К настоящему времени получены убедительные доказательства, что комбинированная терапия легочной артериальной гипертензии (ЛАГ) специфическими препаратами позволяет значительно замедлить прогрессирование ЛАГ. Поэтому в современных рекомендациях комбинированная терапия уже рассматривается как стандарт лечения для существенной доли пациентов с умеренно-тяжелыми и тяжелыми формами ЛАГ. Однако качество жизни и долгосрочный прогноз пациентов, получающих комбинированную терапию, должны стать объектом дальнейших исследований. Проведение будущих исследований является абсолютно необходимым для выявления наиболее оптимальной стратегии терапии пациентов с ЛАГ, таких как начальная комбинированная терапия или быстрая последовательная комбинированная терапия, двойные или тройные комбинации, а также изучение новых сигнальных путей ЛАГ, которые могут стать мишенями для новых специфических препаратов в лечении ЛАГ.
At present, compelling evidence has been obtained that combined therapy of pulmonary arterial hypertension (PAH) with specific drugs can significantly slow progression of PAH. Therefore, in current guidelines combination therapy is already considered as standard treatment for a significant proportion of patients with moderately severe and severe forms of PAH. However, the quality of life and long-term prognosis of patients receiving combination therapy, should be the object of further research. The future research is absolutely necessary to identify the most optimal strategy of treatment of patients with PAH, such as initial combination therapy or rapid sequential combination therapy, double or triple combinations as well as exploring new signaling pathways PAH, which can become targets for new specific drugs PAH.
Keywords: pulmonary hypertension, pulmonary arterial hypertension, specific therapy, combination therapy.
Список литературы
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21. Pitt B, Zannad F, Remme WJ et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999; 341: 709-717.
22. Wedzicha JA, Banerji D, Chapman KR, Vestbo J, Roche N, Ayers RT, Thach C, Fogel R, Patalano F, Vogelmeier C. Indacaterol-glycopyrronium versus salmeterol-fluticasone for COPD. N Engl J Med. 2016; 374: 2222-34.
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25. Humbert M, Barst RJ, Robbins IM et al. Combination of bosentan with epoprostenol in pulmonary arterial hypertension: BREATHE-2. Eur Respir J. 2004; 24: 353-359.
26. Hoeper MM, Leuchte H, Halank M et al. Combining inhaled iloprost with bosentan in patients with idiopathic pulmonary arterial hypertension. Eur Respir J. 2006; 28: 691-694.
27. Simonneau G, Rubin LJ, Galiè N et al. Addition of sildenafil to long-term intravenous epoprostenol therapy in patients with pulmonary arterial hypertension: a randomized trial. Ann Intern Med. 2008; 149: 521-530.
28. Galiè N, Barbera JA, Frost A et al. Initial Use of Ambrisentan plus Tadalafil in Pulmonary Arterial Hypertension. N Engl J Med. 2015; 379: 834-844. doi: 10.1056/NEJMoa1413687.
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33. Fox BD, Shtraichman O, Langleben D et al. Combination therapy for pulmonary arterial hypertension. a systematic review and meta-analysis. Can J Cardiol. 2016; 32: 1520-1530.
34. McLaughlin VV, Oudiz RJ, Frost A et al. Randomized study of adding inhaled iloprost to existing bosentan in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2006; 174: 1257-1263.
35. Tapson VF, Torres F, Kermeen F et al. Oral treprostinil for the treatment of pulmonary arterial hypertension in patients on background endothelin receptor antagonist and/or phosphodiesterase type 5 inhibitor therapy (the FREEDOMC study): A randomized controlled trial. Chest. 2012; 142: 1383-1390.
36. Tapson VF, Jing Z-C, Xu K-F et al. Oral treprostinil for the treatment of pulmonary arterial hypertension in patients receiving background endothelin receptor antagonist and phosphodiesterase type 5 inhibitor therapy (the freedom-c2 study): a randomized controlled trial. Chest. 2013; 144: 952-958.
37. McLaughlin V, Benza RL, Rubin LJ et al. Addition of inhaled treprostinil to oral therapy for pulmonary arterial hypertension: a randomized controlled clinical trial. J Am Coll Cardiol. 2010; 55: 1915-1922.
38. Sitbon O, Channick R, Chin KM et al. Selexipag for the Treatment of Pulmonary Arterial Hypertension. N Engl J Med. 2015; 373:2522-2533. doi: 10.1056/NEJMoa1503184.
39. Pulido T, Adzerikho I, Channick RN et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med. 2013; 369:809-18.
40. McLaughlin V, Channick RN, Ghofrani H-A et al. Bosentan added to sildenafil therapy in patients with pulmonary arterial hypertension. Eur Respir J. 2015; 46: 1-9.
41. Gruenig E, Michelakis E, Vachiéry JL, Vizza CD, Meyer FJ, Doelberg M, Bach D, Dingemanse J, Galiè N. Acute hemodynamic effects of single-dose sildenafil when added to established bosentan therapy in patients with pulmonary arterial hypertension: results of the COMPASS-1 study. J Clin Pharmacol. 2009; 49: 1343-52. doi: 10.1177/ 0091270009341182.
42. Barst RJ, Oudiz RJ, Beardsworth A et al. Tadalafil monotherapy and as add-on to background bosentan in patients with pulmonary arterial hypertension. J Heart Lung Transplant. 2011; 30: 632-643.
43. Ghofrani H-A, Galie N, Grimminger F et al. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013; 369: 330-340.
44. Kemp K, Savale L, O’Callaghan DS et al. Usefulness of first-line combination therapy with epoprostenol and bosentan in pulmonary arterial hypertension: an observational study. J Heart Lung Transplant. 2012; 31: 150-158. doi: 10.1016/j.healun.2011.11.002.
45. Sitbon O, Jaїs X, Savale L et al. Upfront triple combination therapy in pulmonary arterial hypertension: a pilot study. Eur Respir J. 2014; 43: 1691-1697. doi: 10.1183/09031936.00116313.
46. Hoeper MM, McLaughlin VV, Barbera JA et al. Initial combination therapy with ambrisentan and tadalafil and mortality in patients with pulmonary arterial hypertension: a secondary analysis of the results from the randomised, controlled AMBITION study. Lancet Respir Med. 2016; 4: 894-901.
47. Sitbon O, Sattler C, Bertoletti L et al. Initial dual oral combination therapy in pulmonary arterial hypertension. Eur Respir J. 2016; 47: 1727-1736.
48. Jansa P, Pulido T. Macitentan in Pulmonary Arterial Hypertension: A Focus on Combination Therapy in the SERAPHIN Trial. Am J Cardiovasc Drugs. 2017 Dec 26. doi: 10.1007/s40256-017-0260-1. [Epub ahead of print].
49. Coghlan JG, Channick R, Chin K, Di Scala L, Galiè N, Ghofrani HA, Hoeper MM, Lang IM, McLaughlin V, Preiss R, Rubin LJ, Simonneau G, Sitbon O, Tapson VF, Gaine S. Targeting the Prostacyclin Pathway with Selexipag in Patients with Pulmonary Arterial Hypertension Receiving Double Combination Therapy: Insights from the Randomized Controlled GRIPHON Study. Am J Cardiovasc Drugs. 2018 Jan 6. doi: 10.1007/s40256-017-0262-z. [Epub ahead of print].
50. Actelion. The Efficacy and Safety of Initial Triple Versus Initial Dual Oral Combination Therapy in Patients With Newly Diagnosed Pulmonary Arterial Hypertension (TRITON). Clinical Trials. gov. 2017: NCT02558231.
________________________________________________
1. 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 and 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: 67-119. doi: 10.1093/eurheartj/ehv317. Epub 2015 Aug 29.
2. [Chazova IE, Avdeev SN, Tsareva NA, Volkov AV, Martynyuk TV, Nakonechnikov SN. Clinical guidelines for the diagnosis and treatment of pulmonary hypertension. Terapevticheskii Arkhiv. 2014; (9): 4-23. (In Russ.)].
3. Humbert M, Souza R, Galie N, McLaughlin V, Simonneau G, Rubin L. Pulmonary arterial hypertension: bridging the present to the future. Eur Respir Rev. 2012; 21: 126, 267-270.
4. Simonneau G, Gatzolis G, Adatia I et al. Updated clinical classification of pulmonary hypertension. J Am Coll Cardiol. 2013; 62(25 Suppl): D35-41.
5. Hoeper MM, Huscher D, Ghofrani HA et al. Elderly patients diagnosed with idiopathic pulmonary arterial hypertension: results from the COMPERA registry. Int J Cardiol. 2013; 168: 871-880.
6. Humbert M, Sitbon O, Yaici A et al. Survival in incident and prevalent cohort of patients with pulmonary arterial hypertension. Eur Respir J. 2010; 36: 549-555.
7. Frost AE, Badesch DB, Miller DP et al. Evaluation of the predictive value of a clinical worsening definition using 2-year outcomes in patients with pulmonary arterial hypertension: a REVEAL Registry analysis. Chest. 2013; 144: 1521-1529.
8. Nickel N, Golpon H, Greer M et al. The prognostic impact of follow-up assessments in patients with idiopathic pulmonary arterial hypertension. Eur Respir J. 2012; 39: 589–596.
9. Boucly A, Weatherald J, Savale L et al. Risk assessment, prognosis and guideline implementation in pulmonary arterial hypertension. Eur Respir J. 2017; 50: 1700889 [https://doi.org/10.1183/13993003.00889-2017].
10. Hoeper MM, Kramer T, Pan Z et al. Mortality in pulmonary arterial hypertension: prediction by the 2015 European pulmonary hypertension guidelines risk stratification model. Eur Respir J. 2017; 50: 1700740. https://doi.org/10.1183/13993003.00740-2017.
11. Benza RL, Miller DP, Gomberg-Maitland M et al. Predicting survival in pulmonary arterial hypertension: insights from the Registry to Evaluate Early and Long-Term Pulmonary Arterial Hypertension Disease Management (REVEAL). Circulation. 2010; 122: 164-172.
12. Barst RJ, Rubin LJ, Long WA et al. A comparison of continuous intravenous epoprostenol (prostacyclin) with conventional therapy for primary pulmonary hypertension. The Primary Pulmonary Hypertension Study Group. N Engl J Med. 1996; 334: 296-302.
13. McLaughlin VV, Shillington A, Rich S. Survival in primary pulmonary hypertension: the impact of epoprostenol therapy. Circulation. 2002; 106: 1477-1482.
14. Channick RN, Simonneau G, Sitbon O et al. Effects of the dual endothelin-receptor antagonist bosentan in patients with pulmonary hypertension: a randomised placebo-controlled study. Lancet. 2001; 358: 1119-1123.
15. Barst RJ, Langleben D, Badesch D et al. Treatment of pulmonary arterial hypertension with the selective endothelin-A receptor antagonist sitaxsentan. J Am Coll Cardiol. 2006; 47: 2049-2056.
16. Galiè N, Rubin LJ, Hoeper MM et al. Treatment of patients with mildly symptomatic pulmonary arterial hypertension with bosentan (EARLY study): a double-blind, randomised controlled trial. Lancet. 2008; 371: 2093-2100.
17. Galiè N, Brundage BH, Ghofrani HA et al. Tadalafil therapy for pulmonary arterial hypertension. Circulation. 2009; 119: 2894-2903.
18. [Avdeev SN, Tsareva NA, Neklyudova GV, Chuchalin AG. First clinical experience with endothelin receptor antagonist bosentan used in patients with pulmonary hypertension: Results of a one-year study. Terapevticheskii Arkhiv. 2013; (3): 38-43. (In Russ.)].
19. [Avdeev SN. The new endothelin receptor antagonist macitentan: Prospects for therapy of pulmonary arterial hypertension. Terapevticheskii Arkhiv. 2016; (7): 89-97. (In Russ.)].
20. Frishman WH, Landau A, Cretkovic A. Combination drug therapy with calcium-channel blockers in the treatment of systemic hypertension. J Clin Pharmacol. 1993; 33: 752-755.
21. Pitt B, Zannad F, Remme WJ et al. The effect of spironolactone on morbidity and mortality in patients with severe heart failure. Randomized Aldactone Evaluation Study Investigators. N Engl J Med. 1999; 341: 709-717.
22. Wedzicha JA, Banerji D, Chapman KR, Vestbo J, Roche N, Ayers RT, Thach C, Fogel R, Patalano F, Vogelmeier C. Indacaterol-glycopyrronium versus salmeterol-fluticasone for COPD. N Engl J Med. 2016; 374: 2222-34.
23. Lajoie A-C, Bonnet S, Provencher S. Combination therapy in pulmonary arterial hypertension: recent accomplishments and future challenges. Pulmonary Circulation. 2017; 7: 312-325.
24. Sitbon O, Gaine S. Beyond a single pathway: combination therapy in pulmonary arterial hypertension. Eur Respir Rev. 2016; 25:408-417. doi: 10.1183/16000617.0085-2016.
25. Humbert M, Barst RJ, Robbins IM et al. Combination of bosentan with epoprostenol in pulmonary arterial hypertension: BREATHE-2. Eur Respir J. 2004; 24: 353-359.
26. Hoeper MM, Leuchte H, Halank M et al. Combining inhaled iloprost with bosentan in patients with idiopathic pulmonary arterial hypertension. Eur Respir J. 2006; 28: 691-694.
27. Simonneau G, Rubin LJ, Galiè N et al. Addition of sildenafil to long-term intravenous epoprostenol therapy in patients with pulmonary arterial hypertension: a randomized trial. Ann Intern Med. 2008; 149: 521-530.
28. Galiè N, Barbera JA, Frost A et al. Initial Use of Ambrisentan plus Tadalafil in Pulmonary Arterial Hypertension. N Engl J Med. 2015; 379: 834-844. doi: 10.1056/NEJMoa1413687.
29. Galiè N, Palazzini M, Manes A. Pulmonary arterial hypertension: from the kingdom of the near-dead to multiple clinical trial meta-analyses. Eur Heart J. 2010; 31: 2080-2086. doi: 10.1093/eurheartj/ehq152.
30. [Tsareva N, Avdeev S, Nekludova G. Sequential combination therapy for patient with idiopathic pulmonary arterial hypertension (clinical case). Cardiology. 2016; (3): 97-100. (In Russ.)]. doi: https://dx.doi.org/10. 18565/cardio.2016.3.97–100
31. [Tsareva NA, Avdeev SN, Neklyudova GA. Patient with severe idiopathic pulmonary arterial hypertension: Is there a way out? Terapevticheskii Arkhiv. 2017; (9): 100-103. (In Russ.)]. doi: 10.17116/terarkh 2017899100-103
32. Lajole AC, Lauzière G1, Lega JC et al. Combination therapy versus monotherapy for pulmonary arterial hypertension: a meta-analysis. Lancet Resp Med. 2016; 4:291-305. doi: 10.1016/S2213-2600(16) 00027-8.
33. Fox BD, Shtraichman O, Langleben D et al. Combination therapy for pulmonary arterial hypertension. a systematic review and meta-analysis. Can J Cardiol. 2016; 32: 1520-1530.
34. McLaughlin VV, Oudiz RJ, Frost A et al. Randomized study of adding inhaled iloprost to existing bosentan in pulmonary arterial hypertension. Am J Respir Crit Care Med. 2006; 174: 1257-1263.
35. Tapson VF, Torres F, Kermeen F et al. Oral treprostinil for the treatment of pulmonary arterial hypertension in patients on background endothelin receptor antagonist and/or phosphodiesterase type 5 inhibitor therapy (the FREEDOMC study): A randomized controlled trial. Chest. 2012; 142: 1383-1390.
36. Tapson VF, Jing Z-C, Xu K-F et al. Oral treprostinil for the treatment of pulmonary arterial hypertension in patients receiving background endothelin receptor antagonist and phosphodiesterase type 5 inhibitor therapy (the freedom-c2 study): a randomized controlled trial. Chest. 2013; 144: 952-958.
37. McLaughlin V, Benza RL, Rubin LJ et al. Addition of inhaled treprostinil to oral therapy for pulmonary arterial hypertension: a randomized controlled clinical trial. J Am Coll Cardiol. 2010; 55: 1915-1922.
38. Sitbon O, Channick R, Chin KM et al. Selexipag for the Treatment of Pulmonary Arterial Hypertension. N Engl J Med. 2015; 373:2522-2533. doi: 10.1056/NEJMoa1503184.
39. Pulido T, Adzerikho I, Channick RN et al. Macitentan and morbidity and mortality in pulmonary arterial hypertension. N Engl J Med. 2013; 369:809-18.
40. McLaughlin V, Channick RN, Ghofrani H-A et al. Bosentan added to sildenafil therapy in patients with pulmonary arterial hypertension. Eur Respir J. 2015; 46: 1-9.
41. Gruenig E, Michelakis E, Vachiéry JL, Vizza CD, Meyer FJ, Doelberg M, Bach D, Dingemanse J, Galiè N. Acute hemodynamic effects of single-dose sildenafil when added to established bosentan therapy in patients with pulmonary arterial hypertension: results of the COMPASS-1 study. J Clin Pharmacol. 2009; 49: 1343-52. doi: 10.1177/ 0091270009341182.
42. Barst RJ, Oudiz RJ, Beardsworth A et al. Tadalafil monotherapy and as add-on to background bosentan in patients with pulmonary arterial hypertension. J Heart Lung Transplant. 2011; 30: 632-643.
43. Ghofrani H-A, Galie N, Grimminger F et al. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013; 369: 330-340.
44. Kemp K, Savale L, O’Callaghan DS et al. Usefulness of first-line combination therapy with epoprostenol and bosentan in pulmonary arterial hypertension: an observational study. J Heart Lung Transplant. 2012; 31: 150-158. doi: 10.1016/j.healun.2011.11.002.
45. Sitbon O, Jaїs X, Savale L et al. Upfront triple combination therapy in pulmonary arterial hypertension: a pilot study. Eur Respir J. 2014; 43: 1691-1697. doi: 10.1183/09031936.00116313.
46. Hoeper MM, McLaughlin VV, Barbera JA et al. Initial combination therapy with ambrisentan and tadalafil and mortality in patients with pulmonary arterial hypertension: a secondary analysis of the results from the randomised, controlled AMBITION study. Lancet Respir Med. 2016; 4: 894-901.
47. Sitbon O, Sattler C, Bertoletti L et al. Initial dual oral combination therapy in pulmonary arterial hypertension. Eur Respir J. 2016; 47: 1727-1736.
48. Jansa P, Pulido T. Macitentan in Pulmonary Arterial Hypertension: A Focus on Combination Therapy in the SERAPHIN Trial. Am J Cardiovasc Drugs. 2017 Dec 26. doi: 10.1007/s40256-017-0260-1. [Epub ahead of print].
49. Coghlan JG, Channick R, Chin K, Di Scala L, Galiè N, Ghofrani HA, Hoeper MM, Lang IM, McLaughlin V, Preiss R, Rubin LJ, Simonneau G, Sitbon O, Tapson VF, Gaine S. Targeting the Prostacyclin Pathway with Selexipag in Patients with Pulmonary Arterial Hypertension Receiving Double Combination Therapy: Insights from the Randomized Controlled GRIPHON Study. Am J Cardiovasc Drugs. 2018 Jan 6. doi: 10.1007/s40256-017-0262-z. [Epub ahead of print].
50. Actelion. The Efficacy and Safety of Initial Triple Versus Initial Dual Oral Combination Therapy in Patients With Newly Diagnosed Pulmonary Arterial Hypertension (TRITON). Clinical Trials. gov. 2017: NCT02558231.
Авторы
С.Н. АВДЕЕВ 1, Н.А. ЦАРЕВА 1, И.Р. ГАЙСИН 2
1ФГАОУ ВО «Первый МГМУ им. И.М. Сеченова» Минздрава России, Москва, Россия;
2ФГБОУ ВО «Ижевская государственная медицинская академия» Минздрава России, Ижевск, Россия
________________________________________________
S.N. Avdeev 1, N.A. TsarEva 1, I.R. Gaisin 2
1 I.M. Sechenov First Moscow State Medical University, Moscow, Russia;
2 Izhevsk State Medical Academy, Izhevsk, Russia