Лечение артериальной гипертензии в период пандемии COVID-19: вопросы блокады ренин-ангиотензин-альдостероновой системы

Артериальная гипертензия (АГ) является одним из наиболее часто сопутствующих заболеваний, ассоциирующихся с высоким риском смерти у госпитализированных пациентов с COVID-19. Больных с АГ привычно и согласно стандартам лечат с помощью ингибиторов ангиотензинпревращающего фермента (ИАПФ) или блокаторов рецепторов ангиотензина (БРА) II. ИАПФ или БРА II входят в состав фиксированных комбинаций антигипертензивных препаратов, рекомендованных больным с неосложненной АГ, а также при ее сочетании с различной сопутствующей патологией. В период пандемии COVID-19 появились предположения о потенциальной возможности негативного влияния препаратов этих классов на течение и исходы новой коронавирусной инфекции. Возникла необходимость быстрого ответа наиболее авторитетных медицинских организаций на вопрос о применении ИАПФ и БРА II в период пандемии COVID-19. Позиция экспертов вскоре была опубликована, несмотря на отсутствие доказательств, полученных в рандомизированных клинических исследованиях. Имелись ли основания для тревоги в отношении лечения ИАПФ и БРА II при COVID-19? Каковы взаимосвязи между ренин-ангиотензин-альдостероновой системой (РААС) и COVID-19? Появились ли новые данные клинических исследований, способные подтвердить либо опровергнуть представленную ранее позицию профессиональных обществ в отношении применения блокаторов РААС при COVID-19? Какова роль различия механизма действия ИАПФ и БРА II при COVID-19? Возможно ли, что блокаторы РААС окажутся полезными при лечении COVID-19? Изменится ли тактика фармакотерапии АГ в ближайшем будущем? В настоящей обзорной статье обсуждены современные представления по данной проблеме и сформулированы отражающие достигнутый уровень знаний ответы на перечисленные вопросы.

1. Du Toit A. Outbreak of a Novel Coronavirus. Nat Rev Microbiol. 2020;18(3):123. doi: 10.1038/s41579-020-0332-0.

2. Zhou P., Yang X., Wang X., Hu B., Zhang L., Zhang W. et al. A Pneumonia Outbreak Associated with a New Coronavirus of Probable Bat origin. Nature. 2020;579(7798):270–273. doi: 10.1038/s41586-020-2012-7.

3. Li B., Yang J., Zhao F., Zhi L., Wang X., Liu L. et al. Prevalence and Impact of Cardiovascular Metabolic Diseases on COVID-19 in China. Clin Res Cardiol. 2020;109(5):531–538. doi: 10.1007/s00392-020-01626-9.

4. Vaduganathan M., Vardeny O., Michel T., McMurray J.J. V., Pfeffer M.A., Solomon S.D. Renin–Angiotensin–Aldosterone System Inhibitors in Patients with COVID-19. N Engl J Med. 2020;382(17):1653–1659. doi: 10.1056/NEJMsr2005760.

5. Huang C., Wang Y., Li X., Ren L., Zhao J., Hu Y. et al. Clinical Features of Patients Infected with 2019 Novel Coronavirus in Wuhan, China. Lancet. 2020;395(10223):497–506. doi: 10.1016/S0140-6736(20)30183-5.

6. Fang L., Karakiulakis G., Roth M. Are Patients with Hypertension and Diabetes Mellitus at Increased Risk for COVID-19 Infection? Lancet Respir Med. 2020;8(4):e21. doi: 10.1016/S2213-2600(20)30116-8

7. Esler M., Esler D. Can Angiotensin Receptor-Blocking Drugs Perhaps Be Harmful in the COVID-19 Pandemic? J Hypertens. 2020;38(5):781–782. doi: 10.1097/HJH.0000000000002450.

8. De Simone G. Position Statement of the ESC Council on Hypertension on ACE-Inhibitors and Angiotensin Receptor Blockers. European Society of Cardiology Council on Hypertension; 2020. Available at: https://www.escardio.org/Councils/Council-on-Hypertension-(CHT)/News/positionstatement-of-the-esc-council-on-hypertension-on-aceinhibitors-and-ang.

9. Trifirò G., Crisafulli S., Andò G., Racagni G., Drago F. Should Patients Receiving ACE Inhibitors or Angiotensin Receptor Blockers Be Switched to Other Antihypertensive Drugs to Prevent or Improve Prognosis of Novel Coronavirus Disease 2019 (COVID-19)? Drug Saf. 2020;43(6):507– 509. doi: 10.1007/s40264-020-00935-2.

10. Kreutz R., Algharably E.A. E., Azizi M., Dobrowolski P., Guzik T., Januszewicz A. et al. Hypertension, the Renin-Angiotensin System, and the Risk of Lower Respiratory Tract Infections and Lung Injury: Implications for COVID-19. Cardiovasc Res. 2020;116(10):1688–1699. doi: 10.1093/cvr/cvaa097.

11. Unger T., Borghi C., Charchar F., Khan N.A., Poulter N.R., Prabhakaran D. et al. 2020 International Society of Hypertension Global Hypertension Practice Guidelines. J Hypertens. 2020;38(6):982–1004. doi: 10.1097/HJH.0000000000002453.

12. Bozkurt B., Kovacs R., Harrington B. Joint HFSA/ACC/AHA Statement Addresses Concerns Re: Using RAAS Antagonists in COVID-19. J Card Fail. 2020;26(5):370. doi: 10.1016/j.cardfail.2020.04.013.

13. Cohen J.B., Hanff T.C., Bress A.P., South A.M. Relationship between ACE2 and Other Components of the Renin-Angiotensin System. Curr Hypertens Rep. 2020;22(7):44. doi: 10.1007/s11906-020-01048-y.

14. Hoffmann M., Kleine-Weber H., Schroeder S., Krüger N., Herrler T., Erichsen S. et al. SARS-CoV-2 Cell Entry Depends on ACE2 and TMPRSS2 and Is Blocked by a Clinically Proven Protease Inhibitor. Cell. 2020;181(2):271–280. doi: 10.1016/j.cell.2020.02.052.

15. Ferrario C.M., Jessup J., Chappell M.C., Averill D.B., Brosnihan K.B., Tallant E.A. et al. Effect of Angiotensin-Converting Enzyme Inhibition and Angiotensin II Receptor Blockers on Cardiac Angiotensin-Converting Enzyme 2. Circulation. 2005;111(20):2605–2610. doi: 10.1161/CIRCULATIONAHA.104.510461.

16. Brojakowska A., Narula J., Shimony R., Bander J. Clinical Implications of SARS-CoV-2 Interaction with Renin Angiotensin System: JACC Review Topic of the Week. J Am Coll Cardiol. 2020;75(24):3085–3095. doi: 10.1016/j.jacc.2020.04.028.

17. Wrapp D., Wang N., Corbett K.S., Goldsmith J.A., Hsieh C.L., Abiona O. et al. Cryo-EM Structure of the 2019-nCoV Spike in the Prefusion Conformation. Science. 2020;367(6483):1260–1263. doi: 10.1126/science.abb2507.

18. Reynolds H.R., Adhikari S., Pulgarin C., Troxel A.B., Iturrate E., Johnson S.B. et al. Renin-Angiotensin-Aldosterone System Inhibitors and Risk of COVID-19. N Engl J Med. 2020;382(25):2441–2448. doi: 10.1056/NEJMoa2008975.

19. Guan W.J., Ni Z.Y., Hu Y., Liang W.H., Ou C.Q., He J.X. et al. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020;382(18):1708–1720. doi: 10.1056/NEJMoa2002032.

20. Al-Baadani A.M., Elzein F.E., Alhemyadi S.A., Khan O.A., Albenmousa A.H., Idrees M.M. Characteristics and Outcome of Viral Pneumonia Caused by Influenza and Middle East Respiratory Syndrome-Coronavirus Infections: A 4-Year Experience from a Tertiary Care Center. Ann Thorac Med. 2019;14(3):179–185. doi: 10.4103/atm.ATM_179_18.

21. Wang Z., Chen Z., Zhang L., Wang X., Hao G., Zhang Z. et al. Status of Hypertension in China: Results from the China Hypertension Survey, 2012-2015. Circulation. 2018;137(22):2344–2356. doi: 10.1161/CIRCULATIONAHA.117.032380.

22. Omar M.B. COVID-19 and the Angiotensin-Converting Enzyme (ACE2): Areas for Research. Heart Lung. 2020;49(4):351. doi: 10.1016/j.hrtlng.2020.04.012.

23. Wu C., Chen X., Cai Y., Xia J., Zhou X., Xu S. et al. Risk Factors Associated with Acute Respiratory Distress Syndrome and Death in Patients with Coronavirus Disease 2019 Pneumonia in Wuhan, China. JAMA Intern Med. 2020;180(7):934–943. doi: 10.1001/jamainternmed.2020.0994.

24. Zhou F., Yu T., Du R., Fan G., Liu Y., Liu Z. et al. Clinical Course and Risk Factors for Mortality of Adult Inpatients with COVID-19 in Wuhan, China: A Retrospective Cohort Study. Lancet. 2020;395(10229):1054–1062. doi: 10.1016/S0140-6736(20)30566-3.

25. Wu J.T., Leung K., Bushman M., Kishore N., Niehus R., de Salazar P.M. et al. Estimating Clinical Severity of COVID-19 from the Transmission Dynamics in Wuhan, China. Nat Med. 2020;26(4):506–510. doi: 10.1038/s41591-020-0822-7.

26. Fosbøl E.L., Butt J.H., Østergaard L., Andersson C., Selmer C., Kragholm K. et al. Association of Angiotensin-Converting Enzyme Inhibitor or Angiotensin Receptor Blocker Use With COVID-19 Diagnosis and Mortality. JAMA. 2020;324(2):168–177. doi: 10.1001/jama.2020.11301.

27. Chen N., Zhou M., Dong X., Qu J., Gong F., Han Y. et al. Epidemiological and Clinical Characteristics of 99 Cases of 2019 Novel Coronavirus Pneumonia in Wuhan, China: A Descriptive Study. Lancet. 2020;395(10223):507–513. doi: 10.1016/S0140-6736(20)30211-7.

28. Meng J., Xiao G., Zhang J., He X., Ou M., Bi J. et al. Renin–Angiotensin System Inhibitors Improve the Clinical Outcomes of COVID-19 Patients with Hypertension. Emerg Microbes Infect. 2020;9(1):757–760. doi: 10.1080/22221751.2020.1746200.

29. Feng Y., Ling Y., Bai T., Xie Y., Huang J., Li J. et al. COVID-19 with Different Severity: A Multi-Center Study of Clinical Features. Am J Respir Crit Care Med. 2020;201(11):1380–1388. doi: 10.1164/rccm.202002-0445OC.

30. Li J., Wang X., Chen J., Zhang H., Deng A. Association of Renin–Angiotensin System Inhibitors with Severity or Risk of Death in Patients with Hypertension Hospitalized for Coronavirus Disease 2019 (COVID-19) Infection in Wuhan, China. JAMA Cardiol. 2020;5(7):825–830. doi: 10.1001/jamacardio.2020.1624.

31. Yang G., Tan Z., Zhou L., Yang M., Peng L., Liu J. et al. Effects of ARBs and ACEIs on Virus Infection, Inflammatory Status and Clinical Outcomes in COVID-19 Patients with Hypertension: A Single Center Retrospective Study. Hypertension. 2020;76(1):51–58. doi: 10.1161/HYPERTENSIONAHA.120.15143.

32. Zhang P., Zhu L., Cai J., Lei F., Qin J.J., Xie J. et al. Association of Inpatient Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers with Mortality among Patients with Hypertension Hospitalized with COVID-19. Circ Res. 2020;26(12):1671–1681. doi: 10.1161/CIRCRESAHA.120.317134.

33. Grover A., Oberoi M. A Systematic Review and Meta-Analysis to Evaluate the Clinical Outcomes in COVID-19 Patients on Angiotensin-Converting Enzyme Inhibitors or Angiotensin Receptor Blockers. Eur Heart J Cardiovasc Pharmacother. 2020; 7(2):148–157. doi: 10.1093/ehjcvp/pvaa064.

34. Guo T., Fan Y., Chen M., Wu X., Zhang L., He T. et al. Cardiovascular Implications of Fatal Outcomes of Patients with Coronavirus Disease 2019 (COVID-19). JAMA Cardiol. 2020;5(7):811–818. doi: 10.1001/jamacardio.2020.1017.

35. Richardson S., Hirsch J.S., Narasimhan M., Crawford J.M., McGinn T., Davidson K.W. Presenting Characteristics, Comorbidities, and Outcomes among 5700 Patients Hospitalized with COVID-19 in the New York City Area. JAMA. 2020;323(20):2052–2059. doi: 10.1001/jama.2020.6775.

36. Palmeri V., Colamesta V., La Torre G. Evaluation of Methodological Quality of Studies. Senses Sci. 2016;3(3):235–241. doi: 10.14616/sands-2016-3-235241.

37. Mancia G., Rea F., Ludergnani M., Apolone G., Corrao G. Renin-AngiotensinAldosterone System Blockers and the Risk of COVID-19. N Engl J Med. 2020;382(25):2431–2440. doi: 10.1056/NEJMoa2006923.

38. Reynolds H.R., Adhikari S., Pulgarin C., Troxel A.B., Iturrate E., Johnson S.B. et al. Renin-Angiotensin-Aldosterone System Inhibitors and Risk of COVID-19. N Engl J Med. 2020;382(25):2441–2448. doi: 10.1056/NEJMoa2008975.

39. McEvoy J.W. Coronavirus (COVID-19) ACEi/ARB investigation (CORONACION). U.S. National Library of Medicine. Available at: https://clinicaltrials.gov/ct2/show/NCT04330300.

40. Hôpitaux de Paris. ACE inhibitors or ARBs discontinuation in context of SARS-CoV-2 pandemic (ACORES-2). U.S. National Library of Medicine. Available at: https://clinicaltrials.gov/ct2/show/NCT04329195.

41. University of Minnesota. Losartan for Patients with COVID-19 Not Requiring Hospitalization. U.S. National Library of Medicine. Available at: https://clinicaltrials.gov/ct2/show/NCT04311177.

42. Furuhashi M., Moniwa N., Mita T., Fuseya T., Ishimura S., Ohno K. et al. Urinary Angiotensin-Converting Enzyme 2 in Hypertensive Patients May Be Increased by Olmesartan, an Angiotensin II Receptor Blocker. Am J Hypertens. 2015;28(1):15–21. doi: 10.1093/ajh/hpu086.

43. De Abajo F.J., Rodríguez-Martín S., Lerma V., Mejía-Abril G., Aguilar M., García-Luque A. et al. Use of Renin–Angiotensin–Aldosterone System Inhibitors and Risk of COVID-19 Requiring Admission to Hospital: A CasePopulation Study. Lancet. 2020;395(10238):1705–1714. doi: 10.1016/S0140-6736(20)31030-8.

44. Zen Z. Hypertension in Patients Hospitalized with COVID-19 (HT-COVID19). U.S. National Library of Medicine. Available at: https://clinicaltrials.gov/ct2/show/NCT04318301.

45. Di Castelnuovo A. ACE Inhibitors, Angiotensin II Type-I Receptor Blockers and Severity of COVID-19 (CODIV-ACE). U.S. National Library of Medicine. Available at: https://clinicaltrials.gov/ct2/show/NCT04318418.

46. University of Minnesota. Losartan for Patients with COVID-19 Requiring Hospitalization. U.S. National Library of Medicine. Available at: https://clinicaltrials.gov/ct2/show/NCT04312009.

47. Li Y. Recombinant Human Angiotensinconverting Enzyme 2 (rhACE2) as a Treatment for Patients with COVID-19. U.S. National Library of Medicine. Available at: https://clinicaltrials.gov/ct2/show/NCT04287686.

48. Ye R., Liu Z. ACE2 Exhibits Protective Effects against LPS-Induced Acute Lung Injury in Mice by Inhibiting the LPS-TLR4 Pathway. Exp Mol Pathol. 2020;113:104350. doi: 10.1016/j.yexmp.2019.104350.

49. Kuster G.M., Pfister O., Burkard T., Zhou Q., Twerenbold R., Haaf P. et al. SARS-CoV2: Should Inhibitors of the Renin-Angiotensin System Be Withdrawn in Patients with COVID-19? Eur Heart J. 2020;41(19):1801– 1803. doi: 10.1093/eurheartj/ehaa235.

50. Dijkman R., Jebbink M.F., Deijs M., Milewska A., Pyrc K., Buelow E. et al. Replication-Dependent Downregulation of Cellular AngiotensinConverting Enzyme 2 Protein Expression by Human Coronavirus NL63. J Gen Virol. 2012;93(Pt 9):1924–1929. doi: 10.1099/vI.0.043919-0.

51. Liu Y., Yang Y., Zhang C., Huang F., Wang F., Yuan J. et al. Clinical and Biochemical Indexes from 2019-nCoV Infected Patients Linked to Viral Loads and Lung Injury. Sci China Life Sci. 2020;63(3):364–374. doi: 10.1007/s11427-020-1643-8.

52. Dijkman R., Jebbink M.F., Deijs M., Milewska A., Pyrc K., Buelow E. et al. Replication-Dependent Downregulation of Cellular AngiotensinConverting Enzyme 2 Protein Expression by Human Coronavirus NL63. J Gen Virol. 2012;93(Pt 9):1924–1929. doi: 10.1099/vI.0.043919-0.

53. Gu H., Xie Z., Li T., Zhang S., Lai C., Zhu P. et al. Angiotensin-Converting Enzyme 2 Inhibits Lung Injury Induced by Respiratory Syncytial Virus. Sci Rep. 2016;6:19840. doi: 10.1038/srep19840.

54. Gao C., Cai Y., Zhang K., Zhou L., Zhang Y., Zhang X. et al. Association of Hypertension and Antihypertensive Treatment with COVID-19 Mortality: A Retrospective Observational Study. Eur Heart J. 2020;41(22):2058–2066. doi: 10.1093/eurheartj/ehaa433.

55. Gurwitz D. Angiotensin Receptor Blockers as Tentative SARS-CoV-2 Therapeutics. Drug Dev Res. 2020;81(5):537–540. doi: 10.1002/ddr.21656.

56. Shi S., Qin M., Shen B., Cai Y., Liu T., Yang F. et al. Association of Cardiac Injury with Mortality in Hospitalized Patients with COVID-19 in Wuhan, China. JAMA Cardiol. 2020;5(7):802–810. doi: 10.1001/jamacardio.2020.0950.

57. Halliday B.P., Wassall R., Lota A.S., Khalique Z., Gregson J., Newsome S. et al. Withdrawal of Pharmacological Treatment for Heart Failure in Patients with Recovered Dilated Cardiomyopathy (TRED-HF): An OpenLabel, Pilot, Randomised Trial. Lancet. 2019;393(10166):61–73. doi: 10.1016/S0140-6736(18)32484-X.

58. Di Somma S. Importance of Rapid and Effective Reduction of Blood Pressure in Treating Hypertension for the Prevention of Cardiovascular Diseases: A Lesson from the VALUE Study. High Blood Press Cardiovasc Prev. 2005;12(3):135–140. doi: 10.2165/00151642-200512030-00004.

59. Lopes R.D., Macedo A.V. S., de Barros E. Silva P.G. M., Moll-Bernardes R.J., Dos Santos T.M. et al. Effect of Discontinuing vs Continuing AngiotensinConverting Enzyme Inhibitors and Angiotensin II Receptor Blockers on Days Alive and Out of the Hospital in Patients Admitted with COVID-19: A Randomized Clinical Trial. JAMA. 2021;325(3):254–264. doi: 10.1001/jama.2020.25864.

60. Cohen J.B., Hanff T.C., William P., Sweitzer N., Rosado-Santander N.R., Medina C. et al. Continuation Versus Discontinuation of Renin-Angiotensin System Inhibitors in Patients Admitted to Hospital with COVID-19: A Prospective, Randomised, Open-Label Trial. Lancet Respir Med. 2021;9(3):275–284. doi: 10.1016/S2213-2600(20)30558-0.

61. Yusuf S., Joseph P., Rangarajan S., Islam S., Mente A., Hystad P. et al. Modifiable Risk Factors, Cardiovascular Disease, and Mortality in 155 722 Individuals from 21 High-Income, Middle-Income, and Low-Income Countries (PURE): A Prospective Cohort Study. Lancet. 2020;395(10226):795–808. doi: 10.1016/S0140-6736(19)32008-2.

62. Whelton P.K., Carey R.M., Aronow W.S., Casey D.E. Jr., Collins K.J., Dennison Himmelfarb С. et al. 2017 ACC/AHA/AAPA/ABC/ACPM/AGS/APhA/ASH/ ASPC/NMA/PCNA Guideline for the Prevention, Detection, Evaluation, and Management of High Blood Pressure in Adults: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2018;71(19):e127–e248. doi: 10.1016/j.jacc.2017.11.006.

63. Williams B., Mancia G., Spiering W., Agabiti Rosei E., Azizi M., Burnier M. et al. 2018 ESC/ESH Guidelines for the Management of Arterial Hypertension. Eur Heart J. 2018;39(33):3021–3104. doi: 10.1093/eurheartj/ehy339.

64. Whelton S.P., McEvoy J. W., Shaw L., Psaty B.M., Lima J.A. C., Budoff M. et al. Association of Normal Systolic Blood Pressure Level with Cardiovascular Disease in the Absence of Risk Factors. JAMA Cardiol. 2020;5(9):1011– 1018. doi: 10.1001/jamacardio.2020.1731.

65. Chalmers J., Arima H., Woodward M., Mancia G., Poulter N., Hirakawa Y. et al. Effects of Combination of Perindopril, Indapamide, and Calcium Channel Blockers in Patients with Type 2 Diabetes Mellitus: Results from the Action In Diabetes and Vascular Disease: Preterax and Diamicron Controlled Evaluation (ADVANCE) Trial. Hypertension. 2014;63(2):259–264. doi: 10.1161/HYPERTENSIONAHA.113.02252.

66. Кобалава Ж.Д., Троицкая Е.А., Толкачева В.В. Комбинированная терапия артериальной гипертонии с использованием трехкомпонентной фиксированной комбинации амлодипина, индапамида и периндоприла аргинина в клинической практике: организация и основные результаты программы ДОКАЗАТЕЛЬСТВО. Кардиология. 2018;58(9):21–30. doi: 10.18087/cardio.2018.9.10170.

67. Кобалава Ж.Д., Толкачева В.В., Троицкая Е.А., Колесникова И.А., Маркова М.А. Фиксированная тройная комбинация амлодипин/индапамид/ периндоприла аргинин–рациональный и безопасный выбор для контроля артериального давления в реальной клинической практике (результаты наблюдательной программы ДОКАЗАТЕЛЬСТВО). Российский кардиологический журнал. 2020;25(6):3805. doi: 10.15829/1560-4071-2020-3805.