key: cord-0995369-2c1jpa8n authors: Zhang, Guoyue; Wu, Yue; Xu, Rui; Du, Xianzhi title: Effects of renin‐angiotensin‐aldosterone system inhibitors on disease severity and mortality in patients with COVID‐19: A meta‐analysis date: 2020-12-17 journal: J Med Virol DOI: 10.1002/jmv.26695 sha: 58e21182d145719e9c55314e520781036abd70b6 doc_id: 995369 cord_uid: 2c1jpa8n To investigate the effects of renin‐angiotensin‐aldosterone system (RAAS) inhibitors on the prognosis in patients with coronavirus disease 2019 (COVID‐19). A meta‐analysis was performed. We systematically searched PubMed, the Cochrane Library, the Web of Science, EMBASE, medRxiv, and bioRxiv database through October 30, 2020. The primary and secondary outcomes were mortality and severe COVID‐19, respectively. We included 25 studies with 22,734 COVID‐19 patients, and we compared the outcomes between patients who did and did not receive angiotensin‐converting enzyme inhibitors/angiotensin receptor blockers (ACEIs/ARBs). The use of ACEIs/ARBs was not associated with higher risks of severe disease (odds ratio [OR] = 0.89; 95% confidence interval [CI]: 0.63, 1.15; I (2) = 38.55%), mechanical ventilation (OR = 0.89; 95% CI: 0.61, 1.16; I (2) = 3.19%), dialysis (OR = 1.24; 95% CI: 0.09, 2.39; I (2) = 0.00%), or the length of hospital stay (SMD = 0.05; 95% CI: −0.16, 0.26; I (2) = 84.43%) in COVID‐19 patients. The effect estimates showed an overall protective effect of ACEIs/ARBs against mortality (OR = 0.65; 95% CI: 0.46, 0.85; I (2) = 73.37%), severity/mortality (OR = 0.69; 95% CI: 0.43, 0.95; I (2) = 22.90%), transfer to the intensive care unit among COVID‐19 patients with hypertension (OR = 0.36, 95% CI: 0.19, 0.53, I (2) = 0.00%), hospitalization (OR = 0.79; 95% CI: 0.60, 0.98; I (2) = 0.00%), and acute respiratory distress syndrome (OR = 0.71; 95% CI: 0.46, 0.95; I (2) = 0.00%). The use of RAAS inhibitor was not associated with increased mortality or disease severity in COVID‐19 patients. This study supports the current guidelines that discourage the discontinuation of RAAS inhibitors in COVID‐19 patients. carboxypeptidase that processes angiotensin II to the angiotensin (1-7) fragment, a vasodilatory, anti-inflammatory peptide. 4 ACE2 expression is particularly high in lung epithelial cells but is also present in cardiac myocytes and endothelial cells. [4] [5] [6] High ACE2 and angiotensin 1-7 levels play beneficial roles in cardiovascular and pulmonary diseases, suggesting that this pathway is involved in the overall benefits observed in patients treated with ACEIs and/ or ARBs. There are many similarities between severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) and SARS-CoV. These similarities are important because ACE2 was previously identified as a functional SARS-CoV receptor in vitro 7 and in vivo. 8 It is required for host cell entry and subsequent viral replication. 9 COVID-19 patients with cardiovascular disease are at increased risk of mortality. Quite often, these patients are being treated with drugs targeting the RAAS. The upregulation of ACE2 by ACEIs and ARBs has led to the hypothesis that these antihypertensive drugs might increase a patient's susceptibility to contracting COVID-19 and the likelihood of developing severe disease. Therefore, there is controversy regarding the clinical management of patients undergoing RAAS modulation by ACEIs/ARBs. It is important to determine whether the RAAS inhibitor (ACEI/ ARB) use is associated with increased risks of contracting and developing severe disease. Thus, we performed a meta-analysis of the available studies to explore whether the use of RAAS inhibitors was associated with severe disease and mortality in COVID-19 patients. This study involved a systematic review of the existing observational cohort studies examining the effect of the use of ACEIs/ ARBs on the outcome of COVID-19. We followed the Metaanalyses Of Observational Studies in Epidemiology (MOOSE) checklist. The protocol for this systematic review was registered with PROSPERO (CRD42020209389). Additionally, a manual search of the retrieved articles, related review articles, and meta-analyses was conducted to identify other eligible studies. The inclusion criteria were as follows: (1) study design: observational cohort studies; (2) grouping method: ARBs/ACEIs and non-ARBs/ACEIs group, according to their usage of antihypertensive drugs (the use of ACEIs and ARBs before admission and during hospital stay); and (3) availability of information needed to calculate odds ratios (ORs) or the adjusted data; (4) participants of studies are inpatients or outpatients. Editorials, correspondences, conference abstracts, and commentaries were excluded from our study. The preliminary screening and full-text evaluation were independently performed by two reviewers. The following data were extracted: (1) study information: author name, country, publication journal, study design, study population, sample source, confounder adjustments, and study quality. (2) Participant information: age, sex, comorbidity, and ACEI/ARB use. (3) Outcomes: the primary outcome was mortality in patients with COVID-19. The secondary outcomes were severe COVID-19, acute respiratory distress syndrome (ARDS), the need for mechanical ventilation, the need for dialysis, transfer to the intensive care unit (ICU), length of hospital stay, and hospitalization due to COVID-19. The full texts of the articles selected by one or both of the assessors were retrieved for the final evaluation. Two assessors read the full-text articles and independently extracted the information from the selected studies. A third assessor reviewed the data extraction, and any disagreement was resolved through consensus. The meta-analysis was performed using Stata 16.0 software. Heterogeneity was assessed using I 2 statistics. χ 2 tests were used to assess the homogeneity of the studies. The I 2 statistic reflects the proportion of the total variation observed between trials that is attributable to differences between the trials rather than to sampling error (chance). Random-effects models were used for the pooled analyses, regardless of the degree of heterogeneity. To provide a quantitative estimate of the associations between ACEI/ARB use and outcomes in COVID-19 patients, the ORs and corresponding 95% CIs were extracted from the published articles. When the OR was not given, tabular data were used to calculate the OR. Because the participants differed across the studies with regard to whether they had hypertension, subgroup analyses were performed. Publication bias was estimated visually based on funnel plots and quantitatively with Egger's test. A single study was used to analyze the source of heterogeneity. Furthermore, a meta-regression model was conducted to explore the potential modulators for ACEI/ARB treatment effects. The Newcastle Ottawa Scale was used to assess article quality. The quality of the studies was qualitatively evaluated by two independent assessors. Any disagreement with regard to the quality assessment was resolved through consensus. Studies with scores >7 were considered at low risk of bias, those with scores of 5-7 had a moderate risk of bias, and those with scores <5 had a high risk of bias. Articles with a high risk of bias were excluded. 10 3 | RESULTS Through the literature search, we retrieved 3204 articles. In total, 1448 articles were screened after duplicates were removed. After the titles and abstracts were read, 1233 articles were excluded. Among the remaining 215 papers, 25 articles were included in our study after the full texts were reviewed ( Figure 1 ). Table 3 ). Meta-regression analysis showed that asthma (p = .00) and cerebral vascular diseases (p = .00) have significant modulating effect of ACEIs/ARBs treatment on the mortality of COVID-19 patients (Table 4) . A single study was used to analyze the source of heterogeneity. However, no study is considered a source of heterogeneity (Appendix Figure A1 ). The overall assessment with the random-effects model showed (Table 3 ). In the analysis of the risk of transfer to the ICU, significant differences were observed between subgroups. In the studies involving people with hypertension, there was a significantly lower risk of transfer to the ICU in those taking ACEIs/ ARBs than in those not taking ACEIs/ARBs (OR = 0.36; 95% CI: 0.19, 0.53; I 2 = 0.00%; Figure 3 and Table 3 ). Meta-regression analysis showed that age (p = .01) and malignancy (p = .01) has a significant modulating effect of ACEIs/ARBs treatment on the risk of transfer to the ICU of COVID-19 patients (Table 4) . Furthermore, meta-regression analysis showed that all the modulators have no significant modulating effect of ACEIs/ARBs treatment on the severity of COVID-19 patients (p > .05, Table 4 ). (Table 3) . However, the analysis had a significant publication bias (Appendix Figure A2 ). Meta-regression analysis showed that chronic obstructive pulmonary disease (COPD) has a significant modulating effect of ACEIs/ARBs treatment on the length of hospital stay of COVID-19 patients (p = .01, Table 4 ). This meta-analysis included 25 articles that included more than ACEIs and ARBs are the cornerstone of a prognostically beneficial heart failure therapy with the highest level of evidence with regard to the reduction in mortality. 43 These drugs all have in common the inhibition of the adverse cardiovascular effects arising from the interaction of angiotensin II with angiotensin II receptor type 1. Discontinuation of heart failure therapy leads to the deterioration of cardiac function and heart failure within days to weeks, with a possible consequent increase in mortality. 44 patients. Furthermore, the characteristics of the studies (e.g., methodological differences in the study design and variables used for adjustment), or even differences in recruitment, the timing of outcome measurements and the population (such as unknown environmental factors and/or underlying comorbidities), were certainly very important variables that may explain the heterogeneity of the data set as a whole. Another limitation is that the measurement of ACEI/ARB exposure was through medical record review or prescription, which is less reliable than other methods. Third, the definitions of COVID-19 severity and outcomes were inconsistent among the included studies. 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Position Statement of the ESC Council on Hypertension on ACE-Inhibitors and Angiotensin Receptor Blockers HFSA/ACC/AHA statement addresses concerns Re: using RAAS antagonists in COVID-19 Effects of renin-angiotensin-aldosterone system inhibitors on disease severity and mortality in patients with COVID-19: A meta-analysis APPENDIX A A 2 The result of Begg's test of ACEI/ARB use and the length of hospital stay in COVID-19 patients. ACEI, angiotensinconverting enzyme inhibitor The single study of ACEI/ARB use and the risk of mortality in COVID-19 patients. ACEI, angiotensin-converting enzyme inhibitor The authors declare that there are no conflict of interests. The data that support the findings of this study are available from the corresponding author upon reasonable request. http://orcid.org/0000-0002-9052-5980