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. 2022 Jun 20;2(4):282–290. doi: 10.1016/j.jointm.2022.05.004

The effect of renin–angiotensin–aldosterone system inhibitors in patients with hypertension and COVID-19: A meta-analysis of randomized controlled trials and propensity score-matched studies

Kai Zhang 1, Lanxin Cao 1, Nanxia Xuan 1, Tiancha Huang 1, Baoping Tian 1, Wei Cui 1, Gensheng Zhang 1,2,⁎, Shufang Zhang 3,⁎
PMCID: PMC9212589  PMID: 36785646

Abstract

Background

High-quality evidence for whether the use of renin–angiotensin–aldosterone system (RAAS) inhibitors worsens clinical outcomes for patients with coronavirus disease 2019 (COVID-19) is lacking. The present study aimed to evaluate the effect of RAAS inhibitors on disease severity and mortality in patients with hypertension and COVID-19 using randomized controlled trials (RCTs) and propensity score-matched (PSM) studies.

Methods

A literature search was conducted with PubMed, Embase, and Scopus databases from 31 December 2019 to 10 January 2022. We included RCTs and PSM studies comparing the risk of severe illness or mortality in patients with hypertension and COVID-19 treated or not treated with RAAS inhibitors. Individual trial data were combined to estimate the pooled odds ratio (OR) with a random-effects model.

Results

A total of 17 studies (4 RCTs and 13 PSM studies) were included in the meta-analysis. The use of RAAS inhibitors was not associated with an increased risk of severe illness (OR=1.00, 95% confidence interval [CI]: 0.88–1.14, I2=28%) or mortality (OR=0.96, 95% CI: 0.83–1.11, I2=16%) for patients with hypertension and COVID-19. Furthermore, there was no significant difference in the severity of COVID-19 when patients continued or discontinued treatment with RAAS inhibitors (OR=1.01, 95% CI: 0.78–1.29, I2=0%).

Conclusions

This study suggests that there was no association between treatment with RAAS inhibitors and worsened COVID-19 disease outcomes. Our findings support the current guidelines that RAAS inhibitors should be continued in the setting of the COVID-19 pandemic. However, the benefit of RAAS inhibitor medications for COVID-19 patients should be further validated with more RCTs.

Keywords: COVID-19, Hypertension, RAAS Inhibitors, ACEIs, ARBs, Meta-analysis

Introduction

The coronavirus disease 2019 (COVID-19), caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2), has rapidly developed into a pandemic and threatened global health.[1] As of 21 January 2022, SARS-CoV-2 has resulted in >340.5 million confirmed cases of COVID-19, with >5.5 million deaths.[2] There is currently a lack of specific or effective intervention approved for treating COVID-19. Thus, the presence of risk factors associated with negative clinical outcomes arouses concern for those with COVID-19. Therefore, identifying these risk factors is needed. Previous research suggests that pre-existing chronic diseases, including hypertension, diabetes, cardiovascular disease, and chronic kidney disease, are associated with a greater risk of the development of COVID-19 into a critical or mortal condition.[3], [4] In fact, 21.8% of 1,320,488 COVID-19 patients in the United States and 26.0% of 20,982 COVID-19 patients in China had at least one comorbidity, and hypertension seems to be one of the most common comorbidities.[5], [6]

Inhibitors of the renin–angiotensin–aldosterone system (RAAS), including angiotensin-converting enzyme inhibitors (ACEIs) and angiotensin II receptor blockers (ARBs), are widely used for different clinical indications, and the above-mentioned chronic conditions frequently require treatment with these two classes of medications.[7] Animal and human studies have shown that ACEIs/ARBs may increase the expression of angiotensin-converting enzyme 2, which is a coreceptor for SARS-CoV2.[8], [9], [10], [11] Therefore, it is concerning that treatment with ACEIs and/or ARBs may increase both susceptibility to SARS-CoV2 infection and the risk of its developing into a severe form of COVID-19.[12], [13] On the contrary, a recent study suggested that the ACEI treatment was associated with dampened hyperinflammation related to COVID-19 and increased cell intrinsic antiviral responses, whereas ARBs treatment was associated with enhanced epithelial-immune cell interactions.[14] Therefore, the effect of ACEIs/ARBs on patients with COVID-19 has been at the forefront of clinical debates.

Several observational studies with large sample sizes consistently demonstrated that the use of ACEIs/ARBs was not associated with severe disease or mortality among patients with COVID-19.[15], [16], [17] One study performed multivariable analyses and the adjusted estimates suggested that in-hospital use of ACEIs/ARBs might reduce the risk of severe disease or all-cause mortality for COVID-19 patients with hypertension.[18] However, one study suggested that taking ACEIs/ARBs might be associated with worsened clinical outcomes, such as requiring intensive care or mechanical ventilation.[19] The conflicting results obtained from observational studies combined with the recent completion of randomized controlled trials (RCTs)[20], [21], [22], [23] prompted us to summarize the data thus far to provide an updated perspective and an understanding of the association between the use of ACEIs/ARBs and clinical COVID-19 outcomes. In addition, a large body of statistical literature and meta-epidemiological studies have shown that propensity score-matched (PSM) studies are empirically equivalent to RCTs in their ability to derive unbiased estimates.[24], [25], [26] Therefore, the aim of the updated meta-analysis was to summarize the latest evidence of RCTs and PSM studies to evaluate the association between the use of ACEIs/ARBs and the prognosis of patients with hypertension and COVID-19.

Methods

Study selection

This meta-analysis was conducted in accordance with the updated Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) guidelines[27] (see Supplementary Material 1). The study protocol was registered in PROSPERO (CRD42020187284). Two authors (Kai Zhang and Lanxin Cao) independently searched PubMed, Embase, and Scopus databases for relevant articles published in English from 31 December 2019 to 10 January 2022 (search strategies are listed in Supplementary Material 2). The inclusive criteria were as follows: (1) population: patients with hypertension and COVID-19 infection that was diagnosed on the basis of the standard procedure proposed by the World Health Organization; (2) intervention: patients treated with ACEIs or ARBs; (3) comparator: patients not treated with ACEIs or ARBs; (4) outcomes: severe COVID-19 (characterized by admission to the intensive care unit [ICU], use of mechanical ventilation, in-hospital mortality or defined according to the diagnosis and treatment guidelines for COVID-19); and (5) study design: RCTs and PSM studies. In addition, case reports, non-human studies, studies without adequate information or concerning outcomes, and studies focusing on special populations (e.g., pediatric, pregnant, and cancer patients) were excluded.

Data extraction and quality assessment

Two reviewers (Kai Zhang and Lanxin Cao) independently extracted detailed information (first author, study period, study location, sample size, population characteristics, and outcomes) using a predesigned table. If relevant information was not reported in the article, we contacted the corresponding authors for further information.

Two reviewers (Tiancha Huang and Baoping Tian) independently assessed the quality of the included RCTs using the Cochrane risk of bias tool[28] and the quality of the included PSM studies using the Newcastle-Ottawa Scale for cohort studies.[29] Publication bias was assessed using Egger's regression test. Any discrepancies in all phases were ultimately resolved by arriving at a team consensus.

Statistical synthesis and analysis

We performed pooled analysis to estimate the association between the use of ACEIs/ARBs and the risk of severe illness or mortality. A random-effects model was used to calculate the odds ratio (OR) with a 95% confidence interval (95% CI). For studies reporting hazard ratios (HRs), we converted the HR into an OR using the methodology defined in the Cochrane Handbook for Systematic Reviews of Interventions. We calculated the I2 statistic to quantify the heterogeneity between studies, where I2 values of <25%, 25–75%, and >75% indicate low, moderate, and high heterogeneity, respectively.[30] We stratified studies by study design (RCTs vs. PSM studies) and severity of COVID-19 disease according to the Guidelines of Diagnosis and Treatment of COVID-19 (ninth edition) from the National Health Commission to perform subgroup analyses. Furthermore, a sensitivity analysis was employed to examine the effect of an individual study by omitting each at a time. All analyses were performed with Review Manager 5.3 (Nordic Cochrane Center), and a P-value <0.05 was assumed to have statistical significance.

Results

Study selection and study characteristics

The flow chart [Figure 1] summarizes the search and study selection processes. A total of 1209 articles were initially identified. After removing duplicate articles and screening abstracts, we identified 72 relevant studies. Fifty-five studies were excluded according to our criteria upon reading the full text of the articles. Ultimately, we included 17 studies[16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41] comprising 30,416 patients with hypertension and COVID-19 in our meta-analysis. The basic characteristics of the included studies are summarized in Table 1. Four of the included studies in the meta-analysis were RCTs[20], [21], [22], [23] and the other 13 were observational studies.[16], [17], [18], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41] We used the propensity-matched scores to adjust potential confounders. Patients in five studies[20], [21], [22], [23], [33] receiving ACEIs/ARBs before hospital admission were divided into continuing or discontinuing ACEIs/ARBs therapy groups for the subgroup analysis to evaluate the effect of continuing vs. discontinuing ACEIs/ARBs on severe illness or mortality. The primary outcomes for the included studies were death, severe illness (defined as the need for intensive care or mechanical ventilation), or a composite of ICU admission, mechanical ventilation, and death.

Figure 1.

Figure 1:

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PRISMA 2020 flow diagram for the meta-analysis. PRISMA: Preferred Reporting Items for Systematic Reviews and Meta-Analyses.

Table 1.

Characteristics of included studies.

Reference Publication date Study period and location Study design Population Number of participants Outcomes
Bauer et al.[21] 2021 April 2020 to January 2021, in Austria and Germany Randomized, controlled, open-label trial Adult patients with COVID-19 and chronically treated with ACEIs or ARBs 204 (100 for continuation of ACEIs/ARBs, 104 for discontinuation of ACEIs/ARBs) Composite of ICU admission, mechanical ventilation, and mortality
Lopes et al.[22] 2021 April to June 2020, in Brazil Randomized, controlled, open-label trial Adult patients with mild to moderate COVID-19 who were taking ACEIs or ARBs prior to hospitalization 659 (334 for continuation of ACEIs/ARBs, 325 for discontinuation of ACEIs/ARBs) Mechanical ventilation; 30-day mortality
Cohen et al.[20] 2021 March to August 2020, in the USA, Canada, Mexico, Sweden, Peru, Bolivia, and Argentina Randomized, controlled, open-label trial Adult patients admitted to the hospital with COVID-19 and receiving ACEIs or ARBs before admission 152 (75 for continuation of ACEIs/ARBs, 77 for discontinuation of ACEIs/ARBs) Composite of ICU admission and mechanical ventilation; in-hospital mortality
Najmeddin et al.[23] 2021 April to September 2020, in Iran Randomized, controlled, triple-blind trial Adult patients with COVID-19 and hypertension consuming ACEIs or ARBs 64 (31 for continuation of ACEIs/ARBs, 33 for discontinuation of ACEIs/ARBs) ICU admission; in-hospital mortality
Reynolds et al.[16] 2020 March to April 2020, in the USA PSM (variables: age, sex, race, ethnic, BMI, smoking history, comorbidities, and other classes of medication) Adult patients with COVID-19 and a history of hypertension 2005 (1019 in ACEIs/ARBs group, 986 in non-ACEIs/ARBs group) Composite of ICU admission, mechanical ventilation, and mortality
Bae et al.[32] 2020 January to March 2020, in Korea PSM (variables: age, sex, types of insurance coverage, comorbidities, depression, and duration of CVD) Adult patients with COVID-19 and hypertension 610 (305 in ACEIs/ARBs group and 305 in non-ACEIS/ARBS group) In-hospital mortality
Zhang et al.[18] 2020 31 December 2019 to 20 February 2020, in China PSM (variables: age, gender, fever, cough, dyspnea, comorbidities, and the incidence of increased CRP and creatinine) Adult patients with hypertension hospitalized with COVID-19 522 (174 in ACEIs/ARBs group and 348 in non-ACEIS/ARBS group) In-hospital mortality
de Abajo et al.[33] 2021 1 March to
31 March 2020, in Spain		 PSM (variables: baseline comorbidities, outpatient treatments, hospital of admission, date of admission, severity score at admission, presence of pneumonia, and treatments prescribed in the first 3 days of hospitalization) Adult patients with hypertension and diagnosis of COVID-19 625 (285 for continuation of ACEIs/ARBs, 340 for discontinuation of ACEIS/ARBS) Composite of ICU admission and mortality
Lee et al.[36] 2021 Data up to 15 May 2020, in Korea PSM (variables: age, sex, comorbidities, and use of other classes of antihypertensive medications) Adult patients with hypertension and COVID-19 1070 (535 in ACEIs/ARBs group and 535 in non-ACEIS/ARBS group) Composite of ICU admission and mortality
Park et al.[39] 2021 Data up to 15 May 2020, in Korea PSM (variables: age, sex, medical history including cardiovascular disease, neoplasms, and other diseases) Adult patients with hypertension and COVID-19 1332 (666 in RAAS group and 666 in non-RAAS group) In-hospital mortality
Wang et al.[40] 2020 February to March 2020, in China PSM (variables: age, sex, BMI, previous comorbidities, vital signs, disease severity, ion concentration, hepatic and renal function, blood cell count, CRP, and IL-6) Adult COVID-19 patients with hypertension 124 (62 in ACEIs/ARBs group and 62 in non-ACEIS/ARBS group) ICU admission; in-hospital mortality
Zhong et al.[41] 2020 January to March 2020, in China PSM (variables: age, sex, coronary heart disease, and statin use) Severe COVID-19 patients with hypertension 60 (30 in ACEIs/ARBs group and 30 in non-ACEIS/ARBS group) In-hospital mortality
Aparisi et al.[31] 2021 March to April 2020, in Spain PSM (variables: age, comorbidities, creatinine, and hospital) Adult hypertensive COVID-19 patients 92 (45 in RAAS group and 47 in non-RAAS group) ICU admission; in-hospital mortality
Derington et al.[34] 2021 January to August 2020, in the USA PSM (variables: age, sex, race, income, insurance type, priority group status, current tobacco use, BMI, blood pressure, heart rate, total cholesterol, HDL, LDL, triglycerides, hemoglobin, potassium, creatinine, and glomerular filtration rate) Adult hypertensive COVID-19 patients 485 (210 in ACEIs/ARBs group and 275 in non-ACEIS/ARBS group) ICU admission; in-hospital mortality
Pan et al.[38] 2020 January to February 2020, in China PSM (variables: age, sex, COPDs, asthma, and arrhythmia) COVID-19 Patients with hypertension 282 (41 in RAAS group and 241 in non-RAAS group) ICU admission; in-hospital mortality
Li et al.[17] 2020 28 February 2020 and 18 August 2020, in the USA PSM (variables: race, sex, ethnicity, comorbidities, alcohol or drug dependency, Charlson Comorbidity Index, and BMI) COVID-19 Patients with hypertension 21,420 COVID-19 positive patients ICU admission; in-hospital mortality
Gao et al.[35] 2020 5 February to 15 March 2020, in China PSM (variables: age, sex, medical history of diabetes, insulin-treated diabetes, myocardial infarction, underwent PCI/CABG, renal failure, stroke, heart failure, and COPD) COVID-19 Patients with hypertension 710 (183 in RAAS group and 527 in non-RAAS group) In-hospital mortality
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ACEIs: Angiotensin-converting enzyme inhibitors; ARBs: Angiotensin II receptor blockers; BMI: Body mass index; CABG: Coronary-artery-bypass-grafting; COPD: Chronic obstructive pulmonary disease; COVID-19: Coronavirus disease 2019; CRP: C-reactive protein; CVD: Cerebrovascular disease; HDL: High density lipoprotein; ICU: Intensive care unit; IL-6: Interleukin 6; LDL: Low density lipoprotein; PCI: Percutaneous transluminal coronary intervention; PSM: Propensity score-matched; RAAS: Renin–angiotensin–aldosterone system.

The risk of bias assessment is presented in Supplementary Material 3. Three of the four RCTs were rated as having a high risk of bias because they were open-label trials.[20], [21], [22] Furthermore, all the PSM studies were rated as high quality, each with a total score of >6. In addition, there was no significant publication bias detected with Egger's regression test (P=0.779, Supplementary Material 3).

Meta‐analysis results

All included studies compared clinical severity-related outcomes between COVID-19 patients treated with ACEIs/ARBs and those who were not. In the pooled analysis of all included studies, the use of ACEIs/ARBs was not associated with severe COVID-19 (OR=1.00, 95% CI:0.88–1.14, I2=28%, Figure 2). Sixteen studies reported mortality rates and the results indicated no difference between groups (OR=0.96, 95% CI: 0.83–1.11, I2=16%, Figure 3A). Furthermore, continuation and discontinuation of ACEIs/ARBs had similar effects on disease severity (OR=1.01, 95% CI: 0.78–1.29, I2=0%, Figure 3B).

Figure 2.

Figure 2:

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Forest plot showing the association between the use of ACEIs/ARBs and the risk of severe COVID-19. ACEIs: Angiotensin-converting enzyme inhibitors; ARBs: Angiotensin II receptor blockers; COVID-19: Coronavirus disease 2019; CI: Confidence interval; IV: Independent variable; SE: Standard error.

Figure 3.

Figure 3:

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Forest plot showing the association between (A) the use of ACEIs/ARBs and the risk of mortality; (B) continuation of ACEIs/ARBs and the risk of severe COVID-19. ACEI: Angiotensin-converting enzyme inhibitor; ARBs: Angiotensin II receptor blockers; COVID-19: Coronavirus disease 2019; CI: Confidence interval; IV: Independent variable; SE: Standard error.

We grouped studies according to study design (RCTs vs. PSM studies) and severity of COVID-19 disease (mild vs. severe cases). The subgroup analysis of the RCTs and PSM studies indicated no difference in the risk of severe COVID-19 or death among patients treated with ACEIs/ARBs or not (RCTs: OR=0.99, 95% CI: 0.69–1.42, I2=0%; PSM studies: OR=1.01, 95% CI: 0.87–1.16, I2=38%, Figure 4). Moreover, the use of ACEIs/ARBs was not associated with worsened COVID-19 disease outcomes in patients with mild or severe COVID-19 (mild: OR=1.00, 95% CI: 0.76–1.32, I2=49%; severe: OR=1.03, 95% CI: 0.91–1.17, I2=0%, Figure 5).

Figure 4.

Figure 4:

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Forest plot showing the subgroup analysis of RCTs vs. PSM studies. CI: Confidence interval; IV: Independent variable; PSM: Propensity score-matched; RCTs: Randomized controlled trials; SE: Standard error.

Figure 5.

Figure 5:

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Forest plot showing the subgroup analysis of patients with mild vs. severe COVID-19. COVID-19: Coronavirus disease 2019; CI: Confidence interval; IV: Independent variable; SE: Standard error.

In addition, the sensitivity analysis showed a robust estimation of the pooled effect (Supplementary Material 3). The ORs ranged from 0.96 (95% CI: 0.87–1.05) to 1.04 (95% CI: 0.90–1.20).

Discussion

The interplay between SARS-CoV-2 and inhibitors of the RAAS has led to competing speculation about the effect of these medications on patients with COVID-19.[10] Considering the common use of ACEIs and ARBs worldwide, guidance on the use of these drugs in patients with hypertension and COVID-19 is urgently needed. Thus, we performed this meta-analysis to summarize the existing evidence from RCTs and PSM studies on the effect of treatment with ACEIs/ARBs on disease severity and mortality in COVID-19 patients. Two main findings emerge from the analyses of 17 included studies: first, there were no significant differences in mortality or the risk of developing severe COVID-19 between patients treated with ACEIs/ARBs and those who were not. Second, there were no significant differences in the severe or mortality events in patients prescribed continued use of ACEIs/ARBs vs. discontinuation of their use.

Our results are generally consistent with previous meta-analyses[42], [43], [44], [45], [46] of observational studies that the use of ACEIs/ARBs appears to have no significant effect on mortality or disease severity in patients with COVID-19. However, because a substantial proportion of the trials included in previous meta-analyses did not match for confounders, the crude OR may not accurately reflect the association between the use of RAAS inhibitors and COVID-19 clinical outcomes.

To our knowledge, this study is the first meta-analysis to summarize the evidence from RCTs or PSM studies on this topic. A total of 4 RCTs and 13 PSM studies comprising 30,416 COVID-19 cases were ultimately analyzed. Randomized trials and PSM studies constitute the highest level of evidence in addressing the effects of RAAS inhibitors in patients with hypertension and COVID-19. The accumulating evidence, large sample size, and methods to eliminate confounding factors enhanced the statistical power of this study to provide more precise and reliable risk estimates. Furthermore, long-term outcomes are worsened when long-term medications that had been discontinued during hospitalization are not restarted as a result of clinical inertia.[47] Thus, our meta-analysis evaluated this important question, contributing information that is novel, to the best of our knowledge, of the effects of continuing vs. discontinuing therapy with ACEIs or ARBs in patients admitted to the hospital with hypertension and COVID-19. Our findings, derived from four RCTs and one PSM study, support the continued use of ACEIs or ARBs in patients hospitalized with COVID-19. These findings provide solid evidence from properly adjusted estimates across different countries on the absence of risk from treatment with RAAS inhibitors during the pandemic, strongly supporting the recommendation from scientific societies that patients should not discontinue ACEIs or ARBs therapy during the COVID-19 pandemic.

Nonetheless, our study has some limitations and the findings need to be interpreted cautiously. First, although a great number of existing observational studies took important steps, such as multivariate analysis, to minimize the effects of bias and confounding, these studies were not included in our analyses. This may introduce selective bias. Moreover, even if the PSM method was applied to eliminate selection bias resulting from measured patient characteristics that affect both treatment and outcomes in observational studies, potential bias and confounding factors could not be fully controlled. Thus, more RCTs that are well designed are needed to further confirm the effects of ACEIs/ARBs in COVID-19 patients.

Second, although we focused on patients with a history of hypertension, we did not have access to data related to the control of blood pressure and did not consider the dose of ACEIs, ARBs, or other drugs that patients may have received. Moreover, we did not define the criteria for chronic treatment of ACEIs/ARBs. The descriptions were insufficient to distinguish between study participants, a factor this is likely to contribute to the increased heterogeneity in this study. Moreover, the control groups were heterogenous by nature because we compared the use of RAAS inhibitors with the absence of RAAS inhibitors, rather than with the use of specific antihypertensive drug alternatives. This may have introduced further confounding by indication.

Another important limitation is the heterogeneity that was observed in the analyses. The existence of clinical heterogeneity is expected to lead to a degree of statistical heterogeneity in the results. The definitions of the outcomes were inconsistent among the included studies and we investigated the two well-defined outcomes of severe COVID-19 and death. However, the threshold for ICU admission and mechanical ventilation is likely to vary from institution to institution. In addition, retrospective design and data extraction from electronic health record systems may introduce selection bias and treatment misclassification. For instance, the status of ACEIs/ARBs use was determined through medical record review in some of the included studies, which is less reliable than other methods.

Conclusions

In conclusion, our results suggest that the use of ACEIs/ARBs in patients with COVID-19 is not associated with an increased risk of severe disease or death. These findings support the recommendation of major international cardiovascular societies that treatment with ACEIs/ARBs should be continued during the COVID-19 outbreak. Furthermore, the benefit of ACEIs/ARBs in COVID-19 treatment should be validated in more RCTs in the future. Long-term follow-up of patients is needed to evaluate whether the use of RASS inhibitors during the acute phase of infection may influence the long-term sequelae in patients with hypertension and COVID-19.

Ethics Statement

This article is a meta-analysis and does not require ethics committee approval or a consent statement.

Funding

This work was supported in part by grants from the National Natural Science Foundation of China (Grant No. 82100012, Kai Zhang) and the Medical and Health Research Program of Zhejiang Province (Grant No. 2022498722, Kai Zhang).

Conflicts of Interest

The authors declare that they have no known competing financial interests or personal relationships that could have appeared to influence the work reported in this paper.

Managing Editor: Jingling Bao

Footnotes

Supplementary material associated with this article can be found, in the online version, at doi:10.1016/j.jointm.2022.05.004.

Contributor Information

Gensheng Zhang, Email: genshengzhang@zju.edu.cn.

Shufang Zhang, Email: zhangsf08@zju.edu.cn.

Appendix. Supplementary materials

mmc1.docx (31.4KB, docx)
mmc2.docx (16.9KB, docx)
mmc3.docx (392.6KB, docx)

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