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. 2021 Jul 9;16(1):102–110. doi: 10.1007/s11684-021-0850-9

Renin-angiotensin system inhibitor is associated with the reduced risk of all-cause mortality in COVID-19 among patients with/without hypertension

Huai-yu Wang 1,#, Suyuan Peng 1,#, Zhanghui Ye 2, Pengfei Li 2, Qing Li 2, Xuanyu Shi 1, Rui Zeng 3, Ying Yao 4, Fan He 3, Junhua Li 3, Liu Liu 3, Shuwang Ge 3, Xianjun Ke 5, Zhibin Zhou 5, Gang Xu 3, Ming-hui Zhao 7,8, Haibo Wang 6, Luxia Zhang 1,2,7,✉, Erdan Dong 9
PMCID: PMC8267232  PMID: 34241787

Abstract

Consecutively hospitalized patients with confirmed coronavirus disease 2019 (COVID-19) in Wuhan, China were retrospectively enrolled from January 2020 to March 2020 to investigate the association between the use of renin–angiotensin system inhibitor (RAS-I) and the outcome of this disease. Associations between the use of RAS-I (angiotensin-converting enzyme inhibitor (ACEI) or angiotensin receptor blocker (ARB)), ACEI, and ARB and in-hospital mortality were analyzed using multivariate Cox proportional hazards regression models in overall and subgroup of hypertension status. A total of 2771 patients with COVID-19 were included, with moderate and severe cases accounting for 45.0% and 36.5%, respectively. A total of 195 (7.0%) patients died. RAS-I (hazard ratio (HR)= 0.499, 95% confidence interval (CI) 0.325–0.767) and ARB (HR = 0.410, 95% CI 0.240–0.700) use was associated with a reduced risk of all-cause mortality among patients with COVID-19. For patients with hypertension, RAS-I and ARB applications were also associated with a reduced risk of mortality with HR of 0.352 (95% CI 0.162–0.764) and 0.279 (95% CI 0.115–0.677), respectively. RAS-I exhibited protective effects on the survival outcome of COVID-19. ARB use was associated with a reduced risk of all-cause mortality among patients with COVID-19.

Keywords: COVID-19, RAS inhibitor, hypertension, all-cause mortality

Acknowledgements

This study was supported by grants from Special Research Fund of PKU for Prevention and Control of COVID-19 and the Fundamental Research Funds for the Central Universities (Nos. PKU2020P-KYZX003 and BMU2020HKYZX007), the National Natural Science Foundation of China (Nos. 91846101, 81771938, 81301296, 81900665, 81570667, 81470948, and 81670633), Major Research Plan of the National Natural Science Foundation of China (No. 91742204), The International (Regional) Cooperation and Exchange Projects (NSFC-DFG, No. 81761138041), Beijing Nova Programme Interdisciplinary Cooperation Project (No. Z1911-00001119008), the National Key R&D Program of the Ministry of Science and Technology of China (Nos. 2016YFC1305405, 2019-YFC2005000, 2018YFC1314003-1, and 2015BAI12B07), National Key Research and Development Program (No. 2016YFC0906103), the University of Michigan Health System-Peking University Health Science Center Joint Institute for Translational and Clinical Research (Nos. BMU20160466, BMU2018JI012, and BMU2019JI005), Beijing Advanced Discipline Construction Project (No. BMU-2019GJJXK001), PKU-Baidu Fund (No. 2019BD017) and from Peking University (Nos. BMU2018MX020 and PKU2017LCX05).

Footnotes

Compliance with ethics guidelines

Huai-yu Wang, Suyuan Peng, Zhanghui Ye, Pengfei Li, Qing Li, Xuanyu Shi, Rui Zeng, Ying Yao, Fan He, Junhua Li, Liu Liu, Shuwang Ge, Xianjun Ke, Zhibin Zhou, Gang Xu, Ming-hui Zhao, Haibo Wang, Luxia Zhang, and Erdan Dong declare no conflict of interests. This study was conducted with the authorization of National Health Commission of the People Republic of China and was approved by the Ethics Committee of Peking University Health Science Center (IRB00001052-20032).

Huai-yu Wang and Suyuan Peng equally contributed to this study.

References

  • 1.Patel AB, Verma A. COVID-19 and angiotensin-converting enzyme inhibitors and angiotensin receptor blockers: what is the evidence? JAMA. 2020;323(18):1769–1770. doi: 10.1001/jama.2020.4812. [DOI] [PubMed] [Google Scholar]
  • 2.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;382(18):1708–1720. doi: 10.1056/NEJMoa2002032. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 3.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;46(4):586–590. doi: 10.1007/s00134-020-05985-9. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 4.Zhou G, Chen S, Chen Z. Advances in COVID-19: the virus, the pathogenesis, and evidence-based control and therapeutic strategies. Front Med. 2020;14(2):117–125. doi: 10.1007/s11684-020-0773-x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 5.Simöes E, Silva AC, Teixeira MM. ACE inhibition, ACE2 and angiotensin-(1-7) axis in kidney and cardiac inflammation and fibrosis. Pharmacol Res. 2016;107:154–162. doi: 10.1016/j.phrs.2016.03.018. [DOI] [PubMed] [Google Scholar]
  • 6.South AM, Diz DI, Chappell MC. COVID-19, ACE2, and the cardiovascular consequences. Am J Physiol Heart Circ Physiol. 2020;318(5):H1084–H1090. doi: 10.1152/ajpheart.00217.2020. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 7.Imai Y, Kuba K, Rao S, Huan Y, Guo F, Guan B, Yang P, Sarao R, Wada T, Leong-Poi H, Crackower MA, Fukamizu A, Hui CC, Hein L, Uhlig S, Slutsky AS, Jiang C, Penninger JM. Angiotensin-converting enzyme 2 protects from severe acute lung failure. Nature. 2005;436(7047):112–116. doi: 10.1038/nature03712. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 8.South AM, Tomlinson L, Edmonston D, Hiremath S, Sparks MA. Controversies of renin-angiotensin system inhibition during the COVID-19 pandemic. Nat Rev Nephrol. 2020;16(6):305–307. doi: 10.1038/s41581-020-0279-4. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 9.Li J, Wang X, Chen J, Zhang H, Deng A. Association of renin-angiotensin system inhibitors with severity or risk of death in patients with hypertension hospitalized for coronavirus disease 2019 (COVID-19) infection in Wuhan, China. JAMA Cardiol. 2020;5(7):825–830. doi: 10.1001/jamacardio.2020.1624. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 10.Meng J, Xiao G, Zhang J, He X, Ou M, Bi J, Yang R, Di W, Wang Z, Li Z, Gao H, Liu L, Zhang G. Renin-angiotensin system inhibitors improve the clinical outcomes of COVID-19 patients with hypertension. Emerg Microbes Infect. 2020;9(1):757–760. doi: 10.1080/22221751.2020.1746200. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 11.Reynolds HR, Adhikari S, Pulgarin C, Troxel AB, Iturrate E, Johnson SB, Hausvater A, Newman JD, Berger JS, Bangalore S, Katz SD, Fishman GI, Kunichoff D, Chen Y, Ogedegbe G, Hochman JS. Renin-angiotensin-aldosterone system inhibitors and risk of Covid-19. N Engl J Med. 2020;382(25):2441–2448. doi: 10.1056/NEJMoa2008975. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 12.Mancia G, Rea F, Ludergnani M, Apolone G, Corrao G. Renin-angiotensin-aldosterone system blockers and the risk of Covid-19. N Engl J Med. 2020;382(25):2431–2440. doi: 10.1056/NEJMoa2006923. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 13.Mehta N, Kalra A, Nowacki AS, Anjewierden S, Han Z, Bhat P, Carmona-Rubio AE, Jacob M, Procop GW, Harrington S, Milinovich A, Svensson LG, Jehi L, Young JB, Chung MK. Association of use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers with testing positive for coronavirus disease 2019 (COVID-19) JAMA Cardiol. 2020;5(9):1020–1026. doi: 10.1001/jamacardio.2020.1855. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 14.Xu J, Huang C, Fan G, Liu Z, Shang L, Zhou F, Wang Y, Yu J, Yang L, Xie K, Huang Z, Huang L, Gu X, Li H, Zhang Y, Wang Y, Hayden FG, Horby PW, Cao B, Wang C. Use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in context of COVID-19 outbreak: a retrospective analysis. Front Med. 2020;14(5):601–612. doi: 10.1007/s11684-020-0800-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 15.The National Health Commission of China. Diagnosis and Treatment Protocol for COVID-19 (Trial Version 7). 2020. http://en.nhc.gov.cn/2020-03/29/c_78469.htm (accessed March 29, 2020)
  • 16.ARDS Definition Task Force. Ranieri VM, Rubenfeld GD, Thompson BT, Ferguson ND, Caldwell E, Fan E, Camporota L, Slutsky AS. Acute respiratory distress syndrome: the Berlin Definition. JAMA. 2012;307(23):2526–2533. doi: 10.1001/jama.2012.5669. [DOI] [PubMed] [Google Scholar]
  • 17.Ponikowski P, Voors AA, Anker SD, Bueno H, Cleland JG, Coats AJ, Falk V, González-Juanatey JR, Harjola VP, Jankowska EA, Jessup M, Linde C, Nihoyannopoulos P, Parissis JT, Pieske B, Riley JP, Rosano GM, Ruilope LM, Ruschitzka F, Rutten FH, van der Meer P, Authors/Task Force Members; Document Reviewers 2016 ESC Guidelines for the diagnosis and treatment of acute and chronic heart failure: The Task Force for the diagnosis and treatment of acute and chronic heart failure of the European Society of Cardiology (ESC). Developed with the special contribution of the Heart Failure Association (HFA) of the ESC. Eur J Heart Fail. 2016;18(8):891–975. doi: 10.1002/ejhf.592. [DOI] [PubMed] [Google Scholar]
  • 18.Reichlin T, Twerenbold R, Reiter M, Steuer S, Bassetti S, Balmelli C, Winkler K, Kurz S, Stelzig C, Freese M, Drexler B, Haaf P, Zellweger C, Osswald S, Mueller C. Introduction of high-sensitivity troponin assays: impact on myocardial infarction incidence and prognosis. Am J Med. 2012;125(12):1205–1213.e1. doi: 10.1016/j.amjmed.2012.07.015. [DOI] [PubMed] [Google Scholar]
  • 19.Kidney Disease: Improving Global Outcomes (KDIGO) CKD Work Group. Kidney Disease: Improving Global Outcomes—CKD Evaluation and Management 2012. https://kdigo.org/guidelines/ckd-evaluation-and-management/ (accessed March 29, 2020)
  • 20.Ng’andu NH. An empirical comparison of statistical tests for assessing the proportional hazards assumption of Cox’s model. Stat Med. 1997;16(6):611–626. doi: 10.1002/(SICI)1097-0258(19970330)16:6<611::AID-SIM437>3.0.CO;2-T. [DOI] [PubMed] [Google Scholar]
  • 21.Chen Y, Yang D, Yang C, Zheng L, Huang K. Response to Comment on Chen et al. Clinical characteristics and outcomes of patients with diabetes and COVID-19 in association with glucose-lowering medication. Diabetes Care. 2020;43:1399–1407. doi: 10.2337/dc20-0660. [DOI] [PubMed] [Google Scholar]
  • 22.Zhang P, Zhu L, Cai J, Lei F, Qin JJ, Xie J, Liu YM, Zhao YC, Huang X, Lin L, Xia M, Chen MM, Cheng X, Zhang X, Guo D, Peng Y, Ji YX, Chen J, She ZG, Wang Y, Xu Q, Tan R, Wang H, Lin J, Luo P, Fu S, Cai H, Ye P, Xiao B, Mao W, Liu L, Yan Y, Liu M, Chen M, Zhang XJ, Wang X, Touyz RM, Xia J, Zhang BH, Huang X, Yuan Y, Loomba R, Liu PP, Li H. Association of inpatient use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers with mortality among patients with hypertension hospitalized with COVID-19. Circ Res. 2020;126(12):1671–1681. doi: 10.1161/CIRCRESAHA.120.317134. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 23.Culver S, Li C, Siragy HM. Intrarenal angiotensin-converting enzyme: the old and the new. Curr Hypertens Rep. 2017;19(10):80. doi: 10.1007/s11906-017-0778-2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 24.Kreutz R, Algharably EAE, Azizi M, Dobrowolski P, Guzik T, Januszewicz A, Persu A, Prejbisz A, Riemer TG, Wang JG, Burnier M. Hypertension, the renin-angiotensin system, and the risk of lower respiratory tract infections and lung injury: implications for COVID-19. Cardiovasc Res. 2020;116(10):1688–1699. doi: 10.1093/cvr/cvaa097. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 25.Anguiano L, Riera M, Pascual J, Soler MJ. Circulating ACE2 in cardiovascular and kidney diseases. Curr Med Chem. 2017;24(30):3231–3241. doi: 10.2174/0929867324666170414162841. [DOI] [PubMed] [Google Scholar]
  • 26.Eberhardt RT, Kevak RM, Kang PM, Frishman WH. Angiotensin II receptor blockade: an innovative approach to cardiovascular pharmacotherapy. J Clin Pharmacol. 1993;33(11):1023–1038. doi: 10.1002/j.1552-4604.1993.tb01939.x. [DOI] [PubMed] [Google Scholar]
  • 27.Aghaaliakbari F, Abbasi MA, Ranjbar M, Jamshidi Makiani M, Farrokhpour M, Safarnezhad Tameshkel F, Karbalaie Niya MH, Doltkhah S, Yaghoobzadeh K, Savaj S. Angiotensin converting enzyme inhibitors, a risk factor of poor outcome in diabetic patients with COVID-19 infection. Iran J Kidney Dis. 2020;14(6):482–487. [PubMed] [Google Scholar]
  • 28.Gutiérrez F, Masiá M, Mirete C, Soldán B, Rodríguez JC, Padilla S, Hernández I, Royo G, Martin-Hidalgo A. The influence of age and gender on the population-based incidence of community-acquired pneumonia caused by different microbial pathogens. J Infect. 2006;53(3):166–174. doi: 10.1016/j.jinf.2005.11.006. [DOI] [PubMed] [Google Scholar]
  • 29.Woodhead M, Blasi F, Ewig S, Garau J, Huchon G, Ieven M, Ortqvist A, Schaberg T, Torres A, van der Heijden G, Read R, Verheij TJ, Joint Taskforce of the European Respiratory SocietyEuropean Society for Clinical MicrobiologyInfectious Diseases Guidelines for the management of adult lower respiratory tract infections—full version. Clin Microbiol Infect. 2011;17(Suppl 6):E1–E59. doi: 10.1111/j.1469-0691.2011.03672.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 30.Chou CH, Hung CS, Liao CW, Wei LH, Chen CW, Shun CT, Wen WF, Wan CH, Wu XM, Chang YY, Wu VC, Wu KD, Lin YH, TAIPAI Study Group IL-6 trans-signalling contributes to aldoster-one-induced cardiac fibrosis. Cardiovasc Res. 2018;114(5):690–702. doi: 10.1093/cvr/cvy013. [DOI] [PubMed] [Google Scholar]
  • 31.Siedlinski M, Jozefczuk E, Xu X, Teumer A, Evangelou E, Schnabel RB, Welsh P, Maffia P, Erdmann J, Tomaszewski M, Caulfield MJ, Sattar N, Holmes MV, Guzik TJ. White blood cells and blood pressure: a Mendelian randomization study. Circulation. 2020;141(16):1307–1317. doi: 10.1161/CIRCULATIONAHA.119.045102. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • 32.Imai Y, Kuba K, Penninger JM. The discovery of angiotensin-converting enzyme 2 and its role in acute lung injury in mice. Exp Physiol. 2008;93(5):543–548. doi: 10.1113/expphysiol.2007.040048. [DOI] [PMC free article] [PubMed] [Google Scholar]

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