Clinical Research in Cardiology

, Volume 104, Issue 7, pp 582–590 | Cite as

Non-vitamin K antagonist oral anticoagulants in the cardioversion of patients with atrial fibrillation: systematic review and meta-analysis

  • Daniel Caldeira
  • João Costa
  • Joaquim J. Ferreira
  • Gregory Y. H. Lip
  • Fausto J. Pinto
Original Paper



Non-vitamin K antagonist oral anticoagulants (NOACs) are at least non-inferior to Vitamin K Antagonists (VKAs) for stroke prevention on patients with non-valvular atrial fibrillation (AF). We aimed to evaluate the efficacy and safety of NOACs in patients undergoing cardioversion through a systematic review and meta-analysis.


MEDLINE, Cochrane Library, and Web of Science® databases (until September 2014) were searched for studies fulfilling inclusion criteria. Two reviewers independently selected randomized controlled trials (RCTs) evaluating NOACs and VKA in patients with AF undergoing cardioversion. The primary outcome was ischemic stroke or systemic embolism (IS/SE). Secondary outcomes were major bleeding, myocardial infarction, and mortality. Risk ratio (RR) and 95 % confidence intervals were derived through random-effects meta-analysis. Heterogeneity was evaluated through I 2 test.


Four RCTs (3 post-hoc analysis) evaluating apixaban, dabigatran, and rivaroxaban in 3,512 patients with AF were included. The risk of IS/SE with NOACs was similar to VKA (RR 0.60, 95 % CI 0.20–1.80; I 2 = 17 %). There was no significant increase in major bleeding (RR 1.27, 95 % CI 0.58–2.81; I 2 = 0 %), myocardial infarction (RR 0.71, 95 % CI 0.10–5.04; I 2 = 0 %), or mortality (RR 0.87, 95 % CI 0.24–3.08; I 2 = 0 %) with NOACs.


This systematic review and meta-analysis suggests that NOACs may be as safe as VKAs in the setting of AF cardioversion.


Meta-analysis Electric countershock Stroke Anticoagulants Cardioversion Transesophageal echocardiography 



We thank the Portuguese Collaborating Center of the Iberoamerican Cochrane Network. This was an academic project not funded by any government or non-government grant.

Conflict of interest

DC, and JC do not have any competing interests to disclose. JJF had speaker and consultant fees with GlaxoSmithKline, Novartis, TEVA, Lundbeck, Solvay, Abbott, Bial, Merck-Serono, Grunenthal, and Merck Sharp and Dohme. GYHL had consultant fees from Bayer, Astellas, Merck, Astra Zeneca, Sanofi, BMS/Pfizer, Biotronik, Portola, and Boehringer Ingelheim; and has been on the speakers bureau for Bayer, BMS/Pfizer, Boehringer Ingelheim, and Sanofi-Aventis. FJP had consultant and speaker fees with Astra Zeneca, Bayer, and Boehringer Ingelheim.

Supplementary material

392_2015_821_MOESM1_ESM.tif (126 kb)
Flowchart of studies’ selection process. (TIFF 125 kb)
392_2015_821_MOESM2_ESM.tif (170 kb)
Risk of bias according to Cochrane Risk of Bias tool. (TIFF 170 kb)
392_2015_821_MOESM3_ESM.tif (25 kb)
Funnel plot. (TIFF 24 kb)
392_2015_821_MOESM4_ESM.pdf (124 kb)
Supplementary material 4 (PDF 123 kb)


  1. 1.
    Wokhlu A, Monahan KH, Hodge DO, Asirvatham SJ, Friedman PA, Munger TM, Bradley DJ, Bluhm CM, Haroldson JM, Packer DL (2010) Long-term quality of life after ablation of atrial fibrillation the impact of recurrence, symptom relief, and placebo effect. J Am Coll Cardiol 55:2308–2316PubMedCrossRefGoogle Scholar
  2. 2.
    Bjerkelund CJ, Orning OM (1969) The efficacy of anticoagulant therapy in preventing embolism related to D.C. electrical conversion of atrial fibrillation. Am J Cardiol 23:208–216PubMedCrossRefGoogle Scholar
  3. 3.
    Klein AL, Grimm RA, Murray RD, Apperson-Hansen C, Asinger RW, Black IW, Davidoff R, Erbel R, Halperin JL, Orsinelli DA, Porter TR, Stoddard MF, Assessment of Cardioversion Using Transesophageal Echocardiography Investigators (2001) Use of transesophageal echocardiography to guide cardioversion in patients with atrial fibrillation. N Engl J Med 344:1411–1420Google Scholar
  4. 4.
    Caldeira D, Barra M, Pinto FJ, Ferreira JJ, Costa J (2014) Intracranial hemorrhage risk with the new oral anticoagulants: a systematic review and meta-analysis. J Neurol. doi: 10.1007/s00415-014-7462-0 PubMedGoogle Scholar
  5. 5.
    De Caterina R, Husted S, Wallentin L, Andreotti F, Arnesen H, Bachmann F, Baigent C, Huber K, Jespersen J, Kristensen SD, Lip GY, Morais J, Rasmussen LH, Siegbahn A, Verheugt FW, Weitz JI, European Society of Cardiology Working Group on Thrombosis Task Force on Anticoagulants in Heart Disease (2013) General mechanisms of coagulation and targets of anticoagulants (section I). Position Paper of the ESC working group on thrombosis-task force on anticoagulants in heart disease. Thromb Haemost 109:569–579Google Scholar
  6. 6.
    Caldeira D, Barra M, Santos AT, de Abreu D, Pinto FJ, Ferreira JJ, Costa J (2014) Risk of drug-induced liver injury with the new oral anticoagulants: systematic review and meta-analysis. Heart 100:550–556PubMedCrossRefGoogle Scholar
  7. 7.
    Ruff CT, Giugliano RP, Braunwald E, Hoffman EB, Deenadayalu N, Ezekowitz MD, Camm AJ, Weitz JI, Lewis BS, Parkhomenko A, Yamashita T, Antman EM (2014) Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a meta-analysis of randomised trials. Lancet 383:955–962PubMedCrossRefGoogle Scholar
  8. 8.
    Skjøth F, Larsen TB, Rasmussen LH, Lip GY (2014) Efficacy and safety of edoxaban in comparison with dabigatran, rivaroxaban and apixaban for stroke prevention in atrial fibrillation. An indirect comparison analysis. Thromb Haemost 111:981–988PubMedCrossRefGoogle Scholar
  9. 9.
    Caldeira D, Costa J, Pinto FJ, Ferreira JJ (2014) The risk of infection with new oral anticoagulants: a meta-analysis. Int J Cardiol 172:267–268PubMedCrossRefGoogle Scholar
  10. 10.
    Nielsen PB, Lane DA, Rasmussen LH, Lip GY, Larsen TB (2014) Renal function and non-vitamin K oral anticoagulants in comparison with warfarin on safety and efficacy outcomes in atrial fibrillation patients: a systemic review and meta-regression analysis. Clin Res Cardiol. doi: 10.1007/s00392-014-0797-9 PubMedGoogle Scholar
  11. 11.
    Liberati A, Altman DG, Tetzlaff J, Mulrow C, Gøtzsche PC, Ioannidis JP, Clarke M, Devereaux PJ, Kleijnen J, Moher D (2009) The PRISMA statement for reporting systematic reviews and meta-analyses of studies that evaluate healthcare interventions: explanation and elaboration. BMJ 339:b2700. doi: 10.1136/bmj.b2700 PubMedCentralPubMedCrossRefGoogle Scholar
  12. 12.
    Higgins JPT, Altman DG, Sterne JAC. Chapter 8: Assessing risk of bias in included studies. In: Higgins JPT, Green S (eds) Cochrane handbook for systematic reviews of interventions version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Accessed in Sep 2014
  13. 13.
    DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7:177–188PubMedCrossRefGoogle Scholar
  14. 14.
    Deeks JJ (2002) Issues in the selection of a summary statistic for meta-analysis of clinical trials with binary outcomes. Stat Med 21:1575–1600PubMedCrossRefGoogle Scholar
  15. 15.
    Deeks JJ, Altman DG, Bradburn MJ (2001) Statistical methods for examining heterogeneity and combining results from several studies in metaanalysis. In Egger M, Davey Smith G, Altman DG (eds) Systematic reviews in health care: meta-analysis in context, 2nd edn. BMJ Publication Group, London, pp 313–335Google Scholar
  16. 16.
    Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315:629–634PubMedCentralPubMedCrossRefGoogle Scholar
  17. 17.
    Peters JL, Sutton AJ, Jones DR, Abrams KR, Rushton L (2006) Comparison of two methods to detect publication bias in meta-analysis. JAMA 295:676–680PubMedCrossRefGoogle Scholar
  18. 18.
    Nagarakanti R, Ezekowitz MD, Oldgren J, Yang S, Chernick M, Aikens TH, Flaker G, Brugada J, Kamensky G, Parekh A, Reilly PA, Yusuf S, Connolly SJ (2011) Dabigatran versus warfarin in patients with atrial fibrillation: an analysis of patients undergoing cardioversion. Circulation 123:131–136PubMedCrossRefGoogle Scholar
  19. 19.
    Piccini JP, Stevens SR, Lokhnygina Y, Patel MR, Halperin JL, Singer DE, Hankey GJ, Hacke W, Becker RC, Nessel CC, Mahaffey KW, Fox KA, Califf RM, Breithardt G, ROCKETAF Steering Committee Investigators (2013) Outcomes after cardioversion and atrial fibrillation ablation in patients treated with rivaroxaban and warfarin in the ROCKET AF trial. J Am Coll Cardiol 61:1998–2006PubMedCrossRefGoogle Scholar
  20. 20.
    Flaker G, Lopes RD, Al-Khatib SM, Hermosillo AG, Hohnloser SH, Tinga B, Zhu J, Mohan P, Garcia D, Bartunek J, Vinereanu D, Husted S, Harjola VP, Rosenqvist M, Alexander JH, Granger CB, ARISTOTLE Committees Investigators (2014) Efficacy and safety of apixaban in patients after cardioversion for atrial fibrillation: insights from the ARISTOTLE Trial (Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation). J Am Coll Cardiol 63:1082–1087PubMedCrossRefGoogle Scholar
  21. 21.
    Cappato R, Ezekowitz MD, Klein AL, Camm AJ, Ma CS, Le Heuzey JY, Talajic M, Scanavacca M, Vardas PE, Kirchhof P, Hemmrich M, Lanius V, Meng IL, Wildgoose P, van Eickels M, Hohnloser SH, on behalf of the X-VeRT Investigators (2014) Rivaroxaban vs. vitamin K antagonists for cardioversion in atrial fibrillation. Eur Heart J. doi: 10.1093/eurheartj/ehu367 PubMedGoogle Scholar
  22. 22.
    Bradburn MJ, Deeks JJ, Berlin JA, Russell Localio A (2007) Much ado about nothing: a comparison of the performance of meta-analytical methods with rare events. Stat Med 26:53–77PubMedCrossRefGoogle Scholar
  23. 23.
    Deeks JJ, Higgins JPT, Altman DG (2011) Chapter 9: Analysing data and undertaking meta-analyses. In: Higgins JPT, Green S (eds) Cochrane handbook for systematic reviews of interventions version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Accessed in Sep 2014
  24. 24.
    Higgins JPT, Deeks JJ, Altman DG (2011) Chapter 16: Special topics in statistics. In: Higgins JPT, Green S (eds), Cochrane Handbook for systematic reviews of interventions version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Accessed in Sep 2014
  25. 25.
    Sterne JAC, Egger M, Moher D (2011) Chapter 10: Addressing reporting biases. In: Higgins JPT, Green S (eds) Cochrane Handbook for systematic reviews of intervention. Version 5.1.0 (updated March 2011). The Cochrane Collaboration, 2011. Accessed in Sep 2014
  26. 26.
    Arnold AZ, Mick MJ, Mazurek RP, Loop FD, Trohman RG (1992) Role of prophylactic anticoagulation for direct current cardioversion in patients with atrial fibrillation or atrial flutter. J Am Coll Cardiol 19:851–855PubMedCrossRefGoogle Scholar
  27. 27.
    European Heart Rhythm Association, European Association for Cardio-Thoracic Surgery, Camm AJ, Kirchhof P, Lip GY, Schotten U, Savelieva I, Ernst S, Van Gelder IC, Al-Attar N, Hindricks G, Prendergast B, Heidbuchel H, Alfieri O, Angelini A, Atar D, Colonna P, De Caterina R, De Sutter J, Goette A, Gorenek B, Heldal M, Hohloser SH, Kolh P, Le Heuzey JY, Ponikowski P, Rutten FH; ESC Committee for Practice Guidelines (2010) Guidelines for the management of atrial fibrillation: the Task Force for the Management of Atrial Fibrillation of the European Society of Cardiology (ESC). Europace. 12:1360–1420Google Scholar
  28. 28.
    Berger M, Schweitzer P (1998) Timing of thromboembolic events after electrical cardioversion of atrial fibrillation or flutter: a retrospective analysis. Am J Cardiol 82:1545–1547PubMedCrossRefGoogle Scholar
  29. 29.
    Corrado G, Beretta S, Sormani L, Tadeo G, Foglia-Manzillo G, Tagliagambe LM, Santarone M (2004) Prevalence of atrial thrombi in patients with atrial fibrillation/flutter and subtherapeutic anticoagulation prior to cardioversion. Eur J Echocardiogr 5:257–261PubMedCrossRefGoogle Scholar
  30. 30.
    Deuling JH, Vermeulen RP, Smit MD, van der Maaten JM, Boersema HM, van den Heuvel AF, Van Gelder IC (2012) Planning and monitoring of patients for electrical cardioversion for atrial fibrillation. Neth Heart J 20:148–154PubMedCentralPubMedCrossRefGoogle Scholar
  31. 31.
    Caldeira D, Costa J, Ferreira JJ, Pinto FJ (2014) 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. doi: 10.1016/j.ijcard.2014.09.099 Google Scholar
  32. 32.
    Heidbuchel H, Verhamme P, Alings M, Antz M, Hacke W, Oldgren J, Sinnaeve P, Camm AJ, Kirchhof P, European Heart Rhythm Association (2013) European Heart Rhythm Association Practical Guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation. Europace. 15:625–651PubMedCrossRefGoogle Scholar
  33. 33.
    Ewen S, Rettig-Ewen V, Mahfoud F, Böhm M, Laufs U (2014) Drug adherence in patients taking oral anticoagulation therapy. Clin Res Cardiol 103:173–182PubMedCrossRefGoogle Scholar
  34. 34.
    Caldeira D, Vaz-Carneiro A, Costa J (2014) The impact of dosing frequency on medication adherence in chronic cardiovascular disease: systematic review and meta-analysis. Rev Port Cardiol 33:431–437PubMedGoogle Scholar
  35. 35.
    Clemens A, Noack H, Brueckmann M, Lip GY (2014) Twice- or once-daily dosing of novel oral anticoagulants for stroke prevention: a fixed-effects meta-analysis with predefined heterogeneity quality criteria. PLoS One 9:e99276PubMedCentralPubMedCrossRefGoogle Scholar
  36. 36.
    Yadlapati A, Groh C, Passman R (2014) Safety of short-term use of dabigatran or rivaroxaban for direct-current cardioversion in patients with atrial fibrillation and atrial flutter. Am J Cardiol 113:1362–1363PubMedCrossRefGoogle Scholar
  37. 37.
    Edoxaban vs. Warfarin in subjects undergoing cardioversion of atrial fibrillation (ENSURE-AF). Identifier: NCT02072434. Accessed in Sep 2014
  38. 38.
    Study of the blood thinner, apixaban, for patients who have an abnormal heart rhythm (atrial fibrillation) and expected to have treatment to put them back into a normal heart rhythm (cardioversion) (EMANATE). Identifier: NCT02100228. Accessed in Sep 2014

Copyright information

© Springer-Verlag Berlin Heidelberg 2015

Authors and Affiliations

  • Daniel Caldeira
    • 1
    • 2
    • 3
  • João Costa
    • 1
    • 2
    • 4
    • 5
  • Joaquim J. Ferreira
    • 1
    • 2
  • Gregory Y. H. Lip
    • 6
  • Fausto J. Pinto
    • 7
  1. 1.Clinical Pharmacology UnitInstituto de Medicina MolecularLisbonPortugal
  2. 2.Laboratório de Farmacologia Clínica e TerapêuticaFaculdade de Medicina da Universidade de LisboaLisbonPortugal
  3. 3.Cardiology DepartmentHospital Garcia de OrtaAlmadaPortugal
  4. 4.Portuguese Collaborating Center of the Iberoamerican Cochrane NetworkLisbonPortugal
  5. 5.Evidence Based Medicine Centre, Faculty of MedicineUniversity of LisbonLisbonPortugal
  6. 6.University of Birmingham Centre for Cardiovascular Sciences, City HospitalBirminghamUK
  7. 7.Cardiology DepartmentCCUL, CAML, Faculty of MedicineLisbonPortugal

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