key: cord-261070-cvj1t0gi
authors: Zhang, Xue; Yu, Jiong; Pan, Li-ya; Jiang, Hai-yin
title: ACEI/ARB Use and Risk of Infection or Severity or Mortality of COVID-19: A Systematic Review and Meta-analysis
date: 2020-05-15
journal: Pharmacol Res
DOI: 10.1016/j.phrs.2020.104927
sha: 
doc_id: 261070
cord_uid: cvj1t0gi

We have sparse knowledge of the effects of angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs) on the risk of COVID-19 infection and the progression of this disease. We systematically assessed these relationships. Unrestricted searches of the PubMed, Embase, and Cochrane Library databases were conducted, with an end date of May 9, 2020, to identify relevant studies that met predetermined inclusion criteria. Random-effects models were adopted to estimate the overall relative risk. Fourteen articles involving more than 19000 COVID-19 cases were included. Our results showed that ACEI/ARB exposure is not associated with a higher risk of COVID-19 infection (OR = 0.99; 95% CI, 0.95-1.04; P = 0.672). Among those with COVID-19 infection, ACEI/ARB exposure is not associated with a higher risk of severity (OR = 0.98; 95%CI 0.87-1.09; P = 0.69) or mortality (OR = 0.73, 95%CI 0.5-1.07; P = 0.111). However, ACEI/ARB exposure was associated with a lower risk of mortality compared those with non-ACEI/ARB antihypertensive drugs (OR = 0.48, 95% CI 0.29-0.81; P = 0.006). In conclusion, current evidence did not confirm previous concern regarding a harmful role of ACEI/ARB in COVID-19 patients. The present study support current professional society guidelines to not discontinue ACEIs or ARBs in the setting of the COVID-19 pandemic or COVID-19 patients.

Since first confirmed case in Wuhan in 2019(1), the Coronavirus Disease 2019 rapidly spread on a global scale and more than three million confirmed infections have been reported according to the World Health Organization (WHO) (2) .

To date, there is no specific or effective therapies approved for treatment of this fatal disease (3) . In many countries, the public health services are being overwhelmed by a rapid rise in new cases of COVID-19, resulting in a high severity or mortality of this infectious disease (4, 5) . Thus, clinicians should identify the risk factors of COVID-19, pay attention to the risk factors of critical disease and death in confirmed cases, and then take appropriate interventions, which may help to prevent infection, enhance the efficacy and reduce the risk of death.

The latest systematic review reported that hypertension and cardiovascular disease (CVD) was associated with a higher risk of severity and mortality in patients with COVID-19 (6) . However, patients with these comorbidities are likely treated with angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin receptor blockers (ARBs), which could upregulate the expression of ACE2 receptor in animal-based studies (7, 8) . Because ACE2 is used by coronaviruses as a functional receptor for their entrance into the cells (9) , there is concern about the potential of an increased risk of COVID-19 positive among those with ACEI/ARB use (10) . Conversely, there evidence from various acute respiratory distress syndrome (ARDS) animal models that exogenous ACE2 supplementation can reduce inflammation and increase oxygenation (11) . Epidemiological studies also observed ACEI/ARB use may reduce the risk of pneumonia in general population(12, 13). These observations have led to concerns that whether ACEI/ARB exposure is associated with the risk or progress of COVID-19. In order to provide more accurate evidences on this topic, we searched the relevant literatures and conducted a meta-analysis. Thus, the aims of the present study were as follows: (1) to determine whether use of ACRI/ARB is associated with an increase in likelihood of viral infectivity; (2) to investigate whether there are differences in severity and mortality between ACRI/ARB users and non-ACRI/ARB users; (3) and, in particular, to evaluate whether ACRI/ARB exposure was associated J o u r n a l P r e -p r o o f with a lower risk of mortality when compared to non-ACRI/ARB antihypertensive drug exposure. Our findings provide vital guidance for current clinical work on the prevention and treatment of COVID-19 infection.

J o u r n a l P r e -p r o o f

To ensure that the work was of high quality, we followed the Preferred Reporting Items of Systematic Reviews and Meta-analysis (PRISMA) statement. A comprehensive search of the PubMed, Embase, and Cochrane Library databases was performed to identify relevant articles published between Jan 1, 2020 and May 9, 

Observational studies met all following criteria were included: (1) study design: a case-control or case-crossover or self-controlled case series (SCCS) or cohort study;

(2) antihypertensive treatment: ACEI/ARB use versus non-ACEI/ARB use; (3) outcomes: the incidence of COVID-19 or critical cases or death. (5) adequate data were used to extract risk estimates if adjusted data were not provided in the studies.

Editorials, correspondences, conference abstracts and commentary articles were excluded in our study. When incomplete information was available, attempts were made to contact the study investigators for additional information.

Two investigators in a double-blinded manner independently extracted all data and any disagreement was resolved by a third investigator. The following information was extracted: name of first author, publication year, research type, study location, age, gender, number of diabetes, number of participants, confounder adjustment, and study quality. For more than one estimates of effect was provided, we chose the most-adjusted estimate. The methodological quality assessment was evaluated based J o u r n a l P r e -p r o o f on the Newcastle Ottawa Scale (NOS) (14) . The NOS features eight criteria and yields scores ranging from 0 (high risk of bias) to 9 (low risk of bias). Studies with NOS scores of >7 were regarded as high quality.

All meta-analytical calculations were performed with STATA software (version 14.0, Stata Corp LP, College Station, Texas). To provide a quantitative estimate of the association of ACEI/ARB use with critical or mortal risk in COVID-19 patients, the ORs (most adjusted, if available) and the corresponding 95% CIs were abstracted from published articles. When the ORs were not given, they were calculated from tabular data. Statistical heterogeneity of the included studies was calculated by χ 2 test and the I 2 statistic; an I 2 of >50% or a P<0.05 for the Q-statistic was considered to indicate substantial heterogeneity (15) . A random-effects model of DerSimonian-Laird rather than a fixed effects model was used for comparison due to the between-study variance(16). Egger's regression test was employed to evaluate the publication bias (17) . Publication bias was not formally assessed because each meta-analysis included fewer than 10 studies. Statistical significance was set at a level of P<0.05 (18) . 

The described search strategy identified 535 studies, of which 232 articles were thereafter excluded because of duplication. 251 articles were discarded after reading the title and abstract, and the remaining 53 articles underwent full-text evaluation.

One study (19) published as poster in our hospital and the author was contacted for additional information. Finally, 12 articles (19) (20) (21) (22) (23) (24) (25) (26) (27) (28) (29) (30) included in our meta-analysis involved more than 19,000 COVID-19 patients from 7 cohort studies and 5 case-control studies. A selection of excluded studies and the reasons for exclusion are listed in Figure 1 .

The characteristics of 12 studies are shown in Table 1 . Four studies (22, 26, 28, 30) were performed in Italy and USA, and one (29) The results of the quality assessment of the included studies are presented in Supplementary Table S1 and S2.

Three studies reported the susceptibility of COVID-19 in relation to ACEI/ARB use; the combined OR of COVID-19 risk was 0.99 (95% CI, 0.95-1.04), no heterogeneity was observed among the studies (I 2 = 0%, P = 0.504; Table 2 ). . When we grouped studies by type of drug, no significant higher risk of COVID-19 was observed among The overall analysis included nine studies, together including 1631 ACEI/ARB-exposed and 11620 unexposed COVID-19 cases; these were used in estimating the risk associated with ACEI/ARB use and mortality. In our overall analysis, the risk of mortality in ACEI/ARB exposed was similar to non-ACEI/ARB exposed in COVID-19 patients (OR=0.73, 95%CI 0.5-1.07, P=0.11). Severe heterogeneity was observed among the studies (I 2 =70.7%; P=0.001; Figure 2 ). In subgroup analyses by type of data, no significant higher risk of mortality was When our analysis limited to the studies only included patient with antihypertensive indication, a significant lower risk of mortality was observed among those with ACEI/ARB use (OR=0.62, 95%CI 0.38-1.02, P=0.059; Figure 3 ). After excluded studies enrolled patients with hypertension but without antihypertensive treatment, the meta-analysis of four studies also found that ACEI/ARB exposure was associated with a lower risk of mortality compared those with non-ACEI/ARB antihypertensive drugs (OR=0.48, 95% CI 0.29-0.81, P=0.006; I 2 =0%).

Seven studies including 3070 ACEI/ARB-exposed and 3830 unexposed COVID-19 cases reported the risk of severity in relation to ACEI/ARB exposure; the combined OR of severity of COVID-19 was 0.98 (95%CI 0.87-1.09, P=0.69; Figure 4 ). 

In the present review, we included 14 articles involving more than 19000 COVID-19 cases. Our findings suggest that ACEI/ARB use did not increase the risk of a positive test for COVID-19 or severity or mortality among patients with COVID-19. However, exposure to ACEI/ARB in those with drug indication or hypertension was associated with a lower risk of mortality. This has potentially important implications in clinical practice.

Several systematic reviews (6, 31, 32) have demonstrated that individuals with underlying illness such as hypertension and cardiovascular disease tend to be susceptible to COVID-19. However, ACEI/ARB was widely used among these patients, which raises the concerns about the potential advantages and disadvantages of ACEI/ARB use (33) . SARS-CoV-2 binds to the extracellular domain of the transmembrane ACE2 receptor to gain entry into host cells (9) . While ACEI and ARB have been shown to upregulate ACE2 expression in animal studies (7, 8) , it is reasonable to hypothesize that hypertensive patients taking these drugs may have a higher risk of COVID-19 infection. Contrary to this hypothesis, our analysis did not provide evidence that patients should stop or substitute the ACEI or ARB medications previously prescribed. This may be result for two reasons. First, the effects of ACEI/ARB on the level of human plasma ACE2 are inconsistent (34) , and no studies evaluate their effect on lung-specific expression of ACE2 (35) . To be relevant in SARS-CoV-2 infection, the effect on ACE2 would need to be present on respiratory epithelium. Second, beta blockers are identified to prevent the ACE2 activity (36) , which could underestimate the risk of ACEI/ARB-associated COVID-19.

Another important issue is the ACEI/ARB use on the clinical outcomes of COVID-patients. Upon binding to ACE2, SARS-CoV subsequently reduce ACE2 expression in host cells, resulting in activation of RAS, which in turn caused severe acute lung injury and exacerbated pneumonia progression (11) . According this theory, RAS inhibitor use may improve the clinical outcomes of the patients with COVID-19.

In our overall analysis, ACEI/ARB exposure is not associated with a lower risk of severity or mortality. This may be explained by the drug indication. The latest J o u r n a l P r e -p r o o f systematic review (6) has identified that COVID-19 patients with hypertension and CVD faced a greater risk of developing into the critical or mortal condition. Several studies (20, 22, 25, 30) included patients without hypertension and CVD in non-ACEI/ARB group, which may underestimate the protective effect of ACEI/ARB use in COVID-19 patients. Further analysis limited to studies only included patients with drug indication found a lower risk of mortality among those with ACEI/ARB use.

This finding is further reinforced by a relatively lower but significant risk observed in patients with hypertension.

To our knowledge, this systematic and meta-analysis is the first to evaluate the role of ACEI/ARB antihypertensive regimen in patients with COVID-19. The key strength of our meta-analysis lies in its large sample size and comprehensive search. With the accumulating evidence and enlarged sample size we have enhanced statistical power to provide more precise and reliable risk estimates. In our included studies, more than 19000 COVID case were included in the severity and mortality analysis. Furthermore, we conducted additional analyses to control for confounding by indication.

Nonetheless, our review has some major limitations. The most important limitation of our meta-analysis is the residual unknown confounders. Previous studies have reported that sex, age, smoking, and diabetes greatly affect the prognosis of the COVID-19. However, these potential confounders considered in the most of included studies. Future research should report analyses stratified by possible risk factors that fully adjust for potential confounders in order to rule out alternative explanations.

Second, the number of eligible high-quality studies was small, which may have influenced the accuracy of our results. Third, the measurement of ACEI/ARB exposure was through medical record review. Therefore, the method that collected the exposure information was unreliable, which may have influenced our findings. Fourth, although only mild heterogeneity was observed in severity analyses, the existence of clinical heterogeneity would be expected to lead to a degree of statistical heterogeneity in the results. The definition of COVID-19 severity and outcomes assessment were inconsistent among the included studies. Fifth, the study population of present review was mainly from hospital, which is susceptible to selection bias.

In conclusion, the results of our meta-analysis did not confirm previous concerns regarding a higher risk of COVID-19 infection, or severity and mortality in COVID-19 patients. However, a lower risk of mortality was observed among those patients with hypertension. Our findings suggested that ACEI/ARB should be continued as antihypertensive therapy for COVID-19 patients.

H.Y.J. and Z.X. conceived the study and revised the manuscript critically for important intellectual content. Z.X., and J.Y. made substantial contributions to its design, acquisition, analysis and interpretation of data. L.Y.P. participated in the design, acquisition, analysis and interpretation of data. All authors read and approved the final manuscript.

This study was supported by Natural Science Foundation of Zhejiang Province (Grant No. LY20H090012).

The authors declare that they have no competing interest. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.

J o u r n a l P r e -p r o o f 

A familial cluster of pneumonia associated with the 2019 novel coronavirus indicating person-to-person transmission: a study of a family cluster

The origin, transmission and clinical therapies on coronavirus disease 2019 (COVID-19) outbreakan update on the status

Efficacy and safety of current therapeutic options for COVID-19 -lessons to be learnt from SARS and MERS epidemic: A systematic review and meta-analysis

Global epidemiology of coronavirus disease 2019 (COVID-19): disease incidence, daily cumulative index, mortality, and their association with country healthcare resources and economic status

Prevalence and severity of corona virus disease 2019 (COVID-19): A systematic review and meta-analysis

Risk factors of critical & mortal COVID-19 cases: A systematic literature review and meta-analysis

Increased expression of angiotensin converting enzyme 2 in conjunction with reduction of neointima by angiotensin II type 1 receptor blockade. Hypertension research : official journal of the

Effect of angiotensin-converting enzyme inhibition and angiotensin II receptor blockers on cardiac angiotensin-converting enzyme 2

A new coronavirus associated with human respiratory disease in China

Is the ACE2 Overexpression a Risk Factor for COVID-19 Infection? Archives of medical research

enzyme inhibitors: results of a meta-analysis of five studies in Asians

Pneumonia risk and use of angiotensin-converting enzyme inhibitors and angiotensin II receptor blockers

Cochrane handbook for systematic reviews of interventions version 5.1.0. The Cochrane collaboration. Available at: www.cochrane-handbook.org

Quantifying heterogeneity in a meta-analysis

Measuring inconsistency in meta-analyses

Bias in meta-analysis detected by a simple, graphical test

The case of the misleading funnel plot

Long term use of ACEI/ARB contributes to the outcomes of COVID-19 patients with hypertension: a multicenter retrospective study2020

COVID-19 with Different Severity: A Multi-center Study of Clinical Features

Association of Inpatient Use of Angiotensin Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers with Mortality Among Patients With Hypertension Hospitalized With COVID-19

Clinical impact of renin-angiotensin system inhibitors on in-hospital mortality of patients with hypertension hospitalized for COVID-19

Renin-angiotensin system inhibitors improve the clinical outcomes of COVID-19 patients with hypertension. Emerging microbes & infections

Effects Of ARBs And ACEIs On Virus Infection, Inflammatory Status And Clinical Outcomes In COVID-19 Patients With Hypertension: A Single Center Retrospective Study

Risk factors for severity and mortality in adult COVID-19 inpatients in Wuhan

Association of Use of Angiotensin-Converting Enzyme Inhibitors and Angiotensin II Receptor Blockers With Testing Positive for Coronavirus Disease 2019 (COVID-19)

Association of Renin-Angiotensin System Inhibitors With Severity or Risk of Death in Patients With Hypertension Hospitalized for Coronavirus Disease 2019 (COVID-19) Infection in Wuhan, China

Renin-Angiotensin-Aldosterone System Blockers and the Risk of Covid-19

Cardiovascular Disease, Drug Therapy, and Mortality in Covid-19

Renin-Angiotensin-Aldosterone System Inhibitors and Risk of Covid-19

Does comorbidity increase the risk of patients with COVID-19: evidence from meta-analysis

Diabetes mellitus is associated with increased mortality and severity of disease in COVID-19 pneumonia -A systematic review, meta-analysis, and meta-regression: Diabetes and COVID-19. Diabetes and Metabolic Syndrome

Does the direct renin inhibitor have a role to play in attenuating severity of the outbreak coronavirus disease 2019 (COVID-19)?

Physiological and pathological regulation of ACE2, the SARS-CoV-2 receptor

Aldosterone System Inhibitors in Patients with Covid-19. The New England journal of medicine

Beta blockers prevent correlation of plasma ACE2 activity with echocardiographic parameters in patients with idiopathic dilated cardiomyopathy