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Current Vascular Pharmacology

Editor-in-Chief

ISSN (Print): 1570-1611
ISSN (Online): 1875-6212

Clinical Trial

Bosentan and Pulmonary Hypertension Caused by COVID-19: A Pilot Randomized Double-blind Clinical Study

In Press, (this is not the final "Version of Record"). Available online 13 June, 2024
Author(s): Fahime Shokrollahi, Ali Pazoki*, Abbas Allami, Shahin Aliakbari and Kimia Rahimi Ardali
Published on: 13 June, 2024

DOI: 10.2174/0115701611299843240607061547

Price: $95

Abstract

Introduction/Objective: Coronavirus disease 2019 (COVID-19) has been the biggest pandemic in history, with severe complications, such as acute respiratory distress syndrome and pulmonary hypertension (PH). An endothelin-1 (ET-1) receptor antagonist, such as bosentan, may be beneficial in treating elevated ET-1 levels. Hence, our study aimed to evaluate the therapeutic effects of bosentan in patients with COVID-19-induced PH.

Methods: A single-centre, randomized, double-blind study involving 72 participants was carried out; 36 received bosentan and the other 36 received a placebo. Pulmonary arterial pressure, tricuspid valve pressure gradient, and right atrial pressure were measured using echocardiography. The Cox proportional hazards regression model was used to investigate the impact of bosentan and patients' age on mortality during a 6-month follow-up period.

Results: In-hospital mortality was significantly lower in the case group (13%) compared with the control group (33.3%) (P=0.003). Additionally, bosentan improved echocardiographic parameters, such as systolic pulmonary artery pressure and tricuspid regurgitation gradient (P=0.011 and P=0.003, respectively). Bosentan use was a significant predictor of long-term mortality rates for 600 days [age-adjusted hazard ratio of 5.24 (95% CI 1.34 to 20.46)].

Conclusion: This study provided a mixed perspective on the use of bosentan therapy in patients with COVID-19-related PH. Bosentan effectively reduced in-hospital mortality and improved echocardiographic measures. However, the treatment group showed an increased requirement for supplemental oxygen therapy and long-term mortality. Further studies with larger sample sizes are necessary to elucidate the effects of bosentan in PH following COVID-19.

[1]
Esakandari H, Nabi-Afjadi M, Fakkari-Afjadi J, Farahmandian N, Miresmaeili SM, Bahreini E. A comprehensive review of COVID-19 characteristics. Biol Proced Online 2020; 22(1): 19.
[http://dx.doi.org/10.1186/s12575-020-00128-2] [PMID: 32774178]
[2]
Allan M, Lièvre M, Laurenson-Schafer H, de Barros S, Jinnai Y, Andrews S. The world health organization COVID-19 surveillance database. Int J Equity Health 2022; 21(Suppl 3): 167.
[3]
Ahamad S, Branch S, Harrelson S, Hussain MK, Saquib M, Khan S. Primed for global coronavirus pandemic: Emerging research and clinical outcome. Eur J Med Chem 2021; 209: 112862.
[http://dx.doi.org/10.1016/j.ejmech.2020.112862] [PMID: 33070079]
[4]
Castiglione L, Droppa M. Pulmonary hypertension and COVID-19. Hamostaseologie 2022; 42(4): 230-8.
[http://dx.doi.org/10.1055/a-1661-0240] [PMID: 34933375]
[5]
Caravita S, Baratto C, Di Marco F, et al. Haemodynamic characteristics of COVID-19 patients with acute respiratory distress syndrome requiring mechanical ventilation. An invasive assessment using right heart catheterization. Eur J Heart Fail 2020; 22(12): 2228-37.
[http://dx.doi.org/10.1002/ejhf.2058] [PMID: 33200458]
[6]
Beshay S, Guha A, Sahay S. Evaluation, diagnosis, and classification of pulmonary hypertension. Methodist DeBakey Cardiovasc J 2021; 17(2): 86-91.
[http://dx.doi.org/10.14797/OCDF4453] [PMID: 34326927]
[7]
Lin P, Jiang F, Li X, Zhao Y, Shi Y, Liang Z. International trends in pulmonary hypertension mortality between 2001 and 2019: Retrospective analysis of the WHO mortality database. Heliyon 2024; 10(4): e26139.
[8]
Beshay S, Sahay S, Humbert M. Evaluation and management of pulmonary arterial hypertension. Respir Med 2020; 171: 106099.
[http://dx.doi.org/10.1016/j.rmed.2020.106099] [PMID: 32829182]
[9]
Farha S. COVID-19 and pulmonary hypertension. Cleve Clin J Med 2020; 87(5): 1-3.
[PMID: 32393596]
[10]
Kadiyska T, Tourtourikov I, Dabchev K, et al. Role of endothelial dysfunction in the severity of COVID-19 infection (Review). Mol Med Rep 2022; 26(5): 351.
[http://dx.doi.org/10.3892/mmr.2022.12867] [PMID: 36196882]
[11]
Xu J, Jiang X, Xu S. Aprocitentan, a dual endothelin-1 (ET-1) antagonist for treating resistant hypertension: Mechanism of action and therapeutic potential. Drug Discov Today 2023; 28(11): 103788.
[http://dx.doi.org/10.1016/j.drudis.2023.103788] [PMID: 37742911]
[12]
Sharif S, Maqbool R, Naz S. Role of endothelin in hypertension: A review. Scientific Reports in Life Sciences 2022; 3(4): 68-83.
[13]
Haryono A, Ramadhiani R, Ryanto GRT, Emoto N. Endothelin and the cardiovascular system: The long journey and where we are going. Biology 2022; 11(5): 759.
[http://dx.doi.org/10.3390/biology11050759] [PMID: 35625487]
[14]
Chester AH, Yacoub MH. The role of endothelin-1 in pulmonary arterial hypertension. Glob Cardiol Sci Pract 2014; 2014(2): 29.
[http://dx.doi.org/10.5339/gcsp.2014.29] [PMID: 25405182]
[15]
Frommer KW, Müller-Ladner U. Expression and function of ETA and ETB receptors in SSc. Rheumatology 2008; 47 (Suppl. 5): v27-8.
[http://dx.doi.org/10.1093/rheumatology/ken274] [PMID: 18784135]
[16]
Chen YF, Oparil S. Endothelin and pulmonary hypertension. J Cardiovasc Pharmacol 2000; 35(4) (Suppl. 2): S49-53.
[http://dx.doi.org/10.1097/00005344-200000002-00012] [PMID: 10976782]
[17]
Miyagawa K, Emoto N. Current state of endothelin receptor antagonism in hypertension and pulmonary hypertension. Ther Adv Cardiovasc Dis 2014; 8(5): 202-16.
[http://dx.doi.org/10.1177/1753944714541511] [PMID: 24990369]
[18]
Li J, Guan J, Long X, Xiang X. Endothelin-1 upregulates the expression of high mobility group box 1 in human bronchial epithelial cells. Pharmacology 2015; 96(3-4): 144-50.
[http://dx.doi.org/10.1159/000435888] [PMID: 26226834]
[19]
Agarwal R, Gomberg-Maitland M. Current therapeutics and practical management strategies for pulmonary arterial hypertension. Am Heart J 2011; 162(2): 201-13.
[http://dx.doi.org/10.1016/j.ahj.2011.05.012] [PMID: 21835279]
[20]
Rosenkranz S. Pulmonary hypertension: Current diagnosis and treatment. Clin Res Cardiol 2007; 96(8): 527-41.
[http://dx.doi.org/10.1007/s00392-007-0526-8] [PMID: 17534570]
[21]
Bhogal S, Mukherjee D, Banerjee S, Tan W, Paul TK. Current trends and future perspectives in the treatment of pulmonary arterial hypertension. Curr Probl Cardiol 2018; 43(5): 191-216.
[http://dx.doi.org/10.1016/j.cpcardiol.2017.10.002] [PMID: 29174585]
[22]
Provencher S, Granton JT. Current treatment approaches to pulmonary arterial hypertension. Can J Cardiol 2015; 31(4): 460-77.
[http://dx.doi.org/10.1016/j.cjca.2014.10.024] [PMID: 25840096]
[23]
Araz O. Current pharmacological approach to ARDS: The place of bosentan. Eurasian J Med 2020; 52(1): 81-5.
[http://dx.doi.org/10.5152/eurasianjmed.2020.19218] [PMID: 32158321]
[24]
Guo Q, Huang J, Fraidenburg DR. Bosentan as rescue treatment in refractory hypoxemia and pulmonary hypertension in a patient with ARDS and H7N9 influenza virus infection. Lung 2014; 192(5): 635-6.
[http://dx.doi.org/10.1007/s00408-014-9602-9] [PMID: 24898108]
[25]
Giannakoulas G, Gatzoulis MA. Pulmonary arterial hypertension in congenital heart disease: Current perspectives and future challenges. Hellenic J Cardiol 2016; 57(4): 218-22.
[http://dx.doi.org/10.1016/j.hjc.2016.05.002] [PMID: 27642135]
[26]
Basyal B, Jarrett H, Barnett CF. Pulmonary hypertension in HIV. Can J Cardiol 2019; 35(3): 288-98.
[http://dx.doi.org/10.1016/j.cjca.2019.01.005] [PMID: 30825951]
[27]
Aslan A, Aslan C, Zolbanin NM, Jafari R. Acute respiratory distress syndrome in COVID-19: Possible mechanisms and therapeutic management. Pneumonia 2021; 13(1): 14.
[http://dx.doi.org/10.1186/s41479-021-00092-9] [PMID: 34872623]
[28]
Batah SS, Fabro AT. Pulmonary pathology of ARDS in COVID-19: A pathological review for clinicians. Respir Med 2021; 176: 106239.
[http://dx.doi.org/10.1016/j.rmed.2020.106239] [PMID: 33246294]
[29]
Farmakis IT, Giannakoulas G. Management of COVID-19 in patients with pulmonary arterial hypertension. Heart Fail Clin 2023; 19(1): 107-14.
[http://dx.doi.org/10.1016/j.hfc.2022.07.003] [PMID: 36435565]
[30]
Puk O, Nowacka A, Smulewicz K, et al. Pulmonary artery targeted therapy in treatment of COVID-19 related ARDS. Literature review. Biomed Pharmacother 2022; 146: 112592.
[http://dx.doi.org/10.1016/j.biopha.2021.112592] [PMID: 35062063]
[31]
COVID-19 Treatment Guidelines: NIH. 2024. Available from: https://www.covid19treatmentguidelines.nih.gov
[32]
Milan A, Magnino C, Veglio F. Echocardiographic indexes for the non-invasive evaluation of pulmonary hemodynamics. J Am Soc Echocardiogr 2010; 23(3): 225-39.
[http://dx.doi.org/10.1016/j.echo.2010.01.003] [PMID: 20206827]
[33]
Libby P, Bonow RO, Mann DL, et al. Braunwald's heart disease: A textbook of cardiovascular medicine. Heart disease. (12th ed.). Philadelphia, PA: Elsevier 2021; p. 206.
[34]
Marjani M, Tabarsi P, Moniri A, et al. NRITLD protocol for the management of patients with COVID-19 admitted to hospitals. Tanaffos 2020; 19(2): 91-9.
[PMID: 33262795]
[35]
Domenighetti G, Suter PM, Schaller MD, Ritz R, Perret C. Treatment with N-acetylcysteine during acute respiratory distress syndrome: A randomized, double-blind, placebo-controlled clinical study. J Crit Care 1997; 12(4): 177-82.
[http://dx.doi.org/10.1016/S0883-9441(97)90029-0] [PMID: 9459113]
[36]
Suter PM, Domenighetti G, Schaller MD, Laverrière MC, Ritz R, Perret C. N-acetylcysteine enhances recovery from acute lung injury in man. A randomized, double-blind, placebo-controlled clinical study. Chest 1994; 105(1): 190-4.
[http://dx.doi.org/10.1378/chest.105.1.190] [PMID: 8275731]
[37]
Beigel JH, Tomashek KM, Dodd LE, et al. Remdesivir for the treatment of Covid-19. N Engl J Med 2020; 383(19): 1813-26.
[http://dx.doi.org/10.1056/NEJMoa2007764] [PMID: 32445440]
[38]
Al-Tawfiq JA, Al-Homoud AH, Memish ZA. Remdesivir as a possible therapeutic option for the COVID-19. Travel Med Infect Dis 2020; 34: 101615.
[http://dx.doi.org/10.1016/j.tmaid.2020.101615] [PMID: 32145386]
[39]
Lamb YN. Remdesivir: First approval. Drugs 2020; 80(13): 1355-63.
[http://dx.doi.org/10.1007/s40265-020-01378-w] [PMID: 32870481]
[40]
Grant W, Lahore H, McDonnell S, et al. Evidence that vitamin D supplementation could reduce risk of influenza and COVID-19 infections and deaths. Nutrients 2020; 12(4): 988.
[http://dx.doi.org/10.3390/nu12040988] [PMID: 32252338]
[41]
Yisak H, Ewunetei A, Kefale B, et al. Effects of vitamin D on COVID-19 infection and prognosis: A systematic review. Risk Manag Healthc Policy 2021; 14: 31-8.
[http://dx.doi.org/10.2147/RMHP.S291584] [PMID: 33447107]
[42]
Ayerbe L, Risco C, Ayis S. The association between treatment with heparin and survival in patients with Covid-19. J Thromb Thrombolysis 2020; 50(2): 298-301.
[http://dx.doi.org/10.1007/s11239-020-02162-z] [PMID: 32476080]
[43]
Billett HH, Reyes-Gil M, Szymanski J, et al. Anticoagulation in COVID-19: Effect of enoxaparin, heparin, and apixaban on mortality. Thromb Haemost 2020; 120(12): 1691-9.
[http://dx.doi.org/10.1055/s-0040-1720978] [PMID: 33186991]
[44]
Horby P, Lim WS, Emberson JR, et al. Dexamethasone in hospitalized patients with Covid-19. N Engl J Med 2021; 384(8): 693-704.
[http://dx.doi.org/10.1056/NEJMoa2021436] [PMID: 32678530]
[45]
Ahmed MH, Hassan A. Dexamethasone for the treatment of coronavirus disease (COVID-19): A review. SN Compr Clin Med 2020; 2(12): 2637-46.
[http://dx.doi.org/10.1007/s42399-020-00610-8] [PMID: 33163859]
[46]
Preechagoon Y, Kawboot S, Onsanit S. The use of bosentan in pulmonary arterial hypertension. Proceedings of the 4th International Conference Current Breakthrough in Pharmacy (ICB-Pharma 2022), . Atlantis Press, 14 December 2022, pp. 55–62.
[47]
Shahbazi S, Vahdat Shariatpanahi Z, Shahbazi E. Bosentan for high-risk outpatients with COVID-19 infection: A randomized, double blind, placebo-controlled trial. EClinicalMedicine 2023; 62: 102117.
[http://dx.doi.org/10.1016/j.eclinm.2023.102117] [PMID: 37554128]
[48]
Berger M, Hecht SR, van Tosh A, Lingam U. Pulsed and continuous wave doppler echocardiographic assessment of valvular regurgitation in normal subjects. J Am Coll Cardiol 1989; 13(7): 1540-5.
[http://dx.doi.org/10.1016/0735-1097(89)90345-8] [PMID: 2786017]
[49]
Chow S-C, Shao J, Wang H, Lokhnygina Y. Sample size calculations in clinical research. (2nd ed.). Chapman and hall/CRC 2017; pp. 1-451.
[50]
Schulz KF, Altman DG, Moher D. CONSORT 2010 statement: Updated guidelines for reporting parallel group randomised trials. J Pharmacol Pharmacother 2010; 1(2): 100-7.
[http://dx.doi.org/10.4103/0976-500X.72352] [PMID: 21350618]
[51]
Kuang HY, Wu YH, Yi QJ, et al. The efficiency of endothelin receptor antagonist bosentan for pulmonary arterial hypertension associated with congenital heart disease. Medicine 2018; 97(10): e0075.
[http://dx.doi.org/10.1097/MD.0000000000010075] [PMID: 29517668]
[52]
Motte S, McEntee K, Naeije R. Endothelin receptor antagonists. Pharmacol Ther 2006; 110(3): 386-414.
[http://dx.doi.org/10.1016/j.pharmthera.2005.08.012] [PMID: 16219361]
[53]
Karavolias GK, Georgiadou P, Gkouziouta A, et al. Short and long term anti-inflammatory effects of bosentan therapy in patients with pulmonary arterial hypertension: Relation to clinical and hemodynamic responses. Expert Opin Ther Targets 2010; 14(12): 1283-9.
[http://dx.doi.org/10.1517/14728222.2010.523421] [PMID: 20958219]
[54]
Koo HS, Kim KC, Hong YM. Gene expressions of nitric oxide synthase and matrix metalloproteinase-2 in monocrotaline-induced pulmonary hypertension in rats after bosentan treatment. Korean Circ J 2011; 41(2): 83-90.
[http://dx.doi.org/10.4070/kcj.2011.41.2.83] [PMID: 21430993]
[55]
Li HF, Wang JX, Xie ZF, et al. Bosentan and ambrisentan in the treatment of idiopathic pulmonary fibrosis: A meta-analysis. Eur Rev Med Pharmacol Sci 2024; 28(3): 1183-93.
[PMID: 38375723]
[56]
Janda S, Quon BS, Swiston J. HIV and pulmonary arterial hypertension: A systematic review. HIV Med 2010; 11(10): 620-34.
[http://dx.doi.org/10.1111/j.1468-1293.2010.00829.x] [PMID: 20408888]
[57]
Sitbon O. HIV-related pulmonary arterial hypertension: Clinical presentation and management. AIDS 2008; 22 (Suppl. 3): S55-62.
[http://dx.doi.org/10.1097/01.aids.0000327517.62665.ec] [PMID: 18845923]
[58]
Chinello P, Cicalini S, Cortese A, Cicini MP, Petrosillo N. Bosentan and sildenafil in the treatment of HIV-associated pulmonary hypertension. Infect Dis Rep 2011; 3(2): e14.
[http://dx.doi.org/10.4081/idr.2011.e14] [PMID: 24470911]
[59]
Funke C, Farr M, Werner B, et al. Antiviral effect of Bosentan and Valsartan during coxsackievirus B3 infection of human endothelial cells. J Gen Virol 2010; 91(8): 1959-70.
[http://dx.doi.org/10.1099/vir.0.020065-0] [PMID: 20392896]
[60]
Sohn DW, Kim HK, Kim MA, et al. Beneficial and adverse effects of bosentan treatment in korean patients with pulmonary artery hypertension. Korean Circ J 2009; 39(3): 105-10.
[http://dx.doi.org/10.4070/kcj.2009.39.3.105] [PMID: 19949596]
[61]
Chen X, Zhai Z, Huang K, Xie W, Wan J, Wang C. Bosentan therapy for pulmonary arterial hypertension and chronic thromboembolic pulmonary hypertension: A systemic review and meta-analysis. Clin Respir J 2018; 12(6): 2065-74.
[http://dx.doi.org/10.1111/crj.12774] [PMID: 29393580]
[62]
Kuang H, Li Q, Du H, Chen M, Yin Y. Efficacy and safety of long-term oral bosentan in different types of pulmonary arterial hypertension: A systematic review and meta-analysis. Am J Cardiovasc Drugs 2021; 21(2): 181-91.
[http://dx.doi.org/10.1007/s40256-020-00426-w] [PMID: 32918210]
[63]
Dong S, Guo X, Wang H, Sun C. Liver injury due to endothelin receptor antagonists: A real-world study based on post-marketing drug monitoring data. Ther Adv Respir Dis 2024; 18: 17534666231223606.
[http://dx.doi.org/10.1177/17534666231223606] [PMID: 38179676]
[64]
Li L-X, Wei B, Yang M, Li M, Jia J-J. Efficacy and safety of bosentan in the treatment of persistent pulmonary hypertension of the newborn: A metaanalysis. Chin J Contemp Pediatr 2022; 24(3): 319-25.
[65]
Betelli M, Breda S, Ramoni V, et al. Pregnancy in systemic sclerosis. J Scleroderma Relat Disord 2018; 3(1): 21-9.
[http://dx.doi.org/10.1177/2397198317747440] [PMID: 35382124]

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