Профилактика ишемического инсульта при фибрилляции предсердий с точки зрения невролога. Стандарты и реальная клиническая практика

Максимова М.Ю., Фонякин А.В., Гераскина Л.А. Профилактика ишемического инсульта при фибрилляции предсердий с точки зрения невролога. Стандарты и реальная клиническая практика. Терапевтический архив. 2021; 93 (10): 1240–1245.
DOI: 10.26442/00403660.2021.10.201105

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Maksimova MYu, Fonyakin AV, Geraskina LA. Prevention of ischemic stroke in atrial fibrillation from the point of view of a neurologist. Standards and real clinical practice. Terapevticheskii Arkhiv (Ter. Arkh.). 2021; 93 (10): 1240–1245. DOI: 10.26442/00403660.2021.10.201105

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Аннотация

В статье представлены аспекты современного состояния проблемы приоритетного выбора перорального антикоагулянта для бессрочной профилактики инсульта и системных тромбоэмболий у пациентов с фибрилляцией предсердий. Изложены преимущества прямых пероральных антикоагулянтов перед варфарином, а также продемонстрирован сопоставительный анализ индивидуальных особенностей основных прямых пероральных антикоагулянтов с точки зрения персонификации превентивной терапии в соответствии с современными стандартами лечения. Вопросы эффективности и безопасности терапии пероральными антикоагулянтами рассмотрены с учетом чистой клинической выгоды. Особое внимание уделено возрастным аспектам выбора антикоагулянта для бессрочной профилактики, представлена оценка антикоагулянтов в соответствии с концепцией FORTA, регламентирующей применение лекарственных препаратов у пожилых пациентов. В заключение сформулированы рекомендации по выбору антикоагулянта у больных с фибрилляцией предсердий при наиболее часто встречающихся клинических ситуациях. Важное правило – выбор конкретного препарата должен быть индивидуализирован на основании факторов риска, переносимости, чистой клинической выгоды, предпочтений пациента, потенциальных нежелательных взаимодействий и других клинических характеристик.

Ключевые слова: профилактика инсульта, фибрилляция предсердий, пероральные антикоагулянты, персонификация терапии

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The article outlines aspects of the current state of the problem of the priority choice of an oral anticoagulant for indefinite prevention of stroke and systemic thromboembolism in patients with atrial fibrillation. The advantages of direct oral angicoagulants over warfarin are presented, as well as a comparative analysis of the individual characteristics of the main direct oral angicoagulants from the point of view of personification of preventive therapy in accordance with modern treatment standards. The efficacy and safety of oral anticoagulant therapy has been reviewed in terms of the net clinical benefit. Particular attention is paid to the age-related aspects of choosing an anticoagulant for indefinite prophylaxis; an assessment of anticoagulants is presented in accordance with the FORTA concept, which regulates the use of drugs in elderly patients. In conclusion, recommendations are formulated for the choice of an anticoagulant in patients with atrial fibrillation in the most common clinical situations. As a general rule, the choice of a particular drug should be individualized based on risk factors, tolerability, net clinical benefit, patient preference, potential adverse interactions, and other clinical characteristics.

Keywords: stroke prevention, atrial fibrillation, oral anticoagulants, therapy personalization

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Список литературы

1. Lloyd-Jones DM, Wang TJ, Leip EP, et al. Lifetime risk for development of atrial fibrillation: the Framingham Heart Study. Circulation. 2004;110(9):1042-6. DOI:10.1161/01.CIR.0000140263.20897.42
2. Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA. 2001;285(18):2370-5. DOI:10.1001/jama.285.18.2370
3. Hindricks G, Potpara T, Dagres N, et al; ESC Scientific Document Group. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J. 2021;42(5):373-498. DOI:10.1093/eurheartj/ehaa612
4. Kleindorfer DO, Towfighi A, Chaturvedi S, et al. 2021 Guideline for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack: A Guideline From the American Heart Association/American Stroke Association. Stroke. 2021;52(7):e364-e467. DOI:10.1161/STR.0000000000000375
5. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke. 1991;22(8):983-8. DOI:10.1161/01.str.22.8.983
6. Lin HJ, Wolf PA, Kelly-Hayes M, et al. Stroke severity in atrial fibrillation. The Framingham Study. Stroke. 1996;27(10):1760-4. DOI:10.1161/01.str.27.10.1760
7. Yaghi S, Chang AD, Akiki R, et al. The left atrial appendage morphology is associated with embolic stroke subtypes using a simple classification system: A proof of concept study. J Cardiovasc Comput Tomogr. 2020;14(1):27-33. DOI:10.1016/j.jcct.2019.04.005
8. Hart RG, Benavente O, McBride R, Pearce LA. Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis. Ann Intern Med. 1999;131(7):492-501. DOI:10.7326/0003-4819-131-7-199910050-00003
9. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Int Med. 2007;146(12):857-67.DOI:10.7326/0003-4819-146-12-200706190-00007
10. Samsa GP, Matchar DB, Goldstein LB, et al. Quality of anticoagulation management among patients with atrial fibrillation: results of a review of medical records from 2 communities. Arch Intern Med. 2000;160(7):967-73. DOI:10.1001/archinte.160.7.967
11. Baker WL, Cios DA, Sander SD, Coleman CI. Meta-analysis to assess the quality of warfarin control in atrial fibrillation patients in the United States. J Manag Care Pharm. 2009;15(3):244-52. DOI:10.18553/jmcp.2009.15.3.244
12. Гаврисюк Е.В., Игнатьев И.В., Сычев Д.А., Маринин В.Ф. Анализ применения непрямого антикоагулянта варфарина у пациентов с постоянной формой фибрилляции предсердий в поликлинических условиях. Клиническая фармакология и терапия. 2012;1:42-7 [Gavrisiuk EV, Ignatiev IV, Sychev DA, Marinin VF. Analysis of the use of the indirect anticoagulant warfarin in patients with permanent atrial fibrillation in an outpatient setting. Klinicheskaya pharmakologiya i terapiya. 2012;1:42-7 (in Russian)].
13. ACTIVE Writing Group of the ACTIVE Investigators, Connolly S, Pogue J, Hart R, 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):1903-12. DOI:10.1016/S0140-6736(06)68845-4
14. Connolly SJ, Ezekowitz MD, Yusuf S, et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139-51. DOI:10.1056/NEJMoa0905561
15. ROCKET AF Study Investigators. Rivaroxaban-once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation: rationale and design of the ROCKET AF study. Am Heart J. 2010;159(3):340-347.e1. DOI:10.1016/j.ahj.2009.11.025
16. Patel MR, Mahaffey KW, Garg J, et al; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883-91. DOI:10.1056/NEJMoa1009638
17. Granger CB, Alexander JH, McMurray JJ, et al; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11):981-92. DOI:10.1056/NEJMoa1107039
18. Connolly SJ, Eikelboom J, Joyner C, et al; AVERROES Steering Committee and Investigators. Apixaban in patients with atrial fibrillation. N Engl J Med. 2011;364(9):806-17. DOI:10.1056/NEJMoa1007432
19. Culebras A, Messé SR, Chaturvedi S, et al. Summary of evidence-based guideline update: prevention of stroke in nonvalvular atrial fibrillation: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2014;82(8):716-24. DOI:10.1212/WNL.0000000000000145
20. Lip GY, Larsen TB, Skjøth F, Rasmussen LH. Indirect comparisons of new oral anticoagulant drugs for efficacy and safety when used for stroke prevention in atrial fibrillation. J Am Coll Cardiol. 2012;60(8):738-46. DOI:10.1016/j.jacc.2012.03.019
21. Potpara TS, Polovina MM, Licina MM, et al. Novel oral anticoagulants for stroke prevention in atrial fibrillation: focus on apixaban. Adv Ther. 2012;29(6):491-507. DOI:10.1007/s12325-012-0026-8
22. Cucchiara BL, Kasner SE. Apixaban in atrial fibrillation: from bleeding cows to 21st century medicinal chemistry. Stroke. 2011;42(8):2376-8. DOI:10.1161/STROKEAHA.111.619338
23. O'Donnell MJ, Eikelboom JW, Yusuf S, et al. Effect of apixaban on brain infarction and microbleeds: AVERROES-MRI assessment study. Am Heart J. 2016;178:145-50. DOI:10.1016/j.ahj.2016.03.019
24. Frost C, Song Y, Barrett YC, et al. A randomized direct comparison of the pharmacokinetics and pharmacodynamics of apixaban and rivaroxaban. Clin Pharmacol. 2014;6:179-87. DOI:10.2147/CPAA.S61131
25. Gong IY, Kim RB. Importance of pharmacokinetic profile and variability as determinants of dose and response to dabigatran, rivaroxaban, and apixaban. Can J Cardiol. 2013;29(7 Suppl.):S24-33. DOI:10.1016/j.cjca.2013.04.002
26. Frost C, Nepal S, Wang J, et al. Safety, pharmacokinetics and pharmacodynamics of multiple oral doses of apixaban, a factor Xa inhibitor, in healthy subjects. Br J Clin Pharmacol. 2013;76(5):776-86. DOI:10.1111/bcp.12106
27. Lip GYH, Keshishian A, Li X, et al. Effectiveness and safety of oral anticoagulants among nonvalvular atrial fibrillation patients. Stroke. 2018;49(12):2933-44. DOI:10.1161/STROKEAHA.118.020232
28. Steg PG, Bhatt DL. Is There really a benefit to net clinical benefit in testing antithrombotics? Circulation. 2018;137(14):1429-31. DOI:10.1161/CIRCULATIONAHA.117.033442.
29. Renda G, di Nicola M, De Caterina R. Net clinical benefit of non-vitamin k antagonist oral anticoagulants versus warfarin in phase iii atrial fibrillation trials. Am J Med. 2015;128(9):1007-14.e2. DOI:10.1016/j.amjmed.2015.03.034
30. Моисеев С.В. Антикоагулянтная терапия у пациентов в возрасте 75–80 лет и старше с неклапанной фибрилляцией предсердий. Клиническая фармакология и терапия. 2017;4:5-14 [Moissev SV. Anticoagulant therapy in patients aged 75–80 years and older with nonvalvular atrial fibrillation. Klinicheskaya pharmakologiya i terapiya. 2017;4:5-14 (in Russian)].
31. Patti G, Cavallari I, Hanon O, De Caterina R. The safety and efficacy of non-vitamin K antagonist oral anticoagulants in atrial fibrillation in the elderly. Int J Cardiol. 2018;265:118-24. DOI:10.1016/j.ijcard.2018.02.066
32. Diener HC, Aisenberg J, Ansell J, et al. Choosing a particular oral anticoagulant and dose for stroke prevention in individual patients with non-valvular atrial fibrillation: part 1. Eur Heart J. 2017;38(12):852-9. DOI:10.1093/eurheartj/ehv643
33. Wehling M. Drug therapy in the elderly: too much or too little, what to do? A new assessment system: fit for aged (FORTA). Dtsch Med Wochenschr. 2008;133(44):2289-91. DOI:10.1055/s-0028-1091275
34. Wehling M. Arzneimitteltherapie im Alter: Zu viel und zu wenig, was tun? Ein neues Bewertungssystem: fit for the aged (FORTA) [Drug therapy in the elderly: too much or too little, what to do? A new assessment system: fit for the aged (FORTA)]. Dtsch Med Wochenschr. 2008;133(44):2289-91. DOI:10.1055/s-0028-1091275
35. Pazan F, Collins R, Gil VM, et al. A structured literature review and international consensus validation of forta labels of oral anticoagulants for long-term treatment of atrial fibrillation in older patients (OAC-FORTA 2019). Drugs Aging. 2020;37(7):539-48.
DOI:10.1007/s40266-020-00771-0
36. Кочетков А.И., Остроумова О.Д., Ляхова Н.Л., Буторов В.Н. Как улучшить антикоагулянтную терапию у пациента с фибрилляцией предсердий? Consilium Medicum. 2020;22(5):40-8 [Kochetkov AI, Ostroumova OD, Liahova NL, Butorov VN. How to improve anticoagulant therapy in a patient with atrial fibrillation? Consilium Medicum. 2020;22(5):40-8 (in Russian)]. DOI:10.26442/20751753.2020.5.200151
37. Diener HC, Aisenberg J, Ansell J, et al. Choosing a particular oral anticoagulant and dose for stroke prevention in individual patients with non-valvular atrial fibrillation: part 2. Eur Heart J. 2017;38(12):860-8. DOI:10.1093/eurheartj/ehw069

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1. Lloyd-Jones DM, Wang TJ, Leip EP, et al. Lifetime risk for development of atrial fibrillation: the Framingham Heart Study. Circulation. 2004;110(9):1042-6. DOI:10.1161/01.CIR.0000140263.20897.42
2. Go AS, Hylek EM, Phillips KA, et al. Prevalence of diagnosed atrial fibrillation in adults: national implications for rhythm management and stroke prevention: the AnTicoagulation and Risk Factors in Atrial Fibrillation (ATRIA) Study. JAMA. 2001;285(18):2370-5. DOI:10.1001/jama.285.18.2370
3. Hindricks G, Potpara T, Dagres N, et al; ESC Scientific Document Group. 2020 ESC Guidelines for the diagnosis and management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS): The Task Force for the diagnosis and management of atrial fibrillation of the European Society of Cardiology (ESC) Developed with the special contribution of the European Heart Rhythm Association (EHRA) of the ESC. Eur Heart J. 2021;42(5):373-498. DOI:10.1093/eurheartj/ehaa612
4. Kleindorfer DO, Towfighi A, Chaturvedi S, et al. 2021 Guideline for the Prevention of Stroke in Patients With Stroke and Transient Ischemic Attack: A Guideline From the American Heart Association/American Stroke Association. Stroke. 2021;52(7):e364-e467. DOI:10.1161/STR.0000000000000375
5. Wolf PA, Abbott RD, Kannel WB. Atrial fibrillation as an independent risk factor for stroke: the Framingham Study. Stroke. 1991;22(8):983-8. DOI:10.1161/01.str.22.8.983
6. Lin HJ, Wolf PA, Kelly-Hayes M, et al. Stroke severity in atrial fibrillation. The Framingham Study. Stroke. 1996;27(10):1760-4. DOI:10.1161/01.str.27.10.1760
7. Yaghi S, Chang AD, Akiki R, et al. The left atrial appendage morphology is associated with embolic stroke subtypes using a simple classification system: A proof of concept study. J Cardiovasc Comput Tomogr. 2020;14(1):27-33. DOI:10.1016/j.jcct.2019.04.005
8. Hart RG, Benavente O, McBride R, Pearce LA. Antithrombotic therapy to prevent stroke in patients with atrial fibrillation: a meta-analysis. Ann Intern Med. 1999;131(7):492-501. DOI:10.7326/0003-4819-131-7-199910050-00003
9. Hart RG, Pearce LA, Aguilar MI. Meta-analysis: antithrombotic therapy to prevent stroke in patients who have nonvalvular atrial fibrillation. Ann Int Med. 2007;146(12):857-67.DOI:10.7326/0003-4819-146-12-200706190-00007
10. Samsa GP, Matchar DB, Goldstein LB, et al. Quality of anticoagulation management among patients with atrial fibrillation: results of a review of medical records from 2 communities. Arch Intern Med. 2000;160(7):967-73. DOI:10.1001/archinte.160.7.967
11. Baker WL, Cios DA, Sander SD, Coleman CI. Meta-analysis to assess the quality of warfarin control in atrial fibrillation patients in the United States. J Manag Care Pharm. 2009;15(3):244-52. DOI:10.18553/jmcp.2009.15.3.244
12. Gavrisiuk EV, Ignatiev IV, Sychev DA, Marinin VF. Analysis of the use of the indirect anticoagulant warfarin in patients with permanent atrial fibrillation in an outpatient setting. Klinicheskaya pharmakologiya i terapiya. 2012;1:42-7 (in Russian).
13. ACTIVE Writing Group of the ACTIVE Investigators, Connolly S, Pogue J, Hart R, 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):1903-12. DOI:10.1016/S0140-6736(06)68845-4
14. Connolly SJ, Ezekowitz MD, Yusuf S, et al; RE-LY Steering Committee and Investigators. Dabigatran versus warfarin in patients with atrial fibrillation. N Engl J Med. 2009;361(12):1139-51. DOI:10.1056/NEJMoa0905561
15. ROCKET AF Study Investigators. Rivaroxaban-once daily, oral, direct factor Xa inhibition compared with vitamin K antagonism for prevention of stroke and Embolism Trial in Atrial Fibrillation: rationale and design of the ROCKET AF study. Am Heart J. 2010;159(3):340-347.e1. DOI:10.1016/j.ahj.2009.11.025
16. Patel MR, Mahaffey KW, Garg J, et al; ROCKET AF Investigators. Rivaroxaban versus warfarin in nonvalvular atrial fibrillation. N Engl J Med. 2011;365(10):883-91. DOI:10.1056/NEJMoa1009638
17. Granger CB, Alexander JH, McMurray JJ, et al; ARISTOTLE Committees and Investigators. Apixaban versus warfarin in patients with atrial fibrillation. N Engl J Med. 2011;365(11):981-92. DOI:10.1056/NEJMoa1107039
18. Connolly SJ, Eikelboom J, Joyner C, et al; AVERROES Steering Committee and Investigators. Apixaban in patients with atrial fibrillation. N Engl J Med. 2011;364(9):806-17. DOI:10.1056/NEJMoa1007432
19. Culebras A, Messé SR, Chaturvedi S, et al. Summary of evidence-based guideline update: prevention of stroke in nonvalvular atrial fibrillation: report of the Guideline Development Subcommittee of the American Academy of Neurology. Neurology. 2014;82(8):716-24. DOI:10.1212/WNL.0000000000000145
20. Lip GY, Larsen TB, Skjøth F, Rasmussen LH. Indirect comparisons of new oral anticoagulant drugs for efficacy and safety when used for stroke prevention in atrial fibrillation. J Am Coll Cardiol. 2012;60(8):738-46. DOI:10.1016/j.jacc.2012.03.019
21. Potpara TS, Polovina MM, Licina MM, et al. Novel oral anticoagulants for stroke prevention in atrial fibrillation: focus on apixaban. Adv Ther. 2012;29(6):491-507. DOI:10.1007/s12325-012-0026-8
22. Cucchiara BL, Kasner SE. Apixaban in atrial fibrillation: from bleeding cows to 21st century medicinal chemistry. Stroke. 2011;42(8):2376-8. DOI:10.1161/STROKEAHA.111.619338
23. O'Donnell MJ, Eikelboom JW, Yusuf S, et al. Effect of apixaban on brain infarction and microbleeds: AVERROES-MRI assessment study. Am Heart J. 2016;178:145-50. DOI:10.1016/j.ahj.2016.03.019
24. Frost C, Song Y, Barrett YC, et al. A randomized direct comparison of the pharmacokinetics and pharmacodynamics of apixaban and rivaroxaban. Clin Pharmacol. 2014;6:179-87. DOI:10.2147/CPAA.S61131
25. Gong IY, Kim RB. Importance of pharmacokinetic profile and variability as determinants of dose and response to dabigatran, rivaroxaban, and apixaban. Can J Cardiol. 2013;29(7 Suppl.):S24-33. DOI:10.1016/j.cjca.2013.04.002
26. Frost C, Nepal S, Wang J, et al. Safety, pharmacokinetics and pharmacodynamics of multiple oral doses of apixaban, a factor Xa inhibitor, in healthy subjects. Br J Clin Pharmacol. 2013;76(5):776-86. DOI:10.1111/bcp.12106
27. Lip GYH, Keshishian A, Li X, et al. Effectiveness and safety of oral anticoagulants among nonvalvular atrial fibrillation patients. Stroke. 2018;49(12):2933-44. DOI:10.1161/STROKEAHA.118.020232
28. Steg PG, Bhatt DL. Is There really a benefit to net clinical benefit in testing antithrombotics? Circulation. 2018;137(14):1429-31. DOI:10.1161/CIRCULATIONAHA.117.033442.
29. Renda G, di Nicola M, De Caterina R. Net clinical benefit of non-vitamin k antagonist oral anticoagulants versus warfarin in phase iii atrial fibrillation trials. Am J Med. 2015;128(9):1007-14.e2. DOI:10.1016/j.amjmed.2015.03.034
30. Moissev SV. Anticoagulant therapy in patients aged 75–80 years and older with nonvalvular atrial fibrillation. Klinicheskaya pharmakologiya i terapiya. 2017;4:5-14 (in Russian).
31. Patti G, Cavallari I, Hanon O, De Caterina R. The safety and efficacy of non-vitamin K antagonist oral anticoagulants in atrial fibrillation in the elderly. Int J Cardiol. 2018;265:118-24. DOI:10.1016/j.ijcard.2018.02.066
32. Diener HC, Aisenberg J, Ansell J, et al. Choosing a particular oral anticoagulant and dose for stroke prevention in individual patients with non-valvular atrial fibrillation: part 1. Eur Heart J. 2017;38(12):852-9. DOI:10.1093/eurheartj/ehv643
33. Wehling M. Drug therapy in the elderly: too much or too little, what to do? A new assessment system: fit for aged (FORTA). Dtsch Med Wochenschr. 2008;133(44):2289-91. DOI:10.1055/s-0028-1091275
34. Wehling M. Arzneimitteltherapie im Alter: Zu viel und zu wenig, was tun? Ein neues Bewertungssystem: fit for the aged (FORTA) [Drug therapy in the elderly: too much or too little, what to do? A new assessment system: fit for the aged (FORTA)]. Dtsch Med Wochenschr. 2008;133(44):2289-91. DOI:10.1055/s-0028-1091275
35. Pazan F, Collins R, Gil VM, et al. A structured literature review and international consensus validation of forta labels of oral anticoagulants for long-term treatment of atrial fibrillation in older patients (OAC-FORTA 2019). Drugs Aging. 2020;37(7):539-48.
DOI:10.1007/s40266-020-00771-0
36. Kochetkov AI, Ostroumova OD, Liahova NL, Butorov VN. How to improve anticoagulant therapy in a patient with atrial fibrillation? Consilium Medicum. 2020;22(5):40-8 (in Russian). DOI:10.26442/20751753.2020.5.200151
37. Diener HC, Aisenberg J, Ansell J, et al. Choosing a particular oral anticoagulant and dose for stroke prevention in individual patients with non-valvular atrial fibrillation: part 2. Eur Heart J. 2017;38(12):860-8. DOI:10.1093/eurheartj/ehw069

Авторы

М.Ю. Максимова, А.В. Фонякин*, Л.А. Гераскина

ФГБНУ «Научный центр неврологии», Москва, Россия
*fonyakin@mail.ru

________________________________________________

Marina Yu. Maksimova, Andrei V. Fonyakin*, Liudmila A. Geraskina

Research Center of Neurology, Moscow, Russia
*fonyakin@mail.ru

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