Skip to main content
SpringerLink
Log in

Tolerability and Acceptability of Non-Vitamin K Antagonist Oral Anticoagulants in Atrial Fibrillation: Systematic Review and Meta-Analysis

  • Systematic Review
  • Published:
American Journal of Cardiovascular Drugs Aims and scope Submit manuscript

Abstract

Background

The non-vitamin K antagonist oral anticoagulants (NOACs) overcame some limitations of vitamin K antagonists (VKAs), and are at least as effective in stroke prevention, with an additional decrease of intracranial bleeding risk. The transferability of these benefits to the real world requires tolerability (related to adverse events) and acceptability (drug discontinuation) profiles at least similar to VKAs.

Methods

We performed a systematic review with meta-analysis of randomized controlled trials (RCTs) evaluating NOACs versus VKAs in patients with non-valvular atrial fibrillation (AF). Studies were searched in April 2015 through MEDLINE, the Cochrane Collaboration’s Database, Health Technology Assessment (HTA), Web of Science, and regulatory agencies’ documents. Serious adverse events (SAEs) as well as drug-related and patient-related discontinuation rates were the outcomes of interest. Random-effects meta-analysis was performed, and the results expressed as risk ratios (RRs) and 95 % confidence intervals (CIs). Heterogeneity was evaluated with I 2 test.

Results

Five RCTs evaluating four NOACs (apixaban, dabigatran, edoxaban, and rivaroxaban) and 72,720 patients were included. Overall, NOACs were associated with a 4 % risk reduction of SAEs (95 % CI 2–6; I 2 = 0 %). Drug-related and patient-related discontinuation rates were similar between NOACs and VKAs (RR 1.03 [0.88–1.21] and RR 0.99 [0.89–1.10], respectively). Significant heterogeneity (I 2 ≥ 75 %) was found among studies results, which could be, at least partially, explained by the findings of the open-label dabigatran trial.

Conclusions

NOACs were associated with a small, yet significant, risk reduction of SAEs in patients with AF. NOACs’ drug-related and patient-related acceptability profiles were similar to those for VKAs. The results were heterogeneous mainly because of the increased rate of discontinuation associated with dabigatran. Pragmatic trials and cohort studies should be conducted to further address these important clinical questions.

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

Similar content being viewed by others

References

  1. Falck-Ytter Y, Francis CW, Johanson NA, Curley C, Dahl OE, Schulman S, Ortel TL, Pauker SG, Colwell CW Jr, American College of Chest Physicians. Prevention of VTE in orthopedic surgery patients: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141:e278S–325S.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  2. Kearon C, Akl EA, Comerota AJ, Prandoni P, Bounameaux H, Goldhaber SZ, Nelson ME, Wells PS, Gould MK, Dentali F, Crowther M, Kahn SR, American College of Chest Physicians. Antithrombotic therapy for VTE disease: antithrombotic therapy and prevention of thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines. Chest. 2012;141:e419S–94S.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  3. Caldeira D, Barra M, Pinto FJ, Ferreira JJ, Costa J. Intracranial hemorrhage risk with the new oral anticoagulants: a systematic review and meta-analysis. J Neurol 2015;262:516–22. doi:10.1007/s00415-014-7462-0.

    Article  CAS  PubMed  Google Scholar 

  4. Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JP, Clarke M, Devereaux PJ, Kleijnen J, Moher D. The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate health care interventions: explanation and elaboration. PLoS Med. 2009;21(6):e1000100.

    Article  Google Scholar 

  5. Lefebvre C, Manheimer E, Glanville J. Chapter 6: Searching for studies. In: Higgins JPT, Green S, editors. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from http://www.cochrane-handbook.org. Accessed Apr 2015.

  6. Turner RM, Bird SM, Higgins JP. The impact of study size on meta-analyses: examination of underpowered studies in Cochrane reviews. PLoS One. 2013;8:e59202.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  7. Kjaergard LL, Villumsen J, Gluud C. Reported methodologic quality and discrepancies between large and small randomized trials in meta-analyses. Ann Intern Med. 2001;135:982–9.

    Article  CAS  PubMed  Google Scholar 

  8. Zhang Z, Xu X, Ni H. Small studies may overestimate the effect sizes in critical care meta-analyses: a meta-epidemiological study. Crit Care. 2013;17:R2.

    Article  PubMed Central  PubMed  Google Scholar 

  9. Caldeira D, Barra M, Santos AT, de Abreu D, Pinto FJ, Ferreira JJ, Costa J. Risk of drug-induced liver injury with the new oral anticoagulants: systematic review and meta-analysis. Heart. 2014;100:550–6.

    Article  CAS  PubMed  Google Scholar 

  10. Higgins JPT, Altman DG, Sterne JAC. Chapter 8: Assessing risk of bias in included studies. In: Higgins JPT, Green S, editors. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from http://www.cochrane-handbook.org. Accessed Apr 2015.

  11. Cipriani A, Furukawa TA, Salanti G, Geddes JR, Higgins JP, Churchill R, Watanabe N, Nakagawa A, Omori IM, McGuire H, Tansella M, Barbui C. Comparative efficacy and acceptability of 12 new-generation antidepressants: a multiple-treatments meta-analysis. Lancet. 2009;373:746–58.

    Article  CAS  PubMed  Google Scholar 

  12. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials. 1986;7:177–88.

    Article  CAS  PubMed  Google Scholar 

  13. Deeks JJ. Issues in the selection of a summary statistic for meta-analysis of clinical trials with binary outcomes. Stat Med. 2002;21:1575–600.

    Article  PubMed  Google Scholar 

  14. Deeks JJ, Altman DG, Bradburn MJ. Statistical methods for examining heterogeneity and combining results from several studies in metaanalysis. In: Egger M, Davey Smith G, Altman DG, editors. Systematic reviews in health care: meta-analysis in context, 2nd ed. London: BMJ Publication Group; 2001, p. 313–335.

  15. Walter SD. Number needed to treat (NNT): estimation of a measure of clinical benefit. Stat Med. 2001;20:3947–62.

    Article  CAS  PubMed  Google Scholar 

  16. Schünemann HJ, Oxman AD, Vist GE, Higgins JPT, Deeks JJ, Glasziou P, Guyatt GH. Chapter 12: Interpreting results and drawing conclusions. In: Higgins JPT, Green S, editors. Cochrane Handbook for Systematic Reviews of Interventions Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from http://www.cochrane-handbook.org. Accessed Apr 2015.

  17. Beyer-Westendorf J, Büller H. External and internal validity of open label or double-blind trials in oral anticoagulation: better, worse or just different? J Thromb Haemost. 2011;9:2153–8.

    Article  CAS  PubMed  Google Scholar 

  18. Egger M, Davey Smith G, Schneider M, Minder C. Bias in meta-analysis detected by a simple, graphical test. BMJ. 1997;315:629–34.

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Peters JL, Sutton AJ, Jones DR, Abrams KR, Rushton L. Comparison of two methods to detect publication bias in meta-analysis. JAMA. 2006;295:676–80.

    Article  CAS  PubMed  Google Scholar 

  20. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365:981–92.

    Article  CAS  PubMed  Google Scholar 

  21. Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361:1139–51.

    Article  CAS  PubMed  Google Scholar 

  22. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369:2093–104.

    Article  CAS  PubMed  Google Scholar 

  23. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365:883–91.

    Article  CAS  PubMed  Google Scholar 

  24. Hori M, Matsumoto M, Tanahashi N, et al. Rivaroxaban vs. warfarin in Japanese patients with atrial fibrillation—the J-ROCKET AF study. Circ J. 2012;76:2104–11.

    Article  CAS  PubMed  Google Scholar 

  25. Sterne JAC, Egger M, Moher D, editors. Chapter 10: Addressing reporting biases. In: Higgins JPT, Green S, editors. Cochrane Handbook for Systematic Reviews of Intervention. Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Available from http://www.cochrane-handbook.org. Accessed Apr 2015.

  26. Chatterjee S, Sardar P, Giri JS, Ghosh J, Mukherjee D. Treatment discontinuations with new oral agents for long-term anticoagulation: insights from a meta-analysis of 18 randomized trials including 101,801 patients. Mayo Clin Proc. 2014;89:896–907.

    Article  PubMed  Google Scholar 

  27. Caldeira D, Vaz-Carneiro A, Costa J. The impact of dosing frequency on medication adherence in chronic cardiovascular disease: systematic review and meta-analysis. Rev Port Cardiol. 2014;33:431–7.

    PubMed  Google Scholar 

  28. Coleman CI, Limone B, Sobieraj DM, Lee S, Roberts MS, Kaur R, Alam T. Dosing frequency and medication adherence in chronic disease. J Manag Care Pharm. 2012;18:527–39.

    PubMed  Google Scholar 

  29. Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H, Baanstra D, Schnee J, Goldhaber SZ, RE-COVER Study Group. Dabigatran versus warfarin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;61:2342–52.

    Article  Google Scholar 

  30. Caldeira D, Costa J, Pinto FJ, Ferreira JJ. The risk of infection with new oral anticoagulants: a meta-analysis. Int J Cardiol. 2014;172:267–8.

    Article  PubMed  Google Scholar 

  31. Caldeira D, Barra M, Gonçalves N, Pinto FJ, Ferreira JJ, Costa J. Pericardial bleeding risk with non-vitamin K oral anticoagulants: a meta-analysis. Int J Cardiol. 2014;182C:187–8.

    Google Scholar 

  32. Caldeira D, Barra M, Santos AT, de Abreu D, Costa J, Ferreira JJ. Risk of insomnia with non-vitamin K oral anticoagulants: systematic review and meta-analysis. Sleep Breath. 2015. doi:10.1007/s11325-014-1112-8.

    PubMed  Google Scholar 

  33. Caldeira D, Costa J, Ferreira JJ, Pinto FJ. Thromboembolic risk in the initiation, switch and interruption/re-initiation of oral anticoagulants: do newcomers improve outcomes? Insights from a meta-analysis of RCTs. Int J Cardiol. 2014;177:117–9.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

Portuguese Collaborating Centre of the Cochrane Iberoamerican Network.

Contributors

DC contributed to the concept and design, data acquisition, data analysis, and interpretation of the data; wrote the first draft of the manuscript; critically revised the manuscript; and gave final approval of the submitted manuscript. JC contributed to the data acquisition and data analysis; critically revised the manuscript; and gave final approval of the submitted manuscript. NG, FJP, and JJF contributed to the interpretation of data, critically revised the manuscript, and gave final approval of the submitted manuscript.

Funding

This was an academic project not funded by any government or non-government grants.

Ethical approval

Not required.

Competing interests

We declare the following potential conflicts of interests: JJF had speaker and consultant fees with GlaxoSmithKline, Novartis, TEVA, Lundbeck, Solvay, Abbott, Bial, Merck-Serono, Grunenthal, and Merck Sharp and Dohme; FJP had consultant and speaker fees with Astra Zeneca, Bayer and Boehringer Ingelheim; the remaining authors do not have any competing interests to disclose.

Author information

Authors and Affiliations

  1. Clinical Pharmacology Unit, Instituto de Medicina Molecular, Lisbon, Portugal

    Daniel Caldeira, Nilza Gonçalves, Joaquim J. Ferreira & João Costa

  2. Laboratory of Clinical Pharmacology and Therapeutics, Faculty of Medicine, University of Lisbon, Av. Prof. Egas Moniz, Lisboa, 1649-028, Portugal

    Daniel Caldeira, Joaquim J. Ferreira & João Costa

  3. Cardiology Department, Hospital Garcia de Orta, Almada, Portugal

    Daniel Caldeira

  4. Cardiology Department, CCUL, CAML, Faculty of Medicine, Lisbon, Portugal

    Fausto J. Pinto

  5. Evidence Based Medicine Centre (CEMBE), Faculty of Medicine, University of Lisbon, Lisbon, Portugal

    João Costa

  6. Portuguese Collaborating Centre of the Cochrane Iberoamerican Network, Faculty of Medicine, University of Lisbon, Lisbon, Portugal

    João Costa

Authors
  1. Daniel Caldeira
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Nilza Gonçalves
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Joaquim J. Ferreira
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Fausto J. Pinto
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. João Costa
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Daniel Caldeira.

Electronic supplementary material

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Caldeira, D., Gonçalves, N., Ferreira, J.J. et al. Tolerability and Acceptability of Non-Vitamin K Antagonist Oral Anticoagulants in Atrial Fibrillation: Systematic Review and Meta-Analysis. Am J Cardiovasc Drugs 15, 259–265 (2015). https://doi.org/10.1007/s40256-015-0132-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s40256-015-0132-5

Keywords

Search

Navigation