Systemic Corticosteroid Use for COVID-19 in US Outpatient Settings From April 2020 to August 2021 | Critical Care Medicine | JAMA | JAMA Network
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Figure.  Proportion of Patients With COVID-19 Initiating Systemic Corticosteroids Within 14 Days of Diagnosis
Proportion of Patients With COVID-19 Initiating Systemic Corticosteroids Within 14 Days of Diagnosis

FDA indicates Food and Drug Administration; NIH, National Institutes of Health; RECOVERY, Randomised Evaluation of COVID-19 Therapy.

aThe name of the corticosteroid was only available for pharmacy dispensings.

Table.  Characteristics and Comorbidities of Patients With COVID-19 and Those Initiating Systemic Corticosteroids Within 14 Days of Diagnosis
Characteristics and Comorbidities of Patients With COVID-19 and Those Initiating Systemic Corticosteroids Within 14 Days of Diagnosis
1.
National Institutes of Health. Therapeutic management of nonhospitalized adults with COVID-19. Updated February 1, 2022. Accessed March 30, 2022. https://www.covid19treatmentguidelines.nih.gov/management/clinical-management/nonhospitalized-adults--therapeutic-management/
2.
RECOVERY: Randomised Evaluation of COVID-19 Therapy. Low-cost dexamethasone reduces death by up to one third in hospitalised patients with severe respiratory complications of COVID-19. Accessed February 18, 2022. https://www.recoverytrial.net/news/low-cost-dexamethasone-reduces-death-by-up-to-one-third-in-hospitalised-patients-with-severe-respiratory-complications-of-covid-19
3.
Centers for Medicare & Medicaid Services. Medicare program: general information. Accessed March 3, 2021. https://www.cms.gov/Medicare/Medicare-General-Information/MedicareGenInfo/index
4.
Cocoros  NM, Fuller  CC, Adimadhyam  S,  et al.  A COVID-19–ready public health surveillance system.   Pharmacoepidemiol Drug Saf. 2021;30(7):827-837.PubMedGoogle ScholarCrossref
5.
Horby  P, Lim  WS, Emberson  JR,  et al.  Dexamethasone in hospitalized patients with COVID-19.   N Engl J Med. 2021;384(8):693-704.PubMedGoogle Scholar
6.
Crothers  K, DeFaccio  R, Tate  J,  et al.  Dexamethasone in hospitalised coronavirus-19 patients not on intensive respiratory support.   Eur Respir J. Published online November 25, 2021. doi:10.1183/13993003.02532-2021 PubMedGoogle ScholarCrossref
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    2 Comments for this article
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    Asthma Exacerbation
    Binh Ngo, M.D. | Keck USC School of Medicine
    This brief analysis by Bradley et al implies improper use of glucocorticoids in Covid patients. Many Covid patients suffer from asthma. Asthmatic exacerbation is a primary and accepted reason for glucocorticod treatment. Did the authors search their database for prior and concurrent diagnoses of asthma? It is also worth noting questions about the role of inhaled corticosteroids: 2 trials in the United Kingdom reported a benefit with inhaled budesonide in outpatient treatment of Covid-19 (1, 2), while another found no effect of combination inhaled and intranasal ciclesonide (3).

    References

    (1) Yu LM, Bafadhel M, Dorward J,
    et al. Inhaled budesonide for COVID-19 in people at high risk of complications in the community in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial. PRINCIPLE Trial Collaborative Group. Lancet. 2021 Sep 4;398(10303):843-855

    (2) Ramakrishnan S, Nicolau DV Jr, Langford B, et al. Inhaled budesonide in the treatment of early COVID-19 (STOIC): a phase 2, open-label, randomised controlled trial. Lancet Respir Med. 2021 Jul;9(7):763-772. doi: 10.1016/S2213-2600(21)00160-0. Epub 2021 Apr 9. Erratum in: Lancet Respir Med. 2021 Jun;9(6):e55. PMID: 33844996; PMCID: PMC8040526.

    (3) Ezer N, Belga S, Daneman N, et al. Inhaled and intranasal ciclesonide for the treatment of covid-19 in adult outpatients: CONTAIN phase II randomised controlled trial. BMJ. 2021 Nov 2;375:e068060. doi: 10.1136/bmj-2021-068060. PMID: 34728476; PMCID: PMC8561042.

    CONFLICT OF INTEREST: None Reported
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    No Proven Harm
    George Stapleton, MD | Community Hospital Emergency Physician
    The caution against corticosteroids is overstated. There was no statistical difference between dexamethasone and control groups in the sentinel U.K. study on dexamethasone in Covid-19 (1). The anti steroid camp including the NIH hangs its hat largely on a SARS study showing higher viral loads with corticosteroids. The NIH’s warning against prescribing corticosteroids outside of clinical trials early in Covid-19 no doubt tied more clinicians' hands than just mine without clear evidence to support them. There was competing small study clinical evidence to support a benefit of corticosteroids in SARS.

    A deeper look at the U.K. dexamethasone
    study shows a breakdown by duration of symptoms. The patients sick fewer than 7 days showed no difference with steroids. The patients sick greater than 7 days showed the benefit. The duration of symptoms for the patients not requiring oxygen was significantly shorter than 7 days on average. The oxygen requiring group had longer duration of symptoms, and the patients on ventilatory support were sick the longest (1).

    The patients not requiring oxygen had no statistical difference in outcome with dexamethasone, probably mostly because they had the mildest and shortest duration of illness, and the vast majority would be fine with or without treatment.

    There is more recent good evidence supporting the use of inhaled steroids, the best also from the U.K., for nonhospitalized patients sick less than 7 days (2). A second trial found similar benefit but failed to show reduction of symptoms (3).

    For the many Covid-19 patients suffering long Covid symptoms, however, we have gotten nowhere. I would argue that for non-hospitalized patients with significant symptoms like fever, dyspnea, or other cardiopulmonary symptoms other than cough past 7 days of duration, and little likely viral load, there is no reasonable argument against systemic corticosteroids until there is proven harm. And until we get good evidence on how to treat them, I will continue to have a low threshold to prescribe them either inhaled or systemic steroids in an attempt to reduce long Covid morbidity and symptoms.

    References

    (1) RECOVERY Collaborative Group. N Engl J Med 2021; 384:693-704; DOI: 10.1056/NEJMoa2021436

    (2) Yu LM, Bafadhel M, Dorward J, et al. Inhaled budesonide for COVID-19 in people at high risk of complications in the community in the UK (PRINCIPLE): a randomised, controlled, open-label, adaptive platform trial. PRINCIPLE Trial Collaborative Group. Lancet. 2021 Sep 4;398(10303):843-855

    (3) Ramakrishnan S, Nicolau DV Jr, Langford B, et al. Inhaled budesonide in the treatment of early COVID-19 (STOIC): a phase 2, open-label, randomised controlled trial. Lancet Respir Med. 2021 Jul;9(7):763-772. doi: 10.1016/S2213-2600(21)00160-0. Epub 2021 Apr 9. Erratum in: Lancet Respir Med. 2021 Jun;9(6):e55. PMID: 33844996; PMCID: PMC8040526.

    CONFLICT OF INTEREST: None Reported
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    Research Letter
    April 8, 2022

    Systemic Corticosteroid Use for COVID-19 in US Outpatient Settings From April 2020 to August 2021

    Author Affiliations
    • 1Office of Surveillance and Epidemiology, US Food and Drug Administration, Silver Spring, Maryland
    • 2Acumen LLC, Burlingame, California
    • 3Department of Veterans Affairs Center for Medication Safety, Hines, Illinois
    • 4Department of Population Medicine, Harvard Medical School, Boston, Massachusetts
    • 5Aetion Inc, New York, New York
    JAMA. 2022;327(20):2015-2018. doi:10.1001/jama.2022.4877

    In June 2020, preliminary results for the Randomised Evaluation of COVID-19 Therapy (RECOVERY) trial conducted in the UK indicated benefit from dexamethasone in severely ill hospitalized patients with COVID-19 but potential harm in those not requiring oxygen.1,2 In October 2020, the National Institutes of Health (NIH) issued COVID-19 treatment guidelines advising against systemic corticosteroid use in patients with mild to moderate COVID-19.1 Using 2 large US health care claims databases, we examined systemic corticosteroid use among nonhospitalized patients with COVID-19.

    Methods

    Data from Medicare fee-for-service and the US Food and Drug Administration’s (FDA’s) Sentinel System were used. Medicare is a federal health insurance program mostly serving those aged 65 years or older.3 The Sentinel System comprises primarily claims data from commercially insured patients of all ages in a distributed network of data partners.4 The Sentinel Rapid COVID-19 data source used in this analysis included 2 national insurance claims data partners and 2 integrated delivery care systems.

    Nonhospitalized, noninstitutionalized patients with incident COVID-19 between April 2020 and August 2021 (July 2021 for Sentinel) were included. Incident outpatient COVID-19 was defined as a diagnosis code for COVID-19 or positive SARS-CoV-2 laboratory test (Sentinel only) recorded on an outpatient claim, including emergency department claims without subsequent hospitalization. Those with COVID-19 within the prior 183 days and those with use of systemic corticosteroids within the prior 90 days were excluded. Patients were followed up from COVID-19 diagnosis date until the earliest occurrence of a claim for a new oral or injectable corticosteroid in an outpatient setting, hospitalization, death, disenrollment, or 14 days. Demographics, clinical characteristics, and among corticosteroid initiators, corticosteroid type, timing, setting of initiation, prescriber specialty, and concomitant therapies were examined (eTable in the Supplement).

    Analyses were descriptive and performed using SAS version 9.4 (SAS Institute Inc). This study was classified as public health surveillance by the FDA and exempted from review by the institutional review board in accordance with the updated Common Rule.

    Results

    There were 576 885 eligible patients with COVID-19 in Medicare and 766 105 in Sentinel, the mean age was 74.6 years (SD, 7.2 years) and 48.5 years (SD, 19.9 years), respectively, and the proportion of males was 43.2% and 46.7% (Table). Of these, 16.4% in Medicare and 9.4% in Sentinel received systemic corticosteroids in an outpatient setting within 14 days of COVID-19 diagnosis (Figure). The proportion of patients initiating corticosteroids in the South was higher than in any other region. Use increased with age until approximately 79 years. Corticosteroid use increased over time from 2.2% initiating in April 2020 to 21.1% in August 2021 in Medicare, and from 2.2% in April 2020 to 13.8% in July 2021 in Sentinel.

    Among pharmacy dispensings, the most commonly used corticosteroids were dexamethasone in Medicare (43.8%) and prednisone in Sentinel (34.1%). The most common prescriber specialties in Medicare were internal medicine or family/general practice (39.9%) and emergency medicine (18.6%). Treatment often started on the day of COVID-19 diagnosis (58.8% for Medicare vs 51.3% for Sentinel), largely through pharmacy dispensings (70.8%-80.3%) rather than during medical encounters. On the day corticosteroid use was initiated, 24.7% in Medicare had visited the emergency department vs 22.9% in Sentinel. Azithromycin was the most common concomitant therapy (44.8% for Medicare vs 48.8% for Sentinel)—often initiated on the same date as the corticosteroid—followed by monoclonal antibodies (Medicare: 7.1%; Sentinel: 2.0%), inhaled corticosteroids (Medicare: 2.4%; Sentinel: 6.7%), ivermectin (Medicare: 3.9%; Sentinel: 3.5%), and nonoral anticoagulants (Medicare: 3.6%; Sentinel: 3.1%).

    Discussion

    Despite NIH recommendations, increasing numbers of nonhospitalized patients with COVID-19 were prescribed systemic corticosteroids, often on the day of diagnosis. Use appeared to be more prominent in the South and was not restricted to older patients. Limitations of the study included inability to capture date of symptom onset and indication for use, and potential for misclassifying mild to moderate COVID-19 disease due to overburdened resources and limited ability to accurately capture elements to define disease severity, including oxygen use. Given the increasing use of corticosteroids through August 2021, the potential safety signal,2,5,6 and the lack of efficacy data in patients with mild to moderate COVID-19,1 it is critical that prescribers consider the NIH guidelines in the therapeutic management of nonhospitalized patients with COVID-19.

    Section Editors: Jody W. Zylke, MD, Deputy Editor; Kristin Walter, MD, Associate Editor.
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    Article Information

    Accepted for Publication: March 15, 2022.

    Published Online: April 8, 2022. doi:10.1001/jama.2022.4877

    Corresponding Author: Marie C. Bradley, PhD, MPharm, MScPH, Office of Surveillance and Epidemiology, Center for Drug Evaluation and Research, US Food and Drug Administration, 10903 New Hampshire Ave, Silver Spring, MD 20903 (marie.bradley@fda.hhs.gov).

    Author Contributions: Mr Chillarige and Dr Martinez had full access to all the data in the study and take responsibility for the integrity of the data and the accuracy of the data analysis.

    Concept and design: Bradley, Perez-Vilar, Chillarige, Martinez, Weckstein, Dal Pan.

    Acquisition, analysis, or interpretation of data: Bradley, Perez-Vilar, Chillarige, Dong, Martinez, Weckstein.

    Drafting of the manuscript: Bradley, Perez-Vilar.

    Critical revision of the manuscript for important intellectual content: All authors.

    Statistical analysis: Chillarige, Dong, Martinez, Weckstein.

    Obtained funding: Dal Pan.

    Administrative, technical, or material support: Bradley, Martinez, Weckstein, Dal Pan.

    Supervision: Bradley, Perez-Vilar, Chillarige, Dal Pan.

    Conflict of Interest Disclosures: Mr Chillarige reported receiving personal fees from Acumen LLC. Mr Weckstein reported being employed by and having an ownership interest (stock options or existing equity) in Aetion, a technology company that provides analytic software and services to the health care industry. No other disclosures were reported.

    Funding/Support: This study was funded through interagency agreement 21-182 between the US Food and Drug Administration (FDA) and the Centers for Medicare & Medicaid Services (CMS) (task order 75FCMC21F0067) for which Acumen LLC is the contractor, with additional funding from the FDA and the Centers for Drug Evaluation and Research (contract 75F40119D10037). The Sentinel System Initiative is funded by the FDA through contract 75F40119F19001 from the US Department of Health and Human Services (DHHS).

    Role of the Funder/Sponsor: The authors who were employees or contractors of the FDA, the CMS, or the Veterans Health Administration (VHA) played a role in the design; however, other officials at the FDA, the CMS, and the VHA had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation, review, or approval of the manuscript; and decision to submit the manuscript for publication. The manuscript was subjected to administrative review before submission, but this review did not alter its content.

    Disclaimer: The views expressed in this article are those of the authors and do not necessarily reflect those of the FDA, the CMS, the VHA, or the DHHS.

    Additional Contributions: We thank David J. Graham, MD, MPH, Efe Eworuke, PhD, and Hana Lee, PhD (FDA); Jeffrey A. Kelman, MD, MSSc (CMS); Sandia Akhtar, BS, Hai Lyu, MS, and Kushal B. Naik, MBBS, MPH (Acumen LLC); and Austin Cosgrove, BS, Noelle Cocoros, DSc, MPH, and Judith Maro, PhD, MS (Department of Population Medicine, Harvard Medical School). We also thank the institutional partners that provided the data used in the Sentinel analysis: CVS Health Clinical Trial Services (an affiliate of Aetna), HealthPartners Institute, Humana Inc, and Kaiser Permanente Northwest Center. No compensation was received for this work.

    References
    1.
    National Institutes of Health. Therapeutic management of nonhospitalized adults with COVID-19. Updated February 1, 2022. Accessed March 30, 2022. https://www.covid19treatmentguidelines.nih.gov/management/clinical-management/nonhospitalized-adults--therapeutic-management/
    2.
    RECOVERY: Randomised Evaluation of COVID-19 Therapy. Low-cost dexamethasone reduces death by up to one third in hospitalised patients with severe respiratory complications of COVID-19. Accessed February 18, 2022. https://www.recoverytrial.net/news/low-cost-dexamethasone-reduces-death-by-up-to-one-third-in-hospitalised-patients-with-severe-respiratory-complications-of-covid-19
    3.
    Centers for Medicare & Medicaid Services. Medicare program: general information. Accessed March 3, 2021. https://www.cms.gov/Medicare/Medicare-General-Information/MedicareGenInfo/index
    4.
    Cocoros  NM, Fuller  CC, Adimadhyam  S,  et al.  A COVID-19–ready public health surveillance system.   Pharmacoepidemiol Drug Saf. 2021;30(7):827-837.PubMedGoogle ScholarCrossref
    5.
    Horby  P, Lim  WS, Emberson  JR,  et al.  Dexamethasone in hospitalized patients with COVID-19.   N Engl J Med. 2021;384(8):693-704.PubMedGoogle Scholar
    6.
    Crothers  K, DeFaccio  R, Tate  J,  et al.  Dexamethasone in hospitalised coronavirus-19 patients not on intensive respiratory support.   Eur Respir J. Published online November 25, 2021. doi:10.1183/13993003.02532-2021 PubMedGoogle ScholarCrossref
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