Association of Angiotensin‐Converting Enzyme Inhibitors and Angiotensin Receptor Blockers With the Risk of Hospitalization and Death in Hypertensive Patients With COVID‐19

  1. Rohan Khera
  2. Callahan Clark
  3. Yuan Lu
  4. Yinglong Guo
  5. Sheng Ren
  6. Brandon Truax
  7. Erica S. Spatz
  8. Karthik Murugiah
  9. Zhenqiu Lin
  10. Saad B. Omer
  11. Deneen Vojta
  12. Harlan M. Krumholz

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Abstract

Despite its clinical significance, the risk of severe infection requiring hospitalization among outpatients with severe acute respiratory syndrome coronavirus 2 infection who receive angiotensin‐converting enzyme (ACE) inhibitors and angiotensin receptor blockers (ARBs) remains uncertain.

Methods and Results

In a propensity score–matched outpatient cohort (January–May 2020) of 2263 Medicare Advantage and commercially insured individuals with hypertension and a positive outpatient SARS‐CoV‐2, we determined the association of ACE inhibitors and ARBs with COVID‐19 hospitalization. In a concurrent inpatient cohort of 7933 hospitalized with COVID‐19, we tested their association with in‐hospital mortality. The robustness of the observations was assessed in a contemporary cohort (May–August). In the outpatient study, neither ACE inhibitors (hazard ratio [HR], 0.77; 0.53–1.13, P =0.18) nor ARBs (HR, 0.88; 0.61–1.26, P =0.48) were associated with hospitalization risk. ACE inhibitors were associated with lower hospitalization risk in the older Medicare group (HR, 0.61; 0.41–0.93, P =0.02), but not the younger commercially insured group (HR, 2.14; 0.82–5.60, P =0.12; P ‐interaction 0.09). Neither ACE inhibitors nor ARBs were associated with lower hospitalization risk in either population in the validation cohort. In the primary inpatient study cohort, neither ACE inhibitors (HR, 0.97; 0.81–1.16; P =0.74) nor ARBs (HR, 1.15; 0.95–1.38, P =0.15) were associated with in‐hospital mortality. These observations were consistent in the validation cohort.

Conclusions

ACE inhibitors and ARBs were not associated with COVID‐19 hospitalization or mortality. Despite early evidence for a potential association between ACE inhibitors and severe COVID‐19 prevention in older individuals, the inconsistency of this observation in recent data argues against a role for prophylaxis.

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  1. Version published to 10.1161/jaha.120.018086
  2. ScreenIT

    SciScore for 10.1101/2020.05.17.20104943: (What is this?)

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

    Table 1: Rigor

    Institutional Review Board StatementIRB: The Yale Institutional Review Board and the UnitedHealth Group Office of Human Research Affairs exempted this study from other review as all activities were limited to retrospective analysis of de-identified data and accessed in accordance with Health Insurance Portability and Accountability Act regulations.
    Randomizationnot detected.
    Blindingnot detected.
    Power Analysisnot detected.
    Sex as a biological variablenot detected.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    For both studies, a diagnosis of hypertension was based on ICD-10 codes (eTable 1), and drug treatment for hypertension was defined by the receipt of one or more agents included in the 2017 American Heart Association hypertension guidelines.
    American Heart Association
    suggested: (American Heart Association, RRID:SCR_007210)
    Analyses were performed using open source R 3.4.0 (CRAN) and Python 3.8.2.
    Python
    suggested: (IPython, RRID:SCR_001658)

    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:
    The findings of our study should be interpreted in light of the following limitations. First, the study is observational, and despite robust methods, and explicit assessments of residual confounding, understanding the potential protective role of ACE inhibitors in COVID-19 requires a dedicated randomized controlled trial. Second, we do not know the proportion of patients receiving these antihypertensive agents that continued to be treated with these drugs during the illness and the association of their continued use or cessation with patient outcomes. Third, all included data elements are contingent upon individuals seeking care for that ailment or filling a medication using their insurance provider and would not be captured if they chose to self-pay. However, we do not expect that any sizeable proportion of insured individuals would defer insurance coverage for their care. Fourth, we cannot account for differences in timing of presentation of patients relative to their symptom onset. However, we limited the effect of differential presentation by patients across exposure groups by focusing on patients receiving treatment for the same medical comorbidity, i.e. hypertension, and only varying the class of drugs. Moreover, we included patients across the US and accounted for clustering of patients, thereby limiting the effect of local practice patterns that may affect hospitalization thresholds. Therefore, it is unlikely patient’s care seeking behavior would be affected by knowle...

    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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  3. Version published to 10.1101/2020.05.17.20104943v1 on medRxiv