Abstract
The possible effects of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin II receptor blockers (ARBs) on COVID-19 disease severity have generated considerable debate. We performed a single-center, retrospective analysis of hospitalized adult COVID-19 patients in Wuhan, China, who had definite clinical outcome (dead or discharged) by February 15, 2020. Patients on anti-hypertensive treatment with or without ACEI/ARB were compared on their clinical characteristics and outcomes. The medical records from 702 patients were screened. Among the 101 patients with a history of hypertension and taking at least one anti-hypertensive medication, 40 patients were receiving ACEI/ARB as part of their regimen, and 61 patients were on antihypertensive medication other than ACEI/ARB. We observed no statistically significant differences in percentages of in-hospital mortality (28% vs. 34%, P = 0.46), ICU admission (20% vs. 28%, P = 0.37) or invasive mechanical ventilation (18% vs. 26%, P = 0.31) between patients with or without ACEI/ARB treatment. Further multivariable adjustment of age and gender did not provide evidence for a significant association between ACEI/ARB treatment and severe COVID-19 outcomes. Our findings confirm the lack of an association between chronic receipt of renin-angiotensin system antagonists and severe outcomes of COVID-19. Patients should continue previous anti-hypertensive therapy until further evidence is available.
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World Health Organization. Coronavirus disease (COVID-19) outbreak situation. 2020. https://www.who.int/emergencies/diseases/novel-coronavirus-2019 (accessed May 24, 2020)
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
Wang D, Hu B, Hu C, Zhu F, Liu X, Zhang J, Wang B, Xiang H, Cheng Z, Xiong Y, Zhao Y, Li Y, Wang X, Peng Z. Clinical characteristics of 138 hospitalized patients with 2019 novel coronavirus-infected pneumonia in Wuhan, China. JAMA 2020; 323(11): 1061
Guan WJ, Liang WH, Zhao Y, Liang HR, Chen ZS, Li YM, Liu XQ, Chen RC, Tang CL, Wang T, Ou CQ, Li L, Chen PY, Sang L, Wang W, Li JF, Li CC, Ou LM, Cheng B, Xiong S, Ni ZY, Xiang J, Hu Y, Liu L, Shan H, Lei CL, 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, Cheng LL, Ye F, Li SY, Zheng JP, Zhang NF, Zhong NS, He JX; China Medical Treatment Expert Group for COVID-19. Comorbidity and its impact on 1590 patients with COVID-19 in China: a nationwide analysis. Eur Respir J 2020; 55(5): 2000547
Chen T, Wu D, Chen H, Yan W, Yang D, Chen G, Ma K, Xu D, Yu H, Wang H, Wang T, Guo W, Chen J, Ding C, Zhang X, Huang J, Han M, Li S, Luo X, Zhao J, Ning Q. Clinical characteristics of 113 deceased patients with coronavirus disease 2019: retrospective study. BMJ 2020; 368: m1091
Zhou F, Yu T, Du R, Fan G, Liu Y, Liu Z, Xiang J, Wang Y, Song B, Gu X, Guan L, Wei Y, Li H, Wu X, Xu J, Tu S, Zhang Y, Chen H, Cao B. Clinical course and risk factors for mortality of adult inpatients with COVID-19 in Wuhan, China: a retrospective cohort study. Lancet 2020; 395(10229): 1054–1062
Lu J, Lu Y, Wang X, Li X, Linderman GC, Wu C, Cheng X, Mu L, Zhang H, Liu J, Su M, Zhao H, Spatz ES, Spertus JA, Masoudi FA, Krumholz HM, Jiang L. Prevalence, awareness, treatment, and control of hypertension in China: data from 1.7 million adults in a population-based screening study (China PEACE Million Persons Project). Lancet 2017; 390(10112): 2549–2558
Fang L, Karakiulakis G, Roth M. Are patients with hypertension and diabetes mellitus at increased risk for COVID-19 infection? Lancet Respir Med 2020; 8(4): e21
Liao Y, Cheng X, Zeng Q, Chen Z, Wang Z, Yuan J, Wang X, Zhou Z, Wei Y, Cao G. Expert recommendations for management and treatment of cardiovascular diseases under the epidemic situation of novel coronavirus pneumonia in Hubei Province. J Clin Cardiol (Lin Chuang Xin Xue Guan Bing Za Zhi) 2020; 36(3): 201–203 (in Chinese)
Caldeira D, Alarcao J, Vaz-Carneiro A, Costa J. Risk of pneumonia associated with use of angiotensin converting enzyme inhibitors and angiotensin receptor blockers: systematic review and meta-analysis. BMJ, 2012; 345: e4260
Mortensen EM, Nakashima B, Cornell J, Copeland LA, Pugh MJ, Anzueto A, Good C, Restrepo MI, Downs JR, Frei CR, Fine MJ. Population-based study of statins, angiotensin II receptor blockers, and angiotensin-converting enzyme inhibitors on pneumonia-related outcomes. Clin Infect Dis 2012; 55(11): 1466–1473
Kuba K, Imai Y, Rao S, Gao H, Guo F, Guan B, Huan Y, Yang P, Zhang Y, Deng W, Bao L, Zhang B, Liu G, Wang Z, Chappell M, Liu Y, Zheng D, Leibbrandt A, Wada T, Slutsky AS, Liu D, Qin C, Jiang C, Penninger JM. A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury. Nat Med 2005; 11(8): 875–879
Yan Y, Liu Q, Li N, Du J, Li X, Li C, Jin N, Jiang C. Angiotensin II receptor blocker as a novel therapy in acute lung injury induced by avian influenza A H5N1 virus infection in mouse. Sci China Life Sci 2015; 58(2): 208–211
Donoghue M, Hsieh F, Baronas E, Godbout K, Gosselin M, Stagliano N, Donovan M, Woolf B, Robison K, Jeyaseelan R, Breitbart RE, Acton S. A novel angiotensin-converting enzyme-related carboxypeptidase (ACE2) converts angiotensin I to angiotensin 1–9. Circ Res 2000; 87(5): E1–E9
Tipnis SR, Hooper NM, Hyde R, Karran E, Christie G, Turner AJ. A human homolog of angiotensin-converting enzyme. Cloning and functional expression as a captopril-insensitive carboxypeptidase. J Biol Chem 2000; 275(43): 33238–33243
Santos RA, Simoes e Silva AC, Maric C, Silva DM, Machado RP, de Buhr I, Heringer-Walther S, Pinheiro SV, Lopes MT, Bader M, Mendes EP, Lemos VS, Campagnole-Santos MJ, Schultheiss HP, Speth R, Walther T. Angiotensin-(1–7) is an endogenous ligand for the G protein-coupled receptor Mas. Proc Natl Acad Sci USA 2003; 100(14): 8258–8263
Wösten-van Asperen RM, Lutter R, Specht PA, Moll GN, van Woensel JB, van der Loos CM, van Goor H, Kamilic J, Florquin S, Bos AP. Acute respiratory distress syndrome leads to reduced ratio of ACE/ACE2 activities and is prevented by angiotensin-(1–7) or an angiotensin II receptor antagonist. J Pathol 2011; 225(4): 618–627
Li W, Moore MJ, Vasilieva N, Sui J, Wong SK, Berne MA, Somasundaran M, Sullivan JL, Luzuriaga K, Greenough TC, Choe H, Farzan M. Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus. Nature 2003; 426(6965): 450–454
Letko M, Marzi A, Munster V. Functional assessment of cell entry and receptor usage for SARS-CoV-2 and other lineage B betacoronaviruses. Nat Microbiol 2020; 5(4): 562–569
Zhou P, Yang XL, Wang XG, Hu B, Zhang L, Zhang W, Si HR, Zhu Y, Li B, Huang CL, Chen HD, Chen J, Luo Y, Guo H, Jiang RD, Liu MQ, Chen Y, Shen XR, Wang X, Zheng XS, Zhao K, Chen QJ, Deng F, Liu LL, Yan B, Zhan FX, Wang YY, Xiao GF, Shi ZL. A pneumonia outbreak associated with a new coronavirus of probable bat origin. Nature 2020; 579(7798): 270–273
Yan R, Zhang Y, Li Y, Xia L, Guo Y, Zhou Q. Structural basis for the recognition of SARS-CoV-2 by full-length human ACE2. Science 2020; 367(6485): 1444–1448
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; 203(2): 631–637
Zhao Y, Zhao Z, Wang Y, Zhou Y, Ma Y, Zuo W. Single-cell RNA expression profiling of ACE2, the receptor of SARS-CoV-2. bioRxiv 2020; doi: https://doi.org/10.1101/2020.01.26.919985
Gallagher PE, Ferrario CM, Tallant EA. Regulation of ACE2 in cardiac myocytes and fibroblasts. Am J Physiol Heart Circ Physiol 2008; 295(6): H2373–H2379
Burrell LM, Risvanis J, Kubota E, Dean RG, MacDonald PS, Lu S, Tikellis C, Grant SL, Lew RA, Smith AI, Cooper ME, Johnston CI. Myocardial infarction increases ACE2 expression in rat and humans. Eur Heart J 2005; 26(4): 369–375, discussion 322–364
Danser AHJ, Epstein M, Batlle D. Renin-angiotensin system blockers and the COVID-19 pandemic: at present there is no evidence to abandon renin-angiotensin system blockers. Hypertension 2020; 75(6): 1382–1385
Huang Z, Cao J, Yao Y, Jin X, Luo Z, Xue Y, Zhu C, Song Y, Wang Y, Zou Y, Qian J, Yu K, Gong H, Ge J. The effect of RAS blockers on the clinical characteristics of COVID-19 patients with hypertension. Ann Transl Med 2020; 8(7): 430
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, Rohit L, 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; [Epub ahead of print] doi: https://doi.org/10.1161/CIRCRESAHA.120.317134
Mehta N, Kalra A, Nowacki AS, Anjewierden S, Han Z, Bhat P, Carmona-Rubio AE, Jacob M, Procop G W, 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; [Epub ahead of print] doi: https://doi.org/10.1001/jamacardio.2020.1855
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; [Epub ahead of print] doi: https://doi.org/10.1056/NEJMoa2008975
de Abajo FJ, Rodríguez-Martín S, Lerma V, Mejía-Abril G, Aguilar M, García-Luque A, Laredo L, Laosa O, Centeno-Soto GA, Ángeles Gálvez M, Puerro M, González-Rojano E, Pedraza L, de Pablo I, Abad-Santos F, Rodríguez-Mañas L, Gil M, Tobías A, Rodríguez-Miguel A, Rodríguez-Puyol D, Barreira-Hernandez D, Zubiaur P, Santos-Molina E, Pintos-Sánchez E, Navares-Gómez M, Aparicio RM, García-Rosado V, Gutiérrez-Ortega C, Pérez C, Ascaso A, Elvira C. Use of renin-angiotensin-aldosterone system inhibitors and risk of COVID-19 requiring admission to hospital: a case-population study. Lancet 2020; 395(10238): 1705–1714
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; [Epub ahead of print] doi: https://doi.org/10.1056/NEJMoa2006923
Singer M, Deutschman CS, Seymour CW, Shankar-Hari M, Annane D, Bauer M, Bellomo R, Bernard GR, Chiche JD, Coopersmith CM, Hotchkiss RS, Levy MM, Marshall JC, Martin GS, Opal SM, Rubenfeld GD, van der Poll T, Vincent JL, Angus DC. The third international consensus definitions for sepsis and septic shock (sepsis-3). JAMA 2016; 315(8): 801–810
Force ADT, 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
KDIGO. Clinical Practice Guideline for Acute Kidney Injury. 2012. https://kdigo.org/wp-content/uploads/2016/10/KDIGO-2012-AKI-Guideline-English.pdf (accessed May 24, 2020)
Huang C, Wang Y, Li X, Ren L, Zhao J, Hu Y, Zhang L, Fan G, Xu J, Gu X, Cheng Z, Yu T, Xia J, Wei Y, Wu W, Xie X, Yin W, Li H, Liu M, Xiao Y, Gao H, Guo L, Xie J, Wang G, Jiang R, Gao Z, Jin Q, Wang J, Cao B. Clinical features of patients infected with 2019 novel coronavirus in Wuhan, China. Lancet 2020; 395(10223): 497–506
Abe M, Oikawa O, Okada K, Soma M. Urinary angiotensin-converting enzyme 2 increases in diabetic nephropathy by angiotensin II type 1 receptor blocker olmesartan. J Renin Angiotensin Aldosterone Syst 2015; 16(1): 159–164
Furuhashi M, Moniwa N, Mita T, Fuseya T, Ishimura S, Ohno K, Shibata S, Tanaka M, Watanabe Y, Akasaka H, Ohnishi H, Yoshida H, Takizawa H, Saitoh S, Ura N, Shimamoto K, Miura T. Urinary angiotensin-converting enzyme 2 in hypertensive patients may be increased by olmesartan, an angiotensin II receptor blocker. Am J Hypertens 2015; 28(1): 15–21
Soro-Paavonen A, Gordin D, Forsblom C, Rosengard-Barlund M, Waden J, Thorn L, Sandholm N, Thomas MC, Groop PH; FinnDiane Study Group. Circulating ACE2 activity is increased in patients with type 1 diabetes and vascular complications. J Hypertens 2012; 30(2): 375–383
Liu J, Ji H, Zheng W, Wu X, Zhu JJ, Arnold AP, Sandberg K. Sex differences in renal angiotensin converting enzyme 2 (ACE2) activity are 17β-oestradiol-dependent and sex chromosome-independent. Biol Sex Differ 2010; 1(1): 6
Ferrario CM, Jessup J, Gallagher PE, Averill DB, Brosnihan KB, Ann Tallant E, Smith RD, Chappell MC. Effects of renin-angiotensin system blockade on renal angiotensin-(1–7) forming enzymes and receptors. Kidney Int 2005; 68(5): 2189–2196
Bunyavanich S, Do A, Vicencio A. Nasal gene expression of angiotensin-converting enzyme 2 in children and adults. JAMA 2020; [Epub ahead of print] doi: https://doi.org/10.1001/jama.2020.8707
Schouten LR, van Kaam AH, Kohse F, Veltkamp F, Bos LD, de Beer FM, van Hooijdonk RT, Horn J, Straat M, Witteveen E, Glas GJ, Wieske L, van Vught LA, Wiewel MA, Ingelse SA, Cortjens B, van Woensel JB, Bos AP, Walther T, Schultz MJ, Wosten-van Asperen RM; MARS consortium. Age-dependent differences in pulmonary host responses in ARDS: a prospective observational cohort study. Ann Intensive Care 2019; 9(1): 55
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
Gheblawi M, Wang K, Viveiros A, Nguyen Q, Zhong JC, Turner AJ, Raizada MK, Grant MB, Oudit GY. Angiotensin-converting enzyme 2: SARS-CoV-2 receptor and regulator of the renin-angiotensin system: celebrating the 20th anniversary of the discovery of ACE2. Circ Res 2020; 126(10): 1456–1474
Gu A, Farzadeh SN, Chang YJ, Kwong A, Lam S. Patterns of antihypertensive drug utilization among US Adults with diabetes and comorbid hypertension: the national health and nutrition examination survey 1999–2014. Clin Med Insights Cardiol 2019; 13: 1179546819839418
Joint Committee for Guideline Revision. 2018 Chinese Guidelines for Prevention and Treatment of Hypertension—A report of the Revision Committee of Chinese Guidelines for Prevention and Treatment of Hypertension. J Geriatr Cardiol 2019; 16(3): 182–241
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
Peng YD, Meng K, Guan HQ, Leng L, Zhu RR, Wang BY, He MA, Cheng LX, Huang K, Zeng QT. Clinical characteristics and outcomes of 112 cardiovascular disease patients infected by 2019-nCoV. Chin J Cardiol (Zhonghua Xin Xue Guan Bing Za Zhi) 2020; 48(0): E004
Bavishi C, Maddox TM, Messerli FH. Coronavirus disease 2019 (COVID-19) infection and renin angiotensin system blockers. JAMA Cardiol 2020; [Epub ahead of print] doi: https://doi.org/10.1001/jamacardio.2020.1282
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We acknowledge all health-care workers involved in the diagnosis and treatment of patients in Jinyintan Hospital in Wuhan, China. This work was supported by Major Projects of National Science and Technology on New Drug Creation and Development (Nos. 2020ZX09201001 and 2020ZX09201012); Chinese Academy of Medical Sciences (CAMS) Emergency Project of COVID-19 (No. 2020HY320001).
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Dr. Frederick G. Hayden declares he has served as non-compensated consultant to Cidara, GlaxoSmithKline, Gilead Sciences, resTOR-bio, Regeneron, SAB Biotherapeutics on coronavirus interventions, outside the submitted work. All other authors declare no competing interests. The study was performed in accordance with the Helsinki Declaration of 1975, and was approved by the Research Ethics Commission of Jinyintan Hospital (KY-2020-01.01). Informed consent was waived by the Research Ethics Commission.
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Xu, J., Huang, C., Fan, G. et al. Use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers in context of COVID-19 outbreak: a retrospective analysis. Front. Med. 14, 601–612 (2020). https://doi.org/10.1007/s11684-020-0800-y
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DOI: https://doi.org/10.1007/s11684-020-0800-y