ARB/ACEI use and severe COVID-19: a nationwide case-control study

  1. Hee Kyoung Choi
  2. Hee-Jo Koo
  3. Hyeri Seok
  4. Ji Hoon Jeon
  5. Won Suk Choi
  6. Dae Jung Kim
  7. Dae Won Park
  8. Euna Han

Reviewed by

Read the full article See related articles

Listed in

Log in to save this article

Abstract

Background

Angiotensin receptor blockers (ARBs) and angiotensin converting enzyme inhibitors (ACEIs) have anti-inflammatory effects. Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) uses the membrane protein angiotensin-converting enzyme 2 (ACE2), which is increased by ARB/ACEI treatment, as a cell entry receptor. Therefore, the use of ARBs/ACEIs for COVID-19 remains controversial.

Methods

A retrospective case-control study was conducted using COVID-19 patients previously diagnosed with hypertension before COVID-19 onset. The primary outcome was severe infection or all-cause mortality. Cases included ARB/ACEI use for ≥30 days during the 6 months before COVID-19 onset. Primary controls included antihypertensive use other than ARBs/ACEIs (narrow control); secondary controls included all other hypertension patients (broad control). We investigated ARB/ACEI association with outcomes in general and by subgroups (age, sex, and presence of diabetes) using logistic regression models with propensity score matching.

Findings

Of 234427 suspected COVID-19 patients we screened, 1585 hypertension patients were analyzed. In the 892 cases, 428 narrow controls, and 693 broad controls, severe infection or death occurred in 8·6%, 22·2%, and 16·7%, respectively. ARB/ACEI use was associated with a reduced risk of severe infection or death relative to the narrow control group (adjusted odds ratio [aOR] 0·43, 95% confidence interval [CI] 0·28 – 0·65) and broad control group (aOR 0·49, 95% CI 0·33 – 0·71). The association was smaller for newly diagnosed hypertension patients (aOR 0·11, 95% CI 0·03 – 0·42 compared to narrow control group). ARB/ACEI protective effects against severe infection or death were significantly observed in male and diabetic patients.

Interpretation

ARB/ACEI use was associated with a lower risk of severe infection or mortality compared to other antihypertensives or ARB/ACEI nonuse.

Funding

None

Research in context

Evidence before this study

Animal studies reported that ACE2 attenuates lung injury and provides a protective effect against severe pneumonia. Additionally, retrospective studies found that ARBs/ACEIs may have beneficial effects on ARDS patient survival. Previous observational studies have reported no potential harmful association of either ARBs or ACEIs with COVID-19 outcomes.

Added value of this study

By analyzing nationwide claims data in South Korea, we found that previous use of ARB/ACEI was associated with improved outcomes in COVID-19 compared with either nonuse or use of a different class of antihypertensive drugs. The risk of severe infection or death was consistently about 55% lower in those treated with ARB/ACEIs than those who were not exposed to ARB/ACEIs. The protective effect of ARB/ACEI was remained significantly among the male subgroup and patients with diabetes. This association was also observed among COVID-19 patients with newly diagnosed hypertension.

Implications of all the available evidence

These results provide supporting evidence for the continued use of ARBs/ACEIs among patients with COVID-19. Moreover, for newly diagnosed hypertension patients, initiation of ARB/ACEI use may not adversely affect COVID-19 prognosis. Given the poor prognosis of COVID-19 patients with hypertension and lack of curable strategy, these findings may have considerable clinical implications in prevention of poor outcome in patients with hypertension.

Article activity feed

  1. ScreenIT

    SciScore for 10.1101/2020.06.12.20129916: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board StatementIRB: The present study was approved by Yonsei institutional review boards (7001988-202004-HR-843-01E.)
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variableSubgroup analyses: As the ACE2 expression is more likely reduced in older patients,28-30 males,29,30 and diabetic patients,30 subgroup analyses were conducted by sex (male versus female), age (<65 years versus ≥65 years), and diabetes.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Use of Lopinavir/ritonavir (ATC code: J05AR10) or hydroxychloroquine (ATC code: P01BA02) during COVID-19 treatment was also controlled for as a covariate, as these drugs were recommended first-line therapies for COVID-19 in South Korea.
    ATC
    suggested: None
    All analyses were performed with SAS software, version 9·4 (SAS Institute, Cary, NC, USA), and a 2-tailed P < 0·05 was used to indicate statistical significance.
    SAS
    suggested: (SASqPCR, RRID:SCR_003056)
    SAS Institute
    suggested: (Statistical Analysis System, RRID:SCR_008567)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    This study has some limitations due to the characteristics of the claims data. First, a patient’s socioeconomic status-related information was not included. However, as the entire cost of COVID-19 treatment is paid by the NHIS, we do not expect any substantial variations due to socioeconomics in regards to the impact of ARBs/ACEIs on the COVID-19 treatment. Second, data on participant smoking behavior, which is regarded as a major risk factor for severe COVID-19,35,36 was unavailable for analysis. Third, the effects of the degree and duration of ARB/ACEI use on COVID-19 outcomes were not fully assessed. Although a protective effect was observed in even newly diagnosed hypertension patients, more well-designed and controlled studies investigating the protective capabilities of ARB/ACEI treatment on COVID-19 prognosis are needed. In conclusion, the recent use of ARBs or ACEIs was significantly correlated with reduced risk of poor COVID-19 outcomes relative to either use of a different class of antihypertensive medication or nonuse of ACEIs/ARBs among patients with hypertension.

    Results from TrialIdentifier: No clinical trial numbers were referenced.

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  2. Version published to 10.1101/2020.06.12.20129916v1 on medRxiv