COVID-19 Evidence Alerts
from McMaster PLUSTM

Current best evidence for clinical care (more info)

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Etiology Caldeira D, Alves M, Gouveia E Melo R, et al. Angiotensin-converting enzyme inhibitors and angiotensin-receptor blockers and the risk of COVID-19 infection or severe disease: Systematic review and meta-analysis. Int J Cardiol Heart Vasc. 2020 Dec;31:100627. doi: 10.1016/j.ijcha.2020.100627. Epub 2020 Aug 27.

Objective: Animal studies suggested that angiotensin-converting enzyme inhibitors (ACEi) and angiotensin-receptor blockers (ARB) facilitate the inoculation of potentially leading to a higher risk of infection and/or disease severity. We aimed to systematically evaluate the risk of COVID-19 infection and the risk of severe COVID-19 disease associated with previous exposure to (ACEi) and/or ARB).

Methods: MEDLINE, CENTRAL, PsycINFO, Web of Science Core Collection were searched in June 2020 for controlled studies. Eligible studies were included and random-effects meta-analyses were performed. The estimates were expressed as odds ratios (OR) and 95% confidence intervals (95%CI). Heterogeneity was assessed with I2 test. The confidence in the pooled evidence was appraised using the GRADE framework.

Results: Twenty-seven studies were included in the review. ACEi/ARB exposure did not increase the risk of having a positive test for COVID-19 infection (OR 0.99, 95%CI 0.89-1.11; I2 = 36%; 5 studies, GRADE confidence moderate). The exposure to ACEi/ARB did not increase the risk of all-cause mortality among patients with COVID-19 (OR 0.91, 95%CI 0.74-1.11; I2 = 20%; 17 studies; GRADE confidence low) nor severe/critical COVID-19 disease (OR 0.90, 95%CI 0.74-1.11; I2 = 55%; 17 studies; GRADE confidence very low). Exploratory analyses in studies enrolling hypertensive patients showed a association of ACEi/ARB with a significant decrease of mortality risk.

Conclusions: ACEi/ARB exposure does not seem to increase the risk of having the SARS-CoV-2 infection or developing severe stages of the disease including mortality. The potential benefits observed in mortality of hypertensive patients reassure safety, but robust studies are required to increase the confidence in the results.

Discipline / Specialty Area Score
Family Medicine (FM)/General Practice (GP)
Emergency Medicine
General Internal Medicine-Primary Care(US)
Intensivist/Critical Care
Hospital Doctor/Hospitalists
Internal Medicine
Infectious Disease
Comments from MORE raters

Emergency Medicine rater

This systematic review and meta-analysis included 27 studies and evaluates whether ACEi and/or ARB exposure was associated with risk of adverse outcome in COVID-19. The authors found no increased risk of COVID-19 infection or mortality with use of ACEi/ARB. All studies were observational, consisting of cohort and case control studies. The authors also conducted an exploratory analysis of hypertensive patients and suggest ACEi/ARB use may reduce mortality. However, all findings require further study. More robust data are needed, but ACEi/ARB are likely safe in COVID-19.

Emergency Medicine rater

An elegant analysis by Caldeira et al. showed again and reinforced the notion that ACE/ATII inhibition in COVID-19 patients is not associated with worse clinical outcomes, more severe disease and increased mortality. At the beginning of COVID-19 pandemic, suspicions were raised if the use of ACE or ARB inhibitors would increase the bioavailability of ACE2 receptor thus enabling virus an easier entrance into pulmonary vasculature, however, pathophysiologic explanations for such hypothesis were conflicting. Later into the pandemic, observational data started to emerge showing that there is no signal of harm in using these broadly used antihypertensive medications among hospitalized COVID-19 patients. Caldeira et al. essentially confirmed these observations in their analysis.

Emergency Medicine rater

As an Internist, I find these results very useful since they provide evidence for COVID-19 infection handling.

General Internal Medicine-Primary Care(US) rater

This analysis of 27 studies with moderate risk of bias showed that ACE and ARB use in patients was not associated with an increased risk of COVID-19 infection. There also was no increased risk of severe infection, and in some studies there was a slightly lower mortality. The evidence for mortality conclusion was weak and required further study.

General Internal Medicine-Primary Care(US) rater

This is a systematic review, with mixed randomized controlled trials and cohorts, with control (other antihypertensive drugs or any). So, by now, our patients can continue using the ACE/ARB, if they have a medical indication. The study supports the recommendations to warn against discontinuing these drugs in the absence of clear clinical evidence. One author has a conflict of interest and the study has risk of bias, so we should emphasize the need of further data.

Infectious Disease rater

This is a review of clinical evidence of effect of ACEi/ARB use in COVID-19 infection. No adverse effect is apparent. While most Infectious Diseases specialists probably already know this, the analysis in this paper demonstrates the relatively low quality of evidence that is currently available.

Intensivist/Critical Care rater

This is pertinent to COVID and a question that arose early in the pandemic. Numerous articles have been published demonstrating lack of big, significant effect of ACE-inhibition or angiotensin receptor blockers (ARBs). This meta-analysis confirms those studies.

Internal Medicine rater

Many systematic reviews have been and are being conducted on this topic with contrasting results: I doubt that this metanalysis will end the controversy. It was perhaps to be expected to have metanalyses concluding different things on such an hot topic for the reasons discussed by de Vrieze here: 10.1126/science.361.6408.1184.

Internal Medicine rater

There is low confidence in the quality of the evidence, but it's an important study anyway.