Мaцитентан – новый пероральный двойной антагонист рецепторов эндотелина (АРЭ) – с 2015 г. успешно внедрен в российскую практику для лечения пациентов с легочной артериальной гипертензией (ЛАГ). Препарат имеет улучшенные физико-химические свойства, что обеспечивает тканевую специфичность. Среди АРЭ и других препаратов специфической терапии мацитентан является единственным препаратом с показанием «предотвращение прогрессирования ЛАГ». В рандомизированном плацебо-контролируемом исследовании SERAPHIN у 742 пациентов старше 12 лет с ЛАГ мацитентан 10 мг снижал риск заболеваемости и смертности на 45% в сравнении с плацебо. К 6-му месяцу лечения, при благоприятном профиле переносимости, мацитентан обеспечивал достоверный прирост дистанции в тесте 6-минутной ходьбы, улучшение функционального класса (ФК) и гемодинамических параметров – легочного сосудистого сопротивления (ЛСС) и сердечного индекса. Лечение мацитентаном значительно снижало потребность в госпитализации по всем причинам, в том числе связанной с прогрессированием ЛАГ.
В обзоре представлен современный взгляд на возможности применения мацитентана в клинической практике. Показано, что мацитентан является препаратом первого выбора среди АРЭ для лечения пациентов с ЛАГ. В исследовании MERIT-1 по сравнению с плацебо мацитентан у пациентов с неоперабельной хронической тромбоэмболической легочной гипертензией ФК II–IV (ВОЗ) значительно улучшал ЛСС (отношение геометрических средних 0,84; 95% ДИ 0,70–0,99; p=0,041). Доказательная база по применению мацитентана в различных подгруппах ЛАГ, включая портолегочную гипертензию, ЛАГ у детей, а также за рамками группы 1 – при хронической тромбоэмболической легочной гипертензии, патологии левых отделов сердца – пополняется новыми данными, что позволит расширить возможности клинического применения препарата.
Since 2015, macitentan, the new oral dual endothelin receptors antagonist (ERA), has been successfully introduced into clinical practice in the Russian Federation for the treatment of pulmonary arterial hypertension (PAH) patients. It has improved physicochemical properties, which provides tissue specificity. Among ERA and other drugs of specific therapy, macitentan is the only one with indication-prevention of PAH progression. In the randomized, placebo-controlled study SERAPHIN in 742 PAH patients aged >12 years, macitentan 10 mg compared with placebo reduced the risk of morbidity and mortality by 45%. By month 6, macitentan with favorable tolerability profile provided a significant increase in the 6-minute walk test distance, the improvement of the functional class (FC) and hemodynamic parameters – pulmonary vascular resistance (PVR) and cardiac index. Macitentan significantly reduced the need for hospitalization for all reasons, including associated with PAH worsening.
This review presents a modern view on the possibility of using macitentan in the clinical practice. It is shown that the drug is an important choice among ERA for the treatment of PAH patients. In the study MERIT-1 macitentan significantly improved PVR (geometric mean ratio 0.84, 95% CI 0.70–0,99, p=0.041) in inoperable CTEPH patients. The evidence base for the macitantan use in various PAH subgroups, including portopulmonary hypertension, in children as well as beyond group 1 – CTEPH, left heart diseases – is supplementing with the new data, which will expand the possibilities of its clinical use.
1. Чазова И.Е., Авдеев С.Н., Царева Н.А. и др. Клинические рекомендации по диагностике и лечению легочной гипертензии. Терапевтический архив. 2014;86(9):4-23. Доступно по ссылке: https://www.mediasphera.ru/issues/terapevticheskij-arkhiv/2016/10/ 10040366016101063/ [Chazova IE, Avdeev SN, Tsareva NA, et al. Clinical recommendationson the diagnosis and treatment of pulmonary hypertension. Terapevticheskiy Arkhiv = Therapeutic Archive. 2014;86(9):4-23. Available from: https://www.mediasphera.ru/issues/ terapevticheskij-arkhiv/2016/10/10040366016101063/ (In Russ.)].
2. Galiè N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension: The Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J. 2016;37(1):67-119. doi: 10.1093/eurheartj/ehv317
3. Мартынюк Т.В., Чазова И.Е. Стратегия медикаментозного лечения легочной артериальной гипертензии в свете современных зарубежных рекомендаций. Системные гипертензии. 2016;(2):46-65. Доступно по ссылке: https://con-med.ru/magazines/hypertension/231032/231026/ [Martyniuk TV, Chazova IE. Strategy of medical treatment of pulmonary arterial hypertension in the current international recommendations. Sistemnye Gipertenzii = Systemic Hypertension. 2016;13(2):65-73. Available from: https://con-med.ru/magazines/hypertension/231032/231026/ (In Russ.)].
4. Валиева З.С., Мартынюк Т.В., Чазова И.Е. Опыт применения бозентана при легочной артериальной гипертензии: российский и зарубежный опыт. Терапевтический архив. 2017;89(8):95-103 [Valieva ZS, Martyniuk TV, Chazova IE. Bosentan use in pulmonary arterial hypertension: Russian and foreign experience. Terapevticheskiy Arkhiv = Therapeutic Archive. 2017;89(9):95-103 (In Russ.)].
doi: 10.17116 terarkh201789895-103
5. Чазова И.Е., Мартынюк Т.В., Наконечников С.Н. Антагонисты рецепторов эндотелия при легочной артериальной гипертензии: вчера, сегодня и завтра. Российский кардиологический журнал. 2009;(4):73-81 [Chazova IE, Martyniuk TV. Endothelin receptor antagonists in pulmonary arterial hypertension: yesterday, today and tomorrow. Rossiiskii kardiologicheskii zhurnal = Russian Cardiology Journal. 2009;(4):73-81 (In Russ.)]. doi: 10.15829/1560-4071-2009-4-73-81
6. Wagner OF, Christ G, Wojta J, et al. Polar secretion of endothelin-1 by cultured endothelial cells. J Biol Chem. 1992;267:16066-8. https://www.ncbi.nlm.nih.gov/pubmed/1644793
7. Мартынюк Т.В., Наконечников С.Н., Чазова И.Е. Мацитентан: эволюция класса антагонистов рецепторов эндотелина для повышения эффективности и безопасности лечения легочной артериальной гипертензии. Евразийский кардиологический журнал. 2013;(3):15-26 Доступно по ссылке: https://elibrary.ru/item.asp? id=21005238 [Martyniuk TV, Nakonechnikov SN, Chazova IE. Macitentan: evolution of endothelin receptor antagonists for the improment of efficacy anf safety of pulmonary arterial hypertension treatment. Evraziiskii Kardiologicheskii Zhurnal = Eurasian Cardiology Journal. 2013;(3):15-26. Available from: https://elibrary.ru/item.asp?id= 21005238 (In Russ.)].
8. Мартынюк Т.В., Наконечников С.Н., Чазова И.Е. Оптимизация специфической терапии легочной артериальной гипертензии: возможности применения антагонистов рецепторов эндотелина. Евразийский кардиологический журнал. 2017;(2):20-7 [Martynyuk TV, Nakonechnikov SN, Chazova IYe. Optimization of specific therapy for pulmonary arterial hypertension: the possibilities of using endothelin receptor antagonists. Evraziiskii Kardiologicheskii Zhurnal = Eurasian Cardiology Journal. 2017;(2):20-7 (In Russ.)].
9. Galie N, Jansa P, Pulido T, et al. SERAPHIN haemodynamic sub-study: the effect of the dual endothelin receptor antagonist macitentan on haemodynamic parameters and NT-proBNP levels and their association with disease progression in patients with pulmonary arterial hypertension. Eur Heart J. 2017;(0):1-9. doi: 10.1093/eurheartj/ehx025
10. Mehta S, Sastry BK, Souza R, et al. Macitentan improves health-related quality of life for patients with pulmonary arterial hypertension: results from the randomized controlled SERAPHIN trial. Chest. 2017;151:pp.106-118. Available from: www.atsjournals.org/.../ajrccm-conference.2013.187
11. Kim NH, Chin KM, Muros-Le Rouzic E, et al. OPsumit_ Users Registry (OPUS): insights into the safety and tolerability of Opsumit [abstract P1031]. Am J Respir Crit Care Med. 2016;193:A7396. Available from: https://www.nationaljewish.org/.../opus-registry-for-patients
12. Chin K, Channick N, Selej E, et al. OPUS registry: treatment patterns and safety of macitentan in patients with pulmonary arterial hypertension associated with systemic sclerosis. Chest. Annual Meeting 2017, Toronto, Canada. doi: 10.1016/j.chest.2017.08.1036
13. Волков А.В., Мартынюк Т.В., Юдкина Н.Н. Выживаемость пациентов легочной артериальной гипертензией, ассоциированной с системной склеродермией. Терапевтический архив. 2012;(5):24-8. Доступно по ссылке: www.fesmu.ru/elib/Article.aspx?id=261184 [Volkov AV, Martynyuk TV, Yudkina NN, et al. Survival of patients with scleroderma-related pulmonary arterial Hypertension. Terapevticheskiy Arkhiv = Therapeutic Archive. 2012;(5):24-8. Available from: www.fesmu.ru/elib/Article.aspx?id=261184
14. Юдкина Н.Н., Валеева Э.Г., Таран И.Н. и др. Легочная артериальная гипертензия, ассоциированная с системной склеродермией, и идиопатическая легочная гипертензия: сравнительный анализ клинико-демографических особенностей и выживаемости по данным российского национального регистра. Системные гипертензии. 2016;13(2):65-72. Доступно по ссылке: https://elibrary.ru/item.asp? id=27706534 [Yudkina NN, Valeeva EG, Taran IN, et al. Demographic and clinical differences between idiopathic and scleroderma-related pulmonary arterial hypertension: Russian National Registry analysis. Sistemnye Gipertenzii = Systemic Hypertension. 2016;13(2):65-72. Available from: https://elibrary.ru/item.asp?id=27706534 (In Russ.)].
15. McLaughlin V, Bacchetta M, Badesch D, et al. Update on Pulmonary Arterial Hypertension Research: Proceedings from a Meeting of Experts. Curr Med Res Opin. (Online) Journal homepage: http://www. tandfonline.com/loi/icmo20. doi: 10.1080/03007995.2017.1404974
16. Sitbon O, Canuet M, Picard F, et al. Initial Combination Therapy With Macitentan and Tadalafil In Newly Diagnosed Patients With Pulmonary Arterial Hypertension: Results From The Optima Trial. Am J Respir Crit Care Med. 2017;195:A2297. Available from: http://www. atsjournals.org/doi/abs/10.1164/ajrccm-conference.2017.195. 1_MeetingAbstracts.A2297
17. Burgess G, Hoogkamer H, Collings L, et al. Mutual pharmacokinetic interactions between steady-state bosentan and sildenafil. Eur J Clin Pharmacol. 2008;64(1):43-50. doi: 10.1007/s00228-007-0408-z
18. Iglarz M, Binkert C, Morrison K, et al. Pharmacology of macitentan, an orally active tissue-targeting dual endothelin receptor antagonist.
J Pharmacol Exp Ther. 2008;327:736–745. doi: 10.1124/jpet.108. 142976
19. Souza R. SERAPHIN: results from a landmark study. Abstracts from ERS Congress 2012. Available from: www.clinicaltrials.gov. NCT00660179
20. Grünig E, Ohnesorge J, Benjamin N, et al. Plasma Drug Concentrations in Patients with Pulmonary Arterial Hypertension on Combination Treatment. Respiration. 2017;94(1):26-37. doi: 10.1159/ 000470916
21. Tahara N, Dobashi H, Fukuda K, et al. Efficacy and Safety of a Novel Endothelin Receptor Antagonist, Macitentan, in Japanese Patients With Pulmonary Arterial Hypertension. Circ J. 2016;80(6):1478-83. doi: 10.1253/circj.CJ-15-1305
22. Blok IM, Riel A, van Dijk A, et al. From bosentan to macitentan for pulmonary arterial hypertension and adult congenital heart disease: Further improvement? Intern J Cardiol. 2017;227:51-2. doi: 10.1016/ j.ijcard.2016.11.211
23. Ghofrani HA, Simonneau G, D’Armini AM, et al. Macitentan for the treatment of inoperable chronic thromboembolic pulmonary hypertension (MERIT-1): results from the multicentre, phase 2, randomised, double-blind, placebo-controlled study. Lancet Respir Med. 2017.
doi: 10.1016/S2213-2600(17)30305-3
24. Чазова И.Е., Мартынюк Т.В. и др. Клинические рекомендации по диагностике и лечению хронической тромбоэмболической легочной гипертензии (I часть). Терапевтический архив. 2016;88(9):90-101 [Chazova IE, Martynyuk TV, et al. Clinical recommendationson the diagnosis and treatment of chronic thromboembolic pulmonary hypertension (part 1). Terapevticheskiy Arkhiv = Therapeutic Archive. 2016;88(9):90-101 (In Russ.)]. doi: 10.17116/terarkh201688990-101
25. Чазова И.Е., Мартынюк Т.В. и др. Клинические рекомендации по диагностике и лечению хронической тромбоэмболической легочной гипертензии (II часть). Терапевтический архив. 2016;88 (10):63-74 [Chazova IE, Martynyuk TV, et al. Clinical recommendationson the diagnosis and treatment of chronic thromboembolic pulmonary hypertension (part 2). Terapevticheskiy Arkhiv = Therapeutic Archive. 2016;88(10):63-74 (In Russ.)]. doi: 10.17116/terarkh 201688663-73
26. ClinicalTrials.gov. PORTICO (PORtopulmonary Hypertension Treatment wIth maCitentan). December 13, 2017. Available from: https://clinicaltrials.gov/ct2/show/results/NCT02382016
27. ClinicalTrials.gov. TOMORROW (A Study to Assess Whether Macitentan Delays Disease Progression in Children With Pulmonary Arterial Hypertension). January 9, 2018. Available from: https://clinicaltrials.gov/ct2/show/NCT02932410
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1. [Chazova IE, Avdeev SN, Tsareva NA, et al. Clinical recommendationson the diagnosis and treatment of pulmonary hypertension. Terapevticheskiy Arkhiv = Therapeutic Archive. 2014;86(9):4-23. Available from: https://www.mediasphera.ru/issues/ terapevticheskij-arkhiv/2016/10/10040366016101063/ (In Russ.)].
2. Galiè N, Hoeper MM, Humbert M, et al. Guidelines for the diagnosis and treatment of pulmonary hypertension: The Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS), endorsed by the International Society of Heart and Lung Transplantation (ISHLT). Eur Heart J. 2016;37(1):67-119. doi: 10.1093/eurheartj/ehv317
3. [Martyniuk TV, Chazova IE. Strategy of medical treatment of pulmonary arterial hypertension in the current international recommendations. Sistemnye Gipertenzii = Systemic Hypertension. 2016;13(2):65-73. Available from: https://con-med.ru/magazines/hypertension/231032/231026/ (In Russ.)].
4. [Valieva ZS, Martyniuk TV, Chazova IE. Bosentan use in pulmonary arterial hypertension: Russian and foreign experience. Terapevticheskiy Arkhiv = Therapeutic Archive. 2017;89(9):95-103 (In Russ.)].
doi: 10.17116 terarkh201789895-103
5. [Chazova IE, Martyniuk TV. Endothelin receptor antagonists in pulmonary arterial hypertension: yesterday, today and tomorrow. Rossiiskii kardiologicheskii zhurnal = Russian Cardiology Journal. 2009;(4):73-81 (In Russ.)]. doi: 10.15829/1560-4071-2009-4-73-81
6. Wagner OF, Christ G, Wojta J, et al. Polar secretion of endothelin-1 by cultured endothelial cells. J Biol Chem. 1992;267:16066-8. https://www.ncbi.nlm.nih.gov/pubmed/1644793
7. [Martyniuk TV, Nakonechnikov SN, Chazova IE. Macitentan: evolution of endothelin receptor antagonists for the improment of efficacy anf safety of pulmonary arterial hypertension treatment. Evraziiskii Kardiologicheskii Zhurnal = Eurasian Cardiology Journal. 2013;(3):15-26. Available from: https://elibrary.ru/item.asp?id= 21005238 (In Russ.)].
8. [Martynyuk TV, Nakonechnikov SN, Chazova IYe. Optimization of specific therapy for pulmonary arterial hypertension: the possibilities of using endothelin receptor antagonists. Evraziiskii Kardiologicheskii Zhurnal = Eurasian Cardiology Journal. 2017;(2):20-7 (In Russ.)].
9. Galie N, Jansa P, Pulido T, et al. SERAPHIN haemodynamic sub-study: the effect of the dual endothelin receptor antagonist macitentan on haemodynamic parameters and NT-proBNP levels and their association with disease progression in patients with pulmonary arterial hypertension. Eur Heart J. 2017;(0):1-9. doi: 10.1093/eurheartj/ehx025
10. Mehta S, Sastry BK, Souza R, et al. Macitentan improves health-related quality of life for patients with pulmonary arterial hypertension: results from the randomized controlled SERAPHIN trial. Chest. 2017;151:pp.106-118. Available from: www.atsjournals.org/.../ajrccm-conference.2013.187
11. Kim NH, Chin KM, Muros-Le Rouzic E, et al. OPsumit_ Users Registry (OPUS): insights into the safety and tolerability of Opsumit [abstract P1031]. Am J Respir Crit Care Med. 2016;193:A7396. Available from: https://www.nationaljewish.org/.../opus-registry-for-patients
12. Chin K, Channick N, Selej E, et al. OPUS registry: treatment patterns and safety of macitentan in patients with pulmonary arterial hypertension associated with systemic sclerosis. Chest. Annual Meeting 2017, Toronto, Canada. doi: 10.1016/j.chest.2017.08.1036
13. [Volkov AV, Martynyuk TV, Yudkina NN, et al. Survival of patients with scleroderma-related pulmonary arterial Hypertension. Terapevticheskiy Arkhiv = Therapeutic Archive. 2012;(5):24-8. Available from: www.fesmu.ru/elib/Article.aspx?id=261184
14. [Yudkina NN, Valeeva EG, Taran IN, et al. Demographic and clinical differences between idiopathic and scleroderma-related pulmonary arterial hypertension: Russian National Registry analysis. Sistemnye Gipertenzii = Systemic Hypertension. 2016;13(2):65-72. Available from: https://elibrary.ru/item.asp?id=27706534 (In Russ.)].
15. McLaughlin V, Bacchetta M, Badesch D, et al. Update on Pulmonary Arterial Hypertension Research: Proceedings from a Meeting of Experts. Curr Med Res Opin. (Online) Journal homepage: http://www. tandfonline.com/loi/icmo20. doi: 10.1080/03007995.2017.1404974
16. Sitbon O, Canuet M, Picard F, et al. Initial Combination Therapy With Macitentan and Tadalafil In Newly Diagnosed Patients With Pulmonary Arterial Hypertension: Results From The Optima Trial. Am J Respir Crit Care Med. 2017;195:A2297. Available from: http://www. atsjournals.org/doi/abs/10.1164/ajrccm-conference.2017.195. 1_MeetingAbstracts.A2297
17. Burgess G, Hoogkamer H, Collings L, et al. Mutual pharmacokinetic interactions between steady-state bosentan and sildenafil. Eur J Clin Pharmacol. 2008;64(1):43-50. doi: 10.1007/s00228-007-0408-z
18. Iglarz M, Binkert C, Morrison K, et al. Pharmacology of macitentan, an orally active tissue-targeting dual endothelin receptor antagonist.
J Pharmacol Exp Ther. 2008;327:736–745. doi: 10.1124/jpet.108. 142976
19. Souza R. SERAPHIN: results from a landmark study. Abstracts from ERS Congress 2012. Available from: www.clinicaltrials.gov. NCT00660179
20. Grünig E, Ohnesorge J, Benjamin N, et al. Plasma Drug Concentrations in Patients with Pulmonary Arterial Hypertension on Combination Treatment. Respiration. 2017;94(1):26-37. doi: 10.1159/ 000470916
21. Tahara N, Dobashi H, Fukuda K, et al. Efficacy and Safety of a Novel Endothelin Receptor Antagonist, Macitentan, in Japanese Patients With Pulmonary Arterial Hypertension. Circ J. 2016;80(6):1478-83. doi: 10.1253/circj.CJ-15-1305
22. Blok IM, Riel A, van Dijk A, et al. From bosentan to macitentan for pulmonary arterial hypertension and adult congenital heart disease: Further improvement? Intern J Cardiol. 2017;227:51-2. doi: 10.1016/ j.ijcard.2016.11.211
23. Ghofrani HA, Simonneau G, D’Armini AM, et al. Macitentan for the treatment of inoperable chronic thromboembolic pulmonary hypertension (MERIT-1): results from the multicentre, phase 2, randomised, double-blind, placebo-controlled study. Lancet Respir Med. 2017.
doi: 10.1016/S2213-2600(17)30305-3
24. [Chazova IE, Martynyuk TV, et al. Clinical recommendationson the diagnosis and treatment of chronic thromboembolic pulmonary hypertension (part 1). Terapevticheskiy Arkhiv = Therapeutic Archive. 2016;88(9):90-101 (In Russ.)]. doi: 10.17116/terarkh201688990-101
25. [Chazova IE, Martynyuk TV, et al. Clinical recommendationson the diagnosis and treatment of chronic thromboembolic pulmonary hypertension (part 2). Terapevticheskiy Arkhiv = Therapeutic Archive. 2016;88(10):63-74 (In Russ.)]. doi: 10.17116/terarkh 201688663-73
26. ClinicalTrials.gov. PORTICO (PORtopulmonary Hypertension Treatment wIth maCitentan). December 13, 2017. Available from: https://clinicaltrials.gov/ct2/show/results/NCT02382016
27. ClinicalTrials.gov. TOMORROW (A Study to Assess Whether Macitentan Delays Disease Progression in Children With Pulmonary Arterial Hypertension). January 9, 2018. Available from: https://clinicaltrials.gov/ct2/show/NCT02932410
Авторы
Т.В. Мартынюк, С.Н. Наконечников, И.Е. Чазова
Институт клинической кардиологии им. А.Л. Мясникова, ФГБУ «Национальный медицинский исследовательский центр кардиологии» Минздрава России, Москва, Россия
________________________________________________
T.V. Martynyuk, S.N. Nakonechnikov, I.Ye. Chazova
A.L. Myasnikov Institute of Clinical Cardiology, Federal State Institution «National Medical Research Center of Сardiology», Ministry of Health
of Russia, Moscow, Russia