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Efficacy and Safety of Non-Vitamin K Antagonist Oral Anticoagulants After Cardioversion for Nonvalvular Atrial Fibrillation

      Abstract

      Background

      Non-vitamin K oral anticoagulants (NOACs) are proven alternatives to vitamin K antagonists (VKAs) for the prevention of thromboembolism in patients with nonvalvular atrial fibrillation. However, there are few data on the efficacy and safety of NOAC therapy after cardioversion, where the risk of thromboembolic events is heightened.

      Methods

      We performed a random-effects meta-analysis of patients who underwent both electrical and pharmacologic cardioversion for atrial fibrillation in the RE-LY, ROCKET-AF, ARISTOTLE, ENGAGE AF–TIMI 48, and X-VeRT trials. We assessed Mantel-Haenszel pooled estimates of risk ratio (RR) and 95% confidence intervals (CIs) for stroke/systemic embolism and major bleeding at ≤42 days of follow-up.

      Results

      The analysis pooled 3949 patients in whom a total of 4900 cardioversions for atrial fibrillation were performed. Compared with VKAs, NOAC therapy was associated with a similar risk of stroke/systemic embolism (RR 0.84; 95% CI, 0.34-2.04) and major bleeding (RR 1.12; 95% CI, 0.52-2.42); no significant statistical heterogeneity was found among studies (Cochrane Q P = .59, I2 = 0% for stroke/systemic embolism; P = .47; I2 = 0% for major bleeding).

      Conclusions

      The short-term incidences of thromboembolic and major hemorrhagic events after cardioversion on NOACs were low and comparable to those observed on dose-adjusted VKA therapy. Non-vitamin K oral anticoagulants are a reasonable alternative to VKAs in patients undergoing cardioversion.

      Keywords

      Clinical Significance
      • In a meta-analysis of trials comparing the efficacy and safety of non-vitamin K antagonist oral anticoagulants (NOACs) vs warfarin in nonvalvular atrial fibrillation patients undergoing cardioversion, NOACs were associated with a similar risk of stroke/systemic embolism and major bleeding in the early period after cardioversion.
      • All 4 currently available NOACs are as effective and safe as warfarin in nonvalvular atrial fibrillation patients undergoing cardioversion.
      Restoration of sinus rhythm with cardioversion is often necessary in the treatment of atrial fibrillation. The peri-procedural risk of thromboembolic events associated with cardioversion is well recognized, with stroke rates between 5% and 7% in nonanticoagulated patients, and higher than at other time points in atrial fibrillation.
      • Grimm R.A.
      • Stewart W.J.
      • Black I.W.
      • Thomas J.D.
      • Klein A.L.
      Should all patients undergo transesophageal echocardiography before electrical cardioversion of atrial fibrillation?.
      • Stein B.
      • Halperin J.L.
      • Fuster V.
      Should patients with atrial fibrillation be anticoagulated prior to and chronically following cardioversion?.
      There is some evidence, albeit never validated in controlled clinical trials, that risk of stroke/systemic embolism is substantially lower in patients receiving peri-cardioversion vitamin K antagonists (VKAs) than in those receiving no anticoagulation.
      • You J.J.
      • Singer D.E.
      • Howard P.A.
      • et al.
      Antithrombotic therapy for atrial fibrillation: Antithrombotic Therapy and Prevention of Thrombosis, 9th ed: American College of Chest Physicians Evidence-Based Clinical Practice Guidelines.
      Currently available guidelines recommend anticoagulation for ≥3 weeks before elective cardioversion and ≥4 weeks thereafter in patients with atrial fibrillation episodes lasting ≥48 hours or atrial fibrillation of unknown duration, regardless of their stroke risk profile and type of procedure (electrical or oral/intravenous pharmacologic cardioversion).
      • Camm A.J.
      • Lip G.Y.
      • De Caterina R.
      • et al.
      2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association.
      • January C.T.
      • Wann L.S.
      • Alpert J.S.
      • et al.
      2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society.
      Non-vitamin K antagonist oral anticoagulants (NOACs), including the direct thrombin inhibitor dabigatran and the factor Xa inhibitors rivaroxaban, apixaban, and edoxaban, offer potential advantages over VKAs, owing to their rapid onset and offset of action, predictable pharmacokinetics, and rapid anticoagulant effect, allowing the administration of fixed doses without the need for routine coagulation monitoring, with no interactions with dietary vitamin K intake, and much fewer drug interactions. Non-vitamin K antagonist oral anticoagulants were compared with warfarin for the prevention of thromboembolism in 4 phase 3 clinical trials of patients with nonvalvular atrial fibrillation,
      • Connolly S.J.
      • Ezekowitz M.D.
      • Yusuf S.
      • et al.
      Dabigatran versus warfarin in patients with atrial fibrillation.
      • Patel M.R.
      • Mahaffey K.W.
      • Garg J.
      • et al.
      Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.
      • Granger C.B.
      • Alexander J.H.
      • McMurray J.J.
      • et al.
      Apixaban versus warfarin in patients with atrial fibrillation.
      • Giugliano R.P.
      • Ruff C.T.
      • Braunwald E.
      • et al.
      Edoxaban versus warfarin in patients with atrial fibrillation.
      and here showed a consistently favorable benefit–risk profile across a wide range of patients.
      • Ruff C.T.
      • Giugliano R.P.
      • Braunwald E.
      • 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.
      On the basis of these data, NOACs are good alternatives to VKAs for the long-term prevention of thromboembolism in patients with nonvalvular atrial fibrillation. However, there are limited data on outcomes after cardioversion in atrial fibrillation patients treated with NOACs.
      Post hoc analyses from the Randomized Evaluation of Long Term Anticoagulation Therapy (RE-LY; dabigatran),
      • Nagarakanti R.
      • Ezekowitz M.D.
      • Oldgren J.
      • et al.
      Dabigatran versus warfarin in patients with atrial fibrillation: an analysis of patients undergoing cardioversion.
      Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation (ROCKET AF; rivaroxaban),
      • Piccini J.P.
      • Stevens S.R.
      • Lokhnygina Y.
      • et al.
      Outcomes after cardioversion and atrial fibrillation ablation in patients treated with rivaroxaban and warfarin in the ROCKET AF trial.
      Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE; apixaban),
      • Flaker G.
      • Lopes R.D.
      • Al-Khatib S.M.
      • et al.
      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).
      and Effective anticoagulation with factor Xa next generation in atrial fibrillation (ENGAGE AF-TIMI 48)
      • Plitt A.
      • Ezekowitz M.D.
      • De Caterina R.
      • et al.
      Cardioversion of atrial fibrillation in ENGAGE AF-TIMI 48.
      trials have suggested that the use of NOACs during cardioversion poses similar (and very low) risk of stroke/systemic embolism when compared with traditional anticoagulation with VKAs. Furthermore, a prospective, randomized trial in patients undergoing elective cardioversion (eXplore the efficacy and safety of once-daily oral riVaroxaban for the prevention of caRdiovascular events in patients with nonvalvular aTrial fibrillation scheduled for cardioversion [X-VeRT]),
      • Cappato R.
      • Ezekowitz M.D.
      • Klein A.L.
      • et al.
      Rivaroxaban vs. vitamin K antagonists for cardioversion in atrial fibrillation.
      albeit underpowered to provide statistically rigorous results, showed that rivaroxaban was associated with thromboembolic and bleeding risks similar to VKA treatment, both in the early and the delayed cardioversion strategy group.
      Therefore, we performed a systematic review and meta-analysis of available comparative trials, to estimate the efficacy and safety of all currently available NOACs vs VKAs in nonvalvular atrial fibrillation patients undergoing cardioversion.

      Methods

      The present meta-analysis was planned, conducted, and reported in accordance with currently available statements for design, analysis, and reporting of meta-analyses of randomized and observational studies.
      • Stroup D.F.
      • Thacker S.B.
      Epidemiology and education: using public health for teaching mathematics and science.
      • Moher D.
      • Liberati A.
      • Tetzlaff J.
      • Altman D.G.
      PRISMA Group
      Preferred reporting items for systematic reviews and meta-analyses: the PRISMA statement.

       Search Strategy and Selection Criteria

      We searched PubMed, the Clinical Trials Registry (www.clinicaltrials.gov), the Cochrane Library, and Web of Science, as well as abstracts from major cardiologic societies' meetings. Search terms used were “dabigatran” OR “rivaroxaban” OR “apixaban” OR “edoxaban” AND “warfarin” AND “atrial fibrillation” AND “cardioversion.” Web sites, including the-heart.org, escardio.org, and ResearchGate, were also searched for relevant materials. References of the articles identified in this manner were also searched through to locate additional references that—not identified by the search strategy—might be useful for the purpose. This methodologic approach
      • Armstrong R.
      • Jackson N.
      • Doyle J.
      • Waters E.
      • Howes F.
      It's in your hands: the value of handsearching in conducting systematic reviews of public health interventions.
      has been previously validated in our hands.
      • Zimarino M.
      • Corazzini A.
      • Ricci F.
      • Di Nicola M.
      • De Caterina R.
      Late thrombosis after double versus single drug-eluting stent in the treatment of coronary bifurcations: a meta-analysis of randomized and observational studies.
      Two of the authors (F.R. and M.Z.) performed the screening of titles and abstracts, reviewed full-text articles, and determined their eligibility. The search was performed for the period between January 2007 and February 2016 and was limited to the English-language literature. Reviewers were not blinded to study authors or outcomes. Divergences were resolved by contact with corresponding authors or by consensus. We included study-level data derived from randomized, controlled trials comparing NOACs with warfarin in patients with atrial fibrillation undergoing cardioversion. Follow-up duration was ≤42 days.

       Study Selection, Data Collection, and Quality Assessment

      We included 5 randomized, controlled trials reporting early outcome data of atrial fibrillation patients randomized to NOACs or VKAs and submitted to cardioversion.
      Data were collected from the 4 post-hoc analyses of the phase 3 RE-LY,
      • Nagarakanti R.
      • Ezekowitz M.D.
      • Oldgren J.
      • et al.
      Dabigatran versus warfarin in patients with atrial fibrillation: an analysis of patients undergoing cardioversion.
      ROCKET-AF,
      • Piccini J.P.
      • Stevens S.R.
      • Lokhnygina Y.
      • et al.
      Outcomes after cardioversion and atrial fibrillation ablation in patients treated with rivaroxaban and warfarin in the ROCKET AF trial.
      ARISTOTLE,
      • Flaker G.
      • Lopes R.D.
      • Al-Khatib S.M.
      • et al.
      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).
      and ENGAGE AF-TIMI 48
      • Plitt A.
      • Ezekowitz M.D.
      • De Caterina R.
      • et al.
      Cardioversion of atrial fibrillation in ENGAGE AF-TIMI 48.
      trials, and from the original article of the phase 4 X-VeRT trial.
      • Cappato R.
      • Ezekowitz M.D.
      • Klein A.L.
      • et al.
      Rivaroxaban vs. vitamin K antagonists for cardioversion in atrial fibrillation.
      Additional subgroup data were provided through personal communication from the Steering Committee of the ENGAGE AF-TIMI 48 and ROCKET-AF trials for the specific purpose of this meta-analysis.
      Two investigators (FR and MZ) independently abstracted raw data sets related to baseline characteristics of studies, patient populations, and outcomes obtained from original eligible sources, and collected them by using a standardized, ad hoc prepared, data extraction form. The 2 co-primary endpoints were stroke/systemic embolism and major bleeding. The endpoint definitions across the original trials are reported in Supplementary Table (available online). Outcome data were abstracted on an intention-to-treat basis, whenever possible.

       Statistical Analysis

      We reported categorical variables as percentages and continuous variables as means and standard deviation or medians and interquartile range, as appropriate. From abstracted data, we calculated the risk ratio (RR) using the Mantel–Haenszel method for each study outcome to allow for pooling of similar outcomes. We obtained the average effects for the outcomes and 95% confidence interval (CI) using a random-effects model. Heterogeneity of the effect across studies was assessed by means of the Cochrane Q χ2 and I2 statistics. Lack of homogeneity was considered for Cochrane Q χ2 test P ≤.10 and/or for an I2 statistic ≥50%. When heterogeneity was judged significant, the pooled RR was calculated through the analysis of the variance between studies with the “method of moments” or the Der Simonian and Laird method for random effects. We computed the z statistic for each clinical outcome and considered results statistically significant at a P <.05. We performed a Jackknife sensitivity analysis,
      • Miller R.
      The jackknife—a review.
      for each endpoint of interest, to evaluate the robustness of the results and the impact of each single study on the summary estimate of effect; pooled estimates were recalculated multiple times, using a random-effects model, each time with removal of a single study from the baseline group. We assessed the likelihood of publication bias using funnel plots by displaying individual study RR with 95% CIs for the endpoints of interest, and evaluated it by the Egger regression asymmetry test (P <.10 was here considered as indicative of statistically significant publication bias).
      • Borenstein M.
      • Hedges L.V.
      • Higgins J.P.T.
      • Rothstein H.R.
      Introduction to Meta-Analysis.
      Statistical analysis and graphs were done using the Review Manager (RevMan) software package (version 5.3 for OSX; The Nordic Cochrane Centre, The Cochrane Collaboration, 2008, Copenhagen, Denmark), Open MetaAnalyst (version for OSX; Brown University School of Public Health, Providence, RI), and STATA 11.0 version (STATA, College Station, Tex).

      Results

      We identified 5 studies for an overall population of 3949 patients and 4900 (both electrical and pharmacologic) cardioversion procedures (Figure 1).
      Figure thumbnail gr1
      Figure 1Flow chart showing the process of study selection. RCTs = randomized, controlled trials.
      The main characteristics of studies included and related post hoc analyses are reported in Table.
      TableMain Characteristics for Included Studies and Related Post Hoc Analyses
      CharacteristicOriginal Trial
      RE-LY
      • Connolly S.J.
      • Ezekowitz M.D.
      • Yusuf S.
      • et al.
      Dabigatran versus warfarin in patients with atrial fibrillation.
      ROCKET-AF
      • Patel M.R.
      • Mahaffey K.W.
      • Garg J.
      • et al.
      Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.
      ARISTOTLE
      • Granger C.B.
      • Alexander J.H.
      • McMurray J.J.
      • et al.
      Apixaban versus warfarin in patients with atrial fibrillation.
      ENGAGE AF-TIMI 48
      • Giugliano R.P.
      • Ruff C.T.
      • Braunwald E.
      • et al.
      Edoxaban versus warfarin in patients with atrial fibrillation.
      X-VeRT
      • Cappato R.
      • Ezekowitz M.D.
      • Klein A.L.
      • et al.
      Rivaroxaban vs. vitamin K antagonists for cardioversion in atrial fibrillation.
      Year of publication20092011201120132014
      Sample size, n18,11314,26418,20121,1051504
      Study drugDabigatran 110 mg BID, or dabigatram 150 mg BID, or warfarin (target INR 2.5)Rivaroxaban 20 mg OD (or 15 mg OD with CrCl 30-49 mL/min), or warfarin (target INR 2.5)Apixaban 5 mg BID (2.5 mg BD with ≥2 of the following criteria: age ≥80 y, weight ≤60 kg, or serum creatinine ≥1.5 mg/dL, 133 μmol/L), or warfarin (target INR 2.5)Edoxaban 60 mg OD (30 mg OD with ≥1 of the following criteria: CrCl 30-50 mL/min, weight ≤60 kg), or concomitant therapy with strong P-gp inhibitors (verapamil or chinidine), or edoxaban 30 mg OD (15 mg OD with ≥1 of the previous criteria), or warfarin (target INR 2.5)Rivaroxaban 20 mg OD (or 15 mg OD with CrCl 30-49ml/min), or warfarin (target INR 2.5)
      Mean CHADS2 score2.13.52.12.81.4
      Median TTR, % (IQR)67 (54-78)58 (43-71)66 (52-77)68 (57-77)n.a.
      Cardioversion analysisNagarakanti et al
      • Nagarakanti R.
      • Ezekowitz M.D.
      • Oldgren J.
      • et al.
      Dabigatran versus warfarin in patients with atrial fibrillation: an analysis of patients undergoing cardioversion.
      Piccini et al
      • Piccini J.P.
      • Stevens S.R.
      • Lokhnygina Y.
      • et al.
      Outcomes after cardioversion and atrial fibrillation ablation in patients treated with rivaroxaban and warfarin in the ROCKET AF trial.
      Flaker et al
      • Flaker G.
      • Lopes R.D.
      • Al-Khatib S.M.
      • et al.
      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).
      Plitt et al
      • Plitt A.
      • Ezekowitz M.D.
      • De Caterina R.
      • et al.
      Cardioversion of atrial fibrillation in ENGAGE AF-TIMI 48.
      X-VeRT
      • Cappato R.
      • Ezekowitz M.D.
      • Klein A.L.
      • et al.
      Rivaroxaban vs. vitamin K antagonists for cardioversion in atrial fibrillation.
       Study designPost hoc analysis of an open-label RCTPost hoc analysis of a double-blinded RCTPost hoc analysis of a double-blinded RCTPost hoc analysis of a double-blinded RCTOpen-label RCT in patients undergoing elective CV
       Year of publication of CV data201120132014n.a.2014
       Patients undergoing CV, n12702705403651504
       Total CV (electrical and pharmacologic), n19833757436321167
       CHADS2 score<3 (67% of patients)3 (median)1.8/1.9 (mean)
      Apixaban/warfarin.
      ≤3 (88% of patients)1.4 (mean)
       TEE before CV, n415n.a.171n.a.628
       Type of outcome analysisIntention to treatIntention to treatIntention to treatOn treatmentIntention to treat
       Level of data analysisPer procedurePer patientPer procedurePer patientPer patient
      BID = twice daily; CHADS2 = congestive heart failure, Hypertension, Age >75 years, Diabetes mellitus, Stroke; CrCl = creatinine clearance; CV = cardioversion; INR = international normalized ratio; n.a. = not applicable; OD = once daily; RCT = randomized, controlled trial; TEE = transesophageal echocardiography; TTR = time in therapeutic range.
      Apixaban/warfarin.
      When compared with VKAs, patients receiving NOACs had similar risk of stroke and systemic embolism (RR 0.84; 95% CI, 0.34-2.04), without significant statistical heterogeneity among studies (Cochrane Q P = .59; I2 = 0%) (Figure 2).
      Figure thumbnail gr2
      Figure 2Outcome comparison between non-vitamin K oral anticoagulants (NOACs) and vitamin K antagonists (VKAs) in patients with atrial fibrillation undergoing cardioversion. Forest plot with individual and summary estimates of the risk ratio and 95% confidence interval (CI) of stroke/systemic embolism. A random-effects model was applied to estimate risk ratio and 95% CI. Squares and diamond sizes are proportional to study weight.
      Major bleeding for patients treated with NOACs and VKAs was also similar (RR 1.12; 95% CI, 0.52-2.42); again, no significant statistical heterogeneity was found among studies (Cochrane Q P = .47; I2 = 0%) (Figure 3).
      Figure thumbnail gr3
      Figure 3Outcome comparison between non-vitamin K oral anticoagulants (NOACs) and vitamin K antagonists (VKAs) in patients with atrial fibrillation undergoing cardioversion. Forest plot with individual and summary estimates of the risk ratio and 95% confidence interval (CI) of major bleeding. A random-effect model was applied to estimate risk ratio and 95% CI. Squares and diamond sizes are proportional to study weight.
      Publication bias or “small study effect” was excluded by both visual inspection of the funnel plot for stroke/systemic embolism (Supplementary Figure 1A, available online) and major bleeding (Supplementary Figure 1B, available online) and the Egger's test of intercept (P = NS for stroke/systemic embolism and major bleeding).
      Jackknife sensitivity analysis showed that no single study significantly affected the pooled RRs for stroke/systemic embolism (Supplementary Figure 2A, available online) and major bleeding (Supplementary Figure 2B, available online).

      Discussion

      The present meta-analysis suggests that NOACs are as safe as VKAs in prevention of stroke or systemic embolism in patients undergoing cardioversion for nonvalvular atrial fibrillation. Previous meta-analyses had evaluated the efficacy and safety outcomes after cardioversion in patients treated with some NOACs compared with VKAs,
      • Caldeira D.
      • Costa J.
      • Ferreira J.J.
      • Lip G.Y.
      • Pinto F.J.
      Non-vitamin K antagonist oral anticoagulants in the cardioversion of patients with atrial fibrillation: systematic review and meta-analysis.
      • Coleman C.M.
      • Khalaf S.
      • Mould S.
      • et al.
      Novel oral anticoagulants for DC cardioversion procedures: utilization and clinical outcomes compared with warfarin.
      • Sen P.
      • Kundu A.
      • Sardar P.
      • et al.
      Outcomes after cardioversion in atrial fibrillation patients treated with non-vitamin K antagonist oral anticoagulants (NOACs): insights from a meta-analysis.
      but the present is the first meta-analysis including data on all the currently available NOACs. Our findings document a substantial equivalence in the early period after cardioversion between NOACs and VKAs for the prevention of thromboembolic and major hemorrhagic events.
      High-dose NOACs (dabigatran 150 mg twice daily, rivaroxaban 20 mg once daily, apixaban 5 mg twice daily, and edoxaban 60 mg once daily) have been shown to reduce the composite of stroke or systemic embolic events overall by 19% compared with warfarin, throughout the trials, whereas the efficacy of low-dose NOAC regimens was similar to that of warfarin.
      • Ruff C.T.
      • Giugliano R.P.
      • Braunwald E.
      • 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.
      Furthermore, high-dose NOACs were associated with a comparable risk of major bleeding.
      • Ruff C.T.
      • Giugliano R.P.
      • Braunwald E.
      • 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.
      The present analysis expands and confirms such data in patients undergoing cardioversion, focusing on early outcomes (30-42 days) with all dose drug regimens. We found a comparable risk of stroke and systemic embolism for NOACs and VKAs. As to major bleeding, our findings are also consistent with those of the larger overall population included in the randomized, controlled trials.
      Anticoagulation is currently recommended for at least 3 weeks before and 4 weeks after cardioversion,
      • Camm A.J.
      • Lip G.Y.
      • De Caterina R.
      • et al.
      2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association.
      • January C.T.
      • Wann L.S.
      • Alpert J.S.
      • et al.
      2014 AHA/ACC/HRS guideline for the management of patients with atrial fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the Heart Rhythm Society.
      even in low-risk groups, because of the presumed heightened risk of stroke or systemic embolism due to thrombus dislodgement after sinus rhythm restoration. Because of their rapid onset of action and predictable pharmacokinetics, NOACs may provide considerable advantages compared with VKAs in this setting, because the narrow therapeutic window of VKAs and the slow onset of the effect causes fluctuations in anticoagulation, with the consequent need of careful monitoring of the international normalized ratio. This is particularly crucial in the peri-cardioversion period, when subtherapeutic levels of the drug increase thromboembolic risk and impose delays in cardioversion. Therefore, the opportunity to achieve a faster and more stable control of anticoagulation in patients needing cardioversion would be an unquestionable theoretical advantage in terms of time to procedure and patients' safety. Moreover, NOACs may be useful when immediate cardioversion is required owing to patient hemodynamic instability, or with an atrial fibrillation lasting <48 hours, without the need of heparin bridging and switching to another anticoagulant. These theoretical advantages are now complemented by the reassuring outcome data here presented.
      Our analysis included data from patients undergoing both elective and emergency cardioversion. We were not able to calculate separate outcomes according to cardioversion type. In addition, the X-VeRT trial randomized patients to early (1-5 days) or late (21-25 days) elective cardioversion, but not to emergency cardioversion. Therefore, there are no data currently available on the efficacy and safety of NOACs during “acute” cardioversion. Moreover, although there is no clue for a different risk of stroke between electrical and pharmacologic cardioversion, we could not differentiate between the 2, because information on this was not available from the analyzed sources.
      Transesophageal echocardiography, aimed at ruling out the presence of atrial thrombi, is useful to expedite cardioversion.
      • Camm A.J.
      • Lip G.Y.
      • De Caterina R.
      • et al.
      2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association.
      However, transesophageal echocardiography before cardioversion was not a predefined endpoint from any of the studies, and therefore no relevant information may be derived on how its use impacted the results.
      The thromboembolic risk, as assessed by the CHADS2 score, varied widely among patients enrolled in the 4 phase 3 trials on nonvalvular atrial fibrillation
      • Connolly S.J.
      • Ezekowitz M.D.
      • Yusuf S.
      • et al.
      Dabigatran versus warfarin in patients with atrial fibrillation.
      • Patel M.R.
      • Mahaffey K.W.
      • Garg J.
      • et al.
      Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.
      • Granger C.B.
      • Alexander J.H.
      • McMurray J.J.
      • et al.
      Apixaban versus warfarin in patients with atrial fibrillation.
      • Giugliano R.P.
      • Ruff C.T.
      • Braunwald E.
      • et al.
      Edoxaban versus warfarin in patients with atrial fibrillation.
      ; subgroups of patients undergoing cardioversion had usually a lower thromboembolic risk than the source population (Table), with X-Vert patients showing the lowest risk (mean CHADS2 score 1.4). The low risk of such population and the short follow-up were responsible for the limited number of adverse events recorded, which prevented us from conducting an evaluation of NOACs efficacy and safety based on thromboembolic risk.
      The ongoing phase 4 randomized clinical trials EdoxabaN vs warfarin in subjectS UndeRgoing cardiovErsion of Atrial Fibrillation (ENSURE-AF) with edoxaban
      • Lip G.Y.
      • Merino J.
      • Ezekowitz M.
      • 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.
      and Eliquis evaluated in acute cardioversion coMpared to usuAl treatmeNts for AnTicoagulation in subjEcts with nonvalvular atrial fribrillation (EMANATE) with apixaban

      ClincalTrials.gov. 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. Available at: http://clinicaltrials.gov/show/NCT02100228. Accessed April 15, 2016.

      will provide more exhaustive answers on NOAC safety in the peri-cardioversion period.

       Study Limitations

      Despite providing the best evidence available so far on this topic, the main limitation of this analysis is that results are still underpowered to detect minor differences, owing to small sample size and the low rate of events. For this reason, the precision with which the true mean effect size can be estimated is relatively low, as reflected in the wide CI. Conclusions, therefore, still remain provisional. Noenetheless, the I2 statistic likely excluded the presence of statistical heterogeneity as a possible source of bias.
      Second, our analysis is based on aggregate data abstracted from original publications or obtained from investigators, but not on individual patient data. This prevented us from conducting subgroup analysis or meta-regressions.
      Third, original randomized, controlled trials had different designs: 2 of these, RE-LY and X-VERT, were open-label, whereas the others were double-blinded. This introduces a certain degree of heterogeneity, which is a further limitation to conclusions.
      Fourth, data of post hoc analyses were collected inconsistently in the various trials, as per-patient or per-procedure. This accounts for an uncertainty on the estimates, which is, however, unlikely to introduce any systematic bias.
      Fifth, another important source of heterogeneity is the outcome analysis, whether intention-to-treat or on-treatment. We tried to uniform results retrieving intention-to-treat analysis data, with the only exception of the ENGAGE AF-TIMI 48 trial (for which data available are for the on-treatment analysis). However, in some trials, investigators had the possibility to replace the blinded study medication temporarily with open-label VKAs for the cardioversion period, and this might have interfered with the intention-to-treat analysis. Moreover, not all the patients enrolled in the X-VeRT trial underwent cardioversion, although they were included in the intention-to-treat analysis.
      Sixth, we could not differentiate between electrical and pharmacologic cardioversion.
      Finally, we did not know the quality of anticoagulation in patients treated with VKAs and undergoing cardioversion, because the time in therapeutic range was not reported.

      Conclusion

      Despite limitations, the present meta-analysis provides the largest data set currently available supporting the hypothesis that all 4 currently available NOACs (dabigatran, rivaroxaban, apixaban, and edoxaban) are as effective and safe as VKAs in nonvalvular atrial fibrillation patients undergoing cardioversion.

      Supplementary Data

      Figure thumbnail fx1
      Supplementary Figure 1Assessment of publication bias. Begg's funnel plot of studies according to the risk ratio (RR) of stroke/systemic embolism (A) and major bleeding (B) vs the standard error of risk ratio.
      Figure thumbnail fx2
      Supplementary Figure 2Jackknife sensitivity analysis. To evaluate whether the summary estimate of the effect could have been significantly affected by a single study, pooled estimates for stroke/systemic embolism (A) and major bleeding (B) were recalculated, using a random-effects model, by omitting one study at a time. Each line represents a reanalysis of the data with exclusion of one study at a time to assess the influence of this particular study on the overall result.
      Supplementary TableEndpoint Definitions Across the Original Trials
      RE-LY
      • Connolly S.J.
      • Ezekowitz M.D.
      • Yusuf S.
      • et al.
      Dabigatran versus warfarin in patients with atrial fibrillation.
      ROCKET-AF
      • Patel M.R.
      • Mahaffey K.W.
      • Garg J.
      • et al.
      Rivaroxaban versus warfarin in nonvalvular atrial fibrillation.
      ARISTOTLE
      • Granger C.B.
      • Alexander J.H.
      • McMurray J.J.
      • et al.
      Apixaban versus warfarin in patients with atrial fibrillation.
      ENGAGE AF-TIMI 48
      • Giugliano R.P.
      • Ruff C.T.
      • Braunwald E.
      • et al.
      Edoxaban versus warfarin in patients with atrial fibrillation.
      X-VERT
      • Cappato R.
      • Ezekowitz M.D.
      • Klein A.L.
      • et al.
      Rivaroxaban vs. vitamin K antagonists for cardioversion in atrial fibrillation.
      Stroke: sudden onset of a focal neurologic deficit in a location consistent with the territory of a major cerebral artery and categorized as ischemic, hemorrhagic, or unspecified.Stroke: sudden, focal neurologic deficit resulting from a presumed cerebrovascular cause that is not reversible within 24 h and not due to a readily identifiable cause, such as a tumor or seizure.Stroke: abrupt onset of a nontraumatic, focal neurologic deficit lasting at least 24 h.Stroke: abrupt onset, over minutes to hours, of a focal neurologic deficit that is generally in the distribution of a single brain artery, not due to an identifiable nonvascular cause (ie, brain tumor or trauma), either associated with symptoms lasting >24 h or result in death within 24 h of symptom onset.Stroke: abrupt onset of a focal neurologic deficit that is not initiated by an identifiable non-vascular cause and that either is associated with symptoms lasting >24 h or results in death within 24 h of symptom onset.
      Systemic embolism: acute vascular occlusion of an extremity or organ documented by means of imaging, surgery, or autopsy.Systemic embolism: abrupt episode of arterial insufficiency associated with clinical, surgical, or radiologic evidence of arterial occlusion in the absence of other likely mechanisms.Systemic embolism: symptoms consistent with acute loss of blood to a noncerebral artery confirmed by autopsy, angiography, vascular imaging, or other objective testing.Systemic embolism: abrupt episode of arterial insufficiency associated with clinical or radiologic evidence of arterial occlusion in the absence of other likely mechanisms.Systemic embolism: abrupt episode of arterial insufficiency associated with clinical, surgical, or radiologic evidence of arterial occlusion in the absence of other likely mechanisms.
      Major bleeding: reduction in the Hb level of at least 20 g/L, transfusion of at least 2 U of blood, or symptomatic bleeding in a critical area or organ.Major bleeding: fatal bleeding, and/or symptomatic bleeding in a critical area or organ or intra-muscular with compartment syndrome, and/or bleeding causing a fall in Hb level of ≥20 g/L, or leading to transfusion of ≥2 U of whole blood or red cells.Major bleeding: fatal bleeding, and/or symptomatic bleeding in a critical area or organ or intra-muscular with compartment syndrome, and/or bleeding causing a fall in Hb level of 20 g/L (1.24 mmol/L) or more, or leading to transfusion of at least 2U of whole blood or red cells.Major bleeding: clinically overt bleeding event (ie, bleeding that is visualized by examination or radiologic imaging) that meets ≥1 of the following: 1. Fatal bleeding; 2. Symptomatic bleeding in a critical area or organ; 3. Clinically overt bleeding event that causes a fall in Hb level of ≥2.0 g/dL (1.24 mMol/L), adjusted for transfusions (each 1 unit of packed red blood cell or whole blood is counted as a 1.0-g/dL decrease in Hb). In the absence of Hb data, a fall of hematocrit of ≥6.0%, adjusted for transfusion, will satisfy the criteria for a major bleeding event.Major bleeding: fatal bleeding, and/or symptomatic bleeding in a critical area or organ or intra-muscular with compartment syndrome, and/or bleeding causing a fall in Hb level of ≥20 g/L, or leading to transfusion of ≥2U of whole blood or red cells.
      ARISTOTLE = Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation; ENGAGE AF-TIMI 48 = Effective anticoagulation with factor Xa next generation in atrial fibrillation; Hb = hemoglobin; ROCKET-AF = Rivaroxaban Once Daily Oral Direct Factor Xa Inhibition Compared with Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation; X-VeRT = eXplore the efficacy and safety of once-daily oral riVaroxaban for the prevention of caRdiovascular events in patients with nonvalvular aTrial fibrillation scheduled for cardioversion.

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