharmacotherapy, University of Utah, Salt Lake City, UT, USA

    Daniel M. Witt

  6. Population Health Research Institute, McMaster University, Hamilton, ON, Canada

    Stuart Connolly

  7. Department of Nutrition and Food Hygiene, School of Public Health, Soochow University, Suzhou, China

    Zhongxiao Wan

Authors
  1. Guowei Li
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Anne Holbrook
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Yanling Jin
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Yonghong Zhang
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Mitchell A. H. Levine
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Lawrence Mbuagbaw
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Daniel M. Witt
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Mark Crowther
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Stuart Connolly
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Chatree Chai-Adisaksopha
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Zhongxiao Wan
    View author publications

    You can also search for this author in PubMed Google Scholar

  12. Ji Cheng
    View author publications

    You can also search for this author in PubMed Google Scholar

  13. Lehana Thabane
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding authors

Correspondence to Guowei Li or Lehana Thabane.

Electronic supplementary material

Below is the link to the electronic supplementary material.

Supplementary material 1 (DOCX 440 kb)

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Li, G., Holbrook, A., Jin, Y. et al. Comparison of treatment effect estimates of non-vitamin K antagonist oral anticoagulants versus warfarin between observational studies using propensity score methods and randomized controlled trials. Eur J Epidemiol 31, 541–561 (2016). https://doi.org/10.1007/s10654-016-0178-y

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10654-016-0178-y

Keywords

Search

Navigation