Статья
Желудочно-кишечные кровотечения у пациентов с ишемической болезнью сердца: возможности профилактики
Широкое применение антитромботических препаратов (АТП) у пациентов с ишемической болезнью сердца (ИБС), с одной стороны, обеспечивает значительное снижение риска развития угрожающих жизни сердечно-сосудистых осложнений, с другой – чревато опасностью развития желудочно-кишечного кровотечения (ЖКК), которое может возникать у 0,5–1,0 % больных. Основными мерами профилактики ЖКК в этих случаях являются строгое соблюдение показаний к назначению АТП, выявление и анализ факторов риска ЖКК, по возможности их устранение. Для оценки степени риска кровотечений у больных ИБС следует использовать следующие шкалы: PRECISE-DAPT и DAPT, HAS-BLED. При наличии неустранимых факторов риска врачебная тактика по отношению к дальнейшему ведению больного должна быть сугубо индивидуальной с определением характера повреждения, степени риска имеющегося и возможного осложнения, объема необходимых лечебно-диагностических мероприятий. Применение АТП требует контроля состояния пациента с целью своевременного выявления осложнений со стороны желудочно-кишечного тракта и их эффективного лечения.
1. Мороз Е.В., Артемкин Э.Н., Крюков Е.В., Чернецов В.А. Осложнения со стороны желудочно-кишечного тракта при антитромботической терапии. Общая реаниматология. 2018;14(3):15-26. DOI: 10.15360/1813-9779-2018-3-15-26
2. Valgimigli M, Bueno H, Byrne RA, Collet J-P, Costa F, Jeppsson A et al. 2017 ESC focused update on dual antiplatelet therapy in coronary artery disease developed in collaboration with EACTS. European Journal of Cardio-Thoracic Surgery. 2018;53(1):34–78. DOI: 10.1093/ejcts/ezx334
3. Mehta SR, Bainey KR, Cantor WJ, Lordkipanidzé M, MarquisGravel G, Robinson SD et al. 2018 Canadian Cardiovascular Society/Canadian Association of Interventional Cardiology Focused Update of the Guidelines for the Use of Antiplatelet Therapy. Canadian Journal of Cardiology. 2018;34(3):214–33. DOI: 10.1016/j.cjca.2017.12.012
4. Siller-Matula JM, Huber K, Christ G, Schror K, Kubica J, Herkner H et al. Impact of clopidogrel loading dose on clinical outcome in patients undergoing percutaneous coronary intervention: a systematic review and meta-analysis. Heart. 2011;97(2):98–105. DOI: 10.1136/hrt.2010.195438
5. Eikelboom JW, Wallentin L, Connolly SJ, Ezekowitz M, Healey JS, Oldgren J et al. Risk of Bleeding With 2 Doses of Dabigatran Compared With Warfarin in Older and Younger Patients With Atrial FibrillationClinical Perspective: An Analysis of the Randomized Evaluation of Long-Term Anticoagulant Therapy (RE-LY) Trial. Circulation. 2011;123(21):2363–72. DOI: 10.1161/CIRCULATIONAHA.110.004747
6. Schulman S, Kearon C, Kakkar AK, Mismetti P, Schellong S, Eriksson H et al. Dabigatran versus Warfarin in the Treatment of Acute Venous Thromboembolism. New England Journal of Medicine. 2009;361(24):2342–52. DOI: 10.1056/NEJMoa0906598
7. Patel MR, Mahaffey KW, Garg J, Pan G, Singer DE, Hacke W et al. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. New England Journal of Medicine. 2011;365(10):883–91. DOI: 10.1056/NEJMoa1009638
8. Giugliano RP, Ruff CT, Braunwald E, Murphy SA, Wiviott SD, Halperin JL et al. Edoxaban versus warfarin in patients with atrial fibrillation. The New England Journal of Medicine. 2013;369(22):2093–104. DOI: 10.1056/NEJMoa1310907
9. Granger CB, Alexander JH, McMurray JJV, Lopes RD, Hylek EM, Hanna M et al. Apixaban versus warfarin in patients with atrial fibrillation. New England Journal of Medicine. 2011;365(11):981–92. DOI: 10.1056/NEJMoa1107039
10. Miller CS, Dorreen A, Martel M, Huynh T, Barkun AN. Risk of Gastrointestinal Bleeding in Patients Taking Non-Vitamin K Antagonist Oral Anticoagulants: A Systematic Review and Meta-analysis. Clinical Gastroenterology and Hepatology. 2017;15(11):1674-1683.e3. DOI: 10.1016/j.cgh.2017.04.031
11. Бойцов С.А., Погосова Н.В., Бубнова М.Г., Драпкина О.М., Гаврилова Н.Е., Еганян Р.А. и др. Кардиоваскулярная профилактика 2017. Российские национальные рекомендации. Российский кардиологический журнал. 2018;23(6):7–122. DOI: 10.15829/1560-4071-2018-6-7-122
12. GUSTO Investigators. An International Randomized Trial Comparing Four Thrombolytic Strategies for Acute Myocardial Infarction. New England Journal of Medicine. 1993;329(10):673–82. DOI: 10.1056/NEJM199309023291001
13. Rao AK, Pratt C, Berke A, Jaffe A, Ockene I, Schreiber TL et al. Thrombolysis in myocardial infarction (TIMI) trial – Phase I: Hemorrhagic manifestations and changes in plasma fibrinogen and the fibrinolytic system in patients treated with recombinant tissue plasminogen activator and streptokinase. Journal of the American College of Cardiology. 1988;11(1):1–11. DOI: 10.1016/0735-1097(88)90158-1
14. Serebruany VL, Atar D. Assessment of Bleeding Events in Clinical Trials – Proposal of a New Classification. The American Journal of Cardiology. 2007;99(2):288–90. DOI: 10.1016/j.amjcard.2006.07.091
15. Pisters R, Lane DA, Nieuwlaat R, de Vos CB, Crijns HJGM, Lip GYH. A novel user-friendly score (HAS-BLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest. 2010;138(5):1093–100. DOI: 10.1378/chest.10-0134
16. Vicente V, Martín A, Lecumberri R, Coll-Vinent B, Suero C, González-Porras JR 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: Revista De La Sociedad Espanola De Medicina De Emergencias. 2017;29(1):18–26. PMID: 28825264
17. Lanas-Gimeno A, Lanas A. Risk of gastrointestinal bleeding during anticoagulant treatment. Expert Opinion on Drug Safety. 2017;16(6):673–85. DOI: 10.1080/14740338.2017.1325870
18. Albaladejo P, Samama C-M, Sié P, Kauffmann S, Mémier V, Suchon P et al. Management of Severe Bleeding in Patients Treated with Direct Oral Anticoagulants: An Observational Registry Analysis. Anesthesiology. 2017;127(1):111–20. DOI: 10.1097/ALN.0000000000001631
19. Lauffenburger JC, Rhoney DH, Farley JF, Gehi AK, Fang G. Predictors of Gastrointestinal Bleeding Among Patients with Atrial Fibrillation After Initiating Dabigatran Therapy. Pharmacotherapy: The Journal of Human Pharmacology and Drug Therapy. 2015;35(6):560–8. DOI: 10.1002/phar.1597
20. Ивашкин В.Т., Шептулин А.А., Маев И.В., Баранская Е.К., Трухманов А.С., Лапина Т.Л. Клинические рекомендации Российской гастроэнтерологической ассоциации по диагностике и лечению эрозивно-язвенных поражений желудка и двенадцатиперстной кишки, вызванных нестероидными противовоспалительными препаратами. Российский журнал гастроэнтерологии, гепатологии, колопроктологии. 2014;24(5):89-94
21. Malfertheiner P, Megraud F, O’Morain CA, Gisbert JP, Kuipers EJ, Axon AT et al. Management of Helicobacter pylori infection – the Maastricht V/Florence Consensus Report. Gut. 2017;66(1):6–30. DOI: 10.1136/gutjnl-2016-312288
22. Каратеев А.Е., Насонов Е.Л., Яхно Н.Н., Ивашкин В.Т., Чичасова Н.В., Алексеева Л.И. и др. Клинические рекомендации «Рациональное применение нестероидных противовоспалительных препаратов (НПВП) в клинической практике». Современная ревматология. 2015;9(1):4- 23. DOI: 10.14412/1996-7012-2015-1-4-23
23. Cryer B, Feldman M. Effects of very low dose daily, long-term aspirin therapy on gastric, duodenal, and rectal prostaglandin levels and on mucosal injury in healthy humans. Gastroenterology. 1999;117(1):17–25. PMID: 10381905
24. Antithrombotic Trialists’ Collaboration. Collaborative meta-analysis of randomised trials of antiplatelet therapy for prevention of death, myocardial infarction, and stroke in high risk patients. BMJ. 2002;324(7329):71–86. DOI: 10.1136/bmj.324.7329.71
25. Cooke AR, Hunt JN. Absorption of acetylsalicylic acid from unbuffered and buffered gastric contents. The American Journal of Digestive Diseases. 1970;15(2):95–102. PMID: 4905590
26. Graham DY. Aspirin and the Stomach. Annals of Internal Medicine. 1986;104(3):390–8. DOI: 10.7326/0003-4819-104-3-390
27. Fork FT, Lafolie P, Tóth E, Lindgärde F. Gastroduodenal Tolerance of 75 mg Clopidogrel versus 325 mg Aspirin in Healthy Volunteers: A Gastroscopic Study. Scandinavian Journal of Gastroenterology. 2000;35(5):464–9. DOI: 10.1080/003655200750023705
28. Кириченко А.А., Эбзеева Е.Ю. Ацетилсалициловая кислота при вторичной профилактике сердечно-сосудистых осложнений. Consilium Medicum. 2019;21(5):28-31. DOI: 10.26442/20751753.2019.5.190454
29. Leung WK, Bjarnason I, Wong VW, Sung JJ, Chan FK. Small bowel enteropathy associated with chronic low-dose aspirin therapy. The Lancet. 2007;369(9561):614. DOI: 10.1016/ S0140-6736(07)60282-7
30. Endo H, Sakai E, Kato T, Umezawa S, Higurashi T, Ohkubo H et al. Small bowel injury in low-dose aspirin users. Journal of Gastroenterology. 2015;50(4):378–86. DOI: 10.1007/s00535-014-1028-x
31. Watanabe T, Sugimori S, Kameda N, Machida H, Okazaki H, Tanigawa T et al. Small Bowel Injury by Low-Dose EntericCoated Aspirin and Treatment With Misoprostol: A Pilot Study. Clinical Gastroenterology and Hepatology. 2008;6(11):1279– 82. DOI: 10.1016/j.cgh.2008.06.021
32. Smecuol E, Pinto Sanchez MI, Suarez A, Argonz JE, Sugai E, Vazquez H et al. Low-Dose Aspirin Affects the Small Bowel Mucosa: Results of a Pilot Study With a Multidimensional Assessment. Clinical Gastroenterology and Hepatology. 2009;7(5):524–9. DOI: 10.1016/j.cgh.2008.12.019
33. Utzeri E, Usai P. Role of non-steroidal anti-inflammatory drugs on intestinal permeability and nonalcoholic fatty liver disease. World Journal of Gastroenterology. 2017;23(22):3954–63. DOI: 10.3748/wjg.v23.i22.3954
34. Wallace JL, Syer S, Denou E, de Palma G, Vong L, McKnight W et al. Proton Pump Inhibitors Exacerbate NSAID-Induced Small Intestinal Injury by Inducing Dysbiosis. Gastroenterology. 2011;141(4):1314-1322.e5. DOI: 10.1053/j.gastro.2011.06.075
35. Endo H, Sakai E, Taniguchi L, Kessoku T, Komiya Y, Ezuka A et al. Risk factors for small-bowel mucosal breaks in chronic low-dose aspirin users: data from a prospective multicenter capsule endoscopy registry. Gastrointestinal Endoscopy. 2014;80(5):826–34. DOI: 10.1016/j.gie.2014.03.024
36. Каратеев А.Е., Мороз Е.В., Крюков Е.В. Поражение тонкой кишки, ассоциированное с приемом нестероидных противовоспалительных препаратов. Альманах клинической медицины. 2019;47(6):559-67. DOI: 10.18786/2072-0505-2019-47-048
37. Bjarnason I, Scarpignato C, Holmgren E, Olszewski M, Rainsford KD, Lanas A. Mechanisms of Damage to the Gastrointestinal Tract From Nonsteroidal Anti-Inflammatory Drugs. Gastroenterology. 2018;154(3):500–14. DOI: 10.1053/j.gastro.2017.10.049
38. Каратеев А.Е., Насонов Е.Л., Ивашкин В.Т., Мартынов А.И., Яхно Н.Н., Арутюнов Г.П. и др. Рациональное использование нестероидных противовоспалительных препаратов. Клинические рекомендации. Научно-практическая ревматология. 2018; 56:1-29. DOI: 10.14412/1995-4484-2018-1-29
39. Writing Committee Members, Bhatt DL, Scheiman J, Abraham NS, Antman EM, Chan FKL et al. ACCF/ACG/AHA 2008 Expert Consensus Document on Reducing the Gastrointestinal Risks of Antiplatelet Therapy and NSAID Use: A Report of the American College of Cardiology Foundation Task Force on Clinical Expert Consensus Documents. Circulation. 2008;118(18):1894–909. DOI: 10.1161/CIRCULATIONAHA.108.191087
40. Wallentin L, Becker RC, Budaj A, Cannon CP, Emanuelsson H, Held C et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. The New England Journal of Medicine. 2009;361(11):1045–57. DOI: 10.1056/NEJMoa0904327
41. Montalescot G, Wiviott SD, Braunwald E, Murphy SA, Gibson CM, McCabe CH et al. Prasugrel compared with clopidogrel in patients undergoing percutaneous coronary intervention for ST-elevation myocardial infarction (TRITON-TIMI 38): double-blind, randomised controlled trial. The Lancet. 2009;373(9665):723–31. DOI: 10.1016/S0140-6736(09)60441-4
42. Cheung K-S, Leung WK. Gastrointestinal bleeding in patients on novel oral anticoagulants: Risk, prevention and management. World Journal of Gastroenterology. 2017;23(11):1954– 63. DOI: 10.3748/wjg.v23.i11.1954
43. Desai J, Kolb J, Weitz J, Aisenberg J. Gastrointestinal bleeding with the new oral anticoagulants – defining the issues and the management strategies. Thrombosis and Haemostasis. 2013;110(08):205–12. DOI: 10.1160/TH13-02-0150
44. Kundu A, Sardar P, Sen P, Chatterjee S, Huston J, Nairooz R et al. Patient Taking A Novel Oral Anticoagulant Presents With Major GI Bleeding. Journal of Atrial Fibrillation. 2015;8(3):1218. DOI: 10.4022/jafib.1218
45. Desai J, Granger CB, Weitz JI, Aisenberg J. Novel oral anticoagulants in gastroenterology practice. Gastrointestinal Endoscopy. 2013;78(2):227–39. DOI: 10.1016/j.gie.2013.04.179
46. 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 Metabolism and Disposition. 2008;36(2):386–99. DOI: 10.1124/dmd.107.019083
47. Toya Y, Nakamura S, Tomita K, Matsuda N, Abe K, Abiko Y et al. Dabigatran-induced esophagitis: The prevalence and endoscopic characteristics: Dabigatran-induced esophagitis. Journal of Gastroenterology and Hepatology. 2016;31(3):610–4. DOI: 10.1111/jgh.13024
48. Thomopoulos KC. Acute upper gastrointestinal bleeding in patients on long-term oral anticoagulation therapy: Endoscopic findings, clinical management and outcome. World Journal of Gastroenterology. 2005;11(9):1365–8. DOI: 10.3748/wjg.v11.i9.1365
49. 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. Gastrointestinal Endoscopy. 2003;58(3):369–73. PMID: 14528210
50. Endo H, Hosono K, Inamori M, Nozaki Y, Yoneda K, Fujita K et al. Characteristics of small bowel injury in symptomatic chronic low-dose aspirin users: the experience of two medical centers in capsule endoscopy. Journal of Gastroenterology. 2009;44(6):544–9. DOI: 10.1007/s00535-009-0040-z
51. Балабанцева А.П., Каратеев А.E. Частота и клинико-эндоскопические особенности сочетанных НПВП-индуцированных гастроинтестинальных повреждений. Современная ревматология. 2018;12(4):95-100. DOI: 10.14412/1996-7012-2018-4-95-100
52. Вахрушев Я.М., Загребина Е.А. Энтеропатия, индуцированная нестероидными противовоспалительными препаратами (патогенез, диагностика, лечение). Терапевтический архив. 2012;84(5):74-9
53. Rao SV, Eikelboom J, Steg PhG, Lincoff AM, Weintraub WS, Bassand J-P et al. Standardized reporting of bleeding complications for clinical investigations in acute coronary syndromes: A proposal from the Academic Bleeding Consensus (ABC) Multidisciplinary Working Group. American Heart Journal. 2009;158(6):881-886.e1. DOI: 10.1016/j.ahj.2009.10.008
54. Flack KF, Desai J, Kolb JM, Chatterjee P, Wallentin LC, Ezekowitz M 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. Clinical Gastroenterology and Hepatology. 2017;15(5):682–90. DOI: 10.1016/j.cgh.2016.10.011
55. Sostres C, Gargallo CJ, Arroyo MT, Lanas A. Adverse effects of non-steroidal anti-inflammatory drugs (NSAIDs, aspirin and coxibs) on upper gastrointestinal tract. Best Practice & Research Clinical Gastroenterology. 2010;24(2):121–32. DOI: 10.1016/j.bpg.2009.11.005
56. Барановский А.Ю. Диагностика, профилактика и лечение НПВПиндуцированной колонопатии. Экспериментальная и клиническая гастроэнтерология. 2017;10:4-14. DOI: 10.31146/1682-8658-ecg
57. Tai FWD, McAlindon ME. NSAIDs and the small bowel: Current Opinion in Gastroenterology. 2018;34(3):175–82. DOI: 10.1097/MOG.0000000000000427
58. Sands G, Shell B, Zhang R. Adverse Events in Patients with Blood Loss: A Pooled Analysis of 51 Clinical Studies from the Celecoxib Clinical Trial Database. The Open Rheumatology Journal. 2012;6(1):44–9. DOI: 10.2174/1874312901206010044
59. Канорский С.Г., Гиляревский С.Р., Тарасов А.В., Жук В.С., Явелов И.С. Новые рекомендации EHRA по антикоагулянтной терапии у больных с фибрилляцией предсердий: комментарии российских экспертов. Международный журнал сердца и сосудистых заболеваний. 2018;6(19):44-56
60. Лазебник Л.Б., Голованова Е.В., Алексеенко С.А., Бакулина Н.В., Барановский А.Ю., Белова Г.В. и др. Рекомендации по профилактике и лечению эзофаго-гастро- энтеро-колопатий, индуцированных нестероидными противовоспалительными препаратами (НПВП). Экспериментальная и клиническая гастроэнтерология. 2018;3:4-18. DOI: 10.31146/1682-8658-ecg
61. Мороз Е.В., Каратеев А.Е., Крюков Е.В., Чернецов В.А. Желудочно-кишечные кровотечения при использовании новых пероральных антикоагулянтов: эпидемиология, факторы риска, лечение и профилактика. Научно-практическая ревматология. 2017;55(6):675-84. DOI: 10.14412/1995-4484-2017-675-684
62. Radaelli F, Dentali F, Repici A, Amato A, Paggi S, Rondonotti E et al. Management of anticoagulation in patients with acute gastrointestinal bleeding. Digestive and Liver Disease. 2015;47(8):621–7. DOI: 10.1016/j.dld.2015.03.029
63. Sugano K, Choi M-G, Lin J-T, Goto S, Okada Y, Kinoshita Y et al. Multinational, double-blind, randomised, placebo-controlled, prospective study of esomeprazole in the prevention of recurrent peptic ulcer in low-dose acetylsalicylic acid users: the LAVENDER study. Gut. 2014;63(7):1061–8. DOI: 10.1136/gutjnl-2013-304722
64. Scheiman JM, Lanas A, Veldhuyzen van Zanten S, Baldycheva I, Svedberg L-E, Nagy P. Effect of esomeprazole on gastroduodenal erosions in patients at increased gastrointestinal risk treated with low-dose acetylsalicylic acid: A post-hoc analysis of the OBERON trial. International Journal of Cardiology. 2015;182:500–2. DOI: 10.1016/j.ijcard.2014.12.140
65. Mo C. Proton pump inhibitors in prevention of low-dose aspirin-associated upper gastrointestinal injuries. World Journal of Gastroenterology. 2015;21(17):5382–92. DOI: 10.3748/wjg.v21.i17.5382
66. Niu Q, Wang Z, Zhang Y, Wang J, Zhang P, Wang C et al. Combination Use of Clopidogrel and Proton Pump Inhibitors Increases Major Adverse Cardiovascular Events in Patients With Coronary Artery Disease: A Meta-Analysis. Journal of Cardiovascular Pharmacology and Therapeutics. 2017;22(2):142–52. DOI: 10.1177/1074248416663647
67. Veitch AM, Vanbiervliet G, Gershlick AH, Boustiere C, Baglin TP, Smith L-A 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. Gut. 2016;65(3):374–89. DOI: 10.1136/gutjnl-2015-311110
68. Hawkey CJ, Karrasch JA, Szczepañski L, Walker DG, Barkun A, Swannell AJ et al. Omeprazole Compared with Misoprostol for Ulcers Associated with Nonsteroidal Antiinflammatory Drugs. Omeprazole versus Misoprostol for NSAID-induced Ulcer Management (OMNIUM) Study Group. New England Journal of Medicine. 1998;338(11):727–34. DOI: 10.1056/NEJM199803123381105
69. Yeomans ND, Tulassay Z, Juhász L, Rácz I, Howard JM, van Rensburg CJ et al. A Comparison of Omeprazole with Ranitidine for Ulcers Associated with Nonsteroidal Antiinflammatory Drugs. Acid Suppression Trial: Ranitidine versus Omeprazole for NSAID-associated Ulcer Treatment (ASTRONAUT) Study Group. New England Journal of Medicine. 1998;338(11):719–26. DOI: 10.1056/NEJM199803123381104
70. Ивашкин В.Т., Маев И.В., Лапина Т.Л., Шептулин А.А., Трухманов А.С., Баранская Е.К. и др. Клинические рекомендации Российской гастроэнтерологической ассоциации по диагностике и лечению инфекции Helicobacter pylori у взрослых. Российский журнал гастроэнтерологии, гепатологии, колопроктологии. 2018;28(1):55- 70. DOI: 10.22416/1382-4376-2018-28-1-55-70
71. Каратеев А.Е., Насонов Е.Л., Успенский Ю.П., Пахомова И.Г. Комбинированное лечение язв желудка, индуцированных нестероидными противовоспалительными препаратами. Результаты 4-недельного открытого контролируемого исследования по оценке эффективности комбинации ингибитора протонного насоса и висмута трикалия дицитрата. Терапевтический Архив. 2009;81(6):62-7
72. Mizukami K. Aspirin-induced small bowel injuries and the preventive effect of rebamipide. World Journal of Gastroenterology. 2011;17(46):5117–22. DOI: 10.3748/wjg.v17.i46.5117
73. Tozawa K, Oshima T, Okugawa T, Ogawa T, Ohda Y, Tomita T et al. A Randomized, Double-Blind, Placebo-Controlled Study of Rebamipide for Gastric Mucosal Injury Taking Aspirin With or Without Clopidogrel. Digestive Diseases and Sciences. 2014;59(8):1885–90. DOI: 10.1007/s10620-014-3108-4
74. Kurokawa S, Katsuki S, Fujita T, Saitoh Y, Ohta H, Nishikawa K et al. A randomized, double-blinded, placebo-controlled, multicenter trial, healing effect of rebamipide in patients with low-dose aspirin and/or non-steroidal anti-inflammatory drug induced small bowel injury. Journal of Gastroenterology. 2014;49(2):239–44. DOI: 10.1007/s00535-013-0805-2
75. Watanabe T, Takeuchi T, Handa O, Sakata Y, Tanigawa T, Shiba M et al. A Multicenter, Randomized, Double-Blind, PlaceboControlled Trial of High-Dose Rebamipide Treatment for LowDose Aspirin-Induced Moderate-to-Severe Small Intestinal Damage. PLOS ONE. 2015;10(4):e0122330. DOI: 10.1371/journal.pone.0122330
76. Lim YJ, Chun HJ. Recent Advances in NSAIDs-Induced Enteropathy Therapeutics: New Options, New Challenges. Gastroenterology Research and Practice. 2013;2013:761060. DOI: 10.1155/2013/761060
77. Fornai M, Antonioli L, Pellegrini C, Colucci R, Sacco D, Tirotta E et al. Small bowel protection against NSAID-injury in rats: Effect of rifaximin, a poorly absorbed, GI targeted, antibiotic. Pharmacological Research. 2016;104:186–96. DOI: 10.1016/j.phrs.2015.12.031
78. Scarpignato C, Dolak W, Lanas A, Matzneller P, Renzulli C, Grimaldi M et al. Rifaximin Reduces the Number and Severity of Intestinal Lesions Associated With Use of Nonsteroidal Anti-Inflammatory Drugs in Humans. Gastroenterology. 2017;152(5):980-982.e3. DOI: 10.1053/j.gastro.2016.12.007
79. Endo H, Higurashi T, Hosono K, Sakai E, Sekino Y, Iida H et al. Efficacy of Lactobacillus casei treatment on small bowel injury in chronic low-dose aspirin users: a pilot randomized controlled study. Journal of Gastroenterology. 2011;46(7):894– 905. DOI: 10.1007/s00535-011-0410-1
80. Suzuki T, Masui A, Nakamura J, Shiozawa H, Aoki J, Nakae H et al. Yogurt Containing Lactobacillus gasseri Mitigates Aspirin-Induced Small Bowel Injuries: A Prospective, Randomized, Double-Blind, Placebo-Controlled Trial. Digestion. 2017;95(1):49–54. DOI: 10.1159/000452361
81. Steffel J, Verhamme P, Potpara TS, Albaladejo P, Antz M, Desteghe L et al. The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. European Heart Journal. 2018;39(16):1330–93. DOI: 10.1093/eurheartj/ehy136