Despite previous research to the contrary, chronic use of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) do not exacerbate COVID-19. Rather, these therapies may confer a protective effect, and patients should continue receiving these therapies without an increased risk for worse COVID-19 outcomes. This is according to research results published in JAMA Network Open.

Since the start of the COVID-19 pandemic, numerous observational studies have evaluated the relationship between ACEI and ARB therapy and COVID-19 outcomes, due to the role of angiotensin-converting enzyme 2 as a binding site where viruses can gain cellular entry. Patients taking these medications, then, may experience exacerbated COVID-19 and worse outcomes. To further the clinical understanding of the relationship between clinical COVID-19 outcomes and the use of ACEIs and ARBs, researchers conducted a systematic review and meta-analysis of available literature through September 2020.

A total of 1788 studies were identified, of which 52 met inclusion criteria (participant N=101,949). The available research included 40 cohort studies, 6 case series, 4 case-control studies, 1 randomized clinical trial, and 1 cross sectional study. Of these 52 studies, 10 were classified as being of moderate quality, and 41 were ranked as high quality.

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In total, 41 studies with 69,577 participants compared mortality rates between those receiving and not receiving ACEIs or ARBs. Results of a pooled, unadjusted meta-analysis showed no increases in the risk for death among those on ACEI or ARB therapy (unadjusted odds ratio [OR], 1.05; 95% CI, 0.86-1.29; I2=85%).

This analysis did demonstrate significant mortality reductions in a subgroup of patients with hypertension who received ACEIs or ARBs (unadjusted OR, 0.66; 95% CI, 0.49-0.92), while a mixed subgroup of patients with multiple comorbidities demonstrated a significant mortality increase in the face of ACEI or ARB therapy (unadjusted OR, 1.46; 95% CI, 1.15-1.85).

Results of a pooled analysis of 17 studies with 17,392 total participants with an adjusted mortality analysis demonstrated a reduction in the risk for death among patients receiving vs not receiving ACEIs or ARBs (adjusted OR [aOR], 0.57; 95% CI, 0.43-0.76; I2=54.0%). Researchers noted a significant decrease in the risk for death in both subgroups (hypertension, aOR, 0.51; 95% CI, 0.32-0.84; mixed subgroup, aOR, 0.64; 95% CI, 0.46-0.88).

Forty-eight studies reported unadjusted values for severe adverse events (patient n=98,985). Results of a pooled analysis demonstrated results that were comparable across those treated or not treated with ACEIs or ARBs (unadjusted OR, 1.11; 95% CI, 0.95-1.31; I2=8%). Studies in both the hypertension and mixed comorbidities subgroups (n=26 and 33 studies) reported “statistically significant results” (unadjusted aOR, 0.70; 95% CI, 0.52-0.91 and unadjusted OR, 1.50; 95% CI, 1.25-1.81, respectively).

Twenty-three studies with 23,129 participants reported on the adjusted risk for severe adverse events associated with ACEI or ARB therapy in a cohort of people with COVID-19. A significant decrease in severe adverse events was noted among patients who received ACEI or ARB therapy (aOR, 0.68; 95% CI, 0.53-0.88; I2=67.0%); this reduced risk was significant in 12 studies across the hypertension subgroup (aOR, 0.55; 95% CI, 0.36-0.85).

Finally, results of a sensitivity analysis excluding studies reporting hazard ratios demonstrated “statistically significant results for mortality but nonsignificant results for severe [adverse events].” Studies of moderate and high quality showed a reduced risk of adjusted severe adverse events across both patient subgroups (OR, 0.36; 95% CI, 0.25-0.51 and OR, 0.78; CI, 0.60-1.00, respectively).

Study limitations include insufficient data and variable study design, which did not allow for comparison with a control group; substantial unadjusted and moderate adjusted levels of heterogeneity; and no definition for what constituted chronic use of ACEIs or ARBs.

“[R]eceipt of ACEIs or ARBs was not associated with a higher risk of multivariable-adjusted mortality and severe [adverse events] among patients with COVID-19 who had either hypertension or multiple comorbidities, supporting the recommendations of medical societies,” the researchers concluded. “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.”

Disclosure: One study author declared affiliations with the pharmaceutical industry. Please see the original reference for a full list of authors’ disclosures.


Baral R, Tsampasian V, Debski M, et al. Association between renin-angiotensin-aldosterone system inhibitors and clinical outcomes in patients with COVID-19: a systematic review and meta-analysis. JAMA Network Open. 2021;4(3):e213594. doi:10.1001/jamanetworkopen.2021.3594