1168 Letters to the Editor major bleeding in atrial fibrillation patients: the RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulation Therapy). J Am Coll Cardiol 2014; 63: 321–8. 9 Douxfils J, Dogne JM, Mullier F, Chatelain B, Ronquist-Nii Y, Malmstrom RE, Hjemdahl P. Comparison of calibrated dilute thrombin time and aPTT tests with LC-MS/MS for the therapeutic monitoring of patients treated with dabigatran etexilate. Thromb Haemost 2013; 110: 543–9. 10 Douxfils J, Mullier F, Robert S, Chatelain C, Chatelain B, Dogne JM. Impact of dabigatran on a large panel of routine or specific coagulation assays. Laboratory recommendations for monitoring of dabigatran etexilate. Thromb Haemost 2012; 107: 985–97. 11 Antovic JP, Skeppholm M, Eintrei J, Boija EE, Soderblom L, Norberg EM, Onelov L, Ronquist-Nii Y, Pohanka A, Beck O,
Hjemdahl P, Malmstrom RE. Evaluation of coagulation assays versus LC-MS/MS for determinations of dabigatran concentrations in plasma. Eur J Clin Pharmacol 2013; 69: 1875–81. 12 Skeppholm M, Hjemdahl P, Antovic JP, Muhrbeck J, Eintrei J, Ronquist-Nii Y, Pohanka A, Beck O, Malmstrom RE. On the monitoring of dabigatran treatment in “real life” patients with atrial fibrillation. Thromb Res 2014; 134: 783–9. 13 Hawes EM, Deal AM, Funk-Adcock D, Gosselin R, Jeanneret C, Cook AM, Taylor JM, Whinna HC, Winkler AM, Moll S. Performance of coagulation tests in patients on therapeutic doses of dabigatran: a cross-sectional pharmacodynamic study based on peak and trough plasma levels. J Thromb Haemost 2013; 11: 1493–502. 14 Rao RB. Regarding the effect of dabigatran plasma concentrations. J Am Coll Cardiol 2014; 63: 2885.
Real-world variability in dabigatran levels in patients with atrial fibrillation: reply N . C . C H A N , * J . H I R S H , † J . S . G I N S B E R G † ‡ and J . W . E I K E L B O O M * † ‡ *Population Health Research Institute; †Department of Medicine, McMaster University; and ‡Thrombosis and Atherosclerosis Research Institute, Hamilton, ON, Canada
To cite this article: Chan NC, Hirsh J, Ginsberg JS, Eikelboom JW. Real-world variability in dabigatran levels in patients with atrial fibrillation: reply. J Thromb Haemost 2015; 13: 1168–9. See also Chan NC, Coppens M, Hirsh J, Ginsberg JS, Weitz JI, Vanassche T, Douketis JD, Schulman S, Eikelboom JW. Real-world variability in dabigatran levels in patients with atrial fibrillation. J Thromb Haemost 2015; 13: 353–9 and Douxfils J, Chatelain B, Dogne JM, Mullier F. Realworld variability in dabigatran levels in patients with atrial fibrillation: comment. This issue, pp 1166–8.
Douxfils et al. are concerned about the wide range of trough dabigatran levels among individuals reported in our cohort (< 30 ng mL 1 to 510 ng mL 1) [1], citing their ex vivo study investigating the test performance of various assays [2] and a population pharmacokinetic (PK) substudy of the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial [3]. These studies differ from ours in two important ways. First, the study by Douxfils et al. restricted inclusion to patients (n = 33) with plasma dabigatran levels < 200 ng mL 1. Because we enrolled unselected clinic patients, our results are likely to be more representative of the variability in trough level seen in clinical practice. Second, results are reported differently. In the PK study [3], results are reported for a typical male patient (age 72 years, weight 80.3 kg, and creatinine clearance 68.64 mL min 1) and expressed as an 80% preCorrespondence: Noel C. Chan, Population Health Research Institute, 237 Barton St E, Hamilton ON L7L 2X2, Canada. Tel.: +1 905 527 4322 Ext 40520; fax: +1 905 297 3785. E-mail: [email protected]
diction interval rather than the range of the entire population. We report three measures of variability: range, 10th to 90th centiles, and geometric coefficient of variation. When comparing the 10th to 90th centiles of dabigatran concentrations in the blood, our results are consistent with those of the PK study. Our results are also consistent with those of Reilly et al. [4], who reported pre-dose blood concentration of dabigatran of 1.15 to 608 ng mL 1 and 1.04 to 809 ng mL 1 in patients treated with 110 mg and 150 mg twice daily, respectively. Douxfils et al. propose that the differences in sampling times may have led to overestimation of interindividual and intraindividual variabilities in trough level and recommend that trough levels should be measured at 12 h ≤ 1 h. We found it difficult to standardize trough sampling times (median time of collection was 13.3 4.7 h after last dose) but do not believe that this accounts for our results. According to the PK study by Liesenfeld et al. [3], sampling at 18 h after dabigatran administration for a typical patient should not result in the pre-dose level falling outside the 80% confidence interval for a 12-h trough level. Similarly, sampling at 6 h after administration should not result in a pre-dose level outside the 80% confidence interval for a 12-h trough
DOI: 10.1111/jth.12906 © 2015 International Society on Thrombosis and Haemostasis
Letters to the Editor 1169
level. We also found that differences between visits in the timing of trough sample collection had little impact on intraindividual variability of blood levels. Furthermore, despite more rigorous timing of collection of peak samples (2.5 0.2 h), interindividual variability (gCV) for peak levels was similar to that seen for trough levels. Douxfils et al. suggest that “. . .one cannot assert if it was the same patients that no longer fell within these respective extremes.” We examined changes in trough dabigatran blood levels for individual patients whose initial levels fell in the extreme 20th centiles and confirmed that 40% (26.3% to 55.4%) of patients were misclassified as having extreme levels according to the results of the first trough measurement. At subsequent time points, these individuals had blood levels of dabigatran that fell within the middle quartiles. The aim of our study was to estimate variability in drug levels within and among patients over time, and we did not power the study to examine clinical outcomes. Others have previously reported the association between blood concentrations of dabigatran and clinical outcome [4]. We minimized variability due to preanalytical and analytical issues by strict adherence to standardized protocol for sampling, centrifugation, and storage, similar to those used in the RE-LY substudies. Samples were batch tested after 20–30 samples were obtained. Hemoclot testing was performed at the Hemostasis Reference Laboratory according to manufacturer’s recommendation. Interassay and intra-assay variabilities were tested and reported in our manuscript (both markedly lower than the interindividual and intraindividual variabilities in dabigatran level). Contrary to the assertions by Douxfils et al., we believe that our results for interindividual and intraindividual variabilities in dabigatran drug levels are internally and
© 2015 International Society on Thrombosis and Haemostasis
externally valid, and therefore robust. Our findings also highlight the limitation of a single measurement to reliably classify patients with extreme levels. Further studies are needed to determine whether alternative testing strategies can reliably identify high or low responders. Disclosure of Conflict of Interests J. Eikelboom reports grants and honorarium from Astra Zeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb/Pfizer, Daiichi Sankyo, GlaxoSmithKline, Janssen, Sanofi Aventis, and honorarium from Eli Lilly, outside the submitted work. The other authors state that they have no conflicts of interest. References 1 Chan NC, Coppens M, Hirsh J, Ginsberg JS, Weitz JI, Vanassche T, Douketis JD, Schulman S, Eikelboom JW. Real-world variability in dabigatran levels in patients with atrial fibrillation. J Thromb Haemost 2015; 13: 353–9. 2 Douxfils J, Lessire S, Dincq AS, Hjemdahl P, Ronquist-Nii Y, Pohanka A, Gourdin M, Chatelain B, Dogne JM, Mullier F. Estimation of dabigatran plasma concentrations in the perioperative setting. An ex vivo study using dedicated coagulation assays. Thromb Haemost 2015; 113: 862–9. 3 Liesenfeld KH, Lehr T, Dansirikul C, Reilly PA, Connolly SJ, Ezekowitz MD, Yusuf S, Wallentin L, Haertter S, Staab A. Population pharmacokinetic analysis of the oral thrombin inhibitor dabigatran etexilate in patients with non-valvular atrial fibrillation from the RE-LY trial. J Thromb Haemost 2011; 9: 2168–75. 4 Reilly PA, Lehr T, Haertter S, Connolly SJ, Yusuf S, Eikelboom JW, Ezekowitz MD, Nehmiz G, Wang S, Wallentin L, Investigators R-L. The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulation Therapy). J Am Coll Cardiol 2014; 63: 321–8.
Hjemdahl P, Malmstrom RE. Evaluation of coagulation assays versus LC-MS/MS for determinations of dabigatran concentrations in plasma. Eur J Clin Pharmacol 2013; 69: 1875–81. 12 Skeppholm M, Hjemdahl P, Antovic JP, Muhrbeck J, Eintrei J, Ronquist-Nii Y, Pohanka A, Beck O, Malmstrom RE. On the monitoring of dabigatran treatment in “real life” patients with atrial fibrillation. Thromb Res 2014; 134: 783–9. 13 Hawes EM, Deal AM, Funk-Adcock D, Gosselin R, Jeanneret C, Cook AM, Taylor JM, Whinna HC, Winkler AM, Moll S. Performance of coagulation tests in patients on therapeutic doses of dabigatran: a cross-sectional pharmacodynamic study based on peak and trough plasma levels. J Thromb Haemost 2013; 11: 1493–502. 14 Rao RB. Regarding the effect of dabigatran plasma concentrations. J Am Coll Cardiol 2014; 63: 2885.
Real-world variability in dabigatran levels in patients with atrial fibrillation: reply N . C . C H A N , * J . H I R S H , † J . S . G I N S B E R G † ‡ and J . W . E I K E L B O O M * † ‡ *Population Health Research Institute; †Department of Medicine, McMaster University; and ‡Thrombosis and Atherosclerosis Research Institute, Hamilton, ON, Canada
To cite this article: Chan NC, Hirsh J, Ginsberg JS, Eikelboom JW. Real-world variability in dabigatran levels in patients with atrial fibrillation: reply. J Thromb Haemost 2015; 13: 1168–9. See also Chan NC, Coppens M, Hirsh J, Ginsberg JS, Weitz JI, Vanassche T, Douketis JD, Schulman S, Eikelboom JW. Real-world variability in dabigatran levels in patients with atrial fibrillation. J Thromb Haemost 2015; 13: 353–9 and Douxfils J, Chatelain B, Dogne JM, Mullier F. Realworld variability in dabigatran levels in patients with atrial fibrillation: comment. This issue, pp 1166–8.
Douxfils et al. are concerned about the wide range of trough dabigatran levels among individuals reported in our cohort (< 30 ng mL 1 to 510 ng mL 1) [1], citing their ex vivo study investigating the test performance of various assays [2] and a population pharmacokinetic (PK) substudy of the RE-LY (Randomized Evaluation of Long-Term Anticoagulation Therapy) trial [3]. These studies differ from ours in two important ways. First, the study by Douxfils et al. restricted inclusion to patients (n = 33) with plasma dabigatran levels < 200 ng mL 1. Because we enrolled unselected clinic patients, our results are likely to be more representative of the variability in trough level seen in clinical practice. Second, results are reported differently. In the PK study [3], results are reported for a typical male patient (age 72 years, weight 80.3 kg, and creatinine clearance 68.64 mL min 1) and expressed as an 80% preCorrespondence: Noel C. Chan, Population Health Research Institute, 237 Barton St E, Hamilton ON L7L 2X2, Canada. Tel.: +1 905 527 4322 Ext 40520; fax: +1 905 297 3785. E-mail: [email protected]
diction interval rather than the range of the entire population. We report three measures of variability: range, 10th to 90th centiles, and geometric coefficient of variation. When comparing the 10th to 90th centiles of dabigatran concentrations in the blood, our results are consistent with those of the PK study. Our results are also consistent with those of Reilly et al. [4], who reported pre-dose blood concentration of dabigatran of 1.15 to 608 ng mL 1 and 1.04 to 809 ng mL 1 in patients treated with 110 mg and 150 mg twice daily, respectively. Douxfils et al. propose that the differences in sampling times may have led to overestimation of interindividual and intraindividual variabilities in trough level and recommend that trough levels should be measured at 12 h ≤ 1 h. We found it difficult to standardize trough sampling times (median time of collection was 13.3 4.7 h after last dose) but do not believe that this accounts for our results. According to the PK study by Liesenfeld et al. [3], sampling at 18 h after dabigatran administration for a typical patient should not result in the pre-dose level falling outside the 80% confidence interval for a 12-h trough level. Similarly, sampling at 6 h after administration should not result in a pre-dose level outside the 80% confidence interval for a 12-h trough
DOI: 10.1111/jth.12906 © 2015 International Society on Thrombosis and Haemostasis
Letters to the Editor 1169
level. We also found that differences between visits in the timing of trough sample collection had little impact on intraindividual variability of blood levels. Furthermore, despite more rigorous timing of collection of peak samples (2.5 0.2 h), interindividual variability (gCV) for peak levels was similar to that seen for trough levels. Douxfils et al. suggest that “. . .one cannot assert if it was the same patients that no longer fell within these respective extremes.” We examined changes in trough dabigatran blood levels for individual patients whose initial levels fell in the extreme 20th centiles and confirmed that 40% (26.3% to 55.4%) of patients were misclassified as having extreme levels according to the results of the first trough measurement. At subsequent time points, these individuals had blood levels of dabigatran that fell within the middle quartiles. The aim of our study was to estimate variability in drug levels within and among patients over time, and we did not power the study to examine clinical outcomes. Others have previously reported the association between blood concentrations of dabigatran and clinical outcome [4]. We minimized variability due to preanalytical and analytical issues by strict adherence to standardized protocol for sampling, centrifugation, and storage, similar to those used in the RE-LY substudies. Samples were batch tested after 20–30 samples were obtained. Hemoclot testing was performed at the Hemostasis Reference Laboratory according to manufacturer’s recommendation. Interassay and intra-assay variabilities were tested and reported in our manuscript (both markedly lower than the interindividual and intraindividual variabilities in dabigatran level). Contrary to the assertions by Douxfils et al., we believe that our results for interindividual and intraindividual variabilities in dabigatran drug levels are internally and
© 2015 International Society on Thrombosis and Haemostasis
externally valid, and therefore robust. Our findings also highlight the limitation of a single measurement to reliably classify patients with extreme levels. Further studies are needed to determine whether alternative testing strategies can reliably identify high or low responders. Disclosure of Conflict of Interests J. Eikelboom reports grants and honorarium from Astra Zeneca, Bayer, Boehringer Ingelheim, Bristol Myers Squibb/Pfizer, Daiichi Sankyo, GlaxoSmithKline, Janssen, Sanofi Aventis, and honorarium from Eli Lilly, outside the submitted work. The other authors state that they have no conflicts of interest. References 1 Chan NC, Coppens M, Hirsh J, Ginsberg JS, Weitz JI, Vanassche T, Douketis JD, Schulman S, Eikelboom JW. Real-world variability in dabigatran levels in patients with atrial fibrillation. J Thromb Haemost 2015; 13: 353–9. 2 Douxfils J, Lessire S, Dincq AS, Hjemdahl P, Ronquist-Nii Y, Pohanka A, Gourdin M, Chatelain B, Dogne JM, Mullier F. Estimation of dabigatran plasma concentrations in the perioperative setting. An ex vivo study using dedicated coagulation assays. Thromb Haemost 2015; 113: 862–9. 3 Liesenfeld KH, Lehr T, Dansirikul C, Reilly PA, Connolly SJ, Ezekowitz MD, Yusuf S, Wallentin L, Haertter S, Staab A. Population pharmacokinetic analysis of the oral thrombin inhibitor dabigatran etexilate in patients with non-valvular atrial fibrillation from the RE-LY trial. J Thromb Haemost 2011; 9: 2168–75. 4 Reilly PA, Lehr T, Haertter S, Connolly SJ, Yusuf S, Eikelboom JW, Ezekowitz MD, Nehmiz G, Wang S, Wallentin L, Investigators R-L. The effect of dabigatran plasma concentrations and patient characteristics on the frequency of ischemic stroke and major bleeding in atrial fibrillation patients: the RE-LY Trial (Randomized Evaluation of Long-Term Anticoagulation Therapy). J Am Coll Cardiol 2014; 63: 321–8.
