Risks and Impact of Angiotensin-Converting Enzyme Inhibitors or Angiotensin-Receptor Blockers on SARS-CoV-2 Infection in Adults: A Living Systematic Review

Abstract

Background: The role of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin-receptor blockers (ARBs) in coronavirus disease 2019 (COVID-19) susceptibility, severity, and treatment is unclear.

Purpose: To evaluate, on an ongoing basis, whether use of ACEIs or ARBs either increases risk for severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection or is associated with worse COVID-19 disease outcomes, and to assess the efficacy of these medications for COVID-19 treatment.

Data sources: MEDLINE (Ovid) and Cochrane Database of Systematic Reviews from 2003 to 4 May 2020, with planned ongoing surveillance for 1 year; the World Health Organization database of COVID-19 publications and medRxiv.org through 17 April 2020; and ClinicalTrials.gov to 24 April 2020, with planned ongoing surveillance.

Study selection: Observational studies and trials in adults that examined associations and effects of ACEIs or ARBs on risk for SARS-CoV-2 infection and COVID-19 disease severity and mortality.

Data extraction: Single-reviewer abstraction confirmed by another reviewer, independent evaluation by 2 reviewers of study quality, and collective assessment of certainty of evidence.

Data synthesis: Two retrospective cohort studies found that ACEI and ARB use was not associated with a higher likelihood of receiving a positive SARS-CoV-2 test result, and 1 case-control study found no association with COVID-19 illness in a large community (moderate-certainty evidence). Fourteen observational studies, involving a total of 23 565 adults with COVID-19, showed consistent evidence that neither medication was associated with more severe COVID-19 illness (high-certainty evidence). Four registered randomized trials plan to evaluate ACEIs and ARBs for treatment of COVID-19.

Limitation: Half the studies were small and did not adjust for important confounding variables.

Conclusion: High-certainty evidence suggests that ACEI or ARB use is not associated with more severe COVID-19 disease, and moderate-certainty evidence suggests no association between use of these medications and positive SARS-CoV-2 test results among symptomatic patients. Whether these medications increase the risk for mild or asymptomatic disease or are beneficial in COVID-19 treatment remains uncertain.

Primary funding source: None. (PROSPERO: registration number pending).

Figure 1.

ACE2, the RAS, and SARS-CoV-2 infection. As part of the RAS, ACE2 (green) regulates the levels of angiotensin II. As the functional receptor for SARS-CoV-2, ACE2 may facilitate viral entry into cells. This figure illustrates the role of ACE2 in the RAS and how pharmacologic RAS blockade with ACEIs or ARBs (red) could theoretically increase the amount of ACE2 available for viral binding. ACE2 = angiotensin-converting enzyme 2; ACEI = angiotensin-converting enzyme inhibitor; ARB = angiotensin-receptor blocker; AT₁ = type 1 angiotensin receptor; RAS = renin–angiotensin system; SARS-CoV-2 = severe acute respiratory syndrome coronavirus 2.

Figure 2.

Evidence search and selection based on the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) approach (as of 4 May 2020).