Original article
Alimentary tract
Analysis of Upper Gastrointestinal Adverse Events Among Patients Given Dabigatran in the RE-LY Trial

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Background & Aims

Dabigatran is an oral and direct inhibitor of thrombin. In a study of patients with atrial fibrillation (the RE-LY trial), twice as many subjects given dabigatran reported dyspepsia-like symptoms compared with those given warfarin (controls). We analyzed data from this trial to quantify upper gastrointestinal nonbleeding adverse events (NB-UGI AEs).

Methods

We analyzed the AE database from the RE-LY trial (18,113 subjects) and assigned NB-UGI AEs to 4 groups: those associated with gastroesophageal reflux (GERD), upper abdominal pain and dyspepsia, dysmotility, or gastroduodenal injury. We analyzed frequency, timing, and severity, and clinical variables associated with NB-UGI AEs.

Results

NB-UGI AEs occurred in 16.9% of subjects given dabigatran and in 9.4% of controls (relative risk [RR], 1.81; 95% confidence interval [CI], 1.66%–1.97%; P < .001). Rates of AEs were not associated with the dose of dabigatran. Among subjects with any UGI symptom who were given dabigatran (n = 2045), symptoms were rated as mild in 46.3%, moderate in 44.8%, and severe in 8.9%; these values were similar to those of controls. GERD-associated NB-UGI AEs were most frequent among the 4 groups (compared with controls, RR, 3.71; 95% CI, 2.98%–4.62%; P < .001). Four percent of subjects stopped taking dabigatran because of NB-UGI AEs (most within 3 months of starting therapy), compared with 1.7% of controls (RR, 2.34; 95% CI, 1.90%–2.88%; P < .001). NB-UGI AEs slightly increased risk of major GI bleeding among subjects given dabigatran and controls (6.8% vs 2.3%, P < .001).

Conclusions

Among patients given dabigatran for atrial fibrillation, NB-UGI AEs are generally mild or moderate; 4% stopped taking the drug over a median of 21.7 months. The greatest increase was in GERD-type NB-UGI AEs. These observations should guide management and prevention strategies. ClinicalTrials.gov number, NCT00262600.

Section snippets

RE-LY Trial Design

All analyses were performed using the database from the RE-LY trial (N = 18,113).1, 8 Briefly, the RE-LY trial compared double-blind doses of dabigatran etexilate 110 mg twice daily and 150 mg twice daily with open-label warfarin (target international normalized ratio, 2.0–3.0) in patients with atrial fibrillation. The median follow-up period was 2 years, the primary efficacy outcome was prevention of stroke or systemic embolism, and the main safety outcome was major bleeding. Because the

Rate of Upper Gastrointestinal Adverse Events

The mean duration of treatment with dabigatran was 21.7 months, and the mean duration of treatment with warfarin was 22.6 months. Overall, the NB-UGI AEs at the 2 dabigatran doses (110 mg twice daily and 150 mg twice daily) during the course of the trial were not significantly different (17.6% and 16.3%, respectively; RR, 0.93; 95% CI, 0.86–1.00; P = .06) Likewise, there was no dose response within the individual NB-UGI AE subgroups (gastroesophageal reflux, P = .08; upper abdominal

Discussion

Dabigatran, a new oral, direct thrombin inhibitor, recently was approved for the prevention of stroke and deep venous thromboembolic events, and represents an alternative to warfarin. In the pivotal phase 3 trials, the overall safety profile for dabigatran vs warfarin was favorable, except for a relative increase in dyspepsia-like symptoms and (at the higher dabigatran dose) GI bleeding events. The pathophysiology of these adverse GI effects is not known, and the optimal strategy to prevent or

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Conflicts of interest These authors disclose the following: Peter Bytzer is a member of the Advisory Boards of Boehringer Ingelheim, AstraZeneca, Wyeth, Eisai, Janssen-Cilag, Nycomed, and Reckitt Benckiser; has received grants from AstraZeneca and Reckitt Benckiser; and is a member of the Speakers Bureau for AstraZeneca and Eisai. James Aisenberg is a consultant for Boehringer Ingelheim and has received research support from Merck. Stuart Connolly, co-principal investigator for RE-LY, is a consultant for Boehringer Ingelheim and has received research grants and lecture fees from Boehringer Ingelheim. Michael Ezekowitz, Co–PI for RE-LY, is a consultant for Boehringer Ingelheim, ARYx Therapeutics, Pfizer, Sanofi, Bristol Myers Squibb, Portola, AstraZeneca, Diachi Sanko, Eisai, and Medtronic. Stephan Formella is a full-time employee of Boehringer Ingelheim. Paul Reilly is a Clinical Project Leader for RE-LY and a full-time employee of Boehringer Ingelheim. The remaining author discloses no conflicts.

Funding Supported by Boehringer Ingelheim Pharmaceuticals.

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