GASTROINTESTINAL BLEEDING WITH THE USE OF NEW ORAL ANTICOAGULANTS: EPIDEMIOLOGY, RISK FACTORS, TREATMENT, AND PREVENTION

Novel oral anticoagulants (NOACs), such as the direct thrombin inhibitor dabigatran and the selective factor Xa inhibitors rivaroxaban and apixaban, are increasingly used as an effective antithrombotic drug in real clinical practice. Unfortunately, these medications can cause severe adverse events, including gastrointestinal bleeding, one of the most common events. This complication annually develops in 2–3% of patients taking NOACs. The sources of bleeding can be in both the upper or lower gastrointestinal tract (GIT). The common cause of bleeding is undiagnosed GIT neoplasms, often colorectal cancer. Clinical and cohort studies show that the greatest risk of bleeding is observed with the use of rivaroxaban. The risk factors are advanced age, concurrent administration of nonsteroidal anti-inflammatory drugs, aspirin, and other anticoagulants, gastrointestinal diseases, H. pylori infection, impaired renal and hepatic functions, and alcohol intake. Gastrointestinal bleeding is treated on general principles, by applying endoscopic and surgical techniques. Particular importance is attached to the blockade of the anticoagulant effects of NOACs. For this, the entire range of antidotes, such as idarucizumab (it has been already applied in several countries of the world), andexanet, and ciraparantag, has been recently designed and is undergoing clinical trials. Bleeding prevention involves control of risk factors, rational use of NOACs, prophylactic administration of proton pump inhibitors, timely discontinuation of anticoagulation prior to traumatic medical procedures on the gastrointestinal organs (before certain endoscopic procedures in particular).

1. Сатыбалдыева МА, Решетняк ТМ. Новые оральные антикоагулянты в терапии антифосфолипидного синдрома. Научно-практическая ревматология. 2016;54(2):219-26 [Satybaldyeva MA, Reshetnyak TM. New oral anticoagulants in the therapy of antiphospholipid syndrome. Nauchno-Prakticheskaya Revmatologiya = Rheumatology Science and Practice. 2016;54(2):219-226 (In Russ.)]. doi: 10.14412/1995-4484-2016-219-226

2. Weitz JI, Jaffer IH, Fredenburgh JC. Recent advances in the treatment of venous thromboembolism in the era of the direct oral anticoagulants. F1000Res. 2017 Jun 23;6:985. doi: 10.12688/f1000research.11174.1. eCollection 2017.

3. Pan KL, Singer DE, Ovbiagele B, et al. Effects of non-vitamin K antagonist oral anticoagulants versus warfarin in patients with atrial fibrillation and valvular heart disease: A systematic review and meta-analysis. J Am Heart Assoc. 2017 Jul 18;6(7). doi: 10.1161/JAHA.117.005835

4. Barnes GD, Lucas E, Alexander GC, Goldberger ZD. National trends in ambulatory oral anticoagulant use. Am J Med. 2015 Dec;128(12):1300-5.e2. doi: 10.1016/j.amjmed.2015.05.044. Epub 2015 Jul 2.

5. Deutsch D, Boustiere C, Ferrari E, et al. Direct oral anticoagulants and digestive bleeding: therapeutic management and preventive measures. Ther Adv Gastroenterol. 2017 Jun;10(6):495-505. doi: 10.1177/1756283X17702092. Epub 2017 Apr 17.

6. Cheung KS, Leung WK. Gastrointestinal bleeding in patients on novel oral anticoagulants: Risk, prevention and management. World J Gastroenterol. 2017 Mar 21;23(11):1954-63. doi: 10.3748/wjg.v23.i11.1954

7. Desai J, Kolb JM, Weitz JI, Aisenberg J. Gastrointestinal bleeding with the new oral anticoagulants – defining the issues and the management strategies. Thromb Haemost. 2013 Aug;110(2):205-12. doi: 10.1160/TH13-02-0150. Epub 2013 May 23.

8. Serebruany V, Cherepanov V, Fortmann S, Kim MH. Mortality and oral anticoagulants in the Food and Drug Administration Adverse Event Reporting System. Open Heart. 2017 Jun 1;4(2):e000629. doi: 10.1136/openhrt-2017-000629

9. 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 random-ized evaluation of long-term anticoagulant therapy (RE-LY) trial. Circulation. 2011 May 31;123(21):2363-72. doi: 10.1161/CIRCULATIONAHA.110.004747. Epub 2011 May 16.

10. Weitz JI, Lensing AWA, Prins MH, et al. Rivaroxaban or aspirin for extended treatment of venous thromboembolism. N Engl J Med. 2017;376(13):1211-22. doi: 10.1056/NEJMoa1700518

11. Marik PE, Cavallazzi R. Extended anticoagulant and aspirin treatment for the secondary prevention of thromboembolic disease:

12. A systematic review and meta-analysis. PLoS One. 2015;10(11):e0143252. doi: 10.1371/journal.pone.0143252

13. Deitelzweig S, Neuman WR, Lingohr-Smith M, et al. Incremental economic burden associated with major bleeding among atrial fibrillation patients treated with factor Xa inhibitors. J Med Econ. 2017 Aug 11:1-7. doi: 10.1080/13696998.2017.1362412

14. [Epub ahead of print].

15. Najm WI. Peptic ulcer disease. Prim Care. 2011 Sep;38(3):383-94,vii. doi: 10.1016/j.pop.2011.05.001

16. Snowden FM. Emerging and reemerging diseases: a historical perspective. Immunol Rev. 2008 Oct;225:9-26.

17. doi: 10.1111/j.1600-065X.2008.00677.x

18. Shimamoto T, Yamamichi N, Kodashima S, et al. No association of coffee consumption with gastric ulcer, duodenal ulcer, reflux esophagitis, and non-erosive reflux disease: a cross-sectional study of 8,013 healthy subjects in Japan. PLoS One. 2013 Jun 12;8(6):e65996. doi: 10.1371/journal.pone.0065996

19. Zhou Y, Boudreau DM, Freedman AN. Trends in the use of aspirin and nonsteroidal anti-inflammatory drugs in the general U.S. population. Pharmacoepidemiol Drug Saf. 2014;23(1):43-50. doi: 10.1002/pds.3463

20. Harirforoosh S, Asghar W, Jamali F. Adverse effects of nonsteroidal antiinflammatory drugs: An update of gastrointestinal, cardiovascular and renal complications. J Pharm Pharm Sci (www.cspsCanada.org) 2013;16(5):821-47.

21. doi: 10.18433/J3VW2F

22. Kundu A, Sardar P, Sen P, et al. Patient taking a novel oral anticoagulant presents with major GI bleeding. J Atr Fibrillation. 2015 Oct 31;8(3):1218. doi: 10.4022/jafib.1218

23. Thomopoulos KC, Mimidis KP, Theocharis GJ, et al. Acute upper gastrointestinal bleeding in patients on long-term oral anticoagulation therapy: endoscopic findings, clinical management and outcome. World J Gastroenterol. 2005 Mar 7;11(9):1365-8. doi: 10.3748/wjg.v11.i9.1365

24. Rubin TA, Murdoch M, Nelson DB. Acute GI bleeding in the setting of supratherapeutic international normalized ratio in patients taking warfarin: endoscopic diagnosis, clinical management, and outcomes. Gastrointest Endosc. 2003 Sep;58(3):369-73.

25. Flack KF, Desai J, Kolb JM, et al. Major gastrointestinal bleeding often is caused by occult malignancy in patients receiving warfarin or dabigatran to prevent stroke and systemic embolism from atrial fibrillation. Clin Gastroenterol Hepatol. 2017 May;15(5):682-90. doi: 10.1016/j.cgh.2016.10.011. Epub 2016 Oct 17.

26. Wood M, Shaw P. Pradaxa-induced esophageal ulcer. BMJ Case Rep. 2015 Oct 9;2015. doi: 10.1136/bcr-2015-211371

27. Singh S, Savage L, Klein M, Thomas C. Severe necrotic oesophageal and gastric ulceration associated with dabigatran. BMJ Case Rep. 2013 Apr 22;2013. doi: 10.1136/bcr-2013-009139

28. Izumikawa K, Inaba T, Mizukawa S, et al. Two cases of dabigatran-induced esophageal ulcer indicating the usefulness of drug administration guidance. Nihon Shokakibyo Gakkai Zasshi. 2014 Jun;111(6):1096-104.

29. Scheppach W, Meesmann M. [Exfoliative esophagitis while taking dabigatran]. Dtsch Med Wochenschr. 2015 Apr;140(7):515-8 (In Germ.). doi: 10.1055/s-0041-101313. Epub 2015 Mar 31.

30. Okada M, Okada K. Exfoliative esophagitis and esophageal ulcer induced by dabigatran. Endoscopy. 2012;44 Suppl 2 UCTN:E23-4. doi: 10.1055/s-0031-1291503. Epub 2012 Mar 6.

31. Toya Y, Nakamura S, Tomita K, et al. Dabigatran-induced esophagitis: The prevalence and endoscopic characteristics. J Gastroenterol Hepatol. 2016 Mar;31(3):610-4.

32. doi: 10.1111/jgh.13024

33. Schulman S, Kearon C, Kakkar AK, et al. Dabigatran versus war-farin in the treatment of acute venous thromboembolism. N Engl J Med. 2009;361(24):2342-52.

34. Patel MR, Mahaffey KW, Garg J, et al. Rivaroxaban versus war-farin in nonvalvular atrial fibrillation. N Engl J Med. 2011 Sep 8;365(10):883-91. doi: 10.1056/NEJMoa1009638. Epub 2011 Aug 10.

35. Granger CB, Alexander JH, McMurray JJ, et al. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011 Sep 15;365(11):981-92. doi: 10.1056/NEJMoa1107039. Epub 2011 Aug 27.

36. Giugliano RP, Ruff CT, Braunwald E, et al. Edoxaban versus war-farin in patients with atrial fibrillation. N Engl J Med. 2013 Nov 28;369(22):2093-104. doi: 10.1056/NEJMoa1310907. Epub 2013 Nov 19.

37. Miller CS, Dorreen A, Martel M, et al. Risk of gastrointestinal bleeding in patients taking non-vitamin K antagonist oral anticoagulants: A systematic review and meta-analysis. Clin Gastroenterol Hepatol. 2017 Apr 27. doi: 10.1016/j.cgh.2017.04.031 [Epub ahead of print].

38. Abraham NS, Noseworthy PA, Yao X, et al. Gastrointestinal Safety of Direct Oral Anticoagulants: A large population-based study. Gastroenterology. 2017 Apr;152(5):1014-22.e1.

39. doi: 10.1053/j.gastro.2016.12.018. Epub 2016 Dec 30.

40. Graham DJ, Reichman ME, Wernecke M, et al. Stroke, bleeding, and mortality risks in elderly medicare beneficiaries treated with dabigatran or rivaroxaban for nonvalvular atrial fibrillation. JAMA Intern Med. 2016 Nov 1;176(11):1662-71. doi: 10.1001/jamainternmed.2016.5954

41. Nielsen PB, Skjoth F, Sogaard M, et al. Effectiveness and safety of reduced dose non-vitamin K antagonist oral anticoagulants and warfarin in patients with atrial fibrillation: propensity weighted nationwide cohort study. BMJ. 2017 Feb 10;356:j510. doi: 10.1136/bmj.j510

42. Maura G, Blotiere PO, Bouillon K, et al. Comparison of the short-term risk of bleeding and arterial thromboembolic events in nonvalvular atrial fibrillation patients newly treated with dabigatran or rivaroxaban versus vitamin K antagonists: a French nationwide propensity-matched cohort study. Circulation. 2015 Sep 29;132(13):1252-60. doi: 10.1161/CIRCULATIONA-HA.115.015710. Epub 2015 Jul 21.

43. Helmert S, Marten S, Mizera H, et al. Effectiveness and safety of apixaban therapy in daily-care patients with atrial fibrillation: results from the Dresden NOAC Registry. J Thromb Thrombolysis. 2017 Aug;44(2):169-78. doi: 10.1007/s11239-017-1519-8

44. Hecker J, Marten S, Keller L, et al. Effectiveness and safety of rivaroxaban therapy in daily-care patients with atrial fibrillation. Results from the Dresden NOAC Registry. Thromb Haemost. 2016 May 2;115(5):939-49. doi: 10.1160/TH15-10-0840. Epub 2016 Jan 21.

45. Beyer-Westendorf J, Ebertz F, Fö rster K, et al. Effectiveness and safety of dabigatran therapy in daily-care patients with atrial fibrillation. Results from the Dresden NOAC Registry. Thromb Haemost. 2015 Jun;113(6):1247-57. doi: 10.1160/TH14-11-0954. Epub 2015 Mar 5.

46. Shirai T, Yamamoto T, Kawasugi K, et al. Gastrointestinal bleeding risk of non-vitamin K oral anticoagulants is similar to warfarin –

47. a Japanese retrospective cohort study. Int J Clin Pharmacol Ther. 2016 Nov;54(11):841-6. doi: 10.5414/CP202607

48. Valent F. New oral anticoagulant prescription rate and risk of bleeding in an Italian region. Pharmacoepidemiol Drug Saf. 2017 Jul 31. doi: 10.1002/pds.4279 [Epub ahead of print].

49. Vicente V, Martin A, Lecumberri R, et al. Clinical perspectives on the management of bleeding in patients on oral anticoagulants: the DECOVER Study (DElphi Consensus on oral COagulation and therapy action reVERsal). Emergencias. 2017 Feb;29(1):18-26.

50. Lanas-Gimeno A, Lanas A. Risk of gastrointestinal bleeding during anticoagulant treatment. Expert Opin Drug Saf. 2017 Jun;16(6):673-85. doi: 10.1080/14740338.2017.1325870. Epub 2017 May 17.

51. Albaladejo P, Samama CM, Sie P, et al. Management of severe bleeding in patients treated with direct oral anticoagulants: An observational registry analysis. Anesthesiology. 2017 Jul;127(1):111-20. doi: 10.1097/ALN.0000000000001631

52. Lauffenburger JC, Rhoney DH, Farley JF, et al. Predictors of gastrointestinal bleeding among patients with atrial fibrillation after initiating dabigatran therapy. Pharmacotherapy. 2015 Jun;35(6):560-8. doi: 10.1002/phar.1597. Epub 2015 Jun 4.

53. Pisters R, Lane DA, Nieuwlaat R, et al. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleedingin patients with atrial fibrillation: The Euro Heart Survey. Chest. 2010;138(5):1093. doi: 10.1378/chest.10-0134

54. Radaelli F, Dentali F, Repici A, et al. Management of anticoagulation in patients with acute gastrointestinal bleeding. Dig Liver Dis. 2015 Aug;47(8):621-7. doi: 10.1016/j.dld.2015.03.029. Epub 2015 Apr 13.

55. Biecker E. Diagnosis and therapy of non-variceal upper gastrointestinal bleeding. World J Gastrointest Pharmacol Ther. 2015 Nov 6;6(4):172-82. doi: 10.4292/wjgpt.v6.i4.172

56. Barkun A, Sabbah S, Enns R, et al. The Canadian Registry on Nonvariceal Upper Gastrointestinal Bleedingand Endoscopy (RUGBE): Endoscopic hemostasis and proton pump inhibition are associated with improved outcomes in a real life setting. Am J Gastroenterol 2004;99:1238-46. doi: 10.1111/j.1572-0241.2004.30272.x

57. Almegren M. Reversal of direct oral anticoagulants. Vasc Health Risk Manag. 2017 Jul 19;13:287-92. doi: 10.2147/VHRM.S138890

58. Tummala R, Kavtaradze A, Gupta A, Ghosh RK. Specific antidotes against direct oral anticoagulants: A comprehensive review of clinical trials data. Int J Cardiol. 2016 Jul 1;214:292-8.

59. doi: 10.1016/j.ijcard.2016.03.056. Epub 2016 Mar 28.

60. Pollack CV Jr, Reilly PA, van Ryn J, et al. Idarucizumab for Dabigatran Reversal – Full Cohort Analysis. N Engl J Med. 2017 Aug 3;377(5):431-41. doi: 10.1056/NEJMoa1707278. Epub 2017 Jul 11.

61. Connolly SJ, Milling TJ Jr, Eikelboom JW, et al. Andexanet alfa for acute major bleeding associated with factor Xa inhibitors. N Engl J Med. 2016 Sep 22;375(12):1131-41. doi: 10.1056/NEJMoa1607887. Epub 2016 Aug 30.

62. Milling TJ Jr, Frontera J. Exploring indications for the use of direct oral anticoagulants and the associated risks of major bleeding. Am J Manag Care. 2017 Apr;23(4 Suppl):S67-S80.

63. Heidbuchel H, Verhamme P, Alings M, et al. Updated European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist anticoagulants in patients with non-valvular atrial fibrillation. Europace. 2015 Oct;17(10):1467-507. doi: 10.1093/europace/ euv309. Epub 2015 Aug 31.

64. Veitch AM, Vanbiervliet G, Gershlick AH, et al. Endoscopy in patients on antiplatelet or anticoagulant therapy, including direct oral anticoagulants: British Society of Gastroenterology (BSG) and European Society of Gastrointestinal Endoscopy (ESGE) guidelines. Endoscopy. 2016 Apr;48(4):385-402. doi: 10.1055/s-0042-102652. Epub 2016 Feb 18.

65. Wolf AT, Wasan SK, Saltzman JR. Impact of anticoagulation on rebleeding following endoscopic therapy for nonvariceal upper gastrointestinal hemorrhage. Am J Gastroenterol 2007;102:290-6. doi: 10.1111/j.1572-0241.2006.00969.x

66. Qureshi WT, Mittal C, Patsias I, et al. Restarting anticoagulation and outcomes after major gastrointestinal bleeding in atrial fibrillation. Am J Cardiol. 2014;113:662-8. doi: 10.1016/j.amj-card.2013.10.044

67. Witt DM, Delate T, Garcia DA, et al. Risk of thromboembolism, recurrent hemorrhage, and death after warfarin therapy interruption for gastrointestinal tract bleeding. Arch Intern Med. 2012;172:1484-91. doi: 10.1001/archinternmed.2012.4261

68. Kido K, Scalese MJ. Management of oral anticoagulation therapy after gastrointestinal bleeding: Whether to, When to, and How to Restart an Anticoagulation Therapy. Ann Pharmacother. 2017 Jun 1:1060028017717019. doi: 10.1177/1060028017717019

69. [Epub ahead of print].