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Abstract Background Dabigatran etexilate has become widely used for the prevention of stroke in patients with nonvalvular atrial fibrillation (NVAF). Currently, there is limited information in real-world patients relating to dabigatran etexilate exposure and response. Methods This retrospective cohort study used administrative health data for NVAF patients dispensed dabigatran etexilate between July 1, 2011 and December 31, 2015. Outcomes of cerebrovascular accident (CVA), systemic embolism, and hemorrhage were extracted. Simulated pharmacokinetic parameters were obtained using a published population pharmacokinetic model of dabigatran etexilate. Area under the curve calculated for a 24-hour period at steady state (AUCss), the exposure parameter, was derived using these simulations and the dosing data and the exposure–response relationship were investigated. The risk of adverse outcomes at AUCss quartiles was compared using Poisson regression and expressed using incidence rate ratios (95% confidence interval) adjusted for known potential confounders. Results In total, 2,660 NVAF patients had been dispensed dabigatran etexilate. For these patients there was a decreased risk of hemorrhage (0.51, 0.32–0.79) when dabigatran AUCss was in the second quartile range of 1.70 to 1.96 mg h/L and thromboembolism/CVA (0.34, 0.16–0.76) when in the third quartile range of 1.97 to 2.26 mg h/L. An increased risk of hemorrhage (1.68, 1.18–2.38) was observed when AUCss was in the fourth quartile range of 2.27 to 12.76 mg h/L. Conclusion An exposure–response relationship for dabigatran etexilate was described, where the most effective response was observed when AUCss was in the range of 1.70 to 2.26 mg h/L. Hence, it is feasible to develop guidance for optimal dosing to improve outcomes for patients with NVAF.

Abstract Background Clinical significance of dosing dabigatran with different estimates of renal function for treatment of atrial fibrillation (AF) is unknown. Renal function is routinely estimated by the chronic kidney disease epidemiology initiative equation (CKD-EPI) and used to guide dosing. The aim of this study was to investigate the risk of adverse outcomes for patients with AF when different estimators of renal function are used. Material and Methods AF patient data were extracted from national administrative databases. Renal function was estimated using Cockcroft–Gault, CKD-EPI, and CKD-EPI adjusted for body surface area (CKD-EPI-BSA). Outcomes of cerebrovascular accident (CVA), systemic embolism (SE), and hemorrhage were extracted. Results In total, 2,425 patients were identified, of which there were hospitalizations for 138 (5.7%) hemorrhagic events, 45 (1.9%) CVA/SE, and 33 (1.4%) unspecified CVA. The level of agreement between Cockcroft–Gault with CKD-EPI and CKD-EPI-BSA yielded a weighted kappa statistic of 0.47 and 0.71, respectively. CKD-EPI and CKD-EPI-BSA significantly overestimated renal function in elderly patients resulting in higher recommended doses compared with Cockcroft–Gault. The hazard ratio for a hemorrhagic event was 2.32 (95% confidence interval, 1.22–4.42; p = 0.01) when a high dose was given compared with normal dose, based on Cockcroft–Gault. Conclusion Both CKD-EPI and CKD-EPI-BSA equations significantly overestimated renal function in the elderly population compared with the Cockcroft–Gault equation. This may lead to dose selection errors for dabigatran, particularly for those with severe impairment, increasing the risk of adverse outcome. Hence, CKD-EPI and CKD-EPI-BSA equations should not be substituted for the Cockcroft–Gault equation in the elderly for the purpose of renal dosage adjustments.