br Conclusions br Study limitations br Conflict of
Conflict of interest
Introduction Dabigatran etexilate, an orally administered pro-drug, is rapidly converted by a serum esterase to dabigatran, a potent, direct, and competitive inhibitor of thrombin. It has an absolute bioavailability of 6.5% and a serum calcium sensing receptor of 12–17h, with 80% of the administered dose being excreted by the kidneys. Dabigatran is reported to have low potential for drug–drug interactions, and no drug–food interactions. It also has the advantage of not requiring therapeutic monitoring . The therapeutic effects of dabigatran in patients with atrial fibrillation (AF) have been evaluated in several clinical trials at doses of 220mg twice daily and 300mg daily [2–4]. The Randomized Evaluation of Long-Term Anticoagulation Therapy (RE-LY)  trial was designed to compare two fixed doses of dabigatran (110mg or 150mg twice daily) with open-label use of warfarin in 18,113 patients from 44 countries who had atrial fibrillation, and were at increased risk for stroke. The trial demonstrated that the incidences of stroke and hemorrhage were lower in patients administered dabigatran than in those administered warfarin. However, the only adverse effect (AE) that was significantly more common in dabigatran patients than in warfarin patients was dyspepsia (defined as upper abdominal pain, abdominal pain, abdominal discomfort, epigastric discomfort, and dyspepsia). An analysis of the 326 Japanese participants in the RE-LY trial found that the efficacy and safety profile of dabigatran were essentially the same in Japanese participants as the rest of the study population, but that the incidence of dyspepsia was higher . The RE-COVER double-blind, double-dummy, randomized trial of 6 months of treatment with dabigatran (150mg twice daily) compared with dose-adjusted warfarin in 2539 patients with AF reported a significantly higher incidence of dyspepsia in the dabigatran group (2.9%) versus the warfarin group (0.6%). However, the definition of dyspepsia differed from that chosen by the RE-LY investigators . These large trials suggest that dyspepsia is a relatively common and important side effect of dabigatran treatment. However, none used dyspepsia-like symptoms as a pre-defined endpoint, nor did they record onset, time course and duration, symptom description and localization, or severity of the symptoms. Joyce et al.  reported that patients with AF commonly reported dyspepsia. Self-reported dyspepsia is more common in those with more severe AF and a higher comorbidity burden. The extent of self-reported dyspepsia also correlated with a lower likelihood of reported administration of appropriate AF pharmacotherapy or anticoagulation for stroke prevention. Consequently, we undertook a prospective observational study to evaluate and determine the incidence and severity of dyspepsia in Japanese patients with non-valvular atrial fibrillation (NVAF) at high risk of stroke who had been newly prescribed dabigatran. In addition, we evaluated the efficacy and safety of proton pump inhibitors, H2-receptor antagonists, and gastric mucosal protective drugs in patients who developed symptoms of severe dyspepsia (≥3 of on a Global Overall Severity, GOS score ) after commencing dabigatran by means of a randomized, open-labeled, parallel-group comparison study.
Material and methods The study was approved by the institutional review board at each participating study site. Prior to commencing any study procedure, the purposes and methods of this study were explained to all participants. Written informed consent was obtained from each participant. The study was conducted in accordance with the principles of the Declaration of Helsinki as well as the ethical guidelines for clinical studies .
Results This study was conducted from April 2012 to January 2013 at 19 institutes in Japan. We enrolled 309 patients with NVAF who had been newly prescribed dabigatran. The disposition of study patients is summarized in Fig. 2.