Доказательная база специфических легочных вазодилататоров у взрослых с врожденными пороками сердца

Шмальц А.А., Горбачевский С.В. Доказательная база специфических легочных вазодилататоров у взрослых с врожденными пороками сердца. Терапевтический архив. 2021; 93 (9): 1106–1116. DOI: 10.26442/00403660.2021.09.201022

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Shmalts AA, Gorbachevsky SV. Evidence base for specific pulmonary vasodilators in adults with congenital heart disease. Terapevticheskii Arkhiv (Ter. Arkh.). 2021; 93 (9): 1106–1116. DOI: 10.26442/00403660.2021.09.201022

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Аннотация

После рассмотрения современных определений и классификации легочной гипертензии (ЛГ), ассоциированной с врожденными пороками сердца (ВПС), на основе анализа 59 клинических исследований (из них 14 – рандомизированные контролируемые исследования) зарегистрированных в Российской Федерации препаратов приводится доказательная база терапии ЛГ у взрослых с ВПС. Наличие рандомизированного контролируемого исследования бозентана BREATHE-5 и неконтролируемых исследований других препаратов стало основанием для более высокого класса и уровня доказательности бозентана (IB) по сравнению с другими препаратами (IIaС) при синдроме Эйзенменгера в действующих Европейских (ERS/ESC 2015) и обновленных Российских (2020 г.) рекомендациях по ЛГ. Согласно обновленным Европейским (ESC 2020) рекомендациям по ВПС у взрослых «пациентам с синдромом Эйзенменгера и сниженной переносимостью физической нагрузки (дистанция теста 6-минутной ходьбы <450 м) показана монотерапия антагонистами рецепторов эндотелина, а при отсутствии эффективности – комбинированная терапия (IIaB)», «пациентам низкого и промежуточного риска с корригированными простыми ВПС и прекапиллярной ЛГ рекомендуется пероральная начальная или последовательная комбинированная терапия, пациентов же высокого риска следует лечить начальной комбинацией, включающей парентеральные простаноиды (IA)», и «антагонисты рецепторов эндотелина и ингибиторы фосфодиэстеразы 5 могут быть рассмотрены у отдельных пациентов после операции Фонтена с повышенным давлением в легочной артерии/легочным сосудистым сопротивлением при отсутствии повышения конечного диастолического давления системного желудочка (IIbC)». Лишь 3 (бозентан, мацитентан и селексипаг) из 7 зарегистрированных в РФ специфических легочных вазодилататоров имеют показания «легочная артериальная гипертензия, ассоциированная с ВПС и синдромом Эйзенменгера», или «легочная артериальная гипертензия, ассоциированная с корригированными простыми ВПС», в инструкциях по применению.

Ключевые слова: легочная гипертензия, легочная артериальная гипертензия, врожденные пороки сердца, специфические легочные вазодилататоры

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After reviewing the current definitions and classification of pulmonary hypertension (PH) associated with congenital heart disease (CHD), based on an analysis of 59 clinical trials (of which 14 are randomized controlled trials) drugs registered in the Russian Federation, the evidence base for PH therapy in adults with CHD is provided. The presence of a randomized controlled trial of bosentan BREATHE-5 and uncontrolled trials of other drugs became the basis for a higher class and level of evidence of bosentan (IB) compared to other drugs (IIaC) for Eisenmenger syndrome in the current European (ERS/ESC 2015) and updated Russian (2020) guidelines. According to the updated European (ESC 2020) guidelines for congenital heart disease in adults, “in Eisenmenger patients with reduced exercise capacity (6MWT distance <450 m), a treatment strategy with initial endothelin receptor antagonist monotherapy should be considered followed by combination therapy if patients fail to improve (IIaB)”, “in low- and intermediate-risk patients with repaired simple lesions and pre-capillary PH, initial oral combination therapy or sequential combination therapy is recommended and high-risk patients should be treated with initial combination therapy including parenteral prostanoids (IA)” and “endothelin receptor antagonists and phosphodiesterase 5 inhibitors may be considered in selected patients with elevated pulmonary pressure/resistance in the absence of elevated ventricular end diastolic pressure (IIbC)”. Only three (bosentan, macitentan and selexipag) out of seven specific pulmonary vasodilators registered in the Russian Federation have indications for “pulmonary arterial hypertension associated with congenital heart disease and Eisenmenger syndrome” or “pulmonary arterial hypertension associated with corrected simple congenital heart disease” in the instructions for use.

Keywords: pulmonary hypertension, pulmonary arterial hypertension, congenital heart disease, specific pulmonary vasodilators

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80. Giardini A, Balducci A, Specchia S, et al. Effect of sildenafil on haemodynamic response to exercise and exercise capacity in Fontan patients. Eur Heart J. 2008;29(13):1681-7. DOI:10.1093/eurheartj/ehn215
81. Van De Bruaene A, La Gerche A, Claessen G, et al. Sildenafil improves exercise hemodynamics in Fontan patients. Circ Cardiovasc Imaging. 2014;7(2):265-73. DOI:10.1161/CIRCIMAGING.113.001243
82. Rhodes J, Ubeda-Tikkanen A, Clair M, et al. Effect of inhaled iloprost on the exercise function of Fontan patients: a demonstration of concept. Int J Cardiol. 2013;168(3):2435-40. DOI:10.1016/j.ijcard.2013.03.014
83. Mori H, Park IS, Yamagishi H, et al. Sildenafil reduces pulmonary vascular resistance in single ventricular physiology. Int J Cardiol. 2016;221:122-7. DOI:10.1016/j.ijcard.2016.06.322
84. Hirono K, Yoshimura N, Taguchi M, et al. Bosentan induces clinical and hemodynamic improvement in candidates for right-sided heart bypass surgery. J Thorac Cardiovasc Surg. 2010;140:346-51. DOI:10.1016/j.jtcvs.2010.03.023
85. McLaughlin V, Channick RN, Ghofrani HA, et al. Bosentan added to sildenafil therapy in patients with pulmonary arterial hypertension. Eur Respir J. 2015;46(2):405-13. DOI:10.1183/13993003.02044-2014
86. Beghetti M. Fontan and the pulmonary circulation: a potential role for new pulmonary hypertension therapies. Heart. 2010;96:911-6. DOI:10.1136/hrt.2010.193912

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79. Cedars AM, Saef J, Peterson LR, et al. Effect of Ambrisentan on Exercise Capacity in Adult Patients After the Fontan Procedure. Am J Cardiol. 2016;117(9):1524-32. DOI:10.1016/j.amjcard.2016.02.024
80. Giardini A, Balducci A, Specchia S, et al. Effect of sildenafil on haemodynamic response to exercise and exercise capacity in Fontan patients. Eur Heart J. 2008;29(13):1681-7. DOI:10.1093/eurheartj/ehn215
81. Van De Bruaene A, La Gerche A, Claessen G, et al. Sildenafil improves exercise hemodynamics in Fontan patients. Circ Cardiovasc Imaging. 2014;7(2):265-73. DOI:10.1161/CIRCIMAGING.113.001243
82. Rhodes J, Ubeda-Tikkanen A, Clair M, et al. Effect of inhaled iloprost on the exercise function of Fontan patients: a demonstration of concept. Int J Cardiol. 2013;168(3):2435-40. DOI:10.1016/j.ijcard.2013.03.014
83. Mori H, Park IS, Yamagishi H, et al. Sildenafil reduces pulmonary vascular resistance in single ventricular physiology. Int J Cardiol. 2016;221:122-7. DOI:10.1016/j.ijcard.2016.06.322
84. Hirono K, Yoshimura N, Taguchi M, et al. Bosentan induces clinical and hemodynamic improvement in candidates for right-sided heart bypass surgery. J Thorac Cardiovasc Surg. 2010;140:346-51. DOI:10.1016/j.jtcvs.2010.03.023
85. McLaughlin V, Channick RN, Ghofrani HA, et al. Bosentan added to sildenafil therapy in patients with pulmonary arterial hypertension. Eur Respir J. 2015;46(2):405-13. DOI:10.1183/13993003.02044-2014
86. Beghetti M. Fontan and the pulmonary circulation: a potential role for new pulmonary hypertension therapies. Heart. 2010;96:911-6. DOI:10.1136/hrt.2010.193912

Авторы

А.А. Шмальц*1,2, С.В. Горбачевский1,2

1 ФГБУ «Национальный медицинский исследовательский центр сердечно-сосудистой хирургии им. А.Н. Бакулева» Минздрава России, Москва, Россия;
2 ФГБОУ ДПО «Российская медицинская академия непрерывного профессионального образования» Минздрава России, Москва, Россия
*shmaltzanton@inbox.ru

________________________________________________

Anton A. Shmalts*1,2, Sergey V. Gorbachevsky1,2

1 Bakulev National Medical Research Center of Cardiovascular Surgery, Moscow, Russia;
2 Russian Medical Academy of Continuous Professional Education, Moscow, Russia
*shmaltzanton@inbox.ru

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