Профилактика желудочно-кишечных кровотечений у пациентов, получающих пероральные антикоагулянты: фокус на ингибиторы протонной помпы

В обзоре рассматривается проблема развития желудочно-кишечных кровотечений (ЖКК) у пациентов, получающих пероральные антикоагулянты, и возможности ингибиторов протонной помпы (ИПП) в снижении частоты таких осложнений. Представлены эпидемиологические данные о распространенности ЖКК на фоне приема новых оральных антикоагулянтов (НОАК) и варфарина. Обсуждаются факторы, повышающие риск кровотечений, ассоциированных с применением антикоагулянтов, в т.ч. потенциально возможные межлекарственные взаимодействия и особенности рациона питания больных. Дано описание шкал, оценивающих вероятность развития кровотечений на фоне антикоагулянтной терапии. Во второй части обзора рассматриваются принципы профилактики и минимизации риска ЖКК при назначении НОАК. С точки зрения доказательной медицины подробно обсуждается роль ИПП в снижении риска ЖКК. Детально описаны результаты масштабных рандомизированных, клинических исследований и мета-анализов последних лет, свидетельствующие о способности ИПП благоприятно влиять на риск кровотечений из верхних отделов желудочно-кишечного тракта при приеме НОАК и варфа-рина, особенно при сопутствующей терапии ацетилсалициловой кислотой, благодаря чему ИПП могут рассматриваться в качестве одного из эффективных “инструментов” медикаментозной профилактики указанных осложнений.

1. Naccarelli GV, Johnston SS, Dalal M, et al. Rates and implications for hospitalization of patients >/= 65 years of age with atrial fibrillation/flutter. Am J Cardiol. 2012;109(4):543-9. https://doi.org/10.1016/j.amjcard.2011.10.009.

2. Miyasaka Y, Barnes ME, Gersh BJ, et al. Secular trends in incidence of atrial fibrillation in Olmsted County, Minnesota, 1980 to 2000, and implications on the projections for future prevalence. Circulation. 2006;114(2):119-25. https://doi.org/10.1161/circulationaha.105.595140.

3. Desai NR, Krumme AA, Schneeweiss S, et al. Patterns of initiation of oral anticoagulants in patients with atrial fibrillation-quality and cost implications. Am J Med. 2014;127(11):1075-82.e1. https://doi.org/10.1016/j.amjmed.2014.05.013.

4. Holster IL, Hunfeld NG, Kuipers EJ, et al. On the treatment of new oral anticoagulant-associated gastrointestinal hemorrhage. J Gastrointestin Liver Dis. 2013;22(2):229-31. https://doi.org/10.1053/j.gastro.2013.02.041.

5. Holster IL, Valkhoff VE, Kuipers EJ, et al. New oral anticoagulants increase risk for gastrointestinal bleeding: a systematic review and meta-analysis. Gastroenterology 2013;145(1):105-12.e15. https://doi.org/10.1053/j.gastro.2013.02.041.

6. Coleman CI, Sobieraj DM, Winkler S, et al. Effect of pharmacological therapies for stroke prevention on major gastrointestinal bleeding in patients with atrial fibrillation. Int J Clin Pract. 2012;66(1):53-63. https://doi.org/10.1111/j.1742-1241.2011.02809.x.14.

7. Abraham NS. Novel oral anticoagulants and gastrointestinal bleeding: a case for cardiogastroenterology. Clin Gastroenterol Hepatol. 2013;11(4):324-8. https://doi.org/101016/j.15.cgh.2012.12.013.

8. Abraham NS, Castillo DL. Novel anticoagulants: bleeding risk and management strategies. Curr Opin Gastroenterol. 2013;29(6):676-83. https://doi.org/10.1097/MOG.0b013e328365d415.

9. Abraham NS. Gastrointestinal bleeding in cardiac patients: epidemiology and evolving clinical paradigms. Curr Opin Gastroenterol. 2014;30(6):609-14. https://doi.org/10.1097/MOG.0000000000000122.

10. Barnes GD, Lucas E, Alexander GC, et al. National trends in ambulatory oral anticoagulant use. Am J Med. 2015;128(12):1300-5.e2. https://doi.org/10.1016/j.amjmed.2015.05.044.

11. Ruff CT, Giugliano RP, Braunwald E, et al. Comparison of the efficacy and safety of new oral anticoagulants with warfarin in patients with atrial fibrillation: a metaanalysis of randomised trials. Lancet. 2014;383(9921):955-62. https://doi.org/10.1016/S0140-6736(13)62343-0.

12. Abraham NS. Prevention of Gastrointestinal Bleeding in Patients Receiving Direct Oral Anticoagulants. Am J Gastroenterol. Suppl. 2016;3:2-12. https://doi.org/10.1038/ajgsup.2016.2.

13. Graham DJ, Reichman ME, Wernecke M, et al. Cardiovascular, bleeding, and mortality risks in elderly Medicare patients treated with dabigatran or warfarin for nonvalvular atrial fibrillation. Circulation. 2015;131 (2): 157-64. https://doi.org/10.1161/circulationaha.114.012061.

14. Hernandez I, Baik SH, Pinera A, et al. Risk of bleeding with dabigatran in atrial fibrillation. JAMA Intern Med. 2015;175(1):18-24. https://doi.org/10.1001/jamainternmed.2014.5398.

15. Hylek EM, Held C, Alexander JH, et al. Major bleeding in patients with atrial fibrillation receiving apixaban or warfarin: The ARISTOTLE Trial (apixaban for reduction in stroke and other thromboembolic events in atrial fibrillation): predictors, characteristics, and clinical outcomes. JACC. 2014;63(20):2141-7 https://doi.org/10.1016/j.jacc.2014.02.549.

16. Lin L, Lim WS, Zhou HJ, et al. Clinical and safety outcomes of oral antithrombotics for stroke prevention in atrial fibrillation: a systematic review and network meta-analysis. J Am Med Dir Assoc. 2015; 16(12):1103.e1-19. https://doi.org/101016/j.jamda.2015.09.008.

17. Romanelli RJ, Nolting L, Dolginsky M, et al. Dabigatran versus warfarin for atrial fibrillation in real-world clinical practice. A systematic review and metaanalysis. Circ Cardiovasc Qual Outcomes. 2016;9(2):126-34. https://doi.org/10.1161/CIRCOUTCOMES115.002369.

18. 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;123(21):2363-72. https://doi.org/10.1161/CIRCULATIONAHA.110.004747.

19. Harper P, Young L, Merriman E. Bleeding risk with dabigatran in the frail elderly. N Engl J Med. 2012;366(9):864-6. https://doi.org/10.1056/NEJMc1112874.

20. Kubitza D, Becka M, Zuehlsdorf M, et al. Body weight has limited infl uence on the safety, tolerability, pharmacokinetics, or pharmacodynamics of rivaroxaban (BAY 59-7939) in healthy subjects. J Clin Pharmacol. 2007;47(2):218-26. https://doi.org/10.1177/0091270006296058.

21. Gong IY, Kim RB. Importance of pharmacokinetic profile and variability as determinants of dose and response to dabigatran, rivaroxaban, and apixaban. Can J 43. Cardiol. 2013 ;29(7 Suppl):S24-33. https://doi.org/10.1016/j.cjca.2013.04.002.

22. Steinberg BA, Kim S, Piccini JP, et al. ORBIT-AF Investigators and Patients. Use and associated risks of concomitant aspirin therapy with oral anticoagulation in patients with atrial fibrillation: insights from the Outcomes Registry for Better Informed Treatment of Atrial Fibrillation (ORBIT-AF) Registry. Circulation. 2013;128(7):721-8.. https://doi.org/10.1161/circulationaha.113.002927.

23. Dans AL, Connolly SJ, Wallentin L, et al. Concomitant use of antiplatelet therapy with dabigatran or warfarin in the Randomized Evaluation of Long- Term 45. Anticoagulation Therapy (RE-LY) trial. Circulation. 2013;127(5):634-40. https://doi.org/10.1161/CIRCULATIONAHA.112.115386.

24. Goodman SG, Wojdyla DM , Piccini JP, et al. Factors associated with major bleeding 46. events: insights from the ROCKET AF trial (rivaroxaban oncedaily oral direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and embolism trial in atrial fi brillation). JACC. 2014;63(9):891-900. https://doi.org/10.1016/j.jacc.2013.11.013.

25. Hess CN, James S, Lopes RD, et al. Apixaban plus mono versus dual antiplatelet therapy in acute coronary syndromes: insights from the APPRAISE-2 trial. J Am Coll Cardiol. 2015;66(7):777-87. https://doi.org/10.1016/j.jacc.2015.06.027.

26. Desai J, Kolb JM, Weitz JI, et al. Gastrointestinal bleeding with the new oral anticoagulants - defining the issues and the management strategies. Thromb 48. Haemost. 2013;110(2):205-12. https://doi.org/10.1160/TH13-02-0150.

27. Kirchhof P, Benussi S, Kotecha D, et al. 2016 ESC Guidelines for the Management of Atrial Fibrillation Developed in Collaboration With EACTS. Rev Esp Cardiol (Engl Ed). 49. 2017;70(1):50. https://doi.org/10.1016/j.rec.2016.11.033.

28. Steffel J, Verhamme P, Potpara TS, et al. ESC Scientific Document Group. The 2018 European Heart Rhythm Association Practical Guide on the use of non-vitamin K antagonist oral anticoagulants in patients with atrial fibrillation. Eur Heart J. 2018 Apr 50. 21;39(16):1330-93. https://doi.org/10.1093/eurheartj/ehy136.

29. Sorensen R, Hansen ML, Abildstrom SZ, et al. Risk of bleeding in patients with acute myocardial infarction treated with different combinations of aspirin, clopidogrel, and vitamin K antagonists in Denmark: a retrospective analysis of nationwide registry data. Lancet. 2009;374(9706):1967-74. https://doi.org/10.1016/S0140-6736(09)61751-7.

30. Abraham NS, Hartman C, Richardson P, et al. Risk of lower and upper gastrointestinal bleeding, transfusions, and hospitalizations with complex antithrombotic therapy in elderly patients. Circulation. 2013; 128( 17): 1869-77. https://doi.org/10.1161/CIRCULATIONAHA.113.004747.

31. Buresly K, Eisenberg MJ, Zhang X, et al. Bleeding complications associated with combinations of aspirin, thienopyridine derivatives, and warfarin in elderly patients following acute myocardial infarction. Arch Intern Med. 2005;165(7):784-9. https://doi.org/10.1001/archinte.165.7.784.

32. Hallas J, Dall M, Andries A, et al. Use of single and combined antithrombotic therapy and risk of serious upper gastrointestinal bleeding: population based case-control study. BMJ. 2006;333(7571):726. https://doi.org/10.1136/bmj.38947.697558.AE.

33. Abraham NS, Singh S, Alexander GC, et al. Comparative risk of gastrointestinal bleeding with dabigatran, rivaroxaban, and warfarin: population based cohort study. BMJ. 2015;350:h1857. https://doi.org/10.1136/bmj.h1857.

34. Komocsi A, Vorobcsuk A, Kehl D, et al. Use of new-generation oral anticoagulant agents in patients receiving antiplatelet therapy after an acute coronary syndrome: systematic review and meta-analysis of randomized controlled trials. Arch Intern Med. 2012;172(20):1537-45. https://doi.org/10.1001/archinternmed.2012.4026.

35. Alexander JH, Lopes RD, James S, et al. APPRAISE-2 Investigators. Apixaban with antiplatelet therapy after acute coronary syndrome. N Engl J Med. 2011;365(8):699-708. https://doi.org/10.1056/NEJMoa1105819.

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

37. Russian State Register of Pharmaceutical Products for Medical Purposes. Available at: http://grls.rosminzdrav.ru/Default.aspx (Accessed 12.02.2019). (In Russ.) Государственный реестр лекарственных средств. Available at: http://grls.rosminzdrav.ru/Default.aspx (дата обращения 12.02.2019).

38. Deferme S, Augustijns P. The effect of food components on the absorption of P-gp substrates: a review. J Pharmacy Pharmacolog. 2003;55(2):153-62. https://doi.org/10.1211/002235702603.

39. Drugbank. Available at: https://www.drugbank.ca (Accessed 12.02.2019).

40. Pisters R, Lane DA, Nieuwlaat R, et al. A novel user-friendly score (HASBLED) to assess 1-year risk of major bleeding in patients with atrial fibrillation: the Euro Heart Survey. Chest. 2010;138(5):1093-100. https://doi.org/10.1378/chest.10-0134.

41. Steinberg BA, Beckley PD, Deering TF, et al. Society of Cardiovascular Patient Care. Evaluation and management of the atrial fibrillation patient: a report from the Society of Cardiovascular Patient Care. Crit Pathw Cardiol. 2013;12(3):107-15. https://doi.org/10.1097/HPC.0b013e31829834ed.

42. Lip GY, Frison L, Halperin JL, et al. Comparative validation of a novel risk score for predicting bleeding risk in anticoagulated patients with atrial fibrillation: the HAS-BLED (hypertension, abnormal renal/liver function, stroke, bleeding history or predisposition, labile INR, elderly, drugs/alcohol concomitantly) score. JACC. 2011;57(2):173-80. https://doi.org/10.1016/j.jacc.2010.09.024.

43. Camm AJ, Lip GY, De Caterina R, et al. ESC Committee for Practice Guidelines (CPG). 2012 focused update of the ESC Guidelines for the management of atrial fibrillation: an update of the 2010 ESC Guidelines for the management of atrial fibrillation. Developed with the special contribution of the European Heart Rhythm Association. Eur Heart J. 2012;33(21):2719-47. https://doi.org/10.1093/eurheartj/ehs253.

44. Fang MC, Go AS, Chang Y, et al. A new risk scheme to predict warfarin-associated hemorrhage: The ATRIA (anticoagulation and risk factors in atrial fibrillation) Study. JACC. 2011;58(4):395-401. https://doi.org/10.1016/j.jacc.2011.03.031.

45. Hippisley-Cox J, Coupland C. Predicting risk of upper gastrointestinal bleed and intracranial bleed with anticoagulants: cohort study to derive and validate the QBleed scores. BMJ. 2014;349:g4606. https://doi.org/10.1136/bmj.g4606.

46. Barnes GD, Gu X, Haymart B, et al. The predictive ability of the CHADS2 and CHA2DS2-VASc scores for bleeding risk in atrial fibrillation: the MAQI(2) experience. Thromb Res. 2014;134(2):294-9. https://doi.org/101016/j.thromres.2014.05.034.

47. Bhatt DL, Scheiman J, Abraham NS, 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. https://doi.org/10.1161/CIRCULATIONAHA.108.191087.

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

49. Heidbuchel H, Verhamme P, Alings M, et al. European Heart Rhythm Association. European Heart Rhythm Association Practical Guide on the use of new oral anticoagulants in patients with non-valvular atrial fibrillation. Europace. 2013;15(5):625-51. https://doi.org/10.1093/europace/eut083.

50. Abraham NS, Hlatky MA, Antman EM, et al. ACCF/ACG/AHA. ACCF/ACG/AHA 2010 Expert Consensus Document on the concomitant use of proton pump inhibitors and thienopyridines: a focused update of the 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 Expert Consensus Documents. Circulation. 2010; 122(24):2619-33. https://doi.org/10.1161/CIR.0b013e318202f701.

51. Chan EW, Lau WC, Leung WK, et al. Prevention of dabigatran-related gastrointestinal bleeding with gastroprotective agents: a population-based study. Gastroenterology. 2015;149(3):586-95.e3. https://doi.org/10.1053/j.gastro.2015.05.002

52. Salem JE, Sabouret P, Funck-Brentano C, et al. Pharmacology and mechanisms of action of new oral anticoagulants. Fundam Clin Pharmacol. 2015;29(1):10-20. https://doi.org/10.1111/fcp.12091.

53. Lip GY, Nieuwlaat R, Pisters R, et al. Refining clinical risk stratification for predicting stroke and thromboembolism in atrial fi brillation using a novel risk factor-based approach: the euro heart survey on atrial fibrillation. Chest. 2010;137(2):263-72. https://doi.org/10.1378/chest.09-1584.

54. Strate LL, Liu YL, Huang ES, et al. Use of aspirin or nonsteroidal antiinflammatory drugs increases risk for diverticulitis and diverticular bleeding. Gastroenterology. 2011;140(5):1427-33. https://doi.org/101053/j.gastro.2011.02.004.

55. Brunner G, Creutfeldt W. Omeprazole in the long-term treatment of patients with acid-related disease resistant to ranitidine. Scand J Gastroenterol. 1989;24(Suppl 166):101-5. https://doi.org/10.3109/00365528909091254.

56. Ray WA, Chung CP, Murray KT, et al. Association of oral anticoagulants and proton pump inhibitor cotherapy with hospitalization for upper gastrointestinal tract bleeding. JAMA. 2018;320(21):2221-30. https://doi.org/10.1001/jama.2018.17242.

57. Ray WA, Chung CP, Murray KT, et al. Association of proton pump inhibitors with reduced risk of warfarin-related serious upper gastrointestinal bleeding. Gastroenterology. 2016;151(6):1105-12.e10. https://doi.org/10.1053/j.gastro.2016.08.054.