Современный взгляд на место риоцигуата в лечении легочной гипертензии

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Аннотация

Современные исследования направлены на изучение фундаментальных терапевтических мишеней и создание новых лекарственных препаратов, воздействующих на ранее установленные мишени. Еще до недавних пор единственной терапевтической стратегией воздействия на молекулярный путь «оксид азота – растворимая гуанилатциклаза (рГЦ) – циклический гуанозинмонофосфат» являлось использование ингибиторов фосфодиэстеразы типа 5 (ИФДЭ5), таких как силденафил.
В сентябре 2014 г. в России зарегистрирован первый представитель класса стимуляторов рГЦ – риоцигуат.
В обзоре приведены результаты пяти многоцентровых исследований (CHEST-1 и PATENT-1, CHEST-2 и PATENT-2, RESPITE), которые отражают эффективность и безопасность моно- и комбинированной терапии риоцигуатом у пациентов с некоторыми формами легочной артериальной гипертензии, а также пациентов с неоперабельной или персистирующей/рецидивирующей хронической тромбоэмболической легочной гипертензией (ХТЭЛГ) и возможность оптимизации терапии у пациентов с легочной артериальной гипертензией с помощью замены ИФДЭ-5 на риоцигуат. Также представлена информация о недавно стартовавших международных регистрах EXPERT, CTEPH; анонсировано исследование REPLACE.

Ключевые слова: легочная артериальная гипертензия, оптимизация терапии, риоцигуат.

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Current research is aimed at studying the fundamental therapeutic targets and discovering new drugs acting on previously set targets. Until
recently, the only therapeutic strategy to influence the molecular pathway of nitric oxide (NO) – soluble guanylate cyclase (sGC) – cyclic
guanosine monophosphate (cGMP) was the use of phosphodiesterase type 5 inhibitors (PDE-5 inhibitors), such as sildenafil.
In September 2014, the first member of sGC stimulators riociguat was licensed in Russia.
In the paper, the results of 5 multicenter studies (CHEST-1 and PATENT-1, CHEST-2 and PATENT-2, RESPITE), which reflect the effectiveness and safety of mono – and combination therapy with riociguat in patients suffer from some forms of pulmonary arterial hypertension, and patients with inoperable or persistent/recurrent chronic thromboembolic pulmonary hypertension (CTPH), as well as the possibility of optimizing therapy in patients with PAH using iPDE-5 -> riociguat switching was reviewed. It also provides information on the recently launched international registries EXPERT CTEPH; new REPLACE study was announced.

Keywords: pulmonary arterial hypertension, therapy optimization, riociguat.

Список литературы

1. Чазова И.Е., Мартынюк Т.В., редакторы. Легочная гипертензия. Москва: Практика; 2015. 928 с. [Chazova IE, Martynyuk TV, editors. Legochnaya gipertenziya [Pulmonary hypertension]. Moscow: Praktika; 2015. 928 p. (In Russ.)].
2. Schermuly RT, Stasch JP, Pullamsetti SS, et al. Expression and function of soluble guanylate cyclase in pulmonary arterial hypertension. Eur Respir J. 2008;32:881-91. doi: 10.1183/09031936.00114407
3. Grimminger F, Weimann G, Frey R, et al. First acute haemodynamic study of soluble guanylate cyclase stimulator riociguat in pulmonary hypertension. Eur Respir J. 2009;33:785-92. doi: 10.1183/09031936. 00039808
4. Инструкция по применению лекарственного препарата для медицинского применения Адемпас. Регистрационный номер: ЛП-002639. От 05.10.2017 [Instructions for the use of medicinal products for medical use Adempas. Registration number: ЛП-002639. Of 05/10/2017 (In Russ.)].
5. Ghofrani HA, D’Armini AM, Grimminger F, et al. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Eng J Med. 2013;369:319-29. doi: 10.1056/NEJMoa1209657
6. Ghofrani HA, Galie N, Grimminger F, et al. Riociguat for the treatment of pulmonary arterial hypertension. N Eng J Med. 2013;369:330-40. doi: 10.1056/NEJMoa1209655
7. Государственный регистр лекарственных средств. Доступно по ссылке: http://www.grls.rosminzdrav.ru [The State Register of Medicines. Available at: http://www.grls.rosminzdrav.ru].
8. European Medicines Agency. Available at: http://www.ema.europa.eu
9. Rubin LJ, Galiè N, Grimminger F, Grünig E, Humbert M, Jing ZC, et al. Riociguat for the treatment of pulmonary arterial hypertension: a long-term extension study (PATENT-2). Eur Respir J. 2015 May;45(5):1303-13. doi: 10.1183/09031936.00090614
10. Ghofrani HA, Grimminger F, Grünig E, Huang Y, Jansa P, Jing ZC, et al. Predictors of long-term outcomes in patients treated with riociguat for pulmonary arterial hypertension: data from the PATENT-2 open-label, randomised, long-term extension trial. Lancet Respir Med. 2016;4:361-71. doi: 10.1016/S2213-2600(16)30019-4
11. Ghofrani H-A, Galiè N, Friedrich Grimminger F, et al. Riociguat for the Treatment of Pulmonary Arterial Hypertension. N Engl J Med. 2013;369:330-40. doi: 10.1056/NEJMoa1209655
12. Simonneau G, D'Armini A, Ghofrani H, et al. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension (CTEPH): 1-year results from the CHEST-2 long-term extension study. Chest. 2013;144:1023A. doi: 10.1378/chest.1783236
13. Galie N, Humbert M, Vachiery J-L, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS). Eur Heart J. 2016;37:67-119. doi: 10.1093/eurheartj/ehv317. Available at: http://eurheartj.oxfordjournals.org/content/ehj/37/1/67.full.pdf
14. Ghofrani HA, D'Armini AM, Grimminger F, et al. Riociguat for the Treatment of Chronic Thromboembolic Pulmonary Hypertension.
N Engl J Med. 2013; 369:319-29 + Protocol + Sup. appendix.
doi: 10.1056/NEJMoa1209657
15. Simonneau G, D'Armini AN, Ghofrani H-A, et al. Predictors of long-term outcomes in patients treated with riociguat for chronic thromboembolic pulmonary hypertension: data from the CHEST-2 open-label, randomised, long-term extension trial. Lancet Respir Med. 2016;4:372-80. doi.org/10.1016/S2213-2600(16)30022-4
16. Simonneau G, D'Armini AN, Ghofrani H-A, et al. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension: a long-term extension study (CHEST-2). Eur Respir J. 2015;45:1293-302. doi: 10.1183/09031936.00087114
17. Хроническая тромбоэмболическая легочная гипертензия. Клинические рекомендации. Российское медицинское общество по артериальной гипертонии. Доступно по ссылке: http://cr.rosminzdrav.ru/#!/ schema/137 [Khronicheskaya tromboembolicheskaya legochnaya gipertenziya. Klinicheskie rekomendatsii. Rossiiskoe meditsinskoe obshchestvo po arterial'noi gipertonii [Chronic thromboembolic pulmonary hypertension. Clinical recommendations. Russian Medical Society for Arterial Hypertension]. Available at: http://cr.rosminzdrav.ru/#!/ schema/137 (In Russ.)].
18. Klinger JR, Abman SH, Gladwin MT. Nitric oxide deficiency and endothelial dysfunction in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2013;188:639-46. doi: 10.1164/rccm.201304-0686PP
19. Chockalingam A, Gnanavelu G, Venkatesan S, et al. Efficacy and optimal dose of sildenafil in primary pulmonary hypertension. Int J Cardiol. 2005;99(1):91-5. doi: 10.1016/j.ijcard.2003.12.023
20. Leuchte HH, Schwaiblmair M, Baumgartner RA, et al. Hemodynamic response to sildenafil, nitric oxide, and iloprost in primary pulmonary hypertension. Chest. 2004;125:580-6. doi: 10.1378/chest.125.2.580
21. Stasch JP, Pacher P, Evgenov OV. Soluble guanylate cyclase as an emerging therapeutic target in cardiopulmonary disease. Circulation. 2011;123(20):2263-73. doi: 10.1161/CIRCULATIONAHA.110. 981738
22. Hoeper MM, Simonneau G, Corris PA, et al. RESPITE: switching to riociguat in pulmonary arterial hypertension patients with inadequate response to phosphodiesterase-5 inhibitors. Eur Respir J. 2017;50:1602425. doi: 10.1183/13993003.02425-2016
23. EXPERT, EXPosurE Registry RiociguaT in Patients With Pulmonary Hypertension (EXPERT). ClinicalTrials.gov Identifier: NCT02092818. Available at: https://clinicaltrials.gov/ct2/show/ NCT02092818
24. Klose H, et al. Riociguat For The Treatment Of Pulmonary Hypertension: Safety Data From The Expert Registry. Am J Respir Crit Care Med. 2017;195:A2292. Available at: https://www.atsjournals.org/doi/ pdf/10.1164/ajrccm-conference.2017.195.1_MeetingAbstracts.A2292
25. A Study Investigating Routine Practice of Chronic Thromboembolic Pulmonary Hypertension Management in EMEA Countries (EMEA CTEPH). ClinicalTrials.gov Identifier: NCT02637050. Available at: https://clinicaltrials.gov/ct2/show/NCT02637050
26. Riociguat rEplacing PDE-5i Therapy evaLuated Against Continued PDE-5i thErapy (REPLACE). ClinicalTrials.gov Identifier: NCT02891850. Available at: https://clinicaltrials.gov/ct2/show/ NCT02891850

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1. [Chazova IE, Martynyuk TV, editors. Legochnaya gipertenziya [Pulmonary hypertension]. Moscow: Praktika; 2015. 928 p. (In Russ.)].
2. Schermuly RT, Stasch JP, Pullamsetti SS, et al. Expression and function of soluble guanylate cyclase in pulmonary arterial hypertension. Eur Respir J. 2008;32:881-91. doi: 10.1183/09031936.00114407
3. Grimminger F, Weimann G, Frey R, et al. First acute haemodynamic study of soluble guanylate cyclase stimulator riociguat in pulmonary hypertension. Eur Respir J. 2009;33:785-92. doi: 10.1183/09031936. 00039808
4. [Instructions for the use of medicinal products for medical use Adempas. Registration number: ЛП-002639. Of 05/10/2017 (In Russ.)].
5. Ghofrani HA, D’Armini AM, Grimminger F, et al. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Eng J Med. 2013;369:319-29. doi: 10.1056/NEJMoa1209657
6. Ghofrani HA, Galie N, Grimminger F, et al. Riociguat for the treatment of pulmonary arterial hypertension. N Eng J Med. 2013;369:330-40. doi: 10.1056/NEJMoa1209655
7. Государственный регистр лекарственных средств. Доступно по ссылке: http://www.grls.rosminzdrav.ru [The State Register of Medicines. Available at: http://www.grls.rosminzdrav.ru].
8. European Medicines Agency. Available at: http://www.ema.europa.eu
9. Rubin LJ, Galiè N, Grimminger F, Grünig E, Humbert M, Jing ZC, et al. Riociguat for the treatment of pulmonary arterial hypertension: a long-term extension study (PATENT-2). Eur Respir J. 2015 May;45(5):1303-13. doi: 10.1183/09031936.00090614
10. Ghofrani HA, Grimminger F, Grünig E, Huang Y, Jansa P, Jing ZC, et al. Predictors of long-term outcomes in patients treated with riociguat for pulmonary arterial hypertension: data from the PATENT-2 open-label, randomised, long-term extension trial. Lancet Respir Med. 2016;4:361-71. doi: 10.1016/S2213-2600(16)30019-4
11. Ghofrani H-A, Galiè N, Friedrich Grimminger F, et al. Riociguat for the Treatment of Pulmonary Arterial Hypertension. N Engl J Med. 2013;369:330-40. doi: 10.1056/NEJMoa1209655
12. Simonneau G, D'Armini A, Ghofrani H, et al. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension (CTEPH): 1-year results from the CHEST-2 long-term extension study. Chest. 2013;144:1023A. doi: 10.1378/chest.1783236
13. Galie N, Humbert M, Vachiery J-L, et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and the European Respiratory Society (ERS). Eur Heart J. 2016;37:67-119. doi: 10.1093/eurheartj/ehv317. Available at: http://eurheartj.oxfordjournals.org/content/ehj/37/1/67.full.pdf
14. Ghofrani HA, D'Armini AM, Grimminger F, et al. Riociguat for the Treatment of Chronic Thromboembolic Pulmonary Hypertension.
N Engl J Med. 2013; 369:319-29 + Protocol + Sup. appendix.
doi: 10.1056/NEJMoa1209657
15. Simonneau G, D'Armini AN, Ghofrani H-A, et al. Predictors of long-term outcomes in patients treated with riociguat for chronic thromboembolic pulmonary hypertension: data from the CHEST-2 open-label, randomised, long-term extension trial. Lancet Respir Med. 2016;4:372-80. doi.org/10.1016/S2213-2600(16)30022-4
16. Simonneau G, D'Armini AN, Ghofrani H-A, et al. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension: a long-term extension study (CHEST-2). Eur Respir J. 2015;45:1293-302. doi: 10.1183/09031936.00087114
17. [Chronic thromboembolic pulmonary hypertension. Clinical recommendations. Russian Medical Society for Arterial Hypertension]. Available at: http://cr.rosminzdrav.ru/#!/ schema/137 (In Russ.)].
18. Klinger JR, Abman SH, Gladwin MT. Nitric oxide deficiency and endothelial dysfunction in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2013;188:639-46. doi: 10.1164/rccm.201304-0686PP
19. Chockalingam A, Gnanavelu G, Venkatesan S, et al. Efficacy and optimal dose of sildenafil in primary pulmonary hypertension. Int J Cardiol. 2005;99(1):91-5. doi: 10.1016/j.ijcard.2003.12.023
20. Leuchte HH, Schwaiblmair M, Baumgartner RA, et al. Hemodynamic response to sildenafil, nitric oxide, and iloprost in primary pulmonary hypertension. Chest. 2004;125:580-6. doi: 10.1378/chest.125.2.580
21. Stasch JP, Pacher P, Evgenov OV. Soluble guanylate cyclase as an emerging therapeutic target in cardiopulmonary disease. Circulation. 2011;123(20):2263-73. doi: 10.1161/CIRCULATIONAHA.110. 981738
22. Hoeper MM, Simonneau G, Corris PA, et al. RESPITE: switching to riociguat in pulmonary arterial hypertension patients with inadequate response to phosphodiesterase-5 inhibitors. Eur Respir J. 2017;50:1602425. doi: 10.1183/13993003.02425-2016
23. EXPERT, EXPosurE Registry RiociguaT in Patients With Pulmonary Hypertension (EXPERT). ClinicalTrials.gov Identifier: NCT02092818. Available at: https://clinicaltrials.gov/ct2/show/ NCT02092818
24. Klose H, et al. Riociguat For The Treatment Of Pulmonary Hypertension: Safety Data From The Expert Registry. Am J Respir Crit Care Med. 2017;195:A2292. Available at: https://www.atsjournals.org/doi/ pdf/10.1164/ajrccm-conference.2017.195.1_MeetingAbstracts.A2292
25. A Study Investigating Routine Practice of Chronic Thromboembolic Pulmonary Hypertension Management in EMEA Countries (EMEA CTEPH). ClinicalTrials.gov Identifier: NCT02637050. Available at: https://clinicaltrials.gov/ct2/show/NCT02637050
26. Riociguat rEplacing PDE-5i Therapy evaLuated Against Continued PDE-5i thErapy (REPLACE). ClinicalTrials.gov Identifier: NCT02891850. Available at: https://clinicaltrials.gov/ct2/show/ NCT02891850

Авторы

З.С. Валиева, И.Н. Таран, Т.В. Мартынюк, И.Е. Чазова

ФГБУ «Национальный медицинский исследовательский центр кардиологии» Минздрава России, Москва, Россия

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Z.S. Valieva, I.N. Taran, T.V. Martynyuk, I.Ye. Chazova

National Medical Research Center of Cardiology, Ministry of Health of Russia, Moscow, Russia

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