Specific Therapy Strategy Choice for Patients With Pulmonary Arterial Hypertension and Inoperable Chronic Thromboembolic Pulmonary Hypertension: Switch or Escalate

The review addresses principal approaches to intensifying therapy in patients with pulmonary arterial hypertension (PAH) and chronic thromboembolic pulmonary hypertension (CTEPH). The position of Russian experts on the strategy of switching within one class of PAH-specific therapy is presented. Particular attention is paid to the strategy of therapy optimization in the form of replacing phosphodiesterase type 5 inhibitors with a stimulator of soluble guanylate cyclase (riociguat) in patients with PAH and inoperable/residual CTEPH who cannot not achieve treatment goals on phosphodiesterase type 5 inhibitors. The authors analyzed and identified the criteria justifying the choice of a specific therapy strategy in favor of switching from a phosphodiesterase type 5 inhibitor to riociguat.

1. Avdeev S.N., Barbarash O.L., Valieva Z.S., Volkov A.V., Veselova T.N., Galyavich A.S. et al. 2024 Clinical practice guidelines for Pulmonary hypertension, including chronic thromboembolic pulmonary hypertension. Russian Journal of Cardiology. 2024;29(11):6161 doi: 10.15829/1560-4071-2024-6161.

2. Humbert M., Kovacs G., Hoeper M.M., Badagliacca R., Berger R.M.F, Brida M. et al. ESC/ERS Scientific Document Group. 2022 ESC/ ERS Guidelines for the diagnosis and treatment of pulmonary hypertension. Eur Heart J. 2022;43(38):3618-3731. doi: 10.1093/eurheartj/ehac237.

3. Chazova I.E., Martynyuk T.V., Valieva Z.S., Azizov V.A., Akchurin R.S., Ansheles A.A. et al. Eurasian association of cardiology (EAC) guidelines for the diagnosis and treatment of chronic thromboembolic pulmonary hypertension (2020). Eurasian Heart Journal. 2021;(1):6-43. https://doi.org/10.38109/2225-1685-2021-1-6-43

4. Li J., Yang Z.Y., Wang S., Yuan P., Zhao Q.H., Gong S.G. et al. Efficacy and safety of switching from bosentan or ambrisentan to macitentan in pulmonary arterial hypertension: A systematic review and meta-analysis. Front Cardiovasc Med. 2022; 9:977110. doi: 10.3389/fcvm.2022.977110.

5. Safdar Z., Thakur A., Frost A. Tolerability of switch to Macitentan from Bosentan in pulmonary arterial hypertension, South. Med J. 2017; 110(3): 223–228. https://doi.org/10.14423/smj.0000000000000607.

6. Wu S., Hoang H.B., Yang J.Z., Papamatheakis D.G., Poch D.S., Alotaibi M. et al. Drug-Drug Interactions in the Management of Patients With Pulmonary Arterial Hypertension. Chest. 2022;162(6):1360-1372. doi: 10.1016/j.chest.2022.06.042.

7. Martynyuk T.V., Nakonechnikov S.N., Chazova I.Y. New horizons for the use of the second generation of endothelin receptor antagonist macitentan in patients with pulmonary hypertension. Ter Arkh. 2018;90(4):72-80. doi: 10.26442/terarkh201890472-80.

8. Manzi G., Benza R.L., Argiento P., Casu G., Corda M., Correale M. et al. Gaps in evidence in the treatment of prevalent patients with pulmonary arterial hypertension at intermediate risk: An expert consensus. Vascul Pharmacol. 2024;157:107432. doi: 10.1016/j.vph.2024.107432.

9. Olschewski H., Simonneau G., Galiè N., Higenbottam T., Naeije R., Rubin L.J. et al. Aerosolized Iloprost Randomized Study Group. Inhaled iloprost for severe pulmonary hypertension. N Engl J Med. 2002;347(5):322-9. doi: 10.1056/NEJMoa020204.

10. Chazova I.E., Martynyuk T.V., Shmalts A.A., Gramovich V.V., Danilov N.M., Veselova T.N. et al. Eurasian guidelines for the diagnosis and treatment of pulmonary hypertension (2023). Eurasian Heart Journal. 2024;(1):6-85 https://doi.org/10.38109/2225-1685-2024-1-6-85

11. Lichtblau M., Harzheim D., Ehlken N., Marra A., Pinado F.P., Grünig E. et al. Safety and long-term efficacy of transition from sildenafil to tadalafil due to side effects in patients with pulmonary arterial hypertension. Lung. 2015;193(1):105-12. doi: 10.1007/s00408-014-9657-7.

12. Martynyuk T.V., Shmalts A.A., Gorbachevsky S.V., Chazova I.E. Optimization of specific therapy for pulmonary hypertension: the possibilities of riociguat. Ter Arkh. 2021;93(9):1117-1124. doi: 10.26442/00403660.2021.09.201014.

13. Taran I.N., Martynuk T.V., Nakonechnikov S.N., Chazova I.E. Innovation in the medical treatment of patients with pulmonary arterial hypertension and inoperable, persistent/recurrent chronic thromboembolic pulmonary hypertension: soluble guanilate cyclase stimulator – riociguat. Complex issues of cardiovascular diseases. 2016;(4):87-95. https://doi.org/10.17802/2306-1278-2016-4-87-95.

14. Stasch JP, Pacher P, Evgenov OV. Soluble guanylate cyclase as an emerging therapeutic target in cardiopulmonary disease. Circulation. 2011 May 24;123(20):2263-73. doi: 10.1161/CIRCULATIONAHA.110.981738.

15. Ghofrani HA, Galiè N, Grimminger F, Grünig E, Humbert M, Jing ZC et al. PATENT-1 Study Group. Riociguat for the treatment of pulmonary arterial hypertension. N Engl J Med. 2013;369(4):330-40. doi: 10.1056/NEJMoa1209655.

16. 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

17. 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 May;4(5):361-71. doi: 10.1016/S2213-2600(16)30019-4.

18. Hoeper MM, Simonneau G, Corris PA, Ghofrani HA, Klinger JR, Langleben D et al. RESPITE: switching to riociguat in pulmonary arterial hypertension patients with inadequate response to phosphodiesterase-5 inhibitors. Eur Respir J. 2017; 50: 1602425 [https://doi.org/10.1183/13993003.02425-2016]

19. Taran IN, Belevskaya AA, Saidova MA, Martynyuk TV, Chazova IE. Initial Riociguat Monotherapy and Transition from Sildenafil to Riociguat in Patients with Idiopathic Pulmonary Arterial Hypertension: Influence on Right Heart Remodeling and Right Ventricular-Pulmonary Arterial Coupling. Lung. 2018;196(6):745-753. doi: 10.1007/s00408-018-0160-4.

20. Hoeper MM, Al-Hiti H, Benza RL, Chang SA, Corris PA, Gibbs JSR et al. REPLACE investigators. Switching to riociguat versus maintenance therapy with phosphodiesterase-5 inhibitors in patients with pulmonary arterial hypertension (REPLACE): a multicentre, open-label, randomised controlled trial. Lancet Respir Med. 2021 Jun;9(6):573-584. doi: 10.1016/S2213-2600(20)30532-4.

21. Musashaykhova S.A., Valieva Z.S., Martynyuk T.V. Results of longterm riociguat therapy, including a switching strategy from sildenafil, in patients with pulmonary hypertension of various genesis. Eurasian heart journal. 2023;(4):42-55. https://doi.org/10.38109/2225-1685-2023-4-42-55

22. Taran I.N., Belevskaya A.A., Valieva Z.S., Saidova M.A., Martynyuk T.V. “Portrait” of patients with idiopathic pulmonary hypertension and chronic thromboembolic pulmonary hypertension depending on comorbid status: current and prognosis features. Pulmonologya. 2020;30(4):427-436 https://doi.org/10.18093/0869-0189-2020-30-4-427-436

23. Shariya A.M., Martynyuk T.V. Changing “portrait” of patients with newly diagnosed idiopathic pulmonary hypertension over the past two decades. Eurasian heart journal. 2024;(3):42-49. https://doi.org/10.38109/2225-1685-2024-3-42-49

24. McLaughlin VV, Sitbon O, Chin KM, Galiè N, Hoeper MM, Kiely DG et al. Initial combination therapy with macitentan and tadalafil in patients with pulmonary arterial hypertension, with and without cardiac comorbidities. Eur J Heart Fail. 2024; 26(11):2379-2391. doi: 10.1002/ejhf.3319.

25. Rosenkranz S, Ghofrani HA, Hoeper MM, Langleben D, Hegab S, Rahner C et al. Safety and efficacy of riociguat in patients with pulmonary arterial hypertension and cardiometabolic comorbidities: Data from interventional clinical trials. J Heart Lung Transplant. 2024. 1053-2498(24)01807-2. doi: 10.1016/j.healun.2024.08.018.

26. Ghofrani HA, Simonneau G, D’Armini AM, Fedullo P, Howard LS, Jaïs X 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. 2024 Apr;12(4):e21-e30. doi: 10.1016/S2213-2600(24)00027-4.

27. Sadushi-Kolici R, Jansa P, Kopec G, Torbicki A. Subcutaneous treprostinil for the treatment of severe non-operable chronic thromboembolic pulmonary hypertension (CTREPH): a double-blind, phase 3, randomised controlled trial. Lancet Respir Med. 2019;7(3):239-248. DOI: 10.1016/S2213-2600(18)30367-9.

28. Gall H, Vachiéry JL, Tanabe N, Halank M, Orozco-Levi M, Mielniczuk L 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.

29. Davey R., Benza R.L., Murali S., Raina A. Phosphodiesterase type 5 inhibitor to riociguat transition is associated with hemodynamic and symptomatic improvement in pulmonary hypertension, Pulm. Circ. 2017; 7(2):539–542. DOI: 10.1177/2045893217708566

30. Darocha S, Banaszkiewicz M, Pietrasik A, Piłka M, Florczyk M, Wieteska M. 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;269:283-288. doi: 10.1016/j.ijcard.2018.07.015

31. Wiedenroth CB, Liebetrau C, Breithecker A, Guth S, Lautze HJ, Ortmann E et al. Combined pulmonary endarterectomy and balloon pulmonary angioplasty in patients with chronic thromboembolic pulmonary hypertension. J Heart Lung Transplant. 2016;35(5):591-6. doi: 10.1016/j.healun.2015.10.030

32. Jaïs X, Brenot P, Bouvaist H, Jevnikar M, Canuet M, Chabanne C et al. Balloon pulmonary angioplasty versus riociguat for the treatment of inoperable chronic thromboembolic pulmonary hypertension (RACE): a multicentre, phase 3, open-label, randomised controlled trial and ancillary follow-up study. Lancet Respir Med. 2022 Oct;10(10):961-971. doi: 10.1016/S2213-2600(22)00214-4.

33. National Institutes of Health Clinical Center, National Institutes of Health; 2021. Initial dual oral combination therapy versus standardof-care initial oral monotherapy prior to balloon pulmonary angioplasty in patients with inoperable chronic thromboembolic pulmonary hypertension (IMPACT-CTEPH). NCT04780932. ClinicalTrials.gov. https://www.clinicaltrials.gov/ct2/show/NCT04780932 Updated October 25, 2022