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Digestive Diseases and Sciences

, Volume 63, Issue 7, pp 1878–1889 | Cite as

Locations and Mucosal Lesions Responsible for Major Gastrointestinal Bleeding in Patients on Warfarin or Dabigatran

  • Jennifer M. Kolb
  • Kathryn Friedman Flack
  • Prapti Chatterjee-Murphy
  • Jay Desai
  • Lars C. Wallentin
  • Michael Ezekowitz
  • Stuart Connolly
  • Paul Reilly
  • Martina Brueckmann
  • John Ilgenfritz
  • James Aisenberg
Original Article

Abstract

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.

Methods

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).

Results

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).

Conclusions

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.

Keywords

Gastrointestinal bleeding Gastrointestinal hemorrhage Life-threatening gastrointestinal bleeding Novel oral anticoagulants 

Notes

Acknowledgments

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.

Author’s contribution

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.

Funding

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.

References

  1. 1.
    Sherwood MW, Douketis JD, Patel MR, et al. Outcomes of temporary interruption of rivaroxaban compared with warfarin in patients with nonvalvular. Circulation. 2014;129:1850–1859.CrossRefPubMedPubMedCentralGoogle Scholar
  2. 2.
    Michaels LBR. Relapses of thromboembolic disease after discontinued anticoagulant therapy. A comparison of the incidence after abrupt and after gradual termination of treatment. Am J Cardiol. 1967;20:670–673.CrossRefPubMedGoogle Scholar
  3. 3.
    Landefeld CS, Rosenblatt MW, Goldman L. Bleeding in outpatients treated with warfarin: relation to the prothrombin time and important remediable lesions. Am J Med. 1989;87:153–159.CrossRefPubMedGoogle Scholar
  4. 4.
    Connolly SJ, Ezekowitz MD, Yusuf S, et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;17:1139–1151.CrossRefGoogle Scholar
  5. 5.
    Flack KF, Desai J, Kolb JM, et al. Major gastrointestinal bleeding often is caused by occult malignancy in patients receiving warfarin or dabigatran atrial fibrillation. Clin Gastroenterol Hepatol. 2017;15:682–690.CrossRefPubMedGoogle Scholar
  6. 6.
    Schulman S, Kearon C. Definition of major bleeding in clinical investigations of antihemostatic medicinal products in non-surgical patients. J Thromb Haemost. 2005;3:692–694.CrossRefPubMedGoogle Scholar
  7. 7.
    Connolly SJ, Ezekowitz MD, Yusuf S, Reilly PA, Wallentin LC. Newly identified events in the RE-LY trial. N Engl J Med. 2010;363:1875–1876.CrossRefPubMedGoogle Scholar
  8. 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
  9. 9.
    Sherwood MW, Nessel CC, Hellkamp AS, et al. Gastrointestinal bleeding in patients with atrial fibrillation treated with rivaroxaban or warfarin: ROCKET AF Trial. J Am Coll Cardiol. 2015;66:2271–2281.CrossRefPubMedGoogle Scholar
  10. 10.
    Hylek EM, Held C, Alexander JH, et al. Major bleeding in patients with atrial fibrillation receiving apixaban or warfarin. J Am Coll Cardiol. 2014;63:2141–2147.CrossRefPubMedGoogle Scholar
  11. 11.
    Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2013;369:2093–2104.CrossRefPubMedGoogle Scholar
  12. 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. 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
  14. 14.
    Casado Arroyo R, Polo-Tomas M, Roncales MP, Scheiman J, Lanas A. Lower GI bleeding is more common than upper among patients on dual antiplatelet therapy: long-term follow-up of a cohort of patients commonly using PPI co-therapy. Heart. 2012;98:718–723.CrossRefPubMedGoogle Scholar
  15. 15.
    Nagata N, Niikura R, Yamada A, et al. Acute middle gastrointestinal bleeding risk associated with NSAIDs, antithrombotic drugs, and PPIs: a multicenter case-control study. PLoS One. 2016;11:e0151332.CrossRefPubMedPubMedCentralGoogle Scholar
  16. 16.
    Lanas Á, Carrera-Lasfuentes P, Arguedas Y, et al. Risk of upper and lower gastrointestinal bleeding in patients taking nonsteroidal anti-inflammatory drugs, antiplatelet agents, or anticoagulants. Clin Gastroenterol Hepatol. 2015;13:e2.CrossRefGoogle Scholar
  17. 17.
    Hansen ML, Sorensen R, Clausen MT, et al. Risk of bleeding with single, dual, or triple therapy with warfarin, aspirin, and clopidogrel in patients with atrial fibrillation. Arch Intern Med. 2010;170:1433–1441.CrossRefPubMedGoogle Scholar
  18. 18.
    Chan EW, Lau WCY, Leung WK, et al. Prevention of dabigatran-related gastrointestinal bleeding with gastroprotective agents: a population-based study. Gastroenterology. 2015;149:e3.CrossRefGoogle Scholar
  19. 19.
    Abraham NS. Prevention of gastrointestinal bleeding in patients receiving direct oral anticoagulants. Am J Gastroenterol Suppl. 2016;3:2–12.CrossRefGoogle Scholar
  20. 20.
    Blech S, Ebner T, Ludwig-Schwellinger E, Stangier J, Roth W. The metabolism and disposition of the oral direct thrombin inhibitor, dabigatran, in humans. Drug Metab Dispos. 2008;36:386–399.CrossRefPubMedGoogle Scholar
  21. 21.
    Lanas-Gimeno A, Lanas A. Expert opinion on drug safety risk of gastrointestinal bleeding during anticoagulant treatment. Exp Opin Drug Saf. 2017;16:673–685.CrossRefGoogle Scholar
  22. 22.
    Gerson LB, Fidler JL, Cave DR, Leighton JA. ACG clinical guideline: diagnosis and management of small bowel bleeding. Am J Gastroenterol. 2015;110:1265–1287.CrossRefPubMedGoogle Scholar
  23. 23.
    Manno M, Riccioni ME, Cannizzaro R, Andreoli A, Marmo R, Pennazio M. Diagnostic and therapeutic yield of single balloon enteroscopy in patients with suspected small-bowel disease: results of the Italian multicentre study. Dig Liver Dis. 2013;45:211–215.CrossRefPubMedGoogle Scholar
  24. 24.
    van Turenhout ST, Jacobs MA, van Weyenberg SJ, et al. Diagnostic yield of capsule endoscopy in a tertiary hospital in patients with obscure gastrointestinal bleeding. J Gastrointestin Liver Dis. 2010;19:141–145.PubMedGoogle Scholar
  25. 25.
    Van Weyenberg SJB, Van Turenhout ST, Jacobs MAJM, Bouma G, Mulder CJJ. Video capsule endoscopy for previous overt obscure gastrointestinal bleeding in patients using anti-thrombotic drugs. Dig Endosc. 2012;24:247–254.CrossRefPubMedGoogle Scholar
  26. 26.
    Boal Carvalho P, Rosa B, Moreira MJ, Cotter J. New evidence on the impact of antithrombotics in patients submitted to small bowel capsule endoscopy for the evaluation of obscure gastrointestinal bleeding. Gastroenterol Res Pract. 2014;2014:709217.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC, part of Springer Nature 2018

Authors and Affiliations

  • Jennifer M. Kolb
    • 1
  • Kathryn Friedman Flack
    • 2
  • Prapti Chatterjee-Murphy
    • 3
  • Jay Desai
    • 11
  • Lars C. Wallentin
    • 4
  • Michael Ezekowitz
    • 5
  • Stuart Connolly
    • 6
  • Paul Reilly
    • 7
  • Martina Brueckmann
    • 8
    • 9
  • John Ilgenfritz
    • 10
  • James Aisenberg
    • 11
  1. 1.Department of Gastroenterology and HepatologyUniversity of Colorado HospitalDenverUSA
  2. 2.Department of Internal MedicineHospital of the University of PennsylvaniaPhiladelphiaUSA
  3. 3.Department of Internal MedicineIcahn School of Medicine at Mount SinaiNew YorkUSA
  4. 4.Uppsala Clinical Research CenterUppsala UniversityUppsalaSweden
  5. 5.Sidney Kimmel Medical CollegeThomas Jefferson UniversityPhiladelphiaUSA
  6. 6.Population Health Research InstituteMcMaster University and Hamilton Health SciencesHamiltonCanada
  7. 7.Boehringer Ingelheim PharmaceuticalsRidgefieldUSA
  8. 8.Boehringer Ingelheim International GmbHIngelheimGermany
  9. 9.Faculty of Medicine MannheimUniversity of HeidelbergMannheimGermany
  10. 10.Ilgenfritz Consulting LLCConshohockenUSA
  11. 11.Department of Gastroenterology and HepatologyIcahn School of Medicine at Mount SinaiNew YorkUSA

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