Association Between Renin-Angiotensin-Aldosterone System Inhibitors and Clinical Outcomes in Patients With COVID-19: A Systematic Review and Meta-analysis | Clinical Pharmacy and Pharmacology | JAMA Network Open | JAMA Network
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Figure 1.  Subgroup Analysis of Unadjusted Mortality Among Patients Who Did and Did Not Receive ACEIs or ARBs
Subgroup Analysis of Unadjusted Mortality Among Patients Who Did and Did Not Receive ACEIs or ARBs

Subgroup analysis of mortality in 41 studies of patients who did and did not receive ACEIs or ARBs. A total of 19 studies included a mixed subgroup (a sample population with multiple mixed comorbidities), and 22 studies included a hypertension subgroup (a sample population with hypertension). Diamonds represent 95% CIs for subtotal and total ORs. ACEI indicates angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; and OR, odds ratio.

Figure 2.  Subgroup Analysis of Adjusted Mortality Among Patients Who Did and Did Not Receive ACEIs or ARBs
Subgroup Analysis of Adjusted Mortality Among Patients Who Did and Did Not Receive ACEIs or ARBs

Subgroup analysis of adjusted mortality in 16 studies of patients who did and did not receive ACEIs or ARBs. A total of 7 studies included a mixed subgroup (a sample population with multiple mixed comorbidities), and 9 studies included a hypertension subgroup (a sample population with hypertension). Diamonds represent 95% CIs for subtotal and total ORs. ACEI indicates angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; and OR, odds ratio.

Figure 3.  Subgroup Analysis of Unadjusted Mortality and Severe Adverse Events Among Patients Who Did and Did Not Receive ACEIs or ARBs
Subgroup Analysis of Unadjusted Mortality and Severe Adverse Events Among Patients Who Did and Did Not Receive ACEIs or ARBs

Subgroup analysis of mortality and severe adverse events in 48 studies of patients who did and did not receive ACEIs or ARBs. A total of 22 studies included a mixed subgroup (a sample population with multiple mixed comorbidities), and 26 studies included a hypertension subgroup (a sample population with hypertension). Diamonds represent 95% CIs for subtotal and total ORs. ACEI indicates angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; and OR, odds ratio.

Figure 4.  Subgroup Analysis of Adjusted Mortality and Severe Adverse Events Among Patients Who Did and Did Not Receive ACEIs or ARBs
Subgroup Analysis of Adjusted Mortality and Severe Adverse Events Among Patients Who Did and Did Not Receive ACEIs or ARBs

Subgroup analysis of adjusted mortality and severe adverse events in 23 studies of patients who did and did not receive ACEIs or ARBs. A total of 11 studies included a mixed subgroup (sample population with multiple mixed comorbidities), and 12 studies included a hypertension subgroup (defined as a sample population with hypertension). Diamonds represent 95% CIs for subtotal and total ORs. ACEI indicates angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; and OR, odds ratio.

Table.  Baseline Characteristics of Included Studies
Baseline Characteristics of Included Studies
1.
World Health Organization. WHO coronavirus disease (COVID-19) dashboard. Updated February 13, 2021. Accessed January 18, 2021. https://covid19.who.int/
2.
Guo  T, Fan  Y, Chen  M,  et al.  Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID-19).   JAMA Cardiol. 2020;5(7):811-818. doi:10.1001/jamacardio.2020.1017 PubMedGoogle ScholarCrossref
3.
Li  B, Yang  J, Zhao  F,  et al.  Prevalence and impact of cardiovascular metabolic diseases on COVID-19 in China.   Clin Res Cardiol. 2020;109(5):531-538. doi:10.1007/s00392-020-01626-9 PubMedGoogle ScholarCrossref
4.
Feng  Y, Ling  Y, Bai  T,  et al. COVID-19 with different severities: a multicenter study of clinical features. Am J Respir Crit Care Med. 2020;201(11):1380-1388 doi:10.1164/rccm.202002-0445OC .
5.
Selcuk  M, Cınar  T, Keskin  M,  et al.  Is the use of ACE inb/ARBs associated with higher in-hospital mortality in Covid-19 pneumonia patients?   Clin Exp Hypertens. 2020;42(8):738-742. doi:10.1080/10641963.2020.1783549 PubMedGoogle ScholarCrossref
6.
Mehta  N, Kalra  A, Nowacki  AS,  et al.  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 PubMedGoogle ScholarCrossref
7.
Bravi  F, Flacco  ME, Carradori  T,  et al. Predictors of severe or lethal COVID-19, including angiotensin converting enzyme inhibitors and angiotensin II receptor blockers, in a sample of infected Italian citizens. PLoS One. 2020;15(6):e0235248. doi:10.1371/journal.pone.0235248
8.
Zhou  X, Zhu  J, Xu  T.  Clinical characteristics of coronavirus disease 2019 (COVID-19) patients with hypertension on renin-angiotensin system inhibitors.   Clin Exp Hypertens. 2020;42(7):656-660. doi:10.1080/10641963.2020.1764018 PubMedGoogle ScholarCrossref
9.
Felice  C, Nardin  C, Di Tanna  GL,  et al.  Use of RAAS inhibitors and risk of clinical deterioration in COVID-19: results from an Italian cohort of 133 hypertensives.   Am J Hypertens. 2020;33(10):944-948. doi:10.1093/ajh/hpaa096PubMedGoogle Scholar
10.
Zhou  F, Liu  YM, Xie  J,  et al. Comparative impacts of ACE (angiotensin-converting enzyme) inhibitors versus angiotensin II receptor blockers on the risk of COVID-19 mortality. Hypertension. 2020;76(2):e15-e17. doi:10.1161/HYPERTENSIONAHA.120.15622
11.
Baral  R, White  M, Vassiliou  VS.  Effect of renin-angiotensin-aldosterone system inhibitors in patients with COVID-19: a systematic review and meta-analysis of 28,872 patients.   Curr Atheroscler Rep. 2020;22(10):61. doi:10.1007/s11883-020-00880-6 PubMedGoogle ScholarCrossref
12.
World Health Organization. COVID-19 and the use of angiotensin-converting enzyme inhibitors and receptor blockers: scientific brief. May 7, 2020. Accessed October 20, 2020. https://www.who.int/news-room/commentaries/detail/covid-19-and-the-use-of-angiotensin-converting-enzyme-inhibitors-and-receptor-blockers
13.
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;323(13):1239-1242. doi:10.1001/jama.2020.2648
14.
Wells GA, Shea B, O’Connell D, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. The Ottawa Hospital Research Institute; 2019. Accessed October 20, 2020. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp
15.
Sterne  JAC, Savovic  J, Page  MJ,  et al.  RoB 2: a revised tool for assessing risk of bias in randomised trials.   BMJ. 2019;366:l4898. doi:10.1136/bmj.l4898 PubMedGoogle ScholarCrossref
16.
Wallace  BC, Dahabreh  IJ, Trikalinos  TA, Lau  J, Trow  P, Schmid  CH.  Closing the gap between methodologists and end-users: R as a computational back-end.   J Stat Softw. 2012;49(5):1-15. doi:10.18637/jss.v049.i05 Google ScholarCrossref
17.
Higgins  JPT, Li  T, Deeks  JJ. Chapter 6: choosing effect measures and computing estimates of effect. In: Higgins JPT, Thomas J, Chandler J, et al, eds. Cochrane Handbook for Systematic Reviews of Interventions. Version 6.1. Cochrane; 2020. Accessed October 20, 2020. https://training.cochrane.org/handbook/current/chapter-06
18.
Amat-Santos  IJ, Santos-Martinez  S, Lopez-Otero  D,  et al.  Ramipril in high-risk patients with COVID-19.   J Am Coll Cardiol. 2020;76(3):268-276. doi:10.1016/j.jacc.2020.05.040 PubMedGoogle ScholarCrossref
19.
Conversano  A, Melillo  F, Napolano  A,  et al. Renin-angiotensin-aldosterone system inhibitors and outcome in patients with SARS-CoV-2 pneumonia: a case series study. Hypertension. 2020;76(2):e10-e12. doi:10.1161/HYPERTENSIONAHA
20.
Bae  DJ, Tehrani  DM, Rabadia  SV,  et al.  Angiotensin converting enzyme inhibitor and angiotensin II receptor blocker use among outpatients diagnosed with COVID-19.   Am J Cardiol. 2020;132:150-157. doi:10.1016/j.amjcard.2020.07.007 PubMedGoogle ScholarCrossref
21.
Bean  DM, Kraljevic  Z, Searle  T,  et al.  Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers are not associated with severe COVID-19 infection in a multi-site UK acute hospital trust.   Eur J Heart Fail. 2020;22(6):967-974. doi:10.1002/ejhf.1924 PubMedGoogle ScholarCrossref
22.
Cannata  F, Chiarito  M, Reimers  B,  et al. Continuation versus discontinuation of ACE inhibitors or angiotensin II receptor blockers in COVID-19: effects on blood pressure control and mortality. Eur Heart J Cardiovasc Pharmacother. 2020:6(6):412-414. doi:10.1093/ehjcvp/pvaa056
23.
Chen  C, Wang  F, Chen  P,  et al.  Mortality and pre-hospitalization use of renin-angiotensin system inhibitors in hypertensive COVID-19 patients.   J Am Heart Assoc. 2020;9(21):e017736. doi:10.1161/JAHA.120.017736 PubMedGoogle Scholar
24.
Chen FF, Zhong M, Liu Y, et al. The characteristics and outcomes of 681 severe cases with COVID-19 in China. J Crit Care. 2020;60:32-37. doi:10.1016/j.jcrc.2020.07.003
25.
Chen  Y, Yang  D, Cheng  B,  et al.  Clinical characteristics and outcomes of patients with diabetes and COVID-19 in association with glucose-lowering medication.   Diabetes Care. 2020;43(7):1399-1407. doi:10.2337/dc20-0660 PubMedGoogle ScholarCrossref
26.
Hippisley-Cox  J, Young  D, Coupland  C,  et al.  Risk of severe COVID-19 disease with ACE inhibitors and angiotensin receptor blockers: cohort study including 8.3 million people.   Heart. 2020;106(19):1503-1511. doi:10.1136/heartjnl-2020-317393 PubMedGoogle ScholarCrossref
27.
Fosbol  EL, Butt  JH, Ostergaard  L,  et al. Association of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use with COVID-19 diagnosis and mortality. JAMA. 2020;324(2):168-177. doi:10.1001/jama.2020.11301
28.
Gao  C, Cai  Y, Zhang  K,  et al.  Association of hypertension and antihypertensive treatment with COVID-19 mortality: a retrospective observational study.   Eur Heart J. 2020;41(22):2058-2066. doi:10.1093/eurheartj/ehaa433 PubMedGoogle ScholarCrossref
29.
Gormez  S, Ekicibasi  E, Degirmencioglu  A,  et al.  Association between renin-angiotensin-aldosterone system inhibitor treatment, neutrophil-lymphocyte ratio, D-dimer and clinical severity of COVID-19 in hospitalized patients: a multicenter, observational study.   J Hum Hypertens. 2020:1-10. doi:10.1038/s41371-020-00405-3 PubMedGoogle Scholar
30.
Grasselli  G, Greco  M, Zanella  A,  et al. Risk factors associated with mortality among patients with COVID-19 in intensive care units in Lombardy, Italy. JAMA Intern Med. 2020;180(10):1345-1355. doi:10.1001/jamainternmed.2020.3539
31.
Guo  X, Zhu  Y, Hong  Y. Decreased mortality of COVID-19 with renin-angiotensin-aldosterone system inhibitors therapy in patients with hypertension: a meta-analysis. Hypertension. 2020;76(2):e13-e14. doi:10.1161/HYPERTENSIONAHA.120.15572
32.
Huang  Z, Cao  J, Yao  Y,  et al.  The effect of RAS blockers on the clinical characteristics of COVID-19 patients with hypertension.   Ann Transl Med. 2020;8(7):430. doi:10.21037/atm.2020.03.229 PubMedGoogle ScholarCrossref
33.
Hwang  JM, Kim  JH, Park  JS, Chang  MC, Park  D.  Neurological diseases as mortality predictive factors for patients with COVID-19: a retrospective cohort study.   Neurol Sci. 2020;41(9):2317-2324. doi:10.1007/s10072-020-04541-z PubMedGoogle ScholarCrossref
34.
Iaccarino  G, Grassi  G, Borghi  C, Ferri  C, Salvetti  M, Volpe  M; SARS-RAS Investigators. Age and multimorbidity predict death among COVID-19 patients: results of the SARS-RAS study of the Italian Society of Hypertension. Hypertension. 2020;76(2):366-372. doi:10.1161/HYPERTENSIONAHA.120.15324
35.
Jung  C, Bruno  RR, Wernly  B,  et al. Inhibitors of the renin–angiotensin–aldosterone system and COVID-19 in critically ill elderly patients. Eur Heart J Cardiovasc Pharmacother. 2021;7(1):76-77. doi:10.1093/ehjcvp/pvaa083
36.
Jung  SY, Choi  JC, You  SH, Kim  WY.  Association of renin-angiotensin-aldosterone system inhibitors with coronavirus disease 2019 (COVID-19)–related outcomes in Korea: a nationwide population-based cohort study.   Clin Infect Dis. 2020;71(16):2121-2128. doi:10.1093/cid/ciaa624 PubMedGoogle ScholarCrossref
37.
Khan  KS, Reed-Embleton  H, Lewis  J, Bain  P, Mahmud  S.  Angiotensin converting enzyme inhibitors do not increase the risk of poor outcomes in COVID-19 disease: a multi-centre observational study.   Scott Med J. 2020;65(4):149-153. doi:10.1177/0036933020951926 PubMedGoogle ScholarCrossref
38.
Lam  KW, Chow  KW, Vo  J,  et al.  Continued in-hospital angiotensin-converting enzyme inhibitor and angiotensin II receptor blocker use in hypertensive COVID-19 patients is associated with positive clinical outcome.   J Infect Dis. 2020;222(8):1256-1264. doi:10.1093/infdis/jiaa447 PubMedGoogle ScholarCrossref
39.
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 PubMedGoogle ScholarCrossref
40.
Liabeuf  S, Moragny  J, Bennis  Y,  et al. Association between renin–angiotensin system inhibitors and COVID-19 complications. Eur Heart J Cardiovasc Pharmacother. Published online June 12, 2020. doi:10.1093/ehjcvp/pvaa062
41.
Liu  X, Liu  Y, Chen  K,  et al. Efficacy of ACEIs/ARBs vs CCBs on the progression of COVID-19 patients with hypertension in Wuhan: a hospital-based retrospective cohort study. J Med Virol. 2021;93(2):854-862. doi:10.1002/jmv.26315
42.
Lopez-Otero  D, Lopez-Pais  J, Cacho-Antonio  CE,  et al. Impact of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on COVID-19 in a Western population. Rev Espanola Cardiol. 2020;74(2):175-182. doi:10.1016/j.rec.2020.05.018
43.
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
44.
Matsuzawa  Y, Ogawa  H, Kimura  K,  et al.  Renin-angiotensin system inhibitors and the severity of coronavirus disease 2019 in Kanagawa, Japan: a retrospective cohort study.   Hypertens Res. 2020;43(11):1257-1266. doi:10.1038/s41440-020-00535-8 PubMedGoogle ScholarCrossref
45.
Meng  J, Xiao  G, Zhang  J,  et al.  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 PubMedGoogle ScholarCrossref
46.
Mostaza  JM, Garcia-Iglesias  F, Gonzalez-Alegre  T,  et al; Carlos III COVID Working Group.  Clinical course and prognostic factors of COVID-19 infection in an elderly hospitalized population.   Arch Gerontol Geriatr. 2020;91:104204. doi:10.1016/j.archger.2020.104204 PubMedGoogle Scholar
47.
Oussalah  A, Gleye  S, Urmes  IC,  et al. Long-term ACE inhibitor/ARB use is associated with severe renal dysfunction and acute kidney injury in patients with severe COVID-19: results from a referral center cohort in the northeast of France. Clin Infect Dis. 2020;71(9):2447-2456. doi:10.1093/cid/ciaa677
48.
Pan  W, Zhang  J, Wang  M,  et al. Clinical features of COVID-19 in patients with essential hypertension and the impacts of renin-angiotensin-aldosterone system inhibitors on the prognosis of COVID-19 patients. Hypertension. 2020;76(3):732-741. doi:10.1161/HYPERTENSIONAHA.120.15289
49.
Reynolds  HR, Adhikari  S, Pulgarin  C,  et al.  Renin–angiotensin–aldosterone system inhibitors and risk of COVID-19.   N Engl J Med. 2020;382(25):2441-2448. doi:10.1056/NEJMoa2008975 PubMedGoogle ScholarCrossref
50.
Richardson  S, Hirsch  JS, Narasimhan  M,  et al; the Northwell COVID-19 Research Consortium.  Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area.   JAMA. 2020;323(20):2052-2059. doi:10.1001/jama.2020.6775 PubMedGoogle ScholarCrossref
51.
Rossi  PG, Marino  M, Formisano  D, Venturelli  F, Vicentini  M, Grilli  R; Reggio Emilia COVID-19 Working Group. Characteristics and outcomes of a cohort of COVID-19 patients in the province of Reggio Emilia, Italy. PLoS One. 2020;15(8):e0238281. doi:10.1371/journal.pone.0238281
52.
Sardu  C, Maggi  P, Messina  V,  et al.  Could anti-hypertensive drug therapy affect the clinical prognosis of hypertensive patients with COVID-19 infection? data from centers of southern Italy.   J Am Heart Assoc. 2020;9(17):e016948. doi:10.1161/JAHA.120.016948 PubMedGoogle Scholar
53.
Senkal  N, Meral  R, Medetalibeyoqlu  A, Konyaoqlu  H, Kose  M, Tukek  T.  Association between chronic ACE inhibitor exposure and decreased odds of severe disease in patients with COVID-19.   Anatol J Cardiol. 2020;24(1):21-29. doi:10.14744/AnatolJCardiol.2020.57431PubMedGoogle Scholar
54.
Shah  P, Owens  J, Franklin  J, Jani  Y, Kumar  A, Doshi  R.  Baseline use of angiotensin-converting enzyme inhibitor/AT1 blocker and outcomes in hospitalized coronavirus disease 2019 African-American patients.   J Hypertens. 2020;38(12):2537-2541. doi:10.1097/HJH.0000000000002584 PubMedGoogle ScholarCrossref
55.
Tan  ND, Qiu  Y, Xing  XB, Ghosh  S, Chen  MH, Mao  R.  Associations between angiotensin-converting enzyme inhibitors and angiotensin II receptor blocker use, gastrointestinal symptoms, and mortality among patients with COVID-19.   Gastroenterology. 2020;159(3):1170-1172. doi:10.1053/j.gastro.2020.05.034 PubMedGoogle ScholarCrossref
56.
Tedeschi  S, Giannella  M, Bartoletti  M,  et al.  Clinical impact of renin-angiotensin system inhibitors on in-hospital mortality of patients with hypertension hospitalized for coronavirus disease 2019.   Clin Infect Dis. 2020;71(15):899-901. doi:10.1093/cid/ciaa492 PubMedGoogle ScholarCrossref
57.
Trifiro  G, Massari  M, Da Cas  R,  et al; ITA-COVID-19: RAAS Inhibitor Group.  Renin-angiotensin-aldosterone system inhibitors and risk of death in patients hospitalised with COVID-19: a retrospective Italian cohort study of 43,000 patients.   Drug Saf. 2020;43(12):1297-1308. doi:10.1007/s40264-020-00994-5 PubMedGoogle ScholarCrossref
58.
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. 2020;14(5):601-612. doi:10.1007/s11684-020-0800-y PubMedGoogle ScholarCrossref
59.
Yang  G, Tan  Z, Zhou  L,  et al. Effects of angiotensin II receptor blockers and ACE (angiotensin-converting enzyme) inhibitors on virus infection, inflammatory status, and clinical outcomes in patients with COVID-19 and hypertension: a single-center retrospective study. Hypertension. 2020;76(1):51-58. doi:10.1161/HYPERTENSIONAHA.120.15143
60.
Yuan  Y, Liu  D, Zeng  S,  et al. In-hospital use of ACEI/ARB is associated with lower risk of mortality and critic illness in COVID-19 patients with hypertension. J Infect. 2020:81(5):816-846. doi:10.1016/j.jinf.2020.08.014
61.
Zhang  P, Zhu  L, Cai  J,  et al. 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
62.
Peng  YD, Meng  K, Guan  HQ,  et al.  [Clinical characteristics and outcomes of 112 cardiovascular disease patients infected by 2019-nCoV].   Zhonghua Xin Xue Guan Bing Za Zhi. 2020;48(6):450-455. doi:10.3760/cma.j.cn112148-20200220-00105PubMedGoogle Scholar
63.
de Abajo  FJ, Rodriguez-Martin  S, Lerma  V,  et al; MED-ACE2-COVID19 Study Group.  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. doi:10.1016/S0140-6736(20)31030-8 PubMedGoogle ScholarCrossref
64.
Hu  J, Zhang  X, Zhang  X,  et al.  COVID-19 is more severe in patients with hypertension; ACEI/ARB treatment does not influence clinical severity and outcome.   J Infect. 2020;81(6):979-997. doi:10.1016/j.jinf.2020.05.056 PubMedGoogle ScholarCrossref
65.
Yan  H, Valdes  AM, Vijay  A,  et al.  Role of drugs affecting the renin-angiotensin-aldosterone system on susceptibility and severity of COVID-19: a large case-control study from Zheijang Province, China.  medRxiv. Preprint posted online April 29, 2020. doi:10.1101/2020.04.24.20077875
66.
Xiong  TY, Redwood  S, Prendergast  B, Chen  M.  Coronaviruses and the cardiovascular system: acute and long-term implications.   Eur Heart J. 2020;41(19):1798-1800. doi:10.1093/eurheartj/ehaa231 PubMedGoogle ScholarCrossref
67.
Barochiner  J, Martinez  R.  Use of inhibitors of the renin-angiotensin system in hypertensive patients and COVID-19 severity: a systematic review and meta-analysis.   J Clin Pharm Ther. 2020;45(6):1244-1252. doi:10.1111/jcpt.13246 PubMedGoogle ScholarCrossref
68.
Kreutz  R, Algharably  EAE, Azizi  M,  et al.  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 PubMedGoogle ScholarCrossref
69.
Furuhashi  M, Moniwa  N, Mita  T,  et al.  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. doi:10.1093/ajh/hpu086 PubMedGoogle ScholarCrossref
70.
de Simone G. Position statement of the ESC Council on Hypertension on ACE-inhibitors and angiotensin receptor blockers. European Society of Cardiology; 2020. Accessed May 25, 2020. https://www.escardio.org/Councils/Council-on-Hypertension-(CHT)/News/position-statement-of-the-esc-council-on-hypertension-on-ace-inhibitors-and-ang
71.
Bozkurt B, Kovacs R, Harrington B. HFSA/ACC/AHA statement addresses concerns re: using RAAS antagonists in COVID-19. American College of Cardiology; 2020. Accessed May 3, 2020. https://www.acc.org/latest-in-cardiology/articles/2020/03/17/08/59/hfsa-acc-aha-statement-addresses-concerns-re-using-raas-antagonists-in-covid-19
72.
Kreutz R, Januszewicz A. Letter on the COVID-19 pandemic from the president of the European Society of Hypertension. April 7, 2020. Accessed May 25, 2020. https://www.eshonline.org/esh-content/uploads/2020/06/ESH-LETTER-COVID-19-by-ESH-President-and-Secretary-April-7-2020.pdf
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    Original Investigation
    Cardiology
    March 31, 2021

    Association Between Renin-Angiotensin-Aldosterone System Inhibitors and Clinical Outcomes in Patients With COVID-19: A Systematic Review and Meta-analysis

    Author Affiliations
    • 1Department of Cardiology, Norfolk and Norwich University Hospital, Norwich, United Kingdom
    • 2Department of Cardiology, Norwich Medical School, University of East Anglia, Norwich, United Kingdom
    • 3National Health Service 111 COVID-19 Clinical Assessment Service, Bicester, United Kingdom
    • 4Neasden Medical Centre, London, United Kingdom
    • 5Healix International, Esher, United Kingdom
    • 6Department of Medical Statistics, Norwich Medical School, University of East Anglia, Norwich, United Kingdom
    JAMA Netw Open. 2021;4(3):e213594. doi:10.1001/jamanetworkopen.2021.3594
    Key Points

    Question  Is the receipt of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) associated with worse clinical outcomes among patients with COVID-19?

    Findings  In this systematic review and meta-analysis of 52 studies that evaluated clinical outcomes among 101 949 total patients with COVID-19 who did and did not receive ACEIs or ARBs, a significantly lower risk of multivariable-adjusted mortality and severe adverse events was found among patients who received ACEIs or ARBs compared with patients who did not. A subgroup analysis of patients with hypertension indicated significant decreases in mortality and severe adverse events among patients receiving ACEIs or ARBs in both unadjusted and adjusted analyses.

    Meaning  The study’s findings suggest that ACEIs and ARBs may be associated with protective benefits for patients with COVID-19 and that patients may continue receiving ACEIs and ARBs for the treatment of any condition without an increased risk of worse outcomes unless specifically advised to avoid them by treating clinicians.

    Abstract

    Importance  The chronic receipt of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) has been assumed to exacerbate complications associated with COVID-19 and produce worse clinical outcomes.

    Objective  To conduct an updated and comprehensive systematic review and meta-analysis comparing mortality and severe adverse events (AEs) associated with receipt vs nonreceipt of ACEIs or ARBs among patients with COVID-19.

    Data Sources  PubMed and Embase databases were systematically searched from December 31, 2019, until September 1, 2020.

    Study Selection  The meta-analysis included any study design, with the exception of narrative reviews or opinion-based articles, in which COVID-19 was diagnosed through laboratory or radiological test results and in which clinical outcomes (unadjusted or adjusted) associated with COVID-19 were assessed among adult patients (≥18 years) receiving ACEIs or ARBs.

    Data Extraction and Synthesis  Three authors independently extracted data on mortality and severe AEs associated with COVID-19. Severe AEs were defined as intensive care unit admission or the need for assisted ventilation. For each outcome, a random-effects model was used to compare the odds ratio (OR) between patients receiving ACEIs or ARBs vs those not receiving ACEIs or ARBs.

    Main Outcomes and Measures  Unadjusted and adjusted ORs for mortality and severe AEs associated with COVID-19.

    Results  A total of 1788 records from the PubMed and Embase databases were identified; after removal of duplicates, 1664 records were screened, and 71 articles underwent full-text evaluation. Clinical data were pooled from 52 eligible studies (40 cohort studies, 6 case series, 4 case-control studies, 1 randomized clinical trial, and 1 cross-sectional study) enrolling 101 949 total patients, of whom 26 545 (26.0%) were receiving ACEIs or ARBs. When adjusted for covariates, significant reductions in the risk of death (adjusted OR [aOR], 0.57; 95% CI, 0.43-0.76; P < .001) and severe AEs (aOR, 0.68; 95% CI, 0.53-0.88; P < .001) were found. Unadjusted and adjusted analyses of a subgroup of patients with hypertension indicated decreases in the risk of death (unadjusted OR, 0.66 [95% CI, 0.49-0.91]; P = .01; aOR, 0.51 [95% CI, 0.32-0.84]; P = .008) and severe AEs (unadjusted OR, 0.70 [95% CI, 0.54-0.91]; P = .007; aOR, 0.55 [95% CI, 0.36-0.85]; P = .007).

    Conclusions and Relevance  In this systematic review and meta-analysis, receipt of ACEIs or ARBs was not associated with a higher risk of multivariable-adjusted mortality and severe AEs among patients with COVID-19 who had either hypertension or multiple comorbidities, supporting the recommendations of medical societies. On the contrary, ACEIs and ARBs may be associated with protective benefits, particularly among patients with hypertension. Future randomized clinical trials are warranted to establish causality.

    Introduction

    Coronavirus disease 2019 (COVID-19), a rapidly evolving pandemic infecting more than 93 million people worldwide to date,1 is associated with worse clinical outcomes in patients with existing cardiovascular diseases, including hypertension and diabetes.2,3 Renin-angiotensin-aldosterone system (RAAS) inhibitors, specifically angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), which are frequently used for the treatment of cardiovascular conditions, are subjects of debate because angiotensin-converting enzyme 2 acts as a binding site for the virus to gain cellular entry.4 This debate has elicited several theories suggesting that the chronic receipt of RAAS inhibitors may exacerbate COVID-19 and produce worse outcomes.4

    Several observational studies have since evaluated the association of ACEIs and ARBs (ACEIs/ARBs) with clinical outcomes in patients with COVID-19. Although a few studies have reported an increased risk of severe disease,5,6 most have found no association7,8 or even beneficial associations with the receipt of these drugs.9,10 A previous meta-analysis11 that examined 16 studies with 28 000 total patients reported no significant association between the receipt of ACEIs/ARBs and mortality or severe adverse events (AEs) among individuals with multiple comorbidities (OR, 0.67; 95% CI, 0.44-1.03; P = .07) and a significant association between ACEIs/ARBs and protective benefits among individuals with hypertension (OR, 0.67; 95% CI, 0.50-0.91; P = .01). Since the publication of that meta-analysis, more original studies have been published, allowing increased statistical power to further investigate specific subgroups.

    Given the increasing number of COVID-19 cases and an evolving second wave of infections, it is important to summarize the data thus far to provide an updated perspective and an understanding of the association between ACEIs/ARBs and clinical COVID-19 outcomes. The inclusion of more studies and patients will allow the identification of more accurate associations with smaller CIs, producing findings that are more likely to represent true associations. In addition, the inclusion of only peer-reviewed studies will reinforce the conclusions. Findings from the present meta-analysis will be relevant for the clinical management of millions of patients receiving these drugs worldwide.12

    Methods
    Study Selection

    The PubMed and Embase databases were systematically searched from December 31, 2019, until September 1, 2020, for studies published in English. Terms such as angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, coronavirus disease 2019, and SARS-COV-2 were used for a comprehensive search. Additional details about the search strategy are available in eMethods in the Supplement. The references of retrieved articles were manually screened for relevant studies to expand the search. This study followed the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) reporting guideline.

    All studies identified in our search were screened by 3 authors (R.B., M.D., and V.T.) using article titles and abstracts. Duplicate studies and multiple reports using the same data were removed. Any article identified as having the potential to fulfill our inclusion criteria underwent full-text evaluation. We included studies meeting the following criteria: (1) any study design, with the exception of narrative reviews and opinion-based articles; (2) adult (≥18 years) study population; (3) participants with COVID-19 diagnosed through laboratory or radiological test results; and (4) assessment of clinical or mortality outcomes (unadjusted or adjusted) among patients receiving ACEIs/ARBs. The mortality and clinical severity data of patients receiving ACEIs/ARBs were compared with those of patients not receiving ACEIs/ARBs.

    Data Extraction and Quality Assessment

    Three authors (R.B., V.T., and M.D.) independently extracted relevant data from included studies using a standardized extraction form. Any disagreements were resolved by discussion. The data extracted included the type of study, the number and characteristics of patients receiving ACEIs/ARBs, and mortality and severe AEs associated with COVID-19.

    Severe AEs were defined as intensive care unit admission or the need for invasive or noninvasive ventilation. Studies reporting severe AEs based on information from the Chinese Center for Disease Control and Prevention13 were included. To avoid double-counting of patients in studies reporting multiple severe AE outcomes, we included the outcome with the largest number of patients in our analyses. For instances in which distinct data for ACEIs/ARBs were available, an aggregate was used given the small likelihood of combined receipt of both drugs.

    The Newcastle-Ottawa Scale,14 a 9-point measure assessing the quality of cohort studies and case-control studies or case series, was used to evaluate the observational studies included. The Cochrane Risk of Bias 2 tool was used to assess the risk of bias in randomized clinical trials.15

    Statistical Analysis

    For each outcome, a random-effects model was used to compare the odds ratios (ORs) and 95% CIs between patients who did and did not receive ACEIs/ARBs using Review Manager software, version 5.3 (Nordic Cochrane Center), and OpenMeta[Analyst] software, version 10.12 (Center for Evidence Synthesis, Brown University).16 For studies reporting hazard ratios (HRs), those HRs were converted to ORs using methodology defined in the Cochrane Handbook for Systematic Reviews of Interventions.17 Results from studies were grouped according to a prespecified variable (patients with hypertension [hypertension subgroup] vs patients with multiple mixed comorbidities [mixed subgroup]), and a series of subgroup analyses were performed. We also conducted a sensitivity analysis, in which studies reporting HRs (which were converted to ORs) were excluded to assess the robustness of results.

    Statistical heterogeneity was assessed using the I2 statistic. Potential publication bias was assessed using funnel plots. The statistical significance threshold was P < .05.

    Results

    Our search identified 1788 records from the PubMed and Embase databases; after removal of duplicates, 1664 records were screened, and 71 articles underwent full-text evaluation (eFigure 1 in the Supplement). Of those, 52 studies (40 cohort studies, 6 case series, 4 case-control studies, 1 randomized clinical trial, and 1 cross-sectional study) with 101 949 total participants met inclusion criteria and were included in the meta-analysis. The cohorts and methodological characteristics of the studies are described in the Table. Ten studies were ranked as having moderate quality and 41 studies were ranked as having high quality based on the Newcastle-Ottawa Scale (eTable in the Supplement). Funnel plots indicated no substantial publication biases (eFigure 2 and eFigure 3 in the Supplement).

    Most studies included in the meta-analysis were retrospective20,21,33,44 or observational4,6,26,37,61-63 and were conducted in China,4,8,10,23-25,28,31,32,35,39,41,45,48,55,58-60,62,64-66 Europe,5,7,9,18,19,22,30,34,40,43,46,47,51-53,56,57 or North America.6,20,49,50,54 Two studies22,38 included a subgroup of patients receiving ACEIs/ARBs that were explicitly discontinued during hospital admission. The results from this subgroup of patients were included in the group of patients receiving ACEIs/ARBs and compared with those not receiving ACEIs/ARBs. In studies in which both multivariate and propensity-matched scores were reported,28,42,61 data from the multivariate analyses were used. A total of 26 545 of 101 949 patients (26.0%) overall and 4813 of 11 696 patients (41.2%) in the hypertension subgroup were receiving ACEIs/ARBs (Table).

    Mortality

    A total of 41 studies (69 577 total participants) that compared mortality rates of patients receiving vs not receiving ACEIs/ARBs were included in the meta-analysis. Overall, the results of the pooled unadjusted meta-analysis indicated no increases in the risk of death among those who received ACEIs/ARBs (unadjusted OR, 1.05; 95% CI, 0.86-1.29; P = .61; I2 = 85.0%) compared with those who did not (Figure 1). The subgroup analysis revealed significant reductions in mortality among patients in the hypertension subgroup who were receiving ACEIs/ARBs (unadjusted OR, 0.66; 95% CI, 0.49-0.91; P = .01). In contrast, the mixed subgroup comprising patients with multiple comorbidities indicated significant increases in mortality among those receiving ACEIs/ARBs (unadjusted OR, 1.46; 95% CI, 1.15-1.85; P = .002)

    However, a pooled analysis of 17 studies (17 392 total participants) using an adjusted analysis of mortality found reductions in the risk of death among patients receiving vs not receiving ACEIs/ARBs (adjusted OR [aOR], 0.57; 95% CI, 0.43-0.76; P < .001; I2 = 54.0%) (Figure 2). A significant decrease in the risk of death was observed in both subgroups (for the hypertension subgroup, aOR, 0.51 [95% CI, 0.32-0.84]; P = .008; for the mixed subgroup, aOR, 0.64 [95% CI, 0.46-0.88]; P = .006).

    Severe Adverse Events

    Unadjusted values for severe AEs were reported in 48 studies that included a total of 98 985 participants. A pooled analysis found comparable results among patients who did and did not receive ACEIs/ARBs (unadjusted OR, 1.11; 95% CI, 0.95-1.31; P = .20; I2 = 86.0%) (Figure 3). Notably, the 26 studies including a hypertension subgroup (unadjusted OR, 0.70; 95% CI, 0.54-0.91; P = .007) and the 33 studies including a mixed subgroup (unadjusted OR, 1.50; 95% CI, 1.25-1.81; P < .001) reported statistically significant results.

    A total of 23 studies (23 129 total participants) reported an adjusted risk of severe AEs associated with the receipt of ACEIs/ARBs in a COVID-19 cohort. The adjusted covariates for each study are listed in the Table. A significant decrease in severe AEs was found in patients who received ACEIs/ARBs compared with those who did not (aOR, 0.68; 95% CI, 0.53-0.88; P = .003; I2 = 67.0%) (Figure 4). This reduced risk remained significant among the hypertension subgroup in 12 studies (aOR, 0.55; 95% CI, 0.36-0.85; P = .007). However, in the mixed subgroup, the decreased risk was not statistically significant (OR, 0.79; 95% CI, 0.59-1.07; P = .12). A sensitivity analysis that excluded studies reporting HRs indicated statistically significant results for mortality but nonsignificant results for severe AEs (eFigure 4 and eFigure 5 in the Supplement). Subgroup analyses of studies of moderate quality (OR, 0.36; 95% CI, 0.25-0.51; P < .001) and high quality (OR, 0.78; 95% CI, 0.60-1.00; P = .05) indicated reduced risk of adjusted severe AEs among both hypertension and mixed subgroups (eFigure 6 in the Supplement).

    Discussion

    The results of this systematic review and meta-analysis of 52 studies with 101 949 total patients indicated a significant association between the receipt of ACEIs/ARBs and reductions in mortality and severe AEs among patients in the hypertension subgroup. In the mixed subgroup of patients with multiple comorbidities, this association was observed only when the analysis was adjusted for significant covariates.

    Our results are consistent with those of another meta-analysis67 comprising 18 studies and 17 311 patients with hypertension. This previous meta-analysis reported a lower risk (risk ratio, 0.84; 95% CI, 0.73-0.95; P = .007) of the composite outcome (death, intensive care unit admission, mechanical ventilation, and progression to severe or critical pneumonia) among patients receiving ACEIs/ARBs. The present meta-analysis extends this finding to patients with multiple mixed comorbidities, suggesting that ACEIs/ARBs may have a substantial protective role in COVID-19 outcomes across all patient groups.

    Notably, the protective implications of ACEIs/ARBs in the mixed subgroup were observed only after adjustments to potential and important confounders, such as age and comorbidities. This finding suggests that comorbidities may have an important role in COVID-19 clinical outcomes and that ACEIs/ARBs might be associated with further improvements in potential outcomes. In a large retrospective cohort study by Fosbol et al27 that included 4480 patients with COVID-19, an unadjusted analysis indicated worse outcomes among those who received ACEIs/ARBs. However, after multivariate adjustments, this finding was no longer statistically significant. Similar results were observed in multiple small retrospective cohort studies.29,36,42,54 It is worth noting that most studies included in the meta-analyses were retrospective and observational; with these study designs, unmeasured confounding factors and potential biases are inevitable. In addition, patients receiving ACEIs/ARBs are more likely to have heart failure, cardiovascular disease, hypertension, and comorbidities, which are associated with an increased risk of death among patients with COVID-19.3 Therefore, it is necessary to adjust for these confounders when evaluating the protective benefits of ACEIs/ARBs for mortality and severe AEs.

    The potential mechanisms underlying the beneficial consequences of ACEIs/ARBs remain unknown. Our results suggest that these benefits are not solely associated with better blood pressure control, as patients receiving antihypertensive medications that were not ACEIs/ARBs had comparably inferior clinical outcomes in the adjusted subgroup analysis. Concerns about upregulation of angiotensin-converting enzyme 2 receptors with the receipt of RAAS inhibitors, which are derived from inconsistent results in studies with small samples,68,69 have been challenged by reports of deactivation of RAAS61 with chronic receipt of ACEIs/ARBs. Such downregulation may limit the inflammatory process, reducing acute lung injury among patients with COVID-19.49

    Nevertheless, the findings of the present meta-analysis are consistent with those of national and international scientific experts,70-72 who recommend continuation of ACEIs/ARBs unless they are clinically contraindicated. This meta-analysis also indicated that, after adjustment for case mix, patients with hypertension and COVID-19 who received ACEIs/ARBs were 0.55 times as likely to experience a severe AE than those who did not receive ACEIs/ARBs, with a similar extent of benefit observed in the combined hypertension and mixed comorbidities subgroups. Although our study clarifies the association between RAAS inhibitors and mortality among patients with COVID-19, future randomized clinical trials are warranted to establish causality.

    Limitations

    This study has limitations. First, the study was limited by the insufficient data and varying study designs available, which did not allow for comparison of these analyses with a control group. The meta-analysis was primarily composed of observational studies because studies with higher levels of evidence, such as randomized clinical trials, were lacking. Second, the meta-analysis indicated substantial unadjusted and moderate adjusted levels of heterogeneity, which is typical in observational studies that include patients with diverse characteristics across large geographic regions. Nevertheless, measures were taken to maintain a homogeneous study population. A standard definition for severe AEs was used, and patients with unconfirmed COVID-19 were excluded. Third, we did not define the criteria for chronic receipt of ACEIs/ARBs. Insufficient description was available to distinguish between study participants, which is likely a factor associated with the increased heterogeneity observed in the study. With these limitations in mind, there were no data indicating that the receipt of ACEIs/ARBs was associated with harm if patients subsequently contracted COVID-19; on the contrary, ACEIs/ARBs may be associated with substantial protective benefits.

    Conclusions

    This comprehensive systematic review and meta-analysis of 52 studies indicated no higher risks of multivariable-adjusted mortality or severe AEs associated with the receipt of ACEIs/ARBs, which is consistent with recommendations for the continuation of these medications among patients for whom they are prescribed for the treatment of any condition. On the contrary, ACEIs and ARBs may be associated with protective benefits, particularly among patients with hypertension. Future randomized clinical trials are warranted to confirm the beneficial implications of these medications.

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    Article Information

    Accepted for Publication: February 7, 2021.

    Published: March 31, 2021. doi:10.1001/jamanetworkopen.2021.3594

    Open Access: This is an open access article distributed under the terms of the CC-BY License. © 2021 Baral R et al. JAMA Network Open.

    Corresponding Author: Vassilios S. Vassiliou, MBBS, PhD, Associate Professor, Norwich Medical School, University of East Anglia, Norwich Research Park, Norwich NR4 7UQ, United Kingdom (v.vassiliou@uea.ac.uk).

    Author Contributions: Drs Baral and Tsampasian had full access to all of the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis. Drs Baral and Tsampasian contributed equally.

    Concept and design: Baral, Moran, Garg, Vassiliou.

    Acquisition, analysis, or interpretation of data: Baral, Tsampasian, Debski, Clark, Vassiliou.

    Drafting of the manuscript: Baral, Tsampasian, Clark, Vassiliou.

    Critical revision of the manuscript for important intellectual content: Baral, Tsampasian, Debski, Moran, Garg, Vassiliou.

    Statistical analysis: Baral, Tsampasian, Clark.

    Obtained funding: Vassiliou.

    Administrative, technical, or material support: Baral, Tsampasian.

    Supervision: Garg, Vassiliou.

    Conflict of Interest Disclosures: Dr Vassiliou reported receiving grants from the Norfolk Heart Trust and personal fees from Daiichi Sankyo and Novartis outside the submitted work. No other disclosures were reported.

    References
    1.
    World Health Organization. WHO coronavirus disease (COVID-19) dashboard. Updated February 13, 2021. Accessed January 18, 2021. https://covid19.who.int/
    2.
    Guo  T, Fan  Y, Chen  M,  et al.  Cardiovascular implications of fatal outcomes of patients with coronavirus disease 2019 (COVID-19).   JAMA Cardiol. 2020;5(7):811-818. doi:10.1001/jamacardio.2020.1017 PubMedGoogle ScholarCrossref
    3.
    Li  B, Yang  J, Zhao  F,  et al.  Prevalence and impact of cardiovascular metabolic diseases on COVID-19 in China.   Clin Res Cardiol. 2020;109(5):531-538. doi:10.1007/s00392-020-01626-9 PubMedGoogle ScholarCrossref
    4.
    Feng  Y, Ling  Y, Bai  T,  et al. COVID-19 with different severities: a multicenter study of clinical features. Am J Respir Crit Care Med. 2020;201(11):1380-1388 doi:10.1164/rccm.202002-0445OC .
    5.
    Selcuk  M, Cınar  T, Keskin  M,  et al.  Is the use of ACE inb/ARBs associated with higher in-hospital mortality in Covid-19 pneumonia patients?   Clin Exp Hypertens. 2020;42(8):738-742. doi:10.1080/10641963.2020.1783549 PubMedGoogle ScholarCrossref
    6.
    Mehta  N, Kalra  A, Nowacki  AS,  et al.  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 PubMedGoogle ScholarCrossref
    7.
    Bravi  F, Flacco  ME, Carradori  T,  et al. Predictors of severe or lethal COVID-19, including angiotensin converting enzyme inhibitors and angiotensin II receptor blockers, in a sample of infected Italian citizens. PLoS One. 2020;15(6):e0235248. doi:10.1371/journal.pone.0235248
    8.
    Zhou  X, Zhu  J, Xu  T.  Clinical characteristics of coronavirus disease 2019 (COVID-19) patients with hypertension on renin-angiotensin system inhibitors.   Clin Exp Hypertens. 2020;42(7):656-660. doi:10.1080/10641963.2020.1764018 PubMedGoogle ScholarCrossref
    9.
    Felice  C, Nardin  C, Di Tanna  GL,  et al.  Use of RAAS inhibitors and risk of clinical deterioration in COVID-19: results from an Italian cohort of 133 hypertensives.   Am J Hypertens. 2020;33(10):944-948. doi:10.1093/ajh/hpaa096PubMedGoogle Scholar
    10.
    Zhou  F, Liu  YM, Xie  J,  et al. Comparative impacts of ACE (angiotensin-converting enzyme) inhibitors versus angiotensin II receptor blockers on the risk of COVID-19 mortality. Hypertension. 2020;76(2):e15-e17. doi:10.1161/HYPERTENSIONAHA.120.15622
    11.
    Baral  R, White  M, Vassiliou  VS.  Effect of renin-angiotensin-aldosterone system inhibitors in patients with COVID-19: a systematic review and meta-analysis of 28,872 patients.   Curr Atheroscler Rep. 2020;22(10):61. doi:10.1007/s11883-020-00880-6 PubMedGoogle ScholarCrossref
    12.
    World Health Organization. COVID-19 and the use of angiotensin-converting enzyme inhibitors and receptor blockers: scientific brief. May 7, 2020. Accessed October 20, 2020. https://www.who.int/news-room/commentaries/detail/covid-19-and-the-use-of-angiotensin-converting-enzyme-inhibitors-and-receptor-blockers
    13.
    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;323(13):1239-1242. doi:10.1001/jama.2020.2648
    14.
    Wells GA, Shea B, O’Connell D, et al. The Newcastle-Ottawa Scale (NOS) for assessing the quality of nonrandomised studies in meta-analyses. The Ottawa Hospital Research Institute; 2019. Accessed October 20, 2020. http://www.ohri.ca/programs/clinical_epidemiology/oxford.asp
    15.
    Sterne  JAC, Savovic  J, Page  MJ,  et al.  RoB 2: a revised tool for assessing risk of bias in randomised trials.   BMJ. 2019;366:l4898. doi:10.1136/bmj.l4898 PubMedGoogle ScholarCrossref
    16.
    Wallace  BC, Dahabreh  IJ, Trikalinos  TA, Lau  J, Trow  P, Schmid  CH.  Closing the gap between methodologists and end-users: R as a computational back-end.   J Stat Softw. 2012;49(5):1-15. doi:10.18637/jss.v049.i05 Google ScholarCrossref
    17.
    Higgins  JPT, Li  T, Deeks  JJ. Chapter 6: choosing effect measures and computing estimates of effect. In: Higgins JPT, Thomas J, Chandler J, et al, eds. Cochrane Handbook for Systematic Reviews of Interventions. Version 6.1. Cochrane; 2020. Accessed October 20, 2020. https://training.cochrane.org/handbook/current/chapter-06
    18.
    Amat-Santos  IJ, Santos-Martinez  S, Lopez-Otero  D,  et al.  Ramipril in high-risk patients with COVID-19.   J Am Coll Cardiol. 2020;76(3):268-276. doi:10.1016/j.jacc.2020.05.040 PubMedGoogle ScholarCrossref
    19.
    Conversano  A, Melillo  F, Napolano  A,  et al. Renin-angiotensin-aldosterone system inhibitors and outcome in patients with SARS-CoV-2 pneumonia: a case series study. Hypertension. 2020;76(2):e10-e12. doi:10.1161/HYPERTENSIONAHA
    20.
    Bae  DJ, Tehrani  DM, Rabadia  SV,  et al.  Angiotensin converting enzyme inhibitor and angiotensin II receptor blocker use among outpatients diagnosed with COVID-19.   Am J Cardiol. 2020;132:150-157. doi:10.1016/j.amjcard.2020.07.007 PubMedGoogle ScholarCrossref
    21.
    Bean  DM, Kraljevic  Z, Searle  T,  et al.  Angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers are not associated with severe COVID-19 infection in a multi-site UK acute hospital trust.   Eur J Heart Fail. 2020;22(6):967-974. doi:10.1002/ejhf.1924 PubMedGoogle ScholarCrossref
    22.
    Cannata  F, Chiarito  M, Reimers  B,  et al. Continuation versus discontinuation of ACE inhibitors or angiotensin II receptor blockers in COVID-19: effects on blood pressure control and mortality. Eur Heart J Cardiovasc Pharmacother. 2020:6(6):412-414. doi:10.1093/ehjcvp/pvaa056
    23.
    Chen  C, Wang  F, Chen  P,  et al.  Mortality and pre-hospitalization use of renin-angiotensin system inhibitors in hypertensive COVID-19 patients.   J Am Heart Assoc. 2020;9(21):e017736. doi:10.1161/JAHA.120.017736 PubMedGoogle Scholar
    24.
    Chen FF, Zhong M, Liu Y, et al. The characteristics and outcomes of 681 severe cases with COVID-19 in China. J Crit Care. 2020;60:32-37. doi:10.1016/j.jcrc.2020.07.003
    25.
    Chen  Y, Yang  D, Cheng  B,  et al.  Clinical characteristics and outcomes of patients with diabetes and COVID-19 in association with glucose-lowering medication.   Diabetes Care. 2020;43(7):1399-1407. doi:10.2337/dc20-0660 PubMedGoogle ScholarCrossref
    26.
    Hippisley-Cox  J, Young  D, Coupland  C,  et al.  Risk of severe COVID-19 disease with ACE inhibitors and angiotensin receptor blockers: cohort study including 8.3 million people.   Heart. 2020;106(19):1503-1511. doi:10.1136/heartjnl-2020-317393 PubMedGoogle ScholarCrossref
    27.
    Fosbol  EL, Butt  JH, Ostergaard  L,  et al. Association of angiotensin-converting enzyme inhibitor or angiotensin receptor blocker use with COVID-19 diagnosis and mortality. JAMA. 2020;324(2):168-177. doi:10.1001/jama.2020.11301
    28.
    Gao  C, Cai  Y, Zhang  K,  et al.  Association of hypertension and antihypertensive treatment with COVID-19 mortality: a retrospective observational study.   Eur Heart J. 2020;41(22):2058-2066. doi:10.1093/eurheartj/ehaa433 PubMedGoogle ScholarCrossref
    29.
    Gormez  S, Ekicibasi  E, Degirmencioglu  A,  et al.  Association between renin-angiotensin-aldosterone system inhibitor treatment, neutrophil-lymphocyte ratio, D-dimer and clinical severity of COVID-19 in hospitalized patients: a multicenter, observational study.   J Hum Hypertens. 2020:1-10. doi:10.1038/s41371-020-00405-3 PubMedGoogle Scholar
    30.
    Grasselli  G, Greco  M, Zanella  A,  et al. Risk factors associated with mortality among patients with COVID-19 in intensive care units in Lombardy, Italy. JAMA Intern Med. 2020;180(10):1345-1355. doi:10.1001/jamainternmed.2020.3539
    31.
    Guo  X, Zhu  Y, Hong  Y. Decreased mortality of COVID-19 with renin-angiotensin-aldosterone system inhibitors therapy in patients with hypertension: a meta-analysis. Hypertension. 2020;76(2):e13-e14. doi:10.1161/HYPERTENSIONAHA.120.15572
    32.
    Huang  Z, Cao  J, Yao  Y,  et al.  The effect of RAS blockers on the clinical characteristics of COVID-19 patients with hypertension.   Ann Transl Med. 2020;8(7):430. doi:10.21037/atm.2020.03.229 PubMedGoogle ScholarCrossref
    33.
    Hwang  JM, Kim  JH, Park  JS, Chang  MC, Park  D.  Neurological diseases as mortality predictive factors for patients with COVID-19: a retrospective cohort study.   Neurol Sci. 2020;41(9):2317-2324. doi:10.1007/s10072-020-04541-z PubMedGoogle ScholarCrossref
    34.
    Iaccarino  G, Grassi  G, Borghi  C, Ferri  C, Salvetti  M, Volpe  M; SARS-RAS Investigators. Age and multimorbidity predict death among COVID-19 patients: results of the SARS-RAS study of the Italian Society of Hypertension. Hypertension. 2020;76(2):366-372. doi:10.1161/HYPERTENSIONAHA.120.15324
    35.
    Jung  C, Bruno  RR, Wernly  B,  et al. Inhibitors of the renin–angiotensin–aldosterone system and COVID-19 in critically ill elderly patients. Eur Heart J Cardiovasc Pharmacother. 2021;7(1):76-77. doi:10.1093/ehjcvp/pvaa083
    36.
    Jung  SY, Choi  JC, You  SH, Kim  WY.  Association of renin-angiotensin-aldosterone system inhibitors with coronavirus disease 2019 (COVID-19)–related outcomes in Korea: a nationwide population-based cohort study.   Clin Infect Dis. 2020;71(16):2121-2128. doi:10.1093/cid/ciaa624 PubMedGoogle ScholarCrossref
    37.
    Khan  KS, Reed-Embleton  H, Lewis  J, Bain  P, Mahmud  S.  Angiotensin converting enzyme inhibitors do not increase the risk of poor outcomes in COVID-19 disease: a multi-centre observational study.   Scott Med J. 2020;65(4):149-153. doi:10.1177/0036933020951926 PubMedGoogle ScholarCrossref
    38.
    Lam  KW, Chow  KW, Vo  J,  et al.  Continued in-hospital angiotensin-converting enzyme inhibitor and angiotensin II receptor blocker use in hypertensive COVID-19 patients is associated with positive clinical outcome.   J Infect Dis. 2020;222(8):1256-1264. doi:10.1093/infdis/jiaa447 PubMedGoogle ScholarCrossref
    39.
    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 PubMedGoogle ScholarCrossref
    40.
    Liabeuf  S, Moragny  J, Bennis  Y,  et al. Association between renin–angiotensin system inhibitors and COVID-19 complications. Eur Heart J Cardiovasc Pharmacother. Published online June 12, 2020. doi:10.1093/ehjcvp/pvaa062
    41.
    Liu  X, Liu  Y, Chen  K,  et al. Efficacy of ACEIs/ARBs vs CCBs on the progression of COVID-19 patients with hypertension in Wuhan: a hospital-based retrospective cohort study. J Med Virol. 2021;93(2):854-862. doi:10.1002/jmv.26315
    42.
    Lopez-Otero  D, Lopez-Pais  J, Cacho-Antonio  CE,  et al. Impact of angiotensin-converting enzyme inhibitors and angiotensin receptor blockers on COVID-19 in a Western population. Rev Espanola Cardiol. 2020;74(2):175-182. doi:10.1016/j.rec.2020.05.018
    43.
    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
    44.
    Matsuzawa  Y, Ogawa  H, Kimura  K,  et al.  Renin-angiotensin system inhibitors and the severity of coronavirus disease 2019 in Kanagawa, Japan: a retrospective cohort study.   Hypertens Res. 2020;43(11):1257-1266. doi:10.1038/s41440-020-00535-8 PubMedGoogle ScholarCrossref
    45.
    Meng  J, Xiao  G, Zhang  J,  et al.  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 PubMedGoogle ScholarCrossref
    46.
    Mostaza  JM, Garcia-Iglesias  F, Gonzalez-Alegre  T,  et al; Carlos III COVID Working Group.  Clinical course and prognostic factors of COVID-19 infection in an elderly hospitalized population.   Arch Gerontol Geriatr. 2020;91:104204. doi:10.1016/j.archger.2020.104204 PubMedGoogle Scholar
    47.
    Oussalah  A, Gleye  S, Urmes  IC,  et al. Long-term ACE inhibitor/ARB use is associated with severe renal dysfunction and acute kidney injury in patients with severe COVID-19: results from a referral center cohort in the northeast of France. Clin Infect Dis. 2020;71(9):2447-2456. doi:10.1093/cid/ciaa677
    48.
    Pan  W, Zhang  J, Wang  M,  et al. Clinical features of COVID-19 in patients with essential hypertension and the impacts of renin-angiotensin-aldosterone system inhibitors on the prognosis of COVID-19 patients. Hypertension. 2020;76(3):732-741. doi:10.1161/HYPERTENSIONAHA.120.15289
    49.
    Reynolds  HR, Adhikari  S, Pulgarin  C,  et al.  Renin–angiotensin–aldosterone system inhibitors and risk of COVID-19.   N Engl J Med. 2020;382(25):2441-2448. doi:10.1056/NEJMoa2008975 PubMedGoogle ScholarCrossref
    50.
    Richardson  S, Hirsch  JS, Narasimhan  M,  et al; the Northwell COVID-19 Research Consortium.  Presenting characteristics, comorbidities, and outcomes among 5700 patients hospitalized with COVID-19 in the New York City area.   JAMA. 2020;323(20):2052-2059. doi:10.1001/jama.2020.6775 PubMedGoogle ScholarCrossref
    51.
    Rossi  PG, Marino  M, Formisano  D, Venturelli  F, Vicentini  M, Grilli  R; Reggio Emilia COVID-19 Working Group. Characteristics and outcomes of a cohort of COVID-19 patients in the province of Reggio Emilia, Italy. PLoS One. 2020;15(8):e0238281. doi:10.1371/journal.pone.0238281
    52.
    Sardu  C, Maggi  P, Messina  V,  et al.  Could anti-hypertensive drug therapy affect the clinical prognosis of hypertensive patients with COVID-19 infection? data from centers of southern Italy.   J Am Heart Assoc. 2020;9(17):e016948. doi:10.1161/JAHA.120.016948 PubMedGoogle Scholar
    53.
    Senkal  N, Meral  R, Medetalibeyoqlu  A, Konyaoqlu  H, Kose  M, Tukek  T.  Association between chronic ACE inhibitor exposure and decreased odds of severe disease in patients with COVID-19.   Anatol J Cardiol. 2020;24(1):21-29. doi:10.14744/AnatolJCardiol.2020.57431PubMedGoogle Scholar
    54.
    Shah  P, Owens  J, Franklin  J, Jani  Y, Kumar  A, Doshi  R.  Baseline use of angiotensin-converting enzyme inhibitor/AT1 blocker and outcomes in hospitalized coronavirus disease 2019 African-American patients.   J Hypertens. 2020;38(12):2537-2541. doi:10.1097/HJH.0000000000002584 PubMedGoogle ScholarCrossref
    55.
    Tan  ND, Qiu  Y, Xing  XB, Ghosh  S, Chen  MH, Mao  R.  Associations between angiotensin-converting enzyme inhibitors and angiotensin II receptor blocker use, gastrointestinal symptoms, and mortality among patients with COVID-19.   Gastroenterology. 2020;159(3):1170-1172. doi:10.1053/j.gastro.2020.05.034 PubMedGoogle ScholarCrossref
    56.
    Tedeschi  S, Giannella  M, Bartoletti  M,  et al.  Clinical impact of renin-angiotensin system inhibitors on in-hospital mortality of patients with hypertension hospitalized for coronavirus disease 2019.   Clin Infect Dis. 2020;71(15):899-901. doi:10.1093/cid/ciaa492 PubMedGoogle ScholarCrossref
    57.
    Trifiro  G, Massari  M, Da Cas  R,  et al; ITA-COVID-19: RAAS Inhibitor Group.  Renin-angiotensin-aldosterone system inhibitors and risk of death in patients hospitalised with COVID-19: a retrospective Italian cohort study of 43,000 patients.   Drug Saf. 2020;43(12):1297-1308. doi:10.1007/s40264-020-00994-5 PubMedGoogle ScholarCrossref
    58.
    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. 2020;14(5):601-612. doi:10.1007/s11684-020-0800-y PubMedGoogle ScholarCrossref
    59.
    Yang  G, Tan  Z, Zhou  L,  et al. Effects of angiotensin II receptor blockers and ACE (angiotensin-converting enzyme) inhibitors on virus infection, inflammatory status, and clinical outcomes in patients with COVID-19 and hypertension: a single-center retrospective study. Hypertension. 2020;76(1):51-58. doi:10.1161/HYPERTENSIONAHA.120.15143
    60.
    Yuan  Y, Liu  D, Zeng  S,  et al. In-hospital use of ACEI/ARB is associated with lower risk of mortality and critic illness in COVID-19 patients with hypertension. J Infect. 2020:81(5):816-846. doi:10.1016/j.jinf.2020.08.014
    61.
    Zhang  P, Zhu  L, Cai  J,  et al. 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
    62.
    Peng  YD, Meng  K, Guan  HQ,  et al.  [Clinical characteristics and outcomes of 112 cardiovascular disease patients infected by 2019-nCoV].   Zhonghua Xin Xue Guan Bing Za Zhi. 2020;48(6):450-455. doi:10.3760/cma.j.cn112148-20200220-00105PubMedGoogle Scholar
    63.
    de Abajo  FJ, Rodriguez-Martin  S, Lerma  V,  et al; MED-ACE2-COVID19 Study Group.  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. doi:10.1016/S0140-6736(20)31030-8 PubMedGoogle ScholarCrossref
    64.
    Hu  J, Zhang  X, Zhang  X,  et al.  COVID-19 is more severe in patients with hypertension; ACEI/ARB treatment does not influence clinical severity and outcome.   J Infect. 2020;81(6):979-997. doi:10.1016/j.jinf.2020.05.056 PubMedGoogle ScholarCrossref
    65.
    Yan  H, Valdes  AM, Vijay  A,  et al.  Role of drugs affecting the renin-angiotensin-aldosterone system on susceptibility and severity of COVID-19: a large case-control study from Zheijang Province, China.  medRxiv. Preprint posted online April 29, 2020. doi:10.1101/2020.04.24.20077875
    66.
    Xiong  TY, Redwood  S, Prendergast  B, Chen  M.  Coronaviruses and the cardiovascular system: acute and long-term implications.   Eur Heart J. 2020;41(19):1798-1800. doi:10.1093/eurheartj/ehaa231 PubMedGoogle ScholarCrossref
    67.
    Barochiner  J, Martinez  R.  Use of inhibitors of the renin-angiotensin system in hypertensive patients and COVID-19 severity: a systematic review and meta-analysis.   J Clin Pharm Ther. 2020;45(6):1244-1252. doi:10.1111/jcpt.13246 PubMedGoogle ScholarCrossref
    68.
    Kreutz  R, Algharably  EAE, Azizi  M,  et al.  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 PubMedGoogle ScholarCrossref
    69.
    Furuhashi  M, Moniwa  N, Mita  T,  et al.  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. doi:10.1093/ajh/hpu086 PubMedGoogle ScholarCrossref
    70.
    de Simone G. Position statement of the ESC Council on Hypertension on ACE-inhibitors and angiotensin receptor blockers. European Society of Cardiology; 2020. Accessed May 25, 2020. https://www.escardio.org/Councils/Council-on-Hypertension-(CHT)/News/position-statement-of-the-esc-council-on-hypertension-on-ace-inhibitors-and-ang
    71.
    Bozkurt B, Kovacs R, Harrington B. HFSA/ACC/AHA statement addresses concerns re: using RAAS antagonists in COVID-19. American College of Cardiology; 2020. Accessed May 3, 2020. https://www.acc.org/latest-in-cardiology/articles/2020/03/17/08/59/hfsa-acc-aha-statement-addresses-concerns-re-using-raas-antagonists-in-covid-19
    72.
    Kreutz R, Januszewicz A. Letter on the COVID-19 pandemic from the president of the European Society of Hypertension. April 7, 2020. Accessed May 25, 2020. https://www.eshonline.org/esh-content/uploads/2020/06/ESH-LETTER-COVID-19-by-ESH-President-and-Secretary-April-7-2020.pdf
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