Фибрилляция предсердий и полиморбидность: как выбрать идеальный прямой оральный антикоагулянт?

Фибрилляция предсердий является одной из наиболее часто встречаемых тахиаритмий, распространенность которой в связи с увеличением доли пожилого населения неуклонно растет. Наличие большого числа сопутствующей патологии у пожилых пациентов с фибрилляцией предсердий, увеличивая риск тромбоэмболических событий, оказывает значимое влияние на клиническое течение фибрилляции предсердий, а также на выбор терапевтической тактики, в особенности антикоагулянтной терапии с доказанной эффективностью и низким риском развития кровотечений. Одними из частых сопутствующих заболеваний у пациентов с фибрилляцией предсердий являются нарушение функции почек, анемия, а также ишемическая болезнь сердца, которые не только повышают риск развития инсульта и (или) системной эмболии, но и сопровождаются увеличением риска сердечно-сосудистой смертности, смертности от всех причин, развития геморрагических событий. При этом, по данным исследований, около половины полиморбидных пациентов с фибрилляцией предсердий не получают антикоагулянтную терапию, что свидетельствует о низкой информированности врачей о рациональной, основанной на клинических рекомендациях фармакотерапии данной когорты пациентов. Препаратом выбора с наиболее изученным профилем безопасности и высокой степенью эффективности у таких пациентов является апиксабан из группы прямых оральных антикоагулянтов. В отличие от антагонистов витамина K и других представителей прямых оральных антикоагулянтов, апиксабан, по данным проведенных исследований, ассоциирован с более значимым снижением риска развития тромбоэмболических событий, а главное, в меньшей степени оказывает влияние на риски кровотечений у пациентов с фибрилляцией предсердий и сопутствующей ишемической болезнью сердца, анемией, хронической болезнью почек, и так предрасположенных к возникновению геморрагических осложнений.

1. Lippi G, Sanchis-Gomar F, Cervellin G. Global epidemiology of atrial fibrillation: An increasing epidemic and public health challenge. Int J Stroke. 2021;16(2):217–221. https://doi.org/10.1177/1747493019897870.

2. Kavousi M. Differences in Epidemiology and Risk Factors for Atrial Fibrillation Between Women and Men. Front Cardiovasc Med. 2020;7:3. https://doi.org/10.3389/fcvm.2020.00003.

3. Kornej J, Börschel CS, Benjamin EJ, Schnabel RB. Epidemiology of Atrial Fibrillation in the 21st Century: Novel Methods and New Insights. Circ Res. 2020;127(1):4–20. https://doi.org/10.1161/CIRCRESAHA.120.316340.

4. Ohlrogge AH, Brederecke J, Schnabel RB. Global Burden of Atrial Fibrillation and Flutter by National Income: Results From the Global Burden of Disease 2019 Database. J Am Heart Assoc. 2023;12(17):e030438. https://doi.org/10.1161/JAHA.123.030438.

5. Lloyd-Jones DM, Wang TJ, Leip EP, Larson MG, Levy D, Vasan RS et al. Lifetime risk for development of atrial fibrillation: the Framingham Heart Study. Circulation. 2004;110(9):1042–1046. https://doi.org/10.1161/01.CIR.0000140263.20897.42.

6. Ардашев АВ, Беленков ЮН, Матюкевич МЧ, Снежицкий ВА. Фибрилляция предсердий и смертность: прогностические факторы и терапевтические стратегии. Кардиология. 2021;61(2):91–98. https://doi.org/10.18087/cardio.2021.2.n1348.

7. Benjamin EJ, Wolf PA, D’Agostino RB, Silbershatz H, Kannel WB, Levy D. Impact of atrial fibrillation on the risk of death: the Framingham Heart Study. Circulation. 1998;98(10):946–952. https://doi.org/10.1161/01.cir.98.10.946.

8. Chugh SS, Havmoeller R, Narayanan K, Singh D, Rienstra M, Benjamin EJ et al. Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study. Circulation. 2014;129(8):837–847. https://doi.org/10.1161/CIRCULATIONAHA.113.005119.

9. Miyasaka Y, Barnes ME, Gersh BJ, Cha SS, Bailey KR, Abhayaratna WP 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):119–125. https://doi.org/10.1161/CIRCULATIONAHA.105.595140.

10. Stroke Risk in Atrial Fibrillation Working Group. Independent predictors of stroke in patients with atrial fibrillation: a systematic review. Neurology. 2007;69(6):546–554. https://doi.org/10.1212/01.wnl.0000267275.68538.8d.

11. Forman DE, Goyette RE. Oral anticoagulation therapy for elderly patients with atrial fibrillation: utility of bleeding risk covariates to better understand and moderate risks. Clin Appl Thromb Hemost. 2014;20(1):5–15. https://doi.org/10.1177/1076029613492010.

12. Van den Bussche H, Koller D, Kolonko T, Hansen H, Wegscheider K, Glaeske G et al. Which chronic diseases and disease combinations are specific to multimorbidity in the elderly? Results of a claims data based crosssectional study in Germany. BMC Public Health. 2011;11:101. https://doi.org/10.1186/1471-2458-11-101.

13. LaMori JC, Mody SH, Gross HJ, daCosta DiBonaventura M, Patel AA, Schein JR, Nelson WW. Burden of comorbidities among patients with atrial fibrillation. Ther Adv Cardiovasc Dis. 2013;7(2):53–62. https://doi.org/10.1177/1753944712464101.

14. Kozieł M, Teutsch C, Halperin JL, Rothman KJ, Diener HC, Ma CS et al. Atrial fibrillation and comorbidities: Clinical characteristics and antithrombotic treatment in GLORIA-AF. PLoS ONE. 2021;16(4):e0249524. https://doi.org/10.1371/journal.pone.0249524.

15. Vanbeselaere V, Truyers C, Elli S, Buntinx F, De Witte H, Degryse J et al. Association between atrial fibrillation, anticoagulation, risk of cerebrovascular events and multimorbidity in general practice: a registry-based study. BMC Cardiovasc Disord. 2016;16:61. https://doi.org/10.1186/s12872-016-0235-1.

16. Van Walraven C, Hart RG, Connolly S, Austin PC, Mant J, Hobbs FD et al. Effect of age on stroke prevention therapy in patients with atrial fibrillation: the atrial fibrillation investigators. Stroke. 2009;40(4):1410–1416. https://doi.org/10.1161/STROKEAHA.108.526988.

17. 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. Eur Heart J. 2018;39(16):1330–1393. https://doi.org/10.1093/eurheartj/ehy136.

18. Friberg L, Hammar N, Rosenqvist M. Stroke in paroxysmal atrial fibrillation: report from the Stockholm Cohort of Atrial Fibrillation. Eur Heart J. 2010;31(8):967–975. https://doi.org/10.1093/eurheartj/ehn599.

19. Fumagalli S, Said SA, Laroche C, Gabbai D, Boni S, Marchionni N et al. Management and prognosis of atrial fibrillation in diabetic patients: an EORP-AF General Pilot Registry report. Eur Heart J Cardiovasc Pharmacother. 2018;4(3):172–179. https://doi.org/10.1093/ehjcvp/pvx037.

20. Soliman EZ, Prineas RJ, Go AS, Xie D, Lash JP, Rahman M et al. Chronic kidney disease and prevalent atrial fibrillation: the Chronic Renal Insufficiency Cohort (CRIC). Am Heart J. 2010;159(6):1102–1107. https://doi.org/10.1016/j.ahj.2010.03.027.

21. Ananthapanyasut W, Napan S, Rudolph EH, Harindhanavudhi T, Ayash H, Guglielmi KE, Lerma EV. Prevalence of atrial fibrillation and its predictors in nondialysis patients with chronic kidney disease. Clin J Am Soc Nephrol. 2010;5(2):173–181. https://doi.org/10.2215/CJN.03170509.

22. Wetmore JB, Mahnken JD, Rigler SK, Ellerbeck EF, Mukhopadhyay P, Spertus JA et al. The prevalence of and factors associated with chronic atrial fibrillation in Medicare/Medicaid-eligible dialysis patients. Kidney Int. 2012;81(5):469–476. https://doi.org/10.1038/ki.2011.416.

23. Дружилов МА, Кузнецова ТЮ, Дружилова ОЮ, Арустамова УД, Гаврилов ДВ, Гусев АВ. Фибрилляция предсердий и хроническая болезнь почек: основные клинические характеристики пациентов в отдельных субъектах Российской Федерации. Кардиоваскулярная терапия и профилактика. 2023;22(4):3544. https://doi.org/10.15829/1728-8800-2023-3544.

24. Yao RJR, Holmes DN, Andrade JG, Levin A, Piccini JP, Fordyce CB. Variability in Nonvitamin K Oral Anticoagulant Dose Eligibility and Adjustment According to Renal Formulae and Clinical Outcomes in Patients With Atrial Fibrillation With and Without Chronic Kidney Disease: Insights From ORBIT-AF II. J Am Heart Assoc. 2023;12(6):e026605. https://doi.org/10.1161/JAHA.122.026605.

25. Cha MJ, Cho Y, Oh IY, Choi EK, Oh S. Validation of Conventional Thromboembolic Risk Factors in a Korean Atrial Fibrillation Population – Suggestion for a Novel Scoring System, CHA2DS2-VAK. Circ J. 2018;82(12):2970–2975. https://doi.org/10.1253/circj.CJ-18-0218.

26. Liao JN, Chao TF, Liu CJ, Wang KL, Chen SJ, Lin YJ et al. Incidence and risk factors for new-onset atrial fibrillation among patients with end-stage renal disease undergoing renal replacement therapy. Kidney Int. 2015;87(6):1209–1215. https://doi.org/10.1038/ki.2014.393.

27. Nelson SE, Shroff GR, Li S, Herzog CA. Impact of chronic kidney disease on risk of incident atrial fibrillation and subsequent survival in medicare patients. J Am Heart Assoc. 2012;1(4):e002097. https://doi.org/10.1161/JAHA.112.002097.

28. Arnson Y, Hoshen M, Berliner-Sendrey A, Reges O, Balicer R, Leibowitz M et al. Risk of Stroke, Bleeding, and Death in Patients with Nonvalvular Atrial Fibrillation and Chronic Kidney Disease. Cardiology. 2020;145(3):178–186. https://doi.org/10.1159/000504877.

29. Goto S, Angchaisuksiri P, Bassand JP, Camm AJ, Dominguez H, Illingworth L et al. Management and 1-Year Outcomes of Patients With Newly Diagnosed Atrial Fibrillation and Chronic Kidney Disease: Results From the Prospective GARFIELD – AF Registry. J Am Heart Assoc. 2019;8(3):e010510. https://doi.org/10.1161/JAHA.118.010510.

30. Аракелян МГ, Бокерия ЛА, Васильева ЕЮ, Голицын СП, Голухова ЕЗ, Горев МВ и др. Фибрилляция и трепетание предсердий у взрослых: клинические рекомендации. М.; 2020. 152 с. Режим доступа: https://cr.minzdrav.gov.ru/recomend/382_1.

31. Bonde AN, Lip GY, Kamper AL, Fosbøl EL, Staerk L, Carlson N et al. Renal Function and the Risk of Stroke and Bleeding in Patients With Atrial Fibrillation: An Observational Cohort Study. Stroke. 2016;47(11):2707–2713. https://doi.org/10.1161/STROKEAHA.116.014422.

32. Sitticharoenchai P, Takkavatakarn K, Boonyaratavej S, Praditpornsilpa K, Eiam-Ong S, Susantitaphong P. Non-Vitamin K Antagonist Oral Anticoagulants Provide Less Adverse Renal Outcomes Than Warfarin In Non-Valvular Atrial Fibrillation: A Systematic Review and MetaAnalysis. J Am Heart Assoc. 2021;10(7):e019609. https://doi.org/10.1161/JAHA.120.019609.

33. Hijazi Z, Hohnloser SH, Oldgren J, Andersson U, Connolly SJ, Eikelboom JW et al. Efficacy and safety of dabigatran compared with warfarin in relation to baseline renal function in patients with atrial fibrillation: a RE-LY (Randomized Evaluation of Long-term Anticoagulation Therapy) trial analysis. Circulation. 2014;129(9):961–970. https://doi.org/10.1161/CIRCULATIONAHA.113.003628.

34. Hohnloser SH, Hijazi Z, Thomas L, Alexander JH, Amerena J, Hanna M et al. Efficacy of apixaban when compared with warfarin in relation to renal function in patients with atrial fibrillation: insights from the ARISTOTLE trial. Eur Heart J. 2012;33(22):2821–2830. https://doi.org/10.1093/eurheartj/ehs274.

35. Lindner SM, Fordyce CB, Hellkamp AS, Lokhnygina Y, Piccini JP, Breithardt G et al. Treatment Consistency Across Levels of Baseline Renal Function With Rivaroxaban or Warfarin: A ROCKET AF (Rivaroxaban Once-Daily, Oral, Direct Factor Xa Inhibition Compared With Vitamin K Antagonism for Prevention of Stroke and Embolism Trial in Atrial Fibrillation) Analysis. Circulation. 2017;135(10):1001–1003. https://doi.org/10.1161/CIRCULATIONAHA.116.024666.

36. Bohula EA, Giugliano RP, Ruff CT, Kuder JF, Murphy SA, Antman EM, Braunwald E. Impact of Renal Function on Outcomes With Edoxaban in the ENGAGE AF-TIMI 48 Trial. Circulation. 2016;134(1):24–36. https://doi.org/10.1161/CIRCULATIONAHA.116.022361.

37. Lopes RD, Alexander JH, Al-Khatib SM, Ansell J, Diaz R, Easton JD et al. Apixaban for reduction in stroke and other ThromboemboLic events in atrial fibrillation (ARISTOTLE) trial: design and rationale. Am Heart J. 2010;159(3):331–339. https://doi.org/10.1016/j.ahj.2009.07.035.

38. Hijazi Z, Hohnloser SH, Andersson U, Alexander JH, Hanna M, Keltai M et al. Efficacy and Safety of Apixaban Compared With Warfarin in Patients With Atrial Fibrillation in Relation to Renal Function Over Time: Insights From the ARISTOTLE Randomized Clinical Trial. JAMA Cardiol. 2016;1(4):451–460. https://doi.org/10.1001/jamacardio.2016.1170.

39. Stanifer JW, Pokorney SD, Chertow GM, Hohnloser SH, Wojdyla DM, Garonzik S et al. Apixaban Versus Warfarin in Patients With Atrial Fibrillation and Advanced Chronic Kidney Disease. Circulation. 2020;141(17):1384–1392. https://doi.org/10.1161/CIRCULATIONAHA.119.044059.

40. Michniewicz E, Mlodawska E, Lopatowska P, Tomaszuk-Kazberuk A, Malyszko J. Patients with atrial fibrillation and coronary artery disease – Double trouble. Adv Med Sci. 2018;63(1):30–35. https://doi.org/10.1016/j.advms.2017.06.005.

41. Soliman EZ, Safford MM, Muntner P, Khodneva Y, Dawood FZ, Zakai NA et al. Atrial fibrillation and the risk of myocardial infarction. JAMA Intern Med. 2014;174(1):107–114. https://doi.org/10.1001/jamainternmed.2013.11912.

42. Schmitt J, Duray G, Gersh BJ, Hohnloser SH. Atrial fibrillation in acute myocardial infarction: a systematic review of the incidence, clinical features and prognostic implications. Eur Heart J. 2009;30(9):1038–1045. https://doi.org/10.1093/eurheartj/ehn579.

43. Wang TY, Robinson LA, Ou FS, Roe MT, Ohman EM, Gibler WB et al. Discharge antithrombotic strategies among patients with acute coronary syndrome previously on warfarin anticoagulation: physician practice in the CRUSADE registry. Am Heart J. 2008;155(2):361–368. https://doi.org/10.1016/j.ahj.2007.09.003.

44. Lip GY, Huber K, Andreotti F, Arnesen H, Airaksinen KJ, Cuisset T et al. Management of antithrombotic therapy in atrial fibrillation patients presenting with acute coronary syndrome and/or undergoing percutaneous coronary intervention/stenting. Thromb Haemost. 2010;103(1):13–28. https://doi.org/10.1160/TH09-08-0580.

45. Jabre P, Jouven X, Adnet F, Thabut G, Bielinski SJ, Weston SA, Roger VL. Atrial fibrillation and death after myocardial infarction: a community study. Circulation. 2011;123(19):2094–2100. https://doi.org/10.1161/CIRCULATIONAHA.110.990192.

46. Alasady M, Abhayaratna WP, Leong DP, Lim HS, Abed HS, Brooks AG et al. Coronary artery disease affecting the atrial branches is an independent determinant of atrial fibrillation after myocardial infarction. Heart Rhythm. 2011;8(7):955–960. https://doi.org/10.1016/j.hrthm.2011.02.016.

47. Batra G, Svennblad B, Held C, Jernberg T, Johanson P, Wallentin L, Oldgren J. All types of atrial fibrillation in the setting of myocardial infarction are associated with impaired outcome. Heart. 2016;102(12):926–933. https://doi.org/10.1136/heartjnl-2015-308678.

48. Ibanez B, James S, Agewall S, Antunes MJ, Bucciarelli-Ducci C, Bueno H et al. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J. 2018;39(2):119–177. https://doi.org/10.1093/eurheartj/ehx393.

49. Bahit MC, Lopes RD, Wojdyla DM, Hohnloser SH, Alexander JH, Lewis BS et al. Apixaban in patients with atrial fibrillation and prior coronary artery disease: insights from the ARISTOTLE trial. Int J Cardiol. 2013;170(2):215–220. https://doi.org/10.1016/j.ijcard.2013.10.062.

50. Leon MB, Baim DS, Popma JJ, Gordon PC, Cutlip DE, Ho KK et al. A clinical trial comparing three antithrombotic-drug regimens after coronary-artery stenting. Stent Anticoagulation Restenosis Study Investigators. N Engl J Med. 1998;339(23):1665–1671. https://doi.org/10.1056/NEJM199812033392303.

51. Connolly S, Pogue J, Hart R, Pfeffer M, Hohnloser S, Chrolavicius S et al. Clopidogrel plus aspirin versus oral anticoagulation for atrial fibrillation in the Atrial fibrillation Clopidogrel Trial with Irbesartan for prevention of Vascular Events (ACTIVE W): a randomised controlled trial. Lancet. 2006;367(9526):1903–1912. https://doi.org/10.1016/S0140-6736(06)68845-4.

52. Sørensen R, Hansen ML, Abildstrom SZ, Hvelplund A, Andersson C, Jørgensen C 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):1967–1974. https://doi.org/10.1016/S0140-6736(09)61751-7.

53. Hansen ML, Sørensen R, Clausen MT, Fog-Petersen ML, Raunsø J, Gadsbøll N 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(16):1433–1441. https://doi.org/10.1001/archinternmed.2010.271.

54. Lopes RD, Heizer G, Aronson R, Vora AN, Massaro T, Mehran R et al. Antithrombotic Therapy after Acute Coronary Syndrome or PCI in Atrial Fibrillation. N Engl J Med. 2019;380(16):1509–1524. https://doi.org/10.1056/NEJMoa1817083.

55. Gibson CM, Mehran R, Bode C, Halperin J, Verheugt FW, Wildgoose P et al. Prevention of Bleeding in Patients with Atrial Fibrillation Undergoing PCI. N Engl J Med. 2016;375(25):2423–2434. https://doi.org/10.1056/NEJMoa1611594.

56. Connolly SJ, Ezekowitz MD, Yusuf S, Eikelboom J, Oldgren J, Parekh A et al. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139–1151. https://doi.org/10.1056/NEJMoa0905561.

57. Cannon CP, Bhatt DL, Oldgren J, Lip GYH, Ellis SG, Kimura T et al. Dual Antithrombotic Therapy with Dabigatran after PCI in Atrial Fibrillation. N Engl J Med. 2017;377(16):1513–1524. https://doi.org/10.1056/NEJMoa1708454.

58. Westenbrink BD, Alings M, Connolly SJ, Eikelboom J, Ezekowitz MD, Oldgren J et al. Anemia predicts thromboembolic events, bleeding complications and mortality in patients with atrial fibrillation: insights from the RE-LY trial. J Thromb Haemost. 2015;13(5):699–707. https://doi.org/10.1111/jth.12874.

59. Westenbrink BD, Alings M, Granger CB, Alexander JH, Lopes RD, Hylek EM et al. Anemia is associated with bleeding and mortality, but not stroke, in patients with atrial fibrillation: Insights from the Apixaban for Reduction in Stroke and Other Thromboembolic Events in Atrial Fibrillation (ARISTOTLE) trial. Am Heart J. 2017;185:140–149. https://doi.org/10.1016/j.ahj.2016.12.008.

60. Tu SJ, Hanna-Rivero N, Elliott AD, Clarke N, Huang S, Pitman BM et al. Associations of anemia with stroke, bleeding, and mortality in atrial fibrillation: A systematic review and meta-analysis. J Cardiovasc Electrophysiol. 2021;32(3):686–694. https://doi.org/10.1111/jce.14898.

61. Bonde AN, Blanche P, Staerk L, Gerds TA, Gundlund A, Gislason G et al. Oral anticoagulation among atrial fibrillation patients with anaemia: an observational cohort study. Eur Heart J. 2019;40(46):3782–3790. https://doi.org/10.1093/eurheartj/ehz155.

62. Puurunen M, Kiviniemi T, Nammas W, Schlitt A, Rubboli A, Nyman K et al. Impact of anaemia on clinical outcome in patients with atrial fibrillation undergoing percutaneous coronary intervention: insights from the AFCAS registry. BMJ Open. 2014;4(5):e004700. https://doi.org/10.1136/bmjopen-2013-004700.

63. Alboni P, Stucci N, Messop AC. Il trattamento anticoagulante nei pazienti con fibrillazione atriale non valvolare e anemia cronica: ancora zone grigie. G Ital Cardiol (Rome). 2021;22(4):311–318. https://doi.org/10.1714/3574.35577.

64. Tanaka N, Inoue K, Okada M, Sakata Y, Akao M, Yamashita T et al. Impact of anemia on the clinical outcomes in elderly patients with atrial fibrillation receiving apixaban: J-ELD AF registry subanalysis. Int J Cardiol Heart Vasc. 2022;40:100994. https://doi.org/10.1016/j.ijcha.2022.100994.

65. Di Angelantonio E, Kaptoge S, Wormser D, Willeit P, Butterworth AS, Bansal N et al. Association of Cardiometabolic Multimorbidity With Mortality. JAMA. 2015;314(1):52–60. https://doi.org/10.1001/jama.2015.7008.

66. Fan J, Sun Z, Yu C, Guo Y, Pei P, Yang L et al. Multimorbidity patterns and association with mortality in 0.5 million Chinese adults. Chin Med J (Engl). 2022;135(6):648–657. https://doi.org/10.1097/CM9.0000000000001985.

67. Kato D, Kawachi I, Saito J, Kondo N. Complex multimorbidity and mortality in Japan: a prospective propensity-matched cohort study. BMJ Open. 2021;11(8):e046749. https://doi.org/10.1136/bmjopen-2020-046749.