Managing Endothelial Dysfunction in COVID-19 : A Randomized Controlled Trial at LAUMC

Summary

COVID-19 infection was shown to cause endothelial dysfunction . At the level of the endothelium the pathophysiological mechanisms have been hypothesized and were divided into pro-coagulant, pro-inflammatory, anti-fibrinolytics, impaired barrier function, vasoconstrictor and pro-oxidant. So far, the pro-coagulant and pro-inflammatory pathways have been studied and as a result dexamethasone and anticoagulation became part of the standard therapies for the disease. However, so far, no RCT has been evaluated on targeting the vasoconstrictive and antioxidant pathways with an aim of revealing clinical benefit. So, with this trial we intend to provide a regiment composed of several medications we hypothesize will act on several downstream pathways that would improve endothelial function primarily via the increase in NO production and release. At the time of this proposal there has been no randomized trials evaluating or testing the use of cardiovascular drugs targeting endothelial dysfunction in COVID-19 patients. As previously noted there has been a call to study these drugs and their effect after a strong research regarding their theorized effectiveness. For evidence, there was a recently published meta-analysis evaluating the role of statins in COVID-19 with preliminary findings suggested a reduction in fatal or severe disease by 30% and discredited the suggestion of harm, that emphasized on the need of well-designed randomized controlled trial to confirm the role of statins in COVID-19 patients. Our study would help determine the potential therapeutic effect of the endothelial protocol as adjunct to mainstream management. This study seeks to further our knowledge in treating COVID-19 to ultimately improve clinical outcomes and reduce complications.

Timeline

Start

2021-01-10

Primary completion

2022-03-29

Completion

2022-07-01

Publications

• Background Wu YC, Chen CS, Chan YJ. The outbreak of COVID-19: An overview. J Chin Med Assoc. 2020 Mar;83(3):217-220. doi: 10.1097/JCMA.0000000000000270.
• Background Yuki K, Fujiogi M, Koutsogiannaki S. COVID-19 pathophysiology: A review. Clin Immunol. 2020 Jun;215:108427. doi: 10.1016/j.clim.2020.108427. Epub 2020 Apr 20.
• Background Mason RJ. Pathogenesis of COVID-19 from a cell biology perspective. Eur Respir J. 2020 Apr 16;55(4):2000607. doi: 10.1183/13993003.00607-2020. Print 2020 Apr.
• Background Wu Z, McGoogan JM. Characteristics of and Important Lessons From the Coronavirus Disease 2019 (COVID-19) Outbreak in China: Summary of a Report of 72 314 Cases From the Chinese Center for Disease Control and Prevention. JAMA. 2020 Apr 7;323(13):1239-1242. doi: 10.1001/jama.2020.2648. No abstract available.
• Background Driggin E, Madhavan MV, Bikdeli B, Chuich T, Laracy J, Biondi-Zoccai G, Brown TS, Der Nigoghossian C, Zidar DA, Haythe J, Brodie D, Beckman JA, Kirtane AJ, Stone GW, Krumholz HM, Parikh SA. Cardiovascular Considerations for Patients, Health Care Workers, and Health Systems During the COVID-19 Pandemic. J Am Coll Cardiol. 2020 May 12;75(18):2352-2371. doi: 10.1016/j.jacc.2020.03.031. Epub 2020 Mar 19.
• Background Murthy S, Gomersall CD, Fowler RA. Care for Critically Ill Patients With COVID-19. JAMA. 2020 Apr 21;323(15):1499-1500. doi: 10.1001/jama.2020.3633. No abstract available.
• Background Ruan Q, Yang K, Wang W, Jiang L, Song J. Clinical predictors of mortality due to COVID-19 based on an analysis of data of 150 patients from Wuhan, China. Intensive Care Med. 2020 May;46(5):846-848. doi: 10.1007/s00134-020-05991-x. Epub 2020 Mar 3. No abstract available.
• Background Hu Y, Sun J, Dai Z, Deng H, Li X, Huang Q, Wu Y, Sun L, Xu Y. Prevalence and severity of corona virus disease 2019 (COVID-19): A systematic review and meta-analysis. J Clin Virol. 2020 Jun;127:104371. doi: 10.1016/j.jcv.2020.104371. Epub 2020 Apr 14.
• Background Guan WJ, Ni ZY, Hu Y, Liang WH, Ou CQ, He JX, Liu L, Shan H, Lei CL, Hui DSC, Du B, Li LJ, Zeng G, Yuen KY, Chen RC, Tang CL, Wang T, Chen PY, Xiang J, Li SY, Wang JL, Liang ZJ, Peng YX, Wei L, Liu Y, Hu YH, Peng P, Wang JM, Liu JY, Chen Z, Li G, Zheng ZJ, Qiu SQ, Luo J, Ye CJ, Zhu SY, Zhong NS; China Medical Treatment Expert Group for Covid-19. Clinical Characteristics of Coronavirus Disease 2019 in China. N Engl J Med. 2020 Apr 30;382(18):1708-1720. doi: 10.1056/NEJMoa2002032. Epub 2020 Feb 28.
• Background Guo T, Fan Y, Chen M, Wu X, Zhang L, He T, Wang H, Wan J, Wang X, Lu Z. Cardiovascular Implications of Fatal Outcomes of Patients With Coronavirus Disease 2019 (COVID-19). JAMA Cardiol. 2020 Jul 1;5(7):811-818. doi: 10.1001/jamacardio.2020.1017.
• Background Zhang H, Penninger JM, Li Y, Zhong N, Slutsky AS. Angiotensin-converting enzyme 2 (ACE2) as a SARS-CoV-2 receptor: molecular mechanisms and potential therapeutic target. Intensive Care Med. 2020 Apr;46(4):586-590. doi: 10.1007/s00134-020-05985-9. Epub 2020 Mar 3. No abstract available.
• Background Liu PP, Blet A, Smyth D, Li H. The Science Underlying COVID-19: Implications for the Cardiovascular System. Circulation. 2020 Jul 7;142(1):68-78. doi: 10.1161/CIRCULATIONAHA.120.047549. Epub 2020 Apr 15.
• Background Hamming I, Timens W, Bulthuis ML, Lely AT, Navis G, van Goor H. Tissue distribution of ACE2 protein, the functional receptor for SARS coronavirus. A first step in understanding SARS pathogenesis. J Pathol. 2004 Jun;203(2):631-7. doi: 10.1002/path.1570.
• Background Jung F, Kruger-Genge A, Franke RP, Hufert F, Kupper JH. COVID-19 and the endothelium. Clin Hemorheol Microcirc. 2020;75(1):7-11. doi: 10.3233/CH-209007.
• Background Libby P, Luscher T. COVID-19 is, in the end, an endothelial disease. Eur Heart J. 2020 Sep 1;41(32):3038-3044. doi: 10.1093/eurheartj/ehaa623.
• Background Ashour H, Elsayed MH, Elmorsy S, Harb IA. Hypothesis: The potential therapeutic role of nicorandil in COVID-19. Clin Exp Pharmacol Physiol. 2020 Nov;47(11):1791-1797. doi: 10.1111/1440-1681.13395. Epub 2020 Sep 9.
• Background Kunal S, Gupta K, Gupta S. Statins in COVID-19: A new ray of hope. Heart Lung. 2020 Nov-Dec;49(6):887-889. doi: 10.1016/j.hrtlng.2020.07.012. Epub 2020 Aug 11. No abstract available.
• Background Gornik HL, Creager MA. Arginine and endothelial and vascular health. J Nutr. 2004 Oct;134(10 Suppl):2880S-2887S; discussion 2895S. doi: 10.1093/jn/134.10.2880S.

Drugs

Indications