cardiovascularКардиоваскулярная терапия и профилактикаCardiovascular Therapy and Prevention1728-88002619-0125«SILICEA-POLIGRAF» LLC10.15829/1728-8800-2018-2-35-42cardiovascular-802Research ArticleЛЕГОЧНАЯ АРТЕРИАЛЬНАЯ ГИПЕРТЕНЗИЯPULMONARY АRTERIAL HYPERTENSIONОПЫТ ПРИМЕНЕНИЯ НЕСЕЛЕКТИВНОГО АНТАГОНИСТА ЭНДОТЕЛИНОВЫХ РЕЦЕПТОРОВ МАЦИТЕНТАНА У БОЛЬНЫХ ЛЕГОЧНОЙ АРТЕРИАЛЬНОЙ ГИПЕРТЕНЗИЕЙEXPERIENCE OF USING THE NON­SELECTIVE ENDOTHELIN RECEPTOR ANTAGONIST MACITENTAN IN PATIENTS WITH PULMONARY ARTERIAL HYPERTENSIONСимаковаМ. А.SimakovaM. A.

Кандидат медицинских наук, старший научный сотрудник НИО некоронарогенных заболеваний сердца.

Санкт-Петербург, +7 (921) 589­87­63

Saint­-Petersburg

maria.simakova@gmail.comГончароваН. С.GoncharovaN. S.

Кандидат медицинских наук, старший научный сотрудник отдела.

Санкт-Петербург

Saint­-Petersburg

КарелкинаЕ. В.KarelkinaE. V.

Научный сотрудник отдела.

Санкт-Петербург

Saint­-Petersburg

МоисееваО. М.MoiseevaO. M.

Доктор медицинских наук, заведующая отделом.

Санкт-Петербург

Saint­-Petersburg

ФГБУ “Национальный медицинский исследовательский центр им. В. А. Алмазова” Минздрава РоссииРоссияFSBI “Almazov National Medical Research Centre” of the Ministry of Health of the Russian FederationRussian Federation2018200420181723542Copyright © Симакова М.А., Гончарова Н.С., Карелкина Е.В., Моисеева О.М., 20182018Симакова М.А., Гончарова Н.С., Карелкина Е.В., Моисеева О.М.Simakova M.A., Goncharova N.S., Karelkina E.V., Moiseeva O.M.This work is licensed under a Creative Commons Attribution 4.0 License.https://cardiovascular.elpub.ru/jour/article/view/802Цель

Цель. Представить результаты лечения препаратом мацитентан пациентов, включенных в клиническое исследование SERAPHIN в “НМИЦ им. В. А. Алмазова” (далее — НМИЦ, Центр), определить таргетную терапию больных легочной артериальной гипертензией (ЛАГ) в реальной клинической практике.

Материал и методы

Материал и методы. В работе представлены результаты 151 пациента с ЛАГ, наблюдавшихся в НМИЦ в 2009­2016гг.

Результаты

Результаты. Пятилетняя выживаемость пациентов с ЛАГ, включенных в регистр НМИЦ, составила 77% при идиопатической ЛАГ, 52% при ЛАГ, ассоциированной с системной склеродермией, 81% при ЛАГ, ассоциированной с некорригированными врожденными пороками сердца, 82% у пациентов с корригированными врожденными пороками и 100% при ЛАГ, ассоциированной с инфекцией вируса иммунодефицита человека. Группа ЛАГ­специфической монотерапии составила 47% (n=71), где в числе препаратов, безусловно, лидирует ингибитор фосфодиэстеразы 5 типа (ИФДЭ­5) силденафил — 74% (n=53). Группу ЛАГ комбинированной специфической терапии составили 66 (44%) пациентов: 48 пациентов получали разные варианты двухкомпонентной терапии, 18 пациентов — трехкомпонентную терапию антагонистом эндотелиновых рецепторов в сочетании с ИФДЭ­5 и простаноидами. В исследование SERAPHIN включены 11 больных ЛАГ, при этом 9 пациентов исходно получали терапию генерическим ИФДЭ­5. В группе пациентов, получавших терапию мацитентаном, через 6 мес. выявлен статистически значимый прирост дистанции в тесте с шестиминутной ходьбой (+50 метров), снижение гемодинамических показателей: среднее давление в правом пред сердии (­2,3 мм рт.ст.) и легочное сосудистое сопротивление (­445 дин*сек/см5). Ни у одного больно­го не наблюдалось клинически значимого повышения уровня печеночных трансаминаз или снижения уровня гемоглобина.

Заключение

Заключение. Улучшение прогноза у больных ЛАГ по данным регистра Центра связано как с ранним выявлением заболевания, благодаря развитию специализированной помощи, так и с более частым применением комбинированной терапии. Мацитентан подтвердил свои долгосрочные эффективность и безопасность в качестве монотерапии и в комбинации с ИФДЭ­5.

Aim

Aim. To present the results of treatment with macitentan of patients included in the clinical trial SERAPHIN in Almazov National Medical Research Centre and define target therapy of pulmonary arterial hypertension (PAH) in real clinical practice.

Material and methods

Material and methods. The article presents the results of the 151 patients with PAH followed­up in Almazov National Medical Research Centre from 2009 to 2016.

Results

Results. Five­year survival of PAH patients included in the register of Almazov National Medical Research Centre reached 77% for idiopathic PAH, 52% for PAH associated with systemic scleroderma, 81% for PAH associated with non­repaired congenital heart disease, 82% for patients with repaired congenital shunts and 100% for PAH associated with human immunodeficiency virus infection. The group that received PAH specific monotherapy consisted of 47% (n=71) of patients among which phosphodiesterase type 5 inhibitor (PDE­5i) sildenafil was undoubtedly the most prescribed drug — 74% (n=53). The group that received combined PAH specific therapy consisted of 66 (44%) patients: 48 patients received various two­component therapy, 18 patients — threecomponent therapy with endothelin receptor antagonist in combination with PDE­5i and prostanoids. 11 patients with PAH were included in SERAPHIN study of which 9 patients had been already receiving generic PDE­5i therapy. In macitentan group, a statistically significant increase in the 6­minute walk distance (+50 meters) and a decrease in hemodynamic parameters such as mean right atrial pressure (­2,3 mm Hg) and pulmonary vascular resistance (­445 dyn­sec/cm5) were observed after 6 months. No patient had a clinically significant increase in liver transaminases or a decrease in hemoglobin levels.

Conclusion

Conclusion. Improvement of prognosis in PAH patients according to the register of the Centre is connected both with early detection of the disease, thanks to the development of specialized healthcare, and more frequent use of combination therapy. Macitentan proved its long­term efficacy and safety as monotherapy and in combination with PDE­5i.

легочная артериальная гипертензияантагонисты рецепторов эндотелинамацитентанSERAPHINpulmonary arterial hypertensionendothelin receptor antagonistsmacitentanSERAPHINReferencesSavarese G, Paolillo S, Costanzo P, et al. Do changes of 6­minute walk distance predict clinical events in patients with pulmonary arterial hypertension? A metaanalysis of 22 randomized trials. JACC 2012; 60: 1192­201. DOI: 10.1016/j.jacc.2012.01.083.Savarese G, Paolillo S, Costanzo P, et al. Do changes of 6­minute walk distance predict clinical events in patients with pulmonary arterial hypertension? A metaanalysis of 22 randomized trials. JACC 2012; 60: 1192­201. DOI: 10.1016/j.jacc.2012.01.083.Pulido T, Adzerikho I, Channick RN, et al. SERAPHIN Investigators. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med 2013; 369 (9): 809­18. DOI: 10.1056/NEJMoa1213917.Pulido T, Adzerikho I, Channick RN, et al. SERAPHIN Investigators. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med 2013; 369 (9): 809­18. DOI: 10.1056/NEJMoa1213917.Mehta S, Kutumba B, Sastry S, Souza R. Macitentan Improves Health­Related Quality of Life for Patients With Pulmonary Arterial Hypertension Results From the Randomized Controlled SERAPHIN Trial CHEST 2017; 151 (1): 106­18. DOI: 10.1016/j.chest.2016.08.1473.Mehta S, Kutumba B, Sastry S, Souza R. Macitentan Improves Health­Related Quality of Life for Patients With Pulmonary Arterial Hypertension Results From the Randomized Controlled SERAPHIN Trial CHEST 2017; 151 (1): 106­18. DOI: 10.1016/j.chest.2016.08.1473.Lang R, Badano L, Mor­Avi V, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging 2015; 16 (3): 233­70. DOI: 10.1093/ehjci/jev014.Lang R, Badano L, Mor­Avi V, et al. Recommendations for cardiac chamber quantification by echocardiography in adults: an update from the American Society of Echocardiography and the European Association of Cardiovascular Imaging. Eur Heart J Cardiovasc Imaging 2015; 16 (3): 233­70. DOI: 10.1093/ehjci/jev014.Awdish R, Cajigas H. Definition, epidemiology and registries of pulmonary hypertension. Heart Fail Rev 2016; 21 (3): 223­8. DOI: 10.1007/s10741­015­9510­y.Awdish R, Cajigas H. Definition, epidemiology and registries of pulmonary hypertension. Heart Fail Rev 2016; 21 (3): 223­8. DOI: 10.1007/s10741­015­9510­y.Galiè N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis an d Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J 2016; 37 (1): 67­119. DOI: 10.1093/eurheartj/ehv317.Galiè N, Humbert M, Vachiery JL, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis an d Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS): Endorsed by: Association for European Paediatric and Congenital Cardiology (AEPC), International Society for Heart and Lung Transplantation (ISHLT). Eur Heart J 2016; 37 (1): 67­119. DOI: 10.1093/eurheartj/ehv317.Hoeper M, Kramer T, Zixuan Pan, et al. Mortality in pulmonary arterial hypertension: prediction by the 2015 European pulmonary hypertension guidelines risk stratification model. Eur Respir J 2017; 50: 1700­40. DOI: 10.1183/13993003.00740­2017.Hoeper M, Kramer T, Zixuan Pan, et al. Mortality in pulmonary arterial hypertension: prediction by the 2015 European pulmonary hypertension guidelines risk stratification model. Eur Respir J 2017; 50: 1700­40. DOI: 10.1183/13993003.00740­2017.Benza RL, Miller DP, Gomberg­Maitland M, et al. Predicting Survival in Pulmonary Arterial Hypertension: Insights From the Registry to Evaluate Early and Long­Term Pulmonary Arterial Hypertension Disease Management (REVEAL). Circulation 2010; 122 (2): 164­72. DOI: 10.1161/CIRCULATIONAHA.109.898122.Benza RL, Miller DP, Gomberg­Maitland M, et al. Predicting Survival in Pulmonary Arterial Hypertension: Insights From the Registry to Evaluate Early and Long­Term Pulmonary Arterial Hypertension Disease Management (REVEAL). Circulation 2010; 122 (2): 164­72. DOI: 10.1161/CIRCULATIONAHA.109.898122.Jansa P, Tomás Pulido. Macitentan in Pulmonary Arterial Hypertension: A Focus on Combination Therapy in the SERAPHIN Trial Am J Cardiovasc Drugs 2018; 18: 1­11. DOI: 10.1007/s40256­017­0260­1.Jansa P, Tomás Pulido. Macitentan in Pulmonary Arterial Hypertension: A Focus on Combination Therapy in the SERAPHIN Trial Am J Cardiovasc Drugs 2018; 18: 1­11. DOI: 10.1007/s40256­017­0260­1.Nadeau V, Potus F, Boucherat O, et al. Dual ETA/ETB blockade with macitentan improves both vascular remodelling and angiogenesis in pulmonary arterial hypertension Pulmonary. Circulation 2017; 8 (1): 1­15. DOI: 10.1177/2045893217741429.Nadeau V, Potus F, Boucherat O, et al. Dual ETA/ETB blockade with macitentan improves both vascular remodelling and angiogenesis in pulmonary arterial hypertension Pulmonary. Circulation 2017; 8 (1): 1­15. DOI: 10.1177/2045893217741429.Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002; 346: 896­903. DOI: 10.1056/NEJMoa012212.Rubin LJ, Badesch DB, Barst RJ, et al. Bosentan therapy for pulmonary arterial hypertension. N Engl J Med 2002; 346: 896­903. DOI: 10.1056/NEJMoa012212.Galie N, Rubin L, Hoeper M, et al. Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double­blind, randomised controlled trial. Lancet 2008; 371: 2093­100. DOI: 10.1016/S01406736(08)60919­18.Galie N, Rubin L, Hoeper M, et al. Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double­blind, randomised controlled trial. Lancet 2008; 371: 2093­100. DOI: 10.1016/S01406736(08)60919­18.McLaughlin V, Channick RN, Ghofrani HA, et al. Bosentan added to sildenafil therapy in patients with pulmonary arterial hypertension. Eur Respir J 2015; 46: 405­13. DOI: 10.1183/13993003.02044­2014.McLaughlin V, Channick RN, Ghofrani HA, et al. Bosentan added to sildenafil therapy in patients with pulmonary arterial hypertension. Eur Respir J 2015; 46: 405­13. DOI: 10.1183/13993003.02044­2014.Grünig E, Ohnesorge J, Benjamin N, et al. Plasma Drug Concentrations in Patients with pulmonary arterial hypertension on combination treatment. Respiration 2017; 94 (1): 26­37. DOI: 10.1159/000470916.Grünig E, Ohnesorge J, Benjamin N, et al. Plasma Drug Concentrations in Patients with pulmonary arterial hypertension on combination treatment. Respiration 2017; 94 (1): 26­37. DOI: 10.1159/000470916.Aypar E, Alehan D, Karagöz T, et al. Clinical efficacy and safety of switch from bosentan to macitentan in children and young adults with pulmonary arterial hypertension. Cardiol Young 2018; 28 (4): 542­7. DOI: 10.1017/S1047951117002542.Aypar E, Alehan D, Karagöz T, et al. Clinical efficacy and safety of switch from bosentan to macitentan in children and young adults with pulmonary arterial hypertension. Cardiol Young 2018; 28 (4): 542­7. DOI: 10.1017/S1047951117002542.

The authors declare that there are no conflicts of interest present.