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

Abstract

Background

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.

Methods

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.

Results

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.

Conclusions

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

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References

  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 55:2308–2316

    PubMed  Article  Google 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 23:208–216

    CAS  PubMed  Article  Google 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 344:1411–1420

  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

    PubMed  Google 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 109:569–579

  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 100:550–556

    CAS  PubMed  Article  Google 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 383:955–962

    CAS  PubMed  Article  Google 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 111:981–988

    PubMed  Article  Google 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 172:267–268

    PubMed  Article  Google 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

    PubMed  Google 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

    PubMed Central  PubMed  Article  Google 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. www.cochrane-handbook.org. Accessed in Sep 2014

  13. 13.

    DerSimonian R, Laird N (1986) Meta-analysis in clinical trials. Control Clin Trials 7:177–188

    CAS  PubMed  Article  Google 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 21:1575–1600

    PubMed  Article  Google 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 313–335

  16. 16.

    Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315:629–634

    CAS  PubMed Central  PubMed  Article  Google 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 295:676–680

    CAS  PubMed  Article  Google 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 123:131–136

    CAS  PubMed  Article  Google 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 61:1998–2006

    CAS  PubMed  Article  Google 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 63:1082–1087

    CAS  PubMed  Article  Google 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

    PubMed  Google 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 26:53–77

    PubMed  Article  Google 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. www.cochrane-handbook.org. 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. www.cochrane-handbook.org. 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. www.cochrane-handbook.org. 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 19:851–855

    CAS  PubMed  Article  Google 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. 12:1360–1420

  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 82:1545–1547

    CAS  PubMed  Article  Google 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 5:257–261

    CAS  PubMed  Article  Google 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 20:148–154

    CAS  PubMed Central  PubMed  Article  Google 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. 15:625–651

    PubMed  Article  Google 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 103:173–182

    CAS  PubMed  Article  Google 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 33:431–437

    PubMed  Google 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:e99276

    PubMed Central  PubMed  Article  Google 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 113:1362–1363

    CAS  PubMed  Article  Google Scholar 

  37. 37.

    Edoxaban vs. Warfarin in subjects undergoing cardioversion of atrial fibrillation (ENSURE-AF). ClinicalTrials.gov Identifier: NCT02072434. http://clinicaltrials.gov/show/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). ClinicalTrials.gov Identifier: NCT02100228. http://clinicaltrials.gov/show/NCT02100228. Accessed in Sep 2014

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Acknowledgments

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.

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Correspondence to Daniel Caldeira.

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Caldeira, D., Costa, J., Ferreira, J.J. et al. Non-vitamin K antagonist oral anticoagulants in the cardioversion of patients with atrial fibrillation: systematic review and meta-analysis. Clin Res Cardiol 104, 582–590 (2015). https://doi.org/10.1007/s00392-015-0821-8

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Keywords

  • Meta-analysis
  • Electric countershock
  • Stroke
  • Anticoagulants
  • Cardioversion
  • Transesophageal echocardiography