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

Abstract

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.

Figure 1.. Subgroup Analysis of Unadjusted Mortality Among Patients Who Did and Did Not Receive ACEIs or ARBs

Subgroup analysis of mortality in 41 studies of patients who did and did not receive ACEIs or ARBs. A total of 19 studies included a mixed subgroup (a sample population with multiple mixed comorbidities), and 22 studies included a hypertension subgroup (a sample population with hypertension). Diamonds represent 95% CIs for subtotal and total ORs. ACEI indicates angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; and OR, odds ratio.

Figure 2.. Subgroup Analysis of Adjusted Mortality Among Patients Who Did and Did Not Receive ACEIs or ARBs

Subgroup analysis of adjusted mortality in 16 studies of patients who did and did not receive ACEIs or ARBs. A total of 7 studies included a mixed subgroup (a sample population with multiple mixed comorbidities), and 9 studies included a hypertension subgroup (a sample population with hypertension). Diamonds represent 95% CIs for subtotal and total ORs. ACEI indicates angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; and OR, odds ratio.

Figure 3.. Subgroup Analysis of Unadjusted Mortality and Severe Adverse Events Among Patients Who Did and Did Not Receive ACEIs or ARBs

Subgroup analysis of mortality and severe adverse events in 48 studies of patients who did and did not receive ACEIs or ARBs. A total of 22 studies included a mixed subgroup (a sample population with multiple mixed comorbidities), and 26 studies included a hypertension subgroup (a sample population with hypertension). Diamonds represent 95% CIs for subtotal and total ORs. ACEI indicates angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; and OR, odds ratio.

Figure 4.. Subgroup Analysis of Adjusted Mortality and Severe Adverse Events Among Patients Who Did and Did Not Receive ACEIs or ARBs

Subgroup analysis of adjusted mortality and severe adverse events in 23 studies of patients who did and did not receive ACEIs or ARBs. A total of 11 studies included a mixed subgroup (sample population with multiple mixed comorbidities), and 12 studies included a hypertension subgroup (defined as a sample population with hypertension). Diamonds represent 95% CIs for subtotal and total ORs. ACEI indicates angiotensin-converting enzyme inhibitor; ARB, angiotensin receptor blocker; and OR, odds ratio.