Association of Angiotensin-Converting Enzyme Inhibitor or Angiotensin Receptor Blocker Use With COVID-19 Diagnosis and Mortality | Cardiology | JAMA | JAMA Network
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    Statistical versus Clinical Significance - Which is More Relevant?
    Daniel Lopez-Hernandez, Ph.D., M.Sc., Physician | Institute of Security and Social Services for State Workers
    The authors included patients with hypertension treated with angiotensin-converting enzyme inhibitors (ACEI)/angiotensin receptor blockers (ARB) -ACEI/ARB- therapy in a 3-month period prior to the index date. They reported that among patients diagnosed as having COVID-19, this study found no significant association between prior ACEI/ARB use and mortality or severe COVID-19 after adjusting for age, sex, and comorbidities. Therefore, the authors suggest not discontinuing ACEI/ARB medications that are clinically indicated in patients in the context of the COVID-19 pandemic. Although this difference in the magnitude of mortality and severity of COVID-19 between patients treated with ACEI/ARB therapy and non-user patients is not significant, statistical significance must always be interpreted at the light of the relevance and practical importance of the difference. The models shown do not allow us to know what are the phenotypic characteristics of those patients with a greater susceptibility of severe COVID-19 or death? It would have been very important to use the confounding variables to elucidate in which patients to continue therapy or in whom not, and also include an analysis of mortality only for COVID-19, instead of all-causes (The primary outcome was all-cause death).
    CONFLICT OF INTEREST: None Reported
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    Original Investigation
    June 19, 2020

    Association of Angiotensin-Converting Enzyme Inhibitor or Angiotensin Receptor Blocker Use With COVID-19 Diagnosis and Mortality

    Author Affiliations
    • 1The Heart Center, University Hospital of Copenhagen, Rigshospitalet, Copenhagen, Denmark
    • 2Section of Cardiovascular Medicine, Department of Medicine, Boston Medical Center, Boston University School of Medicine, Boston, Massachusetts
    • 3Department of Endocrinology, Bispebjerg and Frederiksberg Hospital, Copenhagen, Denmark
    • 4Department of Cardiology, Aalborg University Hospital, Aalborg, Denmark
    • 5Department of Cardiology, Copenhagen University Hospital Herlev and Gentofte, Hellerup, Denmark
    • 6Department of Cardiovascular Epidemiology and Research, The Danish Heart Foundation, Copenhagen, Denmark
    • 7Department of Clinical Epidemiology and Department of Cardiology, Hillerød Hospital, Hillerød, Denmark
    JAMA. 2020;324(2):168-177. doi:10.1001/jama.2020.11301
    Key Points

    Question  Is angiotensin-converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB) use associated with greater susceptibility to coronavirus disease 2019 (COVID-19) and with worse outcomes after COVID-19 diagnosis?

    Findings  In a retrospective cohort study of 4480 patients diagnosed as having COVID-19, prior ACEI/ARB use, compared with no use, was not significantly associated with mortality (adjusted hazard ratio, 0.83). In a nested case-control study of a cohort of 494 170 patients with hypertension, use of ACEI/ARB, compared with use of other antihypertensive medications, was not significantly associated with COVID-19 diagnosis (adjusted hazard ratio, 1.05).

    Meaning  Prior use of ACEI/ARB was not significantly associated with COVID-19 diagnosis or with mortality among patients diagnosed as having COVID-19.

    Abstract

    Importance  It has been hypothesized that angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) may make patients more susceptible to coronavirus disease 2019 (COVID-19) and to worse outcomes through upregulation of the functional receptor of the virus, angiotensin-converting enzyme 2.

    Objective  To examine whether use of ACEI/ARBs was associated with COVID-19 diagnosis and worse outcomes in patients with COVID-19.

    Design, Setting, and Participants  To examine outcomes among patients with COVID-19, a retrospective cohort study using data from Danish national administrative registries was conducted. Patients with COVID-19 from February 22 to May 4, 2020, were identified using ICD-10 codes and followed up from day of diagnosis to outcome or end of study period (May 4, 2020). To examine susceptibility to COVID-19, a Cox regression model with a nested case-control framework was used to examine the association between use of ACEI/ARBs vs other antihypertensive drugs and the incidence rate of a COVID-19 diagnosis in a cohort of patients with hypertension from February 1 to May 4, 2020.

    Exposures  ACEI/ARB use was defined as prescription fillings 6 months prior to the index date.

    Main Outcomes and Measures  In the retrospective cohort study, the primary outcome was death, and a secondary outcome was a composite outcome of death or severe COVID-19. In the nested case-control susceptibility analysis, the outcome was COVID-19 diagnosis.

    Results  In the retrospective cohort study, 4480 patients with COVID-19 were included (median age, 54.7 years [interquartile range, 40.9-72.0]; 47.9% men). There were 895 users (20.0%) of ACEI/ARBs and 3585 nonusers (80.0%). In the ACEI/ARB group, 18.1% died within 30 days vs 7.3% in the nonuser group, but this association was not significant after adjustment for age, sex, and medical history (adjusted hazard ratio [HR], 0.83 [95% CI, 0.67-1.03]). Death or severe COVID-19 occurred in 31.9% of ACEI/ARB users vs 14.2% of nonusers by 30 days (adjusted HR, 1.04 [95% CI, 0.89-1.23]). In the nested case-control analysis of COVID-19 susceptibility, 571 patients with COVID-19 and prior hypertension (median age, 73.9 years; 54.3% men) were compared with 5710 age- and sex-matched controls with prior hypertension but not COVID-19. Among those with COVID-19, 86.5% used ACEI/ARBs vs 85.4% of controls; ACEI/ARB use compared with other antihypertensive drugs was not significantly associated with higher incidence of COVID-19 (adjusted HR, 1.05 [95% CI, 0.80-1.36]).

    Conclusions and Relevance  Prior use of ACEI/ARBs was not significantly associated with COVID-19 diagnosis among patients with hypertension or with mortality or severe disease among patients diagnosed as having COVID-19. These findings do not support discontinuation of ACEI/ARB medications that are clinically indicated in the context of the COVID-19 pandemic.

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