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

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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.

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  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

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  2. Version published to 10.1101/2020.06.12.20129916v1 on medRxiv