Association Between Renin-Angiotensin-Aldosterone System Inhibitors and Clinical Outcomes in Patients With COVID-19

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.

article identified as having the potential to fulfill our inclusion criteria underwent full-text evaluation.
We included studies meeting the following criteria: (1) any study design, with the exception of narrative reviews and opinion-based articles; (2) adult (Ն18 years) study population; (3) participants with COVID-19 diagnosed through laboratory or radiological test results; and (4) assessment of clinical or mortality outcomes (unadjusted or adjusted) among patients receiving ACEIs/ARBs. The mortality and clinical severity data of patients receiving ACEIs/ARBs were compared with those of patients not receiving ACEIs/ARBs.

Data Extraction and Quality Assessment
Three authors (R.B., V.T., and M.D.) independently extracted relevant data from included studies using a standardized extraction form. Any disagreements were resolved by discussion. The data extracted included the type of study, the number and characteristics of patients receiving ACEIs/ ARBs, and mortality and severe AEs associated with COVID-19.
Severe AEs were defined as intensive care unit admission or the need for invasive or noninvasive ventilation. Studies reporting severe AEs based on information from the Chinese Center for Disease Control and Prevention 13 were included. To avoid double-counting of patients in studies reporting multiple severe AE outcomes, we included the outcome with the largest number of patients in our analyses. For instances in which distinct data for ACEIs/ARBs were available, an aggregate was used given the small likelihood of combined receipt of both drugs.
The Newcastle-Ottawa Scale, 14 a 9-point measure assessing the quality of cohort studies and case-control studies or case series, was used to evaluate the observational studies included. The Cochrane Risk of Bias 2 tool was used to assess the risk of bias in randomized clinical trials. 15

Statistical Analysis
For each outcome, a random-effects model was used to compare the odds ratios (ORs) and 95% CIs between patients who did and did not receive ACEIs/ARBs using Review Manager software, version 5.3 (Nordic Cochrane Center), and OpenMeta[Analyst] software, version 10.12 (Center for Evidence Synthesis, Brown University). 16 For studies reporting hazard ratios (HRs), those HRs were converted to ORs using methodology defined in the Cochrane Handbook for Systematic Reviews of Interventions. 17 Results from studies were grouped according to a prespecified variable (patients with hypertension [hypertension subgroup] vs patients with multiple mixed comorbidities [mixed subgroup]), and a series of subgroup analyses were performed. We also conducted a sensitivity analysis, in which studies reporting HRs (which were converted to ORs) were excluded to assess the robustness of results.
Statistical heterogeneity was assessed using the I 2 statistic. Potential publication bias was assessed using funnel plots. The statistical significance threshold was P < .05.     (Table).

Severe Adverse Events
Unadjusted values for severe AEs were reported in 48 studies that included a total of 98 985 participants. A pooled analysis found comparable results among patients who did and did not receive

Discussion
The results of this systematic review and meta-analysis of 52 studies with 101 949 total patients indicated a significant association between the receipt of ACEIs/ARBs and reductions in mortality and severe AEs among patients in the hypertension subgroup. In the mixed subgroup of patients with multiple comorbidities, this association was observed only when the analysis was adjusted for significant covariates.  outcomes across all patient groups.

JAMA Network Open | Cardiology
Notably, the protective implications of ACEIs/ARBs in the mixed subgroup were observed only after adjustments to potential and important confounders, such as age and comorbidities. This finding suggests that comorbidities may have an important role in COVID-19 clinical outcomes and that ACEIs/ARBs might be associated with further improvements in potential outcomes. In a large retrospective cohort study by Fosbol et al 27 that included 4480 patients with COVID-19, an unadjusted analysis indicated worse outcomes among those who received ACEIs/ARBs. However, after multivariate adjustments, this finding was no longer statistically significant. Similar results were observed in multiple small retrospective cohort studies. 29,36,42,54 It is worth noting that most studies included in the meta-analyses were retrospective and observational; with these study designs, unmeasured confounding factors and potential biases are inevitable. In addition, patients receiving ACEIs/ARBs are more likely to have heart failure, cardiovascular disease, hypertension, and comorbidities, which are associated with an increased risk of death among patients with COVID-19. 3 Therefore, it is necessary to adjust for these confounders when evaluating the protective benefits of ACEIs/ARBs for mortality and severe AEs. Test for overall effect: z = 3.82; P =.001 Test for subgroup differences: χ 2 = 0.51; df = 1; P =.48; I 2 = 0% 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.  Test for overall effect: z = 3.01; P =.003 Test for subgroup differences: χ 2 = 1.78; df = 1; P =.18; I 2 = 43.9% 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.

Limitations
This study has limitations. First, the study was limited by the insufficient data and varying study designs available, which did not allow for comparison of these analyses with a control group. The meta-analysis was primarily composed of observational studies because studies with higher levels of evidence, such as randomized clinical trials, were lacking. Second, the meta-analysis indicated substantial unadjusted and moderate adjusted levels of heterogeneity, which is typical in observational studies that include patients with diverse characteristics across large geographic regions. Nevertheless, measures were taken to maintain a homogeneous study population. A standard definition for severe AEs was used, and patients with unconfirmed COVID-19 were excluded. Third, we did not define the criteria for chronic receipt of ACEIs/ARBs. Insufficient description was available to distinguish between study participants, which is likely a factor associated with the increased heterogeneity observed in the study. With these limitations in mind, there were no data indicating that the receipt of ACEIs/ARBs was associated with harm if patients subsequently contracted COVID-19; on the contrary, ACEIs/ARBs may be associated with substantial protective benefits.

Conclusions
This comprehensive systematic review and meta-analysis of 52 studies indicated no higher risks of multivariable-adjusted mortality or severe AEs associated with the receipt of ACEIs/ARBs, which is consistent with recommendations for the continuation of these medications among patients for whom they are prescribed for the treatment of any condition. On the contrary, ACEIs and ARBs may be associated with protective benefits, particularly among patients with hypertension. Future randomized clinical trials are warranted to confirm the beneficial implications of these medications.