Locations and Mucosal Lesions Responsible for Major Gastrointestinal Bleeding in Patients on Warfarin or Dabigatran
Background and Aim
Different oral anticoagulants may be associated with gastrointestinal bleeding (GIB) from different locations or mucosal lesions. We aimed to test this hypothesis.
Two blinded gastroenterologists independently analyzed source documents from the randomized evaluation of long-term anticoagulant therapy (RE-LY) trial of dabigatran 150 mg BID (D150), dabigatran 110 mg BID (D110) versus warfarin in non-valvular atrial fibrillation (NVAF).
Major GIB events (total n = 546) and life-threatening GIB events (n = 258) were more common with D150 versus warfarin (RR 1.57 [1.28–1.92] and RR 1.62 [1.20–2.18], respectively) and similar for D110 compared to warfarin (RR 1.11 [0.89–1.38] and RR 1.16 [0.84–1.61], respectively). Fatal bleeding was similarly rare across treatment groups. Lower GI major bleeding and life-threatening bleeding were more common with D150 compared to warfarin (RR 2.23 [1.47, 3.38] and RR 2.64 [1.36, 5.13], respectively) and with D110 compared to warfarin (RR 1.78 [1.16, 2.75] and RR 2.00 [1.00, 4.00], respectively). MGIB from colonic angiodysplasia was increased with dabigatran versus warfarin (P < 0.01 for both dose comparisons). Subacute and chronic MGIB events were more common with D150 than with warfarin (RR 1.72 [1.06, 2.78] and RR 1.66 [1.12, 2.45], respectively), as were hematochezia or melena (RR 1.67 [1.18, 2.36] and RR 1.72 [1.20, 2.47], respectively).
In a chronic NVAF population, D150 but not D110 is associated with increased major and life-threatening GI bleeding in comparison with warfarin. At both dabigatran doses, increased bleeding from the colorectum, in particular from angiodysplasia, is seen.
KeywordsGastrointestinal bleeding Gastrointestinal hemorrhage Life-threatening gastrointestinal bleeding Novel oral anticoagulants
This study was supported by a grant from the Digestive Disease Research Foundation. The funding source was not involved in the study design, data acquisition or interpretation, or manuscript preparation and submission. Boehringer Ingelheim Inc. (the sponsor of the RE-LY trial) provided the source documents to the investigators. The data analysis was performed independent of the sponsor. PR and MB are employees of Boehringer Ingelheim and reviewed and commented on the manuscript, but editorial control was maintained by the independent authors.
JMK, KFF, JD, LCW, ME, SC, and JA conceived and designed the study. JMK, KFF, JD, PCM, PR, and JA acquired the data. JMK, KFF, JD, PCM, JI, and JA analyzed and interpreted the data. JMK, KFF, PCM, and JA drafted the manuscript. KFF, JD, JMK, PCM, LCW, ME, SC, PR, MB, JI, and JA critically revised the manuscript for important intellectual content. JI and PCM performed the statistical analysis. JMK, KFF, and PCM obtained funding. JMK, KFF, PCM, SC, PR, and MB provided administrative, technical, or material support. JD, LCW, ME, and JA supervised the study.
This study was funded by the Digestive Disease Research Foundation. Initial data analyses were performed by Jennifer M. Kolb, Kathryn Friedman Flack, Jay Desai, Prapti Chatterjee-Murphy, John Ilgenfritz, James Aisenberg. No writing support was provided.
Compliance with ethical standards
Conflict of interest
Jennifer M. Kolb, Kathryn Friedman Flack, Prapti Chatterjee-Murphy, and John Ilgenfritz have no conflicts of interest to disclose. Jay Desai reports non-financial support from Boehringer Ingelheim, and he has participated in advisory boards for Boehringer Ingelheim, Bristol-Myers Squibb, and Daiichi Sankyo. Lars C. Wallentin has received grant support/honoraria/consulting fees from Boehringer Ingelheim, Regado Biosciences, Athera Biosciences, AstraZeneca, GlaxoSmithKline, Eli Lilly, Schering-Plough, and Bristol-Myers Squibb. Michael Ezekowitz has served as a consultant for AstraZeneca, Eisai, Pozen Inc., Boehringer Ingelheim, ARYx Therapeutics, Pfizer, Sanofi, Bristol-Myers Squibb, Portola, Daiichi Sankyo, Medtronic, Merck, Johnson & Johnson, Gilead, Janssen Scientific Affairs, and Armetheon. He has received research grant support from Boehringer Ingelheim, Bayer, Daiichi Sankyo, Pfizer, and Bristol-Myers Squibb. Stuart Connolly has received grant support/honoraria/consulting fees from Boehringer Ingelheim, Bristol-Myers Squibb, Sanofi-Aventis, and Portola. Paul Reilly is a full-time employee of Boehringer Ingelheim. Martina Brueckmann is an employee of Boehringer Ingelheim Pharma GmbH & Co. KG. James Aisenberg reports he has participated in advisory boards and consulting for Boehringer Ingelheim and Portola.
- 8.Eikelboom JW, Wallentin L, Connolly SJ, et al. Risk of bleeding with 2 doses of dabigatran compared with warfarin in older and younger patients with atrial fibrillation: an analysis of the randomized evaluation of long-term anticoagulant therapy (RE-LY) trial. Circulation. 2011;31:2363–2372.CrossRefGoogle Scholar
- 12.Abraham NS, Singh S, Alexander GC, et al. Comparative risk of gastrointestinal bleeding with dabigatran, rivaroxaban, and warfarin: population based cohort study. BMJ. 2015 Jan [cited 2016 Apr 30];350:h1857.Google Scholar
- 13.Pollack CV, Gruenenfelder F, Eikelboom J, et al. Initial experience with idarucizumab in dabigatran-treated patients presenting with acute gastrointestinal hemorrhage: interim results from the RE-VERSE AD study. Ann Emerg Med. 2015;66:S2–S3.Google Scholar