Методы лекарственной терапии хронической тромбоэмболической легочной гипертензии: современные подходы к ведению пациентов

В статье обсуждаются эпидемиология, патогенез и подходы к лечению хронической тромбоэмболической легочной гипертензии (ХТЭЛГ). Подчеркивается, что ХТЭЛГ является уникальной потенциально излечимой формой легочной гипертензии. «Золотым стандартом» лечения ХТЭЛГ является легочная тромбэндартерэктомия. Однако около 40 % больных с ХТЭЛГ являются неоперабельными в связи с дистальными поражениями легочного сосудистого русла, недоступными для хирургического вмешательства, тяжестью гемодинамических нарушений или наличием других противопоказаний. Кроме того, почти у 50 % больных с ХТЭЛГ после хирургического вмешательства отмечается персистирующая или рецидивирующая легочная гипертензия, требующая дальнейшего лечения. Этим пациентам в соответствии с современными рекомендациями показана лекарственная терапия. В статье приведены результаты основных клинических исследований препаратов таргетной терапии (антагонисты рецепторов эндотелина, простаноиды, ингибиторы фосфодиэстеразы-5, стимуляторы растворимой гуанилатциклазы). Единственным препаратом, который продемонстрировал выраженную клиническую эффективность с точки зрения улучшения гемодинамики, переносимости физической нагрузки и улучшения качества жизни пациентов, является стимулятор растворимой гуанилатциклазы риоцигуат. Эффективность и безопасность риоцигуата изучена в краткосрочных и длительных исследованиях с периодом наблюдения, достигающим 6 лет. Результаты этих исследований явились основанием для его одобрения регуляторными органами более 50 стран для лечения неоперабельной ХТЭЛГ и персистирующей или рецидивирующей ХТЭЛГ после перенесенной легочной тромбэндартерэктомии. В Евросоюзе, США и многих других странах риоцигуат - единственный препарат, одобренный для применения по данным показаниям.

1. Клинические рекомендации по диагностике и лечению хронической тромбоэмболической легочной гипертензии. Евразийский кардиологический журнал 2016;2:7-27.

2. Alpert J. S., Irwin R. S., Dalen J. E. Pulmonary hypertension. Curr Probl Cardiol 1981;5 (10):1-39.

3. Galie N., Humbert M., VachieryJ. L. et al.; ESC Scientific Document Group. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: The Joint Task Force for the Diagnosis and Treatment ofPulmonary 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):67-119. DOI: 10.1093/eurheartj/ehv317.

4. Mahmud E., Madani M. M., Kim N. H. et al. Chronic Thromboembolic Pulmonary Hypertension: Evolving Therapeutic Approaches for Operable and Inoperable Disease. J Am Coll Cardiol 2018;71 (21):2468-2486. DOI: 10.1016/j.jacc.2018.04.009.

5. Pepke-Zaba J., Jansa P., Kim N. H. et al. Chronic thromboembolic pulmonary hypertension: role of medical therapy. Eur Respir J 2013;41 (4):985-990. DOI: 10.1183/09031936.00201612.

6. Tanabe N., Sugiura T., Tatsumi K. Recent progress in the diagnosis and management of chronic thromboembolic pulmonary hypertension. Respir Investig 2013;51 (3):134-146. DOI: 10.1016/j.resinv.2013.02.005.

7. Pepke-Zaba J., Delcroix M., Lang I. et al. Chronic thromboembolic pulmonary hypertension (CTEPH): results from an international prospective registry. Circulation 2011;124:1973-1981. DOI: 10.1161/CIRCULATIONAHA.110.015008.

8. Gall H., Hoeper M. M., Richter M. J. et al. An epidemiological analysis of the burden of chronic thromboembolic pulmonary hypertension in the USA, Europe and Japan. Eur Respir Rev 2017;26 (143). DOI: 10.1183/16000617.0121-2016.

9. Ende-Verhaar Y. M., Cannegieter S. C., Vonk Noordegraaf A. et al. Incidence of chronic thromboembolic pulmonary hypertension after acute pulmonary embolism: a contemporary view of the published literature. ur Respir J 2017;49 (2). pii: 1601792. DOI: 10.1183/13993003.01792-2016.

10. Kramm T., Wilkens H., Fuge J. et al. Incidence and characteristics of chronic thromboembolic pulmonary hypertension in Germany. Clin Res Cardiol 2018;107 (7):548-553. DOI: 10.1007/s00392-018-1215-5.

11. Condliffe R., Kiely D. G., Gibbs J. S. et al. Improved outcomes in medically and surgically treated chronic thromboembolic pulmonary hypertension. Am J Respir Crit Care Med 2008;177 (10):1122-1127. DOI: 10.1164/rccm.200712-1841OC.

12. Escribano-Subias P., Blanco I., Lopez-Meseguer M. et al., Investigators R Survival in pulmonary hypertension in Spain: insights from the Spanish registry. Eur Respir J 2012;40 (3):596-603. DOI: 10.1183/09031936.00101211.

13. Черепанова Н. А., Дупляков Д. В., Кузьмин В. П., и др. Опыт амбулаторной работы центра легочной гипертензии в Самарской области. Комплексные проблемы сердечно-сосудистых заболеваний 2018;7 (1):108-113.

14. Simonneau G., Torbicki A., Dorfmuller P., Kim N. The pathophysiology of chronic thromboembolic pulmonary hypertension. Eur Respir Rev 2017;26 (143). DOI: 10.1183/16000617.0112-2016.

15. Sharma S., Lang I. M. Current understanding of the pathophysiology of chronic thromboembolic pulmonary hypertension. Thromb Res 2018;164:136-144. DOI: 10.1016/j.thromres.2017.06.011.

16. Olsson K. M., Meyer B., Hinrichs J. et al. Chronic thromboembolic pulmonary hypertension. Dtsch Arztebl Int 2014;111 (50):856-862. DOI: 10.3238/arztebl.2014.0856.

17. Stasch J. P., Evgenov O. V. Soluble guanylate cyclase stimulators in pulmonary hypertension. Handb Exp Pharmacol 2013;218:279-313. DOI: 10.1007/978-3-642-38664-0_12.

18. Ghofrani H. A., Humbert M., Langleben D. et al. Riociguat: Mode of Action and Clinical Development in Pulmonary Hypertension. Chest 2017;151 (2):468-480. DOI: 10.1016/j.chest.2016.05.024.

19. Derbyshire E. R., Marietta M. A. Structure and regulation of soluble guanylate cyclase. Annu Rev Biochem 2012;81:533-559. DOI: 10.1146/annurev-biochem-050410-100030.

20. Benza R., Mathai S., Nathan S. D. sGC stimulators: Evidence for riociguat beyond groups 1 and 4 pulmonary hypertension. Respir Med 2017;122 Suppl 1: S28-S34. DOI: 10.1016/j.rmed.2016.11.01.

21. Makhoul S., Walter E., Pagel O. et al. Effects of the NO/soluble gua-nylate cyclase/cGMP system on the functions of human platelets. Nitric Oxide 2018;76:71-80. DOI: 10.1016/j.niox.2018.03.008.

22. Lang I. Chronic thromboembolic pulmonary hypertension: a distinct disease entity. Eur Respir Rev 2015;24 (136):246-252. DOI: 10.1183/16000617.00001115.

23. Wilkens H., Lang I., Behr J. et al. Chronic thromboembolic pulmonary hypertension (CTEPH): updated Recommendations of the Cologne Consensus Conference 2011. Int J Cardiol 2011;154 Suppl 1: S54-60. DOI: 10.1016/S0167-5273(11)70493-4.

24. Jenkins D., Mayer E., Screaton N., Madani M. State-of-the-art chronic thromboembolic pulmonary hypertension diagnosis and management. Eur Respir Rev 2012;21 (123):32-39. DOI: 10.1183/09059180.00009211.

25. Bochenek M. L., Rosinus N. S., Lankeit M. et al. From thrombosis to fibrosis in chronic thromboembolic pulmonary hypertension. Thromb Haemost 2017;117 (4):769-783. DOI: 10.1160/TH16-10-0790.

26. Bonderman D., Skoro-Sajer N., Jakowitsch J. et al. Predictors of outcome in chronic thromboembolic pulmonary hypertension. Circulation 2007;115:2153-2158.

27. Riedel M., Stanek V., Widimsky J. et al. Longterm follow-up of patients with pulmonary thromboembolism. Late prognosis and evolution of hemodynamic and respiratory data. Chest 1982;81:151-158.

28. Lewczuk J., Piszko P., Jagas J. et al. Prognostic factors in medically treated patients with chronic pulmonary embolism. Chest 2001;119:818-82.

29. Jenkins D. Pulmonary endarterectomy: the potentially curative treatment for patients with chronic thromboembolic pulmonary hypertension. Eur Respir Rev 2015;24 (136):263-271. DOI: 10.1183/16000617.00000815.

30. Taboada D., Pepke-Zaba J., Jenkins D. P. et al. Outcome of pulmonary endarterectomy in symptomatic chronic thromboembolic disease. Eur Respir J 2014;44 (6):1635-1645. DOI: 10.1183/09031936.0005011.

31. Mayer E., Jenkins D., Lindner J. et al. Surgical management and outcome of patients with chronic thromboembolic pulmonary hypertension: results from an international prospective registry. J Thorac Cardiovasc Surg 2011;141702-710. DOI: 10.1016/j.jtcvs.2010.11.024.

32. Madani M. M., Auger W. R., Pretorius V. et al. Pulmonary endarterectomy: recent changes in a single institution's experience of more than 2,700 patients. Ann Thorac Surg 2012;94:97-103. DOI: 10.1016 /j.athoracsur.2012.04.004.

33. Delcroix M., Lang I., Pepke-Zaba J. et al. Long-term outcome of patients with chronic thromboembolic pulmonary hypertension: results from an international prospective registry. Circulation 2016;133:859-871. DOI: 10.1161/CIRCULATIONAHA.115.016522.

34. Cannon J. E., Su L., Kiely D. G. et al. Dynamic risk stratification of patient long-term outcome after pulmonary endarterectomy: results from the United Kingdom National cohort. Circulation 2016;133:1761-1771. DOI: 10.1161/CIRCULATIONAHA.115.019470.

35. Dartevelle P., Fadel E., Mussot S. et al. Chronic thromboembolic pulmonary hypertension. Eur Respir J 2004;23:637-648.

36. Banks D. A., Pretorius G. V., Kerr K. M., Manecke G. R. Pulmonary endarterectomy: part I. Pathophysiology, clinical manifestations, and diagnostic evaluation of chronic thromboembolic pulmonary hypertension. Semin Cardiothorac Vasc Anesth 2014;18:319-330. DOI: 10.1177/1089253214537688.

37. Hoeper M. M. Pharmacological therapy for patients with chronic thromboembolic pulmonary hypertension. Eur Respir Rev 2015;24:272-282. DOI: 10.1183/16000617.00001015.

38. Lang I., Meyer B.C., Ogo T. et al. Balloon pulmonary angioplasty in chronic thromboembolic pulmonary hypertension. Eur Respir Rev 2017;26 (143). pii: 160119. DOI: 10.1183/16000617.0119-2016.

39. Barbera J. A., Roman A., Gomez-Sanchez M. A. et al. Guidelines on the Diagnosis and Treatment of Pulmonary Hypertension: Summary of Recommendations. Arch Bronconeumol 2018;54 (4):205-215. DOI: 10.1016/j.arbres.2017.11.014.

40. Мартынюк Т. В., Дадачева З. Х., Чазова И. Е. Возможности медикаментозного лечения хронической тромбоэмболической легочной гипертензии. Атеротромбоз 2015;1:87-98. https://doi.org/10.21518/2307-1109-2015-1-30-40.

41. Kim N. H., Mayer E. Chronic thromboembolic pulmonary hypertension: the evolving treatment landscape. Eur Respir Rev 2015;24 (136):173-177. DOI: 10.1183/16000617.00001515.

42. Schweikert B., Pittrow D., Vizza C. D. et al. Demographics, clinical characteristics, health resource utilization and cost of chronic thromboembolic pulmonary hypertension patients: retrospective results from six European countries. BMC Health Serv Res 2014;14:246. DOI: 10.1186/1472-6963-14-246.

43. Jensen K. W., Kerr K. M., Fedullo P. F. et al. Pulmonary hypertensive medical therapy in chronic thromboembolic pulmonary hypertension before pulmonary thromboendarterectomy. Circulation 2009;120:1248-1254. DOI: 10.1161/CIRCULATIONAHA.109.865881.

44. Montani D., Chaumais M. C., Guignabert C. et al. Targeted therapies in pulmonary arterial hypertension. Pharmacol Ther 2014;141 (2):172-191. DOI: 10.1016/j.pharmthera.2013.10.002.

45. Ataya A., Cope J., Alnuaimat H. A Review of Targeted Pulmonary Arterial Hypertension-Specific Pharmacotherapy. J Clin Med 2016;5:12. DOI: 10.3390/jcm5120114

46. Patel B. B., Feng Y., Cheng-Lai A. Pulmonary arterial hypertension: a review in pharmacotherapy. Cardiol Rev 2015;23 (1):33-51. DOI: 10.1097/CRD.000000000000004.

47. Abraham T., Wu G., Vastey F. et al. Role of combination therapy in the treatment ofpulmonary arterial hypertension. Pharmacotherapy 2010;30 (4):390-404. DOI: 10.1592/phco.30.4.390.

48. He B., Zhang F., Li X. et al. Meta-analysis of randomized controlled trials on treatment of pulmonary arterial hypertension. Circ J 2010;74 (7):1458-1464.

49. Dasgupta A., Bowman L., DArsigny C. L., Archer S. L. Soluble gua-nylate cyclase: a new therapeutic target for pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension. Clin Pharmacol Ther 2015;97 (1):88-102. DOI: 10.1002/cpt.10.

50. Raina A., Benza R. L., Farber H. W. Replacing a phosphodiesterase-5 inhibitor with riociguat in patients with connective tissue disease-associated pulmonary arterial hypertension: a case series. Pulm Circ 2017;7 (3):741-746. DOI: 10.1177/2045893217721694.

51. Simonneau G., DArmini A. M., 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 (5):372-80. DOI: 10.1016/S2213-2600(16)30022-4.

52. Ambrisentan for Inoperable Chronic Thromboembolic Pulmonary Hypertension. (AMBER I) https://clinicaltrials.gov/ct2/show/study/NCT01884675?sect=X70156;

53. Suntharalingam J., Treacy C. M., Doughty N.J. et al. Long-term use of sildenafil in inoperable chronic thromboembolic pulmonary hypertension. Chest 2008;134 (2):229-236. DOI: 10.1378/chest.07-2681.

54. Olschewski H., Simonneau G., Galie N. et al. Aerosolized Iloprost Randomized Study Group. Inhaled iloprost for severe pulmonary hypertension. N Engl J Med 2002;347 (5):322-329. DOI: 10.1056/NEJMoa020204

55. Jais X., D’Armini A. M., Jansa P. et al.; Bosentan Effects in iNopErable Forms of chronIc Thromboembolic pulmonary hypertension Study Group. Bosentan for treatment of inoperable chronic thromboembolic pulmonary hypertension: BENEFiT (Bosentan Effects in iNopErable Forms of chronIc Thromboembolic pulmonary hypertension), a randomized, placebo-controlled trial. J Am Coll Cardiol 2008;52 (25):2127-2134. DOI: 10.1016/j.jacc.2008.08.059.

56. Ghofrani H. A., D Armini A. M., Grimminger F. et al.; CHEST-1 Study Group. Riociguat for the treatment of chronic thromboembolic pulmonary hypertension. N Engl J Med 2013;369 (4):319-329. DOI: 10.1056/NEJMoa1209657.

57. Kim N. H., D’Armini A. M., Grimminger F. et al. Haemodynamic effects of riociguat in inoperable/recurrent chronic thromboembolic pulmonary hypertension. Heart 2017; 103 (8):599-606. DOI: 10.1136/heartjnl-2016-309621.

58. Lian T. Y., Jiang X., Jing Z. C. Riociguat: a soluble guanylate cyclase stimulator for the treatment of pulmonary hypertension. Drug Des Devel Ther 2017;11:1195-1207. DOI: 10.2147/DDDT.S117277.

59. Jenkins D. New interventions to treat chronic thromboembolic pulmonary hypertension. Heart 2018 Apr 10. heartjnl-2017-312110. DOI: 10.1136/heartjnl-2017-312110.

60. Ghofrani H. A., Simonneau G., DArmini A. M. et al.; MERIT study investigators. 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;5 (10):785-794. DOI: 10.1016/S2213-2600(17)30305-3.

61. Simonneau G., D’Armini A. M., 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 (5):1293-1302. DOI: 0.1183/09031936.00087114.

62. McLaughlin V. V., Jansa P., Nielsen-Kudsk J. E. et al. Riociguat in patients with chronic thromboembolic pulmonary hypertension: results from an early access study. BMC Pulm Med 2017;17 (1):216. DOI: 10.1186/s12890-017-0563-7.

63. Halank M., Hoeper M. M., Ghofrani H. A. et al. Riociguat for pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension: Results from a phase II long-term extension study. Respir Med 2017;128:50-56. DOI: 10.1016/j.rmed.2017.05.008.

64. Gall H., Vachiery J. L., Tanabe N. et al. Real-World Switching to Riociguat: Management and Practicalities in Patients with PAH and CTEPH. Lung 2018;196 (3):305-312. DOI: 10.1007/s00408-018-0100-3.

65. Andersen A., Korsholm K., Mellemkjaer S., Nielsen-Kudsk J. E. Switching from sildenafil to riociguat for the treatment of PAH and inoperable CTEPH: real-life experiences. Respir Med Case Rep 2017;22:39-43. DOI: 10.1016/j.rmcr.2017.06.005.

66. Yamamoto K., Tanabe N., Suda R. et al. Riociguat for patients with chronic thromboembolic pulmonary hypertension: usefulness of transitioning from phosphodiesterase type 5 inhibitor. Respir Invest 2017;55 (4):270-275. DOI: 10.1016/j.resinv.2017.04.004.

67. Poch D. S. Case report: a patient with pulmonary arterial hypertension transitioning from a PDE-5 inhibitor to Riociguat. BMC Pulm Med 2016;16 (1):82. DOI: 10.1186/s12890-016-0229-x.

68. Sulica R., Fenton R., Cefali F. Early observations on the use of riociguat in a large, metropolitan pulmonary arterial hypertension/chronic thromboembolic pulmonary hypertension treatment center. Cardiol Ther 2015;4 (2):209-218. DOI: 10.1007/s40119-015-0046-y.

69. Weir N., Brown A. W., DelaSantine J. et al. Transition from PDE-5 inhibitors to riociguat in pulmonary hypertension. Am J Respir Crit Care Med 2017;195: A2282. https://www.atsjour-nals.org/doi/pdf/10.1164/ajrccm-conference.2017.195.1_Meeting Abstracts. A2282

70. Darocha S., Banaszkiewicz M., Pietrasik A. et al. Sequential treatment with sildenafil and riociguat in patients with persistent or inoperable chronic thromboembolic pulmonary hypertension improves functional class and pulmonary hemodynamics. Int J Cardiol 2018 Jul 3. DOI: 10.1016/j.ijcard.2018.07.015.

71. Hoeper M. M., Simonneau G., Corris P. A. et al. RESPITE: switching to riociguat in pulmonary arterial hypertension patients with inadequate response to phosphodiesterase-5 inhibitors. Eur Respir J 2017;50 (3). 10.1183/13993003.02425-2016.

72. Galie N., Muller K., Scalise A. V., Grunig E. PATENT PLUS: a blinded, randomised and extension study of riociguat plus sildenafil in pulmonary arterial hypertension. Eur Respir J 2015;45 (5):1314-1322. DOI: 10.1183/09031936.00105914.

73. Frey R., Muck W., Kirschbaum N. et al. Riociguat (BAY 63-2521) and warfarin: a pharmacodynamic and pharmacokinetic interaction study. J Clin Pharmacol 2011;51 (7):1051-1060. DOI: 10.1177/0091270010378119.

74. Riociguat Versus Balloon Pulmonary Angioplasty in Non-operable Chronic thromboEmbolic Pulmonary Hypertension (RA.CE) https://clinicaltrials.gov/ct2/show/NCT02634203

75. Riociguat in Patients With Operable CTEPH Prior to Pulmonary Endarterectomy (PEA Bridging Study). Other potential uses of medical therapy in CTEPH https://clinicaltrials.gov/ct2/show/NCT03273257.

76. Prospective, Non-interventional, Multi-center Post-authorization Safety Study of Riociguat for Chronic Thromboembolic Pulmonary Hypertension (CTEPH) (JPMS-CTEPH) https://clinicaltrials.gov/ct2/show/NCT02117791.