Choice of specific and anticoagulant therapy in patients with newly diagnosed chronic thromboembolic pulmonary hypertension, depending on operability status

Aim. To study the features of anticoagulant and specific therapy in newly diagnosed patients with chronic thromboembolic pulmonary hypertension (CTEPH) depending on operability status.

Material and methods. The study included 319 patients with CTEPH, hospitalized for the first time in the E.I. Chazov National Medical Research Center of Cardiology for the period from 2012 to 2021. The diagnosis was established according to current guidelines. Depending on operability status, which was assessed by a multidisciplinary team, two following groups were formed: patients with inoperable CTEPH (n=222) and patients with operable CTEPH who underwent pulmonary thromboendarterectomy (n=97) (time from diagnosis to surgery, 13,3 [6,3; 27,1] months). Demographic, functional status, anticoagulant therapy and specific therapy regimens were analyzed.

Results. At the time of initial admission to the expert center, 80,56% of patients received anticoagulant therapy, most often warfarin in both inoperable (38,74%) and operable patients with CTEPH (55,67%), respectively, and rivaroxaban (25,68% and 20,62%, respectively); 6,27% took only antiplatelet agents, and 13,17% did not receive anticoagulant therapy. In the hospital, inoperable patients were most often prescribed low molecular weight heparins in therapeutic doses (47,3%), warfarin — 38,7%, and to a lesser extent (12,16%) — direct oral anticoagulants (DOACs). Operable patients were more often prescribed warfarin (54,64%), while low molecular weight heparins — in 37,1%, and individual patients were prescribed (8,25%) DOACs.

Specific therapy at the admission time was received by 19,59% of operable and 23,42% of inoperable patients with CTEPH, mainly in the sildenafil monotherapy regimen. After verification of the diagnosis, the majority of patients (64,4% of inoperable and 46,4% of operable patients with CTEPH) received monotherapy with sildenafil (72,82%) and riociguat (46,75%). The addition of a second drug, mainly within the initial combination therapy, was required in 5,15% of operable patients and 10,81% of inoperable patients, while 1,06% and 0,9% of operable and inoperable patients with CTEPH, respectively, received triple specific therapy.

Conclusion. For the first time in Russian practice, anticoagulant and specific therapy were studied in newly diagnosed patients with CTEPH, depending on the operability status.

1. Galie 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). Eur Respir J. 2015;46(4):903-75. doi:10.1183/13993003.01032-2015.

2. Чазова И. Е., Мартынюк Т. В., Валиева З. С. и др. Евразийские рекомендации по диагностике и лечению хронической тромбоэмболической легочной гипертензии (2020). Евразийский Кардиологический Журнал. 2021;(1):6-43. doi:10.38109/2225-1685-2021-1-6-43.

3. Авдеев С. Н., Барбараш О. Л., Баутин А. Е. и др. Легочная гипертензия, в том числе хроническая тромбоэмболическая легочная гипертензия. Клинические рекомендации 2020. Российский кардиологический журнал. 2021;26(12):4683. doi:10.15829/1560-4071-2021-4683.

4. Humbert M, Kovacs G, Hoeper MM, et al. ESC/ERS Scientific Document Group, 2022 ESC/ERS Guidelines for the diagnosis and treatment of pulmonary hypertension: Developed by 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 the International Society for Heart and Lung Transplantation (ISHLT) and the European Reference Network on rare respiratory diseases (ERN-LUNG). European Heart Journal. 2022;ehac237. doi:10.1183/13993003.00879-2022.

5. Pepke-Zaba J, Delcroix M, Lang I, et al. Chronic thromboembolic pulmonary hypertension (CTEPH): results from an international prospective registry. Circulation. 2011;124:1973-81. doi:10.1161/CIRCULATIONAHA.110.015008.

6. 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;141:702-10. doi:10.1016/j.jtcvs.2010.11.024.

7. Freed DH, Thomson BM, Berman M, et al. Survival after pulmonary thromboendarterectomy: effect of residual pulmonary hypertension. J Thorac Cardiovasc Surg. 2011;141:383-7. doi:10.1016/j.jtcvs.2009.12.056.

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

9. van Thor MCJ, Ten Klooster L, Snijder RJ, et al. Long-term clinical value and outcome of riociguat in chronic thromboembolic pulmonary hypertension. Int J Cardiol Heart Vasc. 2019:28;22:163-8. doi:10.1016/j.ijcha.2019.02.004.

10. Dorfmuller P, Günther S, Ghigna MR, et al. Microvascular disease in chronic thromboembolic pulmonary hypertension: a role for pulmonary veins and systemic vasculature. Eur Respir J. 2014:44(5):1275-88. doi:10.1183/09031936.00169113.

11. Humbert M, Guignabert C, Bonnet S, et al. Pathology and pathobiology of pulmonary hypertension: state of the art and research perspectives. Eur Respir J. 2019;53(1):1801887. doi:10.1183/13993003.01887-2018.

12. Stasch JP, Evgenov OV. Soluble guanylate cyclase stimulators in pulmonary hypertension. Handb Exp Pharmacol. 2013;218:279-313. doi:10.1007/978-3-642-38664-0_12.

13. Langer F, Bauer M, Tscholl D, et al. Circulating big endothelin-1: an active role in pulmonary thromboendarterectomy? J Thorac Cardiovasc Surg. 2005;130(5):1342-7. doi:10.1016/j.jtcvs.2005.06.044.

14. Reesink HJ, Meijer RC, Lutter R, et al. Hemodynamic and clinical correlates of endothelin-1 in chronic thromboembolic pulmonary hypertension. Circ J. 2006;70(8):1058-63. doi:10.1253/circj.70.1058.

15. 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(9):859-71. doi:10.1161/CIRCULATIONAHA.115.016522.

16. Jensen KW, Kerr KM, Fedullo PF, et al. Pulmonary hypertensive medical therapy in chronic thromboembolic pulmonary hypertension before pulmonary thromboendarterectomy. Circulation. 2009;120(13):1248-54. doi:10.1161/CIRCULATIONAHA.109.865881.

17. Kerr KM, Elliott CG, Chin K, et al. Results From the United States Chronic Thromboembolic Pulmonary Hypertension Registry: Enrollment Characteristics and 1-Year Follow-up. Chest. 2021;160(5):1822-31. doi:10.1016/j.chest.2021.05.052.

18. Gall H, Preston IR, Hinzmann B, et al. An international physician survey of chronic thromboembolic pulmonary hypertension management. Pulm Circ. 2016;6(4):472-82. doi:10.1086/688084.

19. Demerouti E, Karyofyllis P, Voudris V, et al. Epidemiology and Management of Chronic Thromboembolic Pulmonary Hypertension in Greece. Real-World Data from the Hellenic Pulmonary Hypertension Registry (HOPE). Journal of Clinical Medicine. 2021;10(19):4547. doi:10.3390/jcm10194547.

20. van Thor MCJ, Snijder RJ, Kelder JC, et al. Does combination therapy work in chronic thromboembolic pulmonary hypertension? Int J Cardiol Heart Vasc. 2020;29:100544. doi:10.1016/j.ijcha.2020.100544.

21. Чазова И. Е., Мартынюк Т. В., Валиева З. С. и др. Оценка бремени хронической тромбоэмболической легочной гипертензии в Российской Федерации. Терапевтический архив. 2018;90(9):101-9. doi:10.26442/terarkh2018909101-109.

22. Schweikert B, Pittrow D, Vizza CD, 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.

23. Ghofrani HA, Simonneau G, D’Armini AM, et al. 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):785-94. doi:10.1016/S2213-2600(17)30305-3.

24. Ghofrani HA, Wiedemann R, Rose F, et al. Combination therapy with oral sildenafil and inhaled iloprost for severe pulmonary hypertension. Ann Intern Med. 2002;136(7):515-22. doi:10.7326/0003-4819-136-7-200204020-00008.

25. Voswinckel R, Reichenberger F, Enke B, et al. Acute effects of the combination of sildenafil and inhaled treprostinil on haemodynamics and gas exchange in pulmonary hypertension. Pulm Pharmacol Ther. 2008;21(5):824-32. doi:10.1016/j.pupt.2008.07003.

26. Sadushi-Kolici R, Jansa P, Kopec G, et al. 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):239-48. doi:10.1016/S2213-2600(18)30367-9.

27. Kramm T, Wilkens H, Fuge J, et al. Incidence and characteristics of chronic thromboembolic pulmonary hypertension in Germany. Clin. Res. Cardiol. 2018;107:548-53. doi:10.1007/s00392-018-1215-5.