Meta-Analysis of Risk of Stroke or Transient Ischemic Attack With Dabigatran for Atrial Fibrillation Ablation Partha Sardar, MDa,*, Ramez Nairooz, MDa, Saurav Chatterjee, MDb, Jørn Wetterslev, MD, PhDc, Joydeep Ghosh, MDd, and Wilbert S. Aronow, MDe Dabigatran is a novel oral anticoagulant and may be useful during atrial fibrillation (AF) ablation for prevention of thromboembolic events. However, the benefits and adverse effects of periprocedural dabigatran therapy have not been thoroughly evaluated. A meta-analysis was performed to evaluate the efficacy and safety of dabigatran for anticoagulation in AF ablation. PubMed, The Cochrane Library, EMBASE, Web of Science, and CINAHL databases were searched from January 01, 2001 through July 30, 2013. Two reviewers reviewed the studies for inclusion and extracted data from studies comparing dabigatran with warfarin for AF ablation. A total of 5,513 patients undergoing catheter ablation were included in 17 observational studies and 1 randomized trial. Fourteen events of stroke or transient ischemic attacks were reported in the dabigatran group and 4 in the warfarin group (Peto’s odds ratio 3.94, 95% confidence interval [CI] 1.54 to 10.08, number needed to harm [ 284 patients). The risk of all thromboembolic complications was also higher in the dabigatran group compared with the warfarin group (Peto’s odds ratio 2.81, 95% CI 1.23 to 6.45). No major differences were observed for the risk of major bleeding (odds ratio 0.99, 95% CI 0.55 to 1.78), pericardial tamponade, and groin hematoma. A lower risk of minor bleeding was observed with dabigatran (odds ratio 0.60, 95% CI 0.41 to 0.87). In conclusion, periprocedural use of dabigatran for AF ablation was related to a higher risk of thromboembolic complications including stroke and transient ischemic attack. Ó 2014 Elsevier Inc. All rights reserved. (Am J Cardiol 2014;113:1173e1177)
Recently, the new oral anticoagulant dabigatran has been evaluated in randomized phase 3 trials and approved for use for nonvalvular atrial fibrillation (AF).1 Dabigatran in a dose of 150 mg twice daily showed superiority over warfarin for prevention of stroke or transient ischemic attacks (TIAs) and 110-mg twice-daily dose showed noninferiority for patients with AF. However, data supporting the use of dabigatran in patients with catheter ablation are lacking. Therefore, we performed a meta-analysis to evaluate the efficacy and safety of periprocedural dabigatran versus warfarin therapy in patients with AF undergoing catheter ablation. Methods We searched the published literature from January 1, 2001 through July 30, 2013 using the following key words: dabigatran, oral thrombin inhibitors, atrial fibrillation, and ablation. PubMed, The Cochrane Library (Cochrane Database of Systematic Reviews and the Cochrane Central a Department of Medicine, New York Medical College, New York, New York; bDepartment of Cardiology, St. Luke’s-Roosevelt Hospital Center, Columbia University College of Physicians and Surgeons, New York, New York; cCopenhagen Trial Unit, Center for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; dColumbia University College of Physicians and Surgeons, New York, New York; and eCardiology Division, New York Medical College, Valhalla, New York. Manuscript received October 7, 2013; revised manuscript received and accepted December 16, 2013. See page 1176 for disclosure information. *Corresponding author: Tel: (212) 423-6771; fax: (212) 423-8099. E-mail address: [email protected] (P. Sardar).
0002-9149/14/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2013.12.027
Register of Controlled Trials), EMBASE, Web of Science, and CINAHL databases were searched. We restricted our search to reports published in English and studies of humans. We also manually searched reference lists of all retrieved reports for additional studies. We used the published strengthening Meta-analysis Of Observational Studies in Epidemiology2 checklist to select the studies for this review. We included published studies (full-text reports) and conference abstracts evaluating dabigatran versus warfarin for periprocedural catheter ablation for AF. We excluded studies without a comparator group, and for studies that did not report clinical outcomes, we tried to contact the individual corresponding authors for further details. Two reviewers (RN and PS) independently extracted the data from the eligible studies using the standardized published protocol at PROSPERO, and disagreements were resolved by discussion with other investigators. We extracted the baseline characteristics of each study, details of the study drugs and control (drug, dose, and schedule), follow-up data, and the data related to efficacy and safety outcomes. The quality of the observational case-control studies was assessed by the Newcastle-Ottawa Scale,3 and for randomized controlled trials, we used the domains suggested in The Cochrane Handbook of Systematic Reviews.4 The primary efficacy outcome was stroke or TIA. The primary safety outcome was major bleeding. Other outcomes were the risk of all thromboembolic complications, minor bleeding, pericardial tamponade, and groin hematoma. We used the longest available follow-up data from individual studies for our analysis. www.ajconline.org
1174
The American Journal of Cardiology (www.ajconline.org)
risk ratios estimated from previous meta-analyses with a risk of a type II error of 20% (power of 80%). We also provide the 95% CIs adjusted for sparse data and repetitive testing, which we describe as the SSA-adjusted 95% CIs. We used TSA, version 0.9 beta (www.ctu.dk/tsa; Copenhagen Trial Unit, Center for Clinical Intervention Research, Rigshospitalet, Copenhagen, Denmark) for these analyses (details in the Supplementary Material, online only).9e11 The following sensitivity analysis was performed for the primary efficacy and safety outcomes: (1) for studies published as full-text reports, (2) studies with low or intermediate risk of bias, (3) observational studies only, (4) studies with only dabigatran 150-mg twice-daily dose, (5) studies with dabigatran 110 mg twice daily, (6) prospective studies, (7) studies whose patients were treated with uninterrupted warfarin, (8) studies with at least 30-days follow-up, (9) studies with interrupted dabigatran, (10) studies with bridging low-molecular-weight heparin, and (11) studies conducted in the United States of America. Sensitivity analyses planned a priori were performed to identify the effect of a single study by sequential elimination of each study from the pool and assessing the overall outcomes. Stata 12 software was used (StataCorp LP, College Station, Texas). Results Figure 1. Search strategy according to the Meta-analysis Of Observational Studies in Epidemiology checklist.
The statistical analysis was performed according to the recommendations from the Cochrane Collaboration using Review Manager, version 5.2 (The Nordic Cochrane Center, The Cochrane Collaboration, 2012, Copenhagen, Denmark).5 As outcome proportions were expected to be low, for outcomes with an incidence of 1%, we calculated Peto’s odds ratio (POR) estimates and associated 95% confidence intervals (CIs) using a fixed-effects model for our primary analyses.6 As previously validated, POR is one of the least biased and most powerful methods and provides the best CI coverage for event rates 1%, we used the conventional random-effects model and calculated the summary odds ratio (OR). We assessed heterogeneity across studies using the Cochrane Q statistic. For I2 statistics, we considered I2 75% as high, and the Cochran Q (p 0.1) was considered significant for each outcome. Publication bias was evaluated using Egger’s regression test and through visual inspection of the asymmetry in funnel plots. Two-tailed p values
Recently, the new oral anticoagulant dabigatran has been evaluated in randomized phase 3 trials and approved for use for nonvalvular atrial fibrillation (AF).1 Dabigatran in a dose of 150 mg twice daily showed superiority over warfarin for prevention of stroke or transient ischemic attacks (TIAs) and 110-mg twice-daily dose showed noninferiority for patients with AF. However, data supporting the use of dabigatran in patients with catheter ablation are lacking. Therefore, we performed a meta-analysis to evaluate the efficacy and safety of periprocedural dabigatran versus warfarin therapy in patients with AF undergoing catheter ablation. Methods We searched the published literature from January 1, 2001 through July 30, 2013 using the following key words: dabigatran, oral thrombin inhibitors, atrial fibrillation, and ablation. PubMed, The Cochrane Library (Cochrane Database of Systematic Reviews and the Cochrane Central a Department of Medicine, New York Medical College, New York, New York; bDepartment of Cardiology, St. Luke’s-Roosevelt Hospital Center, Columbia University College of Physicians and Surgeons, New York, New York; cCopenhagen Trial Unit, Center for Clinical Intervention Research, Department 7812, Rigshospitalet, Copenhagen University Hospital, Copenhagen, Denmark; dColumbia University College of Physicians and Surgeons, New York, New York; and eCardiology Division, New York Medical College, Valhalla, New York. Manuscript received October 7, 2013; revised manuscript received and accepted December 16, 2013. See page 1176 for disclosure information. *Corresponding author: Tel: (212) 423-6771; fax: (212) 423-8099. E-mail address: [email protected] (P. Sardar).
0002-9149/14/$ - see front matter Ó 2014 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.amjcard.2013.12.027
Register of Controlled Trials), EMBASE, Web of Science, and CINAHL databases were searched. We restricted our search to reports published in English and studies of humans. We also manually searched reference lists of all retrieved reports for additional studies. We used the published strengthening Meta-analysis Of Observational Studies in Epidemiology2 checklist to select the studies for this review. We included published studies (full-text reports) and conference abstracts evaluating dabigatran versus warfarin for periprocedural catheter ablation for AF. We excluded studies without a comparator group, and for studies that did not report clinical outcomes, we tried to contact the individual corresponding authors for further details. Two reviewers (RN and PS) independently extracted the data from the eligible studies using the standardized published protocol at PROSPERO, and disagreements were resolved by discussion with other investigators. We extracted the baseline characteristics of each study, details of the study drugs and control (drug, dose, and schedule), follow-up data, and the data related to efficacy and safety outcomes. The quality of the observational case-control studies was assessed by the Newcastle-Ottawa Scale,3 and for randomized controlled trials, we used the domains suggested in The Cochrane Handbook of Systematic Reviews.4 The primary efficacy outcome was stroke or TIA. The primary safety outcome was major bleeding. Other outcomes were the risk of all thromboembolic complications, minor bleeding, pericardial tamponade, and groin hematoma. We used the longest available follow-up data from individual studies for our analysis. www.ajconline.org
1174
The American Journal of Cardiology (www.ajconline.org)
risk ratios estimated from previous meta-analyses with a risk of a type II error of 20% (power of 80%). We also provide the 95% CIs adjusted for sparse data and repetitive testing, which we describe as the SSA-adjusted 95% CIs. We used TSA, version 0.9 beta (www.ctu.dk/tsa; Copenhagen Trial Unit, Center for Clinical Intervention Research, Rigshospitalet, Copenhagen, Denmark) for these analyses (details in the Supplementary Material, online only).9e11 The following sensitivity analysis was performed for the primary efficacy and safety outcomes: (1) for studies published as full-text reports, (2) studies with low or intermediate risk of bias, (3) observational studies only, (4) studies with only dabigatran 150-mg twice-daily dose, (5) studies with dabigatran 110 mg twice daily, (6) prospective studies, (7) studies whose patients were treated with uninterrupted warfarin, (8) studies with at least 30-days follow-up, (9) studies with interrupted dabigatran, (10) studies with bridging low-molecular-weight heparin, and (11) studies conducted in the United States of America. Sensitivity analyses planned a priori were performed to identify the effect of a single study by sequential elimination of each study from the pool and assessing the overall outcomes. Stata 12 software was used (StataCorp LP, College Station, Texas). Results Figure 1. Search strategy according to the Meta-analysis Of Observational Studies in Epidemiology checklist.
The statistical analysis was performed according to the recommendations from the Cochrane Collaboration using Review Manager, version 5.2 (The Nordic Cochrane Center, The Cochrane Collaboration, 2012, Copenhagen, Denmark).5 As outcome proportions were expected to be low, for outcomes with an incidence of 1%, we calculated Peto’s odds ratio (POR) estimates and associated 95% confidence intervals (CIs) using a fixed-effects model for our primary analyses.6 As previously validated, POR is one of the least biased and most powerful methods and provides the best CI coverage for event rates 1%, we used the conventional random-effects model and calculated the summary odds ratio (OR). We assessed heterogeneity across studies using the Cochrane Q statistic. For I2 statistics, we considered I2 75% as high, and the Cochran Q (p 0.1) was considered significant for each outcome. Publication bias was evaluated using Egger’s regression test and through visual inspection of the asymmetry in funnel plots. Two-tailed p values
