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

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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.


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.

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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.

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  • 1.00 Self-Assessment points in the American Board of Otolaryngology – Head and Neck Surgery’s (ABOHNS) Continuing Certification program;
  • 1.00 MOC points in the American Board of Pediatrics’ (ABP) Maintenance of Certification (MOC) program;
  • 1.00 Lifelong Learning points in the American Board of Pathology’s (ABPath) Continuing Certification program; and
  • 1.00 CME points in the American Board of Surgery’s (ABS) Continuing Certification program

It is the CME activity provider's responsibility to submit participant completion information to ACCME for the purpose of granting MOC credit.

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