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Association of Renin-Angiotensin System Blockers With Outcomes in Patients with COVID-19

Published:September 14, 2020DOI:https://doi.org/10.1016/j.mayocp.2020.09.010
      To The Editor:
      Conflicting findings have been reported regarding the safety of angiotensin-converting-enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) during the COVID-19 pandemic.
      • 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.
      ,
      • Reynolds H.R.
      • Adhikari S.
      • Pulgarin C.
      • et al.
      Renin-angiotensin-aldosterone system inhibitors and risk of Covid-19.
      In reference to the recently published review outlining the relationship between renin-angiotensin system (RAS) and COVID-19 infection,
      • Sanchis-Gomar F.
      • Lavie C.J.
      • Perez-Quilis C.
      • Henry B.M.
      • Lippi G.
      Angiotensin-converting enzyme 2 and antihypertensives (angiotensin receptor blockers and angiotensin-converting enzyme inhibitors) in coronavirus disease 2019 (COVID-19).
      we present additional data regarding the association of RAS inhibitors with outcomes in patients with COVID-19.
      The COVID-19 pandemic, affecting more than 4.5 million people across the globe, has caused significant morbidity and mortality.
      • Zhu N.
      • Zhang D.
      • Wang W.
      • et al.
      China Novel Coronavirus Investigating and Research Team. A novel coronavirus from patients with pneumonia in China, 2019.
      Angiotensin-converting-enzyme 2 (ACE2) has been implicated in the entry of severe acute respiratory syndrome (SARS)-Cov-2 virus into host cells.
      • Li W.
      • Moore M.J.
      • Vasilieva N.
      • et al.
      Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus.
      As RAS antagonists have been suggested to upregulate ACE2 in few animal models, concerns have been raised that these drugs might be associated with increased risk of infection or severe disease from COVID-19.
      • Ferrario C.M.
      • Jessup J.
      • Chappell M.C.
      • et al.
      Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2.
      ,
      • Messerli F.H.
      • Siontis G.
      • Rexhaj E.
      COVID-19 and renin angiotensin blockers: current evidence and recommendations.
      Whether such patients on ACEIs or ARBs should continue these drugs has become a matter of debate. Accordingly, we performed a meta-analysis to study the cumulative evidence for association of the use of ACEIs and ARBs with risk of mortality and severe illness with COVID-19.
      A comprehensive search in electronic databases (MEDLINE and EMBASE) was performed for studies published between November 1, 2019, and May 31, 2020. The following key terms were used for search in different combinations: coronavirus 2019, COVID-19, SARS-Cov-2, renin-angiotensin system, angiotensin-converting-enzyme, angiotensin-converting-enzyme inhibitors, ACEI, angiotensin receptor blockers, ARB, and outcomes. Inclusion criteria were studies published in peer-reviewed journals and reporting outcomes based on use of ACEIs or ARBs in COVID-19. Two reviewers (A.G. and A.R.) screened the study titles and abstracts, followed by full manuscript evaluation. From individual studies, we collected baseline characteristics of patients including proportion of patients with hypertension and those taking ACEIs or ARBs. The primary outcome was in-hospital mortality. Secondary outcome was severe or critical illness— need for intensive care unit, invasive mechanical ventilation, or mortality—as defined per individual study protocol. We used the Cochrane review manager 5.3 for statistical analysis. Random-effects model with Mantel-Haenszel method was used to calculate the pooled odds ratios (ORs) with 95% confidence intervals (CIs) for each end point. This meta-analysis was conducted in accordance with the Preferred Reporting Items for Systemic Reviews and Meta-Analyses (PRISMA) guidelines.
      • Moher D.
      • Shamseer L.
      • Clarke M.
      • et al.
      PRISMA-P Group
      Preferred reporting items for systematic review and meta-analysis protocols (PRISMA-P) 2015 statement.
      After initial screening and full text review, 15 studies were identified to report outcomes based on use of ACEIs or ARBs in patients with confirmed COVID-19.
      • 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.
      ,
      • Reynolds H.R.
      • Adhikari S.
      • Pulgarin C.
      • et al.
      Renin-angiotensin-aldosterone system inhibitors and risk of Covid-19.
      ,
      • Li W.
      • Moore M.J.
      • Vasilieva N.
      • et al.
      Angiotensin-converting enzyme 2 is a functional receptor for the SARS coronavirus.
      ,
      • Peng Y.D.
      • Meng K.
      • Guan H.Q.
      • et al.
      Clinical characteristics and outcomes of 112 cardiovascular disease patients infected by 2019-nCoV.
      • Mehra M.R.
      • Desai S.S.
      • Kuy S.
      • Henry T.D.
      • Patel A.N.
      Cardiovascular disease, drug therapy, and mortality in Covid-19.
      • Mehta N.
      • Kalra A.
      • Nowacki A.S.
      • 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 May 5.
      • Mancia G.
      • Rea F.
      • Ludergnani M.
      • Apolone G.
      • Corrao G.
      Renin-angiotensin-aldosterone system blockers and the risk of Covid-19.
      • 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.
      • 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.
      • Feng Y.
      • Ling Y.
      • Bai T.
      • et al.
      COVID-19 with different severities: a multi-center study of clinical features.
      • Wang Y.
      • Lu X.
      • Chen H.
      • et al.
      Clinical course and outcomes of 344 intensive care patients with COVID-19.
      • Li X.
      • Xu S.
      • Yu M.
      • et al.
      Risk factors for severity and mortality in adult COVID-19 inpatients in Wuhan.
      • Meng J.
      • Xiao G.
      • Zhang J.
      • et al.
      Renin-angiotensin system inhibitors improve the clinical outcomes of COVID-19 patients with hypertension.
      • de Abajo F.J.
      • Rodríguez-Martín 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.
      • 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.
      One study was excluded because of retraction by the authors.
      • Mehra M.R.
      • Desai S.S.
      • Kuy S.
      • Henry T.D.
      • Patel A.N.
      Cardiovascular disease, drug therapy, and mortality in Covid-19.
      Thus, a total of 14,882 COVID-19–positive patients (n=5323 ACEI/ARB, n=9559 non-ACEI/ARB) among 14 studies were included. Compared with patients not on RAS inhibitors, patients using RAS inhibitors had similar risks for mortality (OR 1.14 [0.73-1.76]; P=.57) and severe illness (1.18 [0.91-1.54]; P=0.21) (Figure). In subanalyses restricted to patients with hypertension, use of ACEIs and ARBs was associated with significantly lower mortality (0.64 [0.45-0.89]), whereas the trend of severe or critical illness (0.76 [0.52-1.12]) remained nonsignificant compared with non-ACEI and ARB users (Supplemental Figure, available online at http://www.mayoclinicproceedings.org).
      Figure thumbnail gr1
      FigureForest plots comparing outcomes between ACEI and ARB users vs nonusers. A, Mortality. B, Severe or critical illness. ACEI = angiotensin-converting-enzyme inhibitor; ARB = angiotensin receptor blocker.
      Currently available data from observational studies have shown contrasting findings regarding the relationship between the use of ACEIs and ARBs and outcomes in patients with COVID-19. In this context, our meta-analysis, including >14,000 patients, reconciles the findings of existing studies and shows that use of ACEIs and ARBs is not associated with increased risk of mortality or severe illness among a broad patient population with COVID-19. Although hypothesis generating, our finding of reduced mortality associated with use of ACEIs and ARBs in patients with hypertension is concordant with few other retrospective studies.
      • 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.
      ,
      • Meng J.
      • Xiao G.
      • Zhang J.
      • et al.
      Renin-angiotensin system inhibitors improve the clinical outcomes of COVID-19 patients with hypertension.
      Of relevance, recent studies have suggested a lower SARS-Cov-2 viral load and inflammatory marker levels in hypertensive patients taking ACEIs or ARBs compared with other antihypertensive medications.
      • 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.
      ,
      • Meng J.
      • Xiao G.
      • Zhang J.
      • et al.
      Renin-angiotensin system inhibitors improve the clinical outcomes of COVID-19 patients with hypertension.
      Our findings have important implications for the management of patients with COVID-19 and cardiovascular disease; SARS-CoV-2–mediated downregulation of ACE2 and immune dysregulation with endothelial dysfunction, myocardial injury, and prothrombotic state might lead to a downward spiral, thus accounting for worse outcomes in these patients.
      • Madjid M.
      • Safavi-Naeini P.
      • Solomon S.D.
      • Vardeny O.
      Potential effects of coronaviruses on the cardiovascular system: a review.
      Although the role of ACE2 as cellular receptor for SARS-CoV-2 entry into host cells is proven, human studies have been inconclusive with respect to the effect of RAS inhibitors on ACE2 levels.
      • Vaduganathan M.
      • Vardeny O.
      • Michel T.
      • McMurray J.
      • Pfeffer M.A.
      • Solomon S.D.
      Renin–angiotensin–aldosterone system inhibitors in patients with Covid-19.
      Furthermore, contradictory to the speculation that RAS inhibitor-mediated ACE2 upregulation might increase risk of infection, ACE2 expression has been suggested to protect against severe lung injury in these patients.
      • Kuba K.
      • Imai Y.
      • Rao S.
      • et al.
      A crucial role of angiotensin converting enzyme 2 (ACE2) in SARS coronavirus-induced lung injury.
      There are several limitations to our study. First, our pooled analyses were based on observational studies that have inherent risk of bias, owing to confounding variables. Patients taking ACEIs or ARBs have increased burden of other comorbidities that might make them more prone to fatality. However, despite this potential bias, we observed no association of use of ACEIs or ARBs with increased risk of mortality or severe illness. Second, ascertainment of drug data is limited in individual retrospective studies. It remains unknown whether continuation or withdrawal of these drugs during hospitalization influenced outcomes in patients admitted with COVID-19.
      In conclusion, our study provides reassurance that there is no increased risk of mortality or severe illness in patients using ACEIs and ARBs compared with nonusers. In patients with hypertension, use of ACEs and ARBs might be associated with reduced mortality: however, these findings need to be confirmed in prospective randomized controlled trials.

      Supplemental Online Material

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      Linked Article

      • Angiotensin-Converting Enzyme 2 and Antihypertensives (Angiotensin Receptor Blockers and Angiotensin-Converting Enzyme Inhibitors) in Coronavirus Disease 2019
        Mayo Clinic ProceedingsVol. 95Issue 6
        • Preview
          Coronavirus disease 2019 (COVID-19), caused by severe acute respiratory syndrome coronavirus 2, is being defined as the worst pandemic disease of modern times. Several professional health organizations have published position papers stating that there is no evidence to change the use of angiotensin-converting enzyme inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) in the management of elevated blood pressure in the context of avoiding or treating COVID-19 infection. In this article, we review the evidence on the relationship between the renin-angiotensin-aldosterone system and COVID-19 infection.
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      • In reply— Association of Renin-Angiotensin System Blockers with Outcomes in Patients With COVID-19
        Mayo Clinic ProceedingsVol. 95Issue 11
        • Preview
          Current guidelines and health professional recommendations endorse the continuation of both antihypertensives angiotensin-converting-enzyme (ACE) inhibitors (ACEIs) or angiotensin receptor blockers (ARBs) for managing hypertension (HTN) during the COVID-19 pandemic. We have emphasized repeatedly that it is highly unlikely that the use of ACEIs and ARBs would be associated with increased severity or mortality risk in patients with COVID-19.1,2 In the meta-analysis of Garg et al,3 which included studies published until May 31, 2020, both mortality and risk of severe disease were not increased among patients using ACEIs and ARBs.
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