ASPECTS OF MODERN COMBINATION SPECIFIC THERAPY OF PULMONARY ARTERIAL HYPERTENSION: THE PROS AND CONS

The treatment algorithm for pulmonary arterial hypertension (PAH) includes three main stages: general measures; induction drug therapy; combined drug therapy and intervention  methods  for patients  who fail to respond adequately  to induction therapy. The specific therapy includes endothelin receptor antagonists  (ARE), prostanoids, phosphodiesterase type 5 inhibitor (PT5I) and soluble guanylate cyclase stimulators (rGCS). The combined specific therapy, which means the simultaneous  use of more than one class of specific drugs, is an attractive approach, taking into account the malignancy and complexity of PAH pathogenesis, and the successful experience  in using medication combinations in the treatment of systemic arterial hypertension  and heart failure. The article shows that down to recent times the issues  of necessity and timeliness of the combined PAH-specific therapy, and the choice of rational combinations, require further study. The COMPASS-2 randomized study did not prove that the adding bosentan to the stable sildenafil therapy is more effective than sildenafil monotherapy, and extends  the time to the development  of the first morbidity event/ mortality in PAH patients. The meta-analysis  of H.l. Liu et al. showed that the monotherapy leads to a significant reduction in mortality in patients with PAH, improvement of functional and hemodynamic status compared with the placebo or standard therapy. The combined therapy is associated  with a significant improvement in functional and hemodynamic status, but the mortality of patients did not decrease reliably compared with the monotherapy. The combined therapy is associated with a significant increase in cancellation frequency due to adverse effects as compared with the monotherapy.

The concept  of the advantage  of rGC stimulants  over PT5I was studied  in an international multicentre  open-label  IIIb phase  RESPITE (Riociguatum Сlinical Effects Studied in Patients With Insufficient Treatment Response  to PDE5) study of the safety and efficacy of the transition from the PT5I therapy to riociguatum therapy in patients with PAH who did not achieve the treatment goals when using PT5I. The study included patients with functional capacity III (WHO),  a distance of 165–440 m in the 6-min walk distance (6MWD), cardiac index <3.0  l/min/m², pulmonary vascular resistance>  400  dyne*s *cm^-5, the average pressure in the pulmonary artery > 30  Hg mm despite receiving stable doses  of sildenafil in the highest  dose of 80 mg 3 times a day or tadalafil in the highest  dose of 40 mg 1 once a day. A part of patients also received an endothelin  receptor antagonist  (ERA). The clinical endpoints included changes in 6MWD, hemodynamics from baseline  to Week 24  of therapy, WHO FC, the NT-proBNP levels,  the quality of life evaluation, and % patients  developing  clinical worsening from baseline to Week 12 and 24 of therapy.

After cancellation of PDE5i, the patients received riociguat. The interim analysis of the study showed that 50% of patients had improved to WHO FC II from III, increased 6MWD from 353  ± 78 to 392  ± 112  m (n = 25); improved hemodynamic parameters and NT-proBNP levels by Week 24, which may indicate that patients with an insufficient response  to PDE5i therapy may benefit  from a transition to riociguat. This approach should be further investigated,  as suggested by 2016 Russian Guidelines for the Diagnosis and Treatment of Pulmonary Hypertension.

1. Мартынюк Т.В., Наконечников С.Н., Чазова И.Е. Современные подходы к лечению пациентов с легочной гипертензией в свете рекомендаций Европейского общества кардиологов. Consilium Medicum, 2005, 11: 957-962.

2. Чазова И.Е., Авдеев С.Н., Царева Н.А., др. Клинические рекомендации по диагностике и лечению легочной гипертензии. Терапевтический архив, 2014, 9: 4-23.

3. Galiè N, Hoeper MM, Humbert M, et al. 2015 ESC/ ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. The 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), the International Society for Heart and Lung Transplantation (ISHLT). European Heart Journal (2016, 37(1): 67-119.

4. Taichman DB, Ornelas J, Chung L et al. Pharmacologic therapy for Pulmonary Arterial Hypertension in Adults CHEST Guideline and Expert Panel Report. CHEST, 2014, 146(2): 449-475.

5. Мартынюк Т.В., Архипова О.А., Кобаль Е.А., др. Применение неселективного антагониста рецепторов эндотелина бозентана у больных идиопатической легочной гипертензией: первый российский опыт и взгляд в будущее. Cистемные гипертензии, 2011, 4: 51-57.

6. Диагностика и лечение артериальной гипертензии. Рекомендации Российского медицинского общества по артериальной гипертонии и Всероссийского научного общества кардиологов. 2013г. Доступно по ссылке: http://www. cardioweb.ru/klinicheskie-rekomendatsii

7. Hunt SA, Abraham WT, Chin MH et al. ACC/AHA 2005 Guideline Update For The Diagnosis And Management Of Chronic Heart Failure In The Adult: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines (Writing Committee to Update the 2001 Guidelines for the Evaluation and Management of Heart Failure): developed in collaboration with the American College of Chest Physicians and the International Society for Heart and Lung Transplantation: endorsed by the Heart Rhythm Society. Circulation, 2005, 112: e154-e235.

8. Galie N, Palazzini M, Manes A. Pulmonary arterial hypertension: from the kingdom of the neardead to multiple clinical trial meta-analyses. Eur Heart J, 2010, 31: 2080-2086.

9. Hoeper MM, Faulenbach C, Golpon H, et al. Combination therapy with bosentan and sildenafil in idiopathic pulmonary arterial hypertension. Eur Respir J, 2004, 24: 1007-1010.

10. Dardi F, Manes A, Palazzini M, et al.Combining bosentan and sildenafil in pulmonary arterial hypertension patients failing monotherapy: realworld insights. Eur Respir J, 2015, 46: 414-421.

11. Парамонов В.М. Оценка эффективности длительной терапии бозентаном, силденфилом и их комбинации у больных идиопатической легочной гипертензией. Автореф. дисс. канд. мед. наук. М., 2016. (Доступно по ссылке: http://rsmu.ru/fileadmin/rsmu/img/about_rsmu/disser/8/d_paramonov_vm.pdf).

12. Mathai SC, Girgis RE, Fisher MR, et al. Addition of sildenafil to bosentan monotherapy in pulmonary arterial hypertension. Eur Respir J, 2007, 29: 469-475.

13. Sitbon O, Humbert M, Nunes H, et al. Long-term intravenous epoprostenol infusion in primary pulmonary hypertension: prognostic factors and survival. J Am Coll Cardiol, 2002, 40: 780-788.

14. Bai Y, Sun L, Hu S, Wei Y. Combination therapy in pulmonary arterial hypertension: a meta-analysis. Cardiology, 2011, 120(3): 157-165.

15. 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.

16. Liu H, Chen X, Li J, et al. Efficacy and Safety of Pulmonary Arterial Hypertension-specific Therapy in Pulmonary Arterial Hypertension A Meta-analysis of Randomized Controlled Trial. CHEST, 2016, 150(2): 353-366.

17. Klinger JR, Abman SH, Gladwin MT. Nitric oxide deficiency and endothelial dysfunction in pulmonary arterial hypertension. Am J Respir Crit Care Med, 2013, 188: 639-646.

18. 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.

19. Leuchte HH, Schwaiblmair M, Baumgartner RA, et al. Hemodynamic response to sildenafil, nitric oxide, and iloprost in primary pulmonary hypertension. Chest, 2004, 125: 580-586.

20. Stasch JP, Pacher P, Evgenov OV. Soluble guanylate cyclase as an emerging therapeutic target in cardiopulmonary disease. Circulation, 2011, 123(20): 2263-2273.

21. Hoeper MM, Klinger JR, Benza RL, et al. Rationale and study design of RESPITE: An open-label, phase 3b study of riociguat in patients with pulmonary arterial hypertension who demonstrate an insufficient response to treatment with phosphodiesterase-5 inhibitors. Respiratory Medicine, 2017, 122: 18-22.

22. Nazzareno Galie et al. 2015 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension – web addenda. The Joint Task Force for the Diagnosis and Treatment of Pulmonary Hypertension of the European Society of Cardiology (ESC) and of the European Respiratory Society (ERS). European Heart Journal. Available at: (doi:10.1093/eurheartj/ehv317)

23. Hoeper MM et al. The RESPITE Study: Riociguat In Patients With PAH And An Inadequate Response To Phosphodiesterase 5 Inhibitors. Am J Crit Care Med, 2016, 193: A6315 (Available on: http://www.atsjournals.org/doi/abs/10.1164/ajrccm-conference.2016.193.1_MeetingAbstracts. A6315).