Figure 1 shows that the majority of the studies had a point estimate to the right of 0. The 2-sided p value from the sign test is 0.023. In Study 9, the treatment effect in the United States seemed to be substantially better than outside the United States, but in Studies 5, 12, 13, 17, and 21, the treatment effect appeared to be substantially worse in the United States than outside of the United States. In the random effects meta-analysis, the estimate of the between-trial variability was 0. The estimate of the mean log- hazard ratio was 0.103 with a standard error of 0.035. Thus, the approximate confidence interval is (0.031 to 0.175) and the 2-sided p value for the test of mean zero difference is p = 0.007. Because the estimate of the between-trial variability was zero, the point estimate and estimated standard error from the fixed effect model are identical to those from the random effect model described. It seems that there may be systematic differences between the treatment effects observed in the United States and non-U.S. regions, with the U.S.-specific treatment effect usually being smaller. Some factors that might contribute to differences in treatment effects between regions include differences in compli- ance, follow-up, and concomitant medications. There are other possible explanations, and in any particular trial the factors that may attenuate the treatment effect may not be anticipated or even measured. In future trials, if there is a concern that there may be a difference in the treatment effect in the United States versus other countries and the U.S.-specific treatment effect is of interest, there are both issues of design and analysis to consider. An analysis could be planned in the protocol to deal with this possible difference. This could include formal tests for interaction or examination of differences in baseline characteristics or background therapy be- tween regions. Planning for a test for qualitative or quantitative interaction is helpful in some cases, but both tests are known to have low power when the differences are moderate, and this situation may not be totally satisfactory for this purpose. In studies in which a goal of the study is to confirm a global treatment effect and a country-specific treatment effect, there should be a plan to obtain a sufficient amount of information in the country or region of interest, and an analysis should be pre-planned to do so. *John Lawrence, PhD Steve Bai, PhD H. M. James Hung, PhD Robert O’Neill, PhD *U.S. Food and Drug Administration 10903 New Hampshire Avenue Silver Spring, Maryland 20993 E-mail: John.Lawrence@fda.hhs.gov http://dx.doi.org/10.1016/j.jacc.2012.04.051 Please note: This paper reflects the views of the authors and should not be construed to represent the Food and Drug Administration’s views or policies. All authors have reported that they have no relationships relevant to the contents of this paper to disclose. REFERENCES 1. Cui L, Hung HMJ, Wang SJ, Tsong Y. Issues related to subgroup analysis in clinical trials. J Biopharm Stat 2002;12:241–52. 2. DerSimonian R, Laird N. Meta-analysis in clinical trials. Control Clin Trials 1986;7:177– 88. 3. Fleming T. Interpretation of subgroup analysis in clinical trials. Drug Inf J 1995;29:1681S–7S. 4. International Conference on Harmonization: Statistical Principles for Clinical Trials (ICH-E9). Silver Spring, MD: Food and Drug Admin- istration, Department of Health and Human Services, 1998. 5. Peto R. Statistical aspects of cancer trials. In: Halnan KE, editor. Treatment of Cancer. London: Chapman and Hall, 1982:867–71. 6. Yusuf S, Wittes J, Probstfield J, Tyroler H. Analysis and interpretation of treatment effects in subgroups of patients in randomized clinical trials. JAMA 1991;266:93–7. Letters to the Editor Safety of Dabigatran Versus Warfarin for Periprocedural Anticoagulation in Patients Undergoing Ablation for Atrial Fibrillation We read with interest the recent report by Lakkireddy et al. (1) regarding periprocedural dabigatran in patients undergoing atrial fibrillation (AF) ablation. This multicenter study noted a signifi- cant increase in bleeding and thromboembolic complications with essentially uninterrupted dabigatran versus uninterrupted warfarin. Their findings emphasize the importance of fully understanding the pharmacokinetics of pharmacologic agents, particularly anti- coagulants, which can cause serious complications. Dabigatran possesses several pharmacokinetic properties that are important to safe periprocedural use. These properties predict the potential for increased complications when used in an uninterrupted manner for ablations. 1. There is an in vitro heparin-dabigatran interaction (2). Dab- igatran potentiates heparin’s antithrombotic properties with quantitatively doubled anticoagulant effect. The increased bleeding complications noted by Lakkireddy et al. (1) suggest that this in vitro interaction very likely occurs in vivo. This interaction is much less apparent with rivaroxaban and apixaban (2). 2. Immediately following hip surgery, dabigatran absorption can be both delayed and reduced (3). Thus, oral dabigatran imme- diately after an AF ablation may not provide anticoagulation during the immediate post-procedural period. Enoxaparin im- mediately post-ablation will avoid this anticoagulant lapse until oral absorption of dabigatran occurs. 3. Dabigatran has no direct antidote, so when bleeding compli- cations occur they may be more difficult to treat than those with warfarin. Based on these pharmacokinetic considerations, we agree it is not appropriate to use dabigatran in a nearly uninterrupted manner. This does not diminish dabigatran’s utility when used in an interrupted manner. We have reported the safety of interrupted dabigatran in 123 patients (4) and have subsequently extended our experience to more than 500 patients (40% of whom were on dabigitran pre-ablation) without a single hemorrhagic or throm- boembolic complication. As emphasized by Lakkireddy et al. (1), 1118 Correspondence JACC Vol. 60, No. 12, 2012 September 18, 2012:1117–21 Downloaded From: http://content.onlinejacc.org/ on 02/13/2013