Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-analysis | Critical Care Medicine | JAMA | JAMA Network
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    5 Comments for this article
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    Putting Effects of Glucocorticoids in COVID-19 Into Clinical Context
    Prof Brian Lipworth, MD | Scottish Centre for Respiratory Research, Ninewells Hospital, Dundee
    The WHO meta-analysis showed an overall 34% (95%CI 18-47) relative reduction in mortality among critically ill patients with COVID-19 when treated with systemic glucocorticoids compared to either usual care or placebo . However it is perhaps more clinically meaningful to consider absolute mortality rates amounting to a difference of 8.7% which in turn translates into an overall number needed to treat (NNT) of 11.5.
    In the RECOVERY trial using dexamethasone comprising 57% of all patients the NNT was 8.3. In the subgroup of three trials using dexamethasone comprising 76.6 % of patients the NNT was 13.0. Labelling 6 mg
    of dexamethasone as low dose is misleading as this is equipotent to 40 mg of prednisolone which is considered to be a medium dose of glucocorticoid when treating patients with airflow obstruction. Finally, as well as exhibiting suppression of pro-inflammatory cytokines in patients with severe COVID-19, glucocorticoids also suppress aldosterone release (1), which could result in improved cardiac outcomes in the presence of augmented renin-angiotensin-aldosterone system activity (2).

    References

    1. Wilson AM, Sims EJ, Struthers AD, Lipworth BJ. Inhaled corticosteroid therapy reduces the early morning peak in cortisol and aldosterone. Clinical science. 1998;95(4):513-517.

    2. Vaduganathan M, Vardeny O, Michel T, McMurray JJV, Pfeffer MA, Solomon SD. Renin–Angiotensin–Aldosterone System Inhibitors in Patients with Covid-19. New England Journal of Medicine. 2020;382(17):1653-1659.
    CONFLICT OF INTEREST: None Reported
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    RECOVERY Trial Influence and "Class Effect" Attribution
    Shyan Goh, MBBS, FRACS | Private
    The WHO working group offers a timely review of current evidence investigating the role of systemic corticosteroids (CS) in curbing mortality rates in critically ill COVID-19 patients, much needed when many research are happening simultaneously.

    Despite the potential heterogenous nature of defining what is meant by "critically ill" including the criteria of initiating mechanical ventilation, the authors made a reasonable assessment incorporating the new Cochrane RoB 2, which potentially has low interrater reliability just 12 months after its introduction. Not surprisingly, dexamethasone (DEXA), compared with usual care or placebo, was associated with lower 28-day all-cause mortality in the subgroup
    analysis, much of the data driven by the UK's RECOVERY trial, the largest study with low variance, with weighted average of 57% in the entire meta-analysis.

    As such, the inclusion of single large study like RECOVERY will make or break any analysis when combined with other small studies, which is normally not an issue when comparing like for like. As the authors admit, the exclusion of RECOVERY in the analysis change the odds ratio calculation when assessing corticosteroids as a class effect.

    Notwithstanding the issue of applicability of RECOVERY (noting that COVID-19 mortality rates in NHS improved by 30% across the board at the same time as the RECOVERY trial, suggesting a critical care learning curve in disease management), it is likely DEXA does not have a significant effect on selected groups of COVID-19 patients. However the effect of a single study with overwhelmingly high weighted average (colloquially termed "the hulk" in some circles) poses a liability when trying to extend the results of drugs under investigation as a "class effect".

    Furthermore there are well-known significant differences in potency (about 50x) and pharmacokinetics between DEXA and hydrocortisone (HC), so the RECOVERY trial can hardly provide an evidence-based guide for HC users in dosing administration.

    While it is laudable WHO provided a timely meta-analysis of available evidence, this appraisal dominated by RECOVERY with unfounded extrapolation as "class effect" undermines the accuracy and future conduct of research in this area.
    CONFLICT OF INTEREST: None Reported
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    Further Clarification
    Imran Iftikhar, MD | Emory University School of Medicine, Division of Pulmonary, Allergy, Critical Care & Sleep Medicine
    Some of the conclusions derived from sub-group analyses are misleading. Five out of seven trials reported mortality data at 28 days and the other two (Steroids-SARI and CAPE COVID) at different time-points. Yet, the forest plots are labelled as mortality at “28 days”. It would have been best to compute rate ratios (using person-time unit) and then meta-analyze the data. It is also not specified in the methods as to why they chose fixed effect model for meta-analysis, when it is clear that the population was so heterogenous (from different geographic areas), in which case it should have been an a priori decision to use a random effects model, which would have shown no significant effect on mortality reduction by steroids. The authors also found comparatively less 28-day all-cause mortality in those not on invasive mechanical ventilation (MV) than in those on invasive MV (sample size of former: only 144 patients), which is essentially the opposite of what was found in the RECOVERY trial, at least in the “oxygen only group” (with a sample size of 3883 for that sub-group). These data from the RECOVERY trial were excluded from the meta-analysis, reportedly because the latter group was thought to be a diverse group of those on nasal prongs to those receiving high-flow oxygen or non-invasive MV. If, however, the number of patients on “nasal prongs” was indeed a majority, then understandably to avoid heterogeneity in the meta-analysis, it would be reasonable to exclude this data from meta-analysis. However, I don’t think that by excluding this data from the sub-group analysis in the meta-analysis, makes that population any less heterogenous. This is because while I cannot comment on the other (yet) non-published trials that were included in JAMA meta-analysis, we know for a fact that of the steroid- treated patients not on invasive MV, about 33% in the REMAP-CAP and 71% in the CAPE COVID trials were on high flow oxygen, and 67% and 29% on non-invasive MV in these trials, respectively, and as an example, all of the above-mentioned patients not on invasive MV from CAPE COVID trial were added in the non-invasive MV sub-group analysis in the meta-analysis. This does not justify exclusion of RECOVERY trial’s data, labeled “oxygen only”. Furthermore, my review of RECOVERY trial’s supplement Figure S2b and its legend (detailing that his group included those on ‘non-invasive MV’) suggests that the group labeled as “oxygen only” may not have been too different in its composition from the other trials included in the meta-analysis. Therefore, if we meta-analyze the data of those not requiring invasive MV (based on the meta-analysis) with the “oxygen only” data from RECOVERY trial, the pooled OR is 0.65 [95% confidence intervals (CI): 0.32 to 1.30, p=0.228] by random effects model, and 0.83 [95% CIs: 0.71 to 0.96, p=0.01] by fixed effect model. In such a meta-analysis, with a diverse population and high baseline heterogeneity one would use random effects model, in which case, there is no mortality benefit in using steroids for critically ill Covid-19 patients not requiring invasive MV. Lastly, sub-group fixed effect OR for hydrocortisone was 0.69 (0.43 to 1.12), was clearly not statistically significant contrary to that noted with dexamethasone, and therefore, authors conclusion that the ORs for the two were similar, is misleading. I believe that the RECOVERY trial’s data of those not on invasive MV needs further clarification and then re-analyzed with other trials in a meta-analysis.
    CONFLICT OF INTEREST: None Reported
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    Misleading Analyses and Statistical Significance
    Jonathan Sterne, MA MSc PhD | University of Bristol, UK
    We thank Dr Iftikhar for his interest in and comments on our paper. We strived to communicate the conclusions of our paper clearly, including the degree of uncertainty associated with some of them. We strongly disagree that any of the conclusions derived from the subgroup analyses reported in our paper were misleading.

    The timing of the mortality measurements is described clearly in our paper, and the reason for labelling the outcome as 28-day mortality is clearly explained. Meta-analyses based on odds ratios are standard in systematic reviews worldwide. It would have been interesting to conduct time-to-event analyses, but these
    were not possible using aggregate data. It is likely that a meta-analysis using hazard ratios would give similar results to those published in our paper.

    We prespecified that our primary analysis would be a fixed-effect meta-analysis. We disagree that it should have been decided a priori to use random-effects meta-analysis. As we explained in the paper, the confidence interval for the random-effects meta-analysis reflects both the uncertainty in estimating the average treatment effect across trials and the uncertainty in estimating the between-trial variance. There was in fact little inconsistency between the results of the different trials, therefore no reason to consider a fixed-effect analysis to be inappropriate.

    The subgroup analysis related to invasive mechanical ventilation was pre-specified. Our meta-analysis related to critically ill patients, but it was not possible to identify whether RECOVERY patients were or were not critically ill at the time of randomization. Therefore, our main meta-analysis was restricted, a priori, to RECOVERY patients who were invasively mechanically ventilated at randomization. The presentation of RECOVERY data in our paper was clear and transparent.

    We refer Dr Iftikhar to our highly-cited and still relevant paper on significance tests (1). He appears to be making the most common mistake associated with dichotomising results as “significant” or “non-significant”, which is to equate “non-significant” with “no difference”. He can avoid this mistake in the future by remembering that “absence of evidence is not evidence of absence”.

    The odds ratio for dexamethasone (0.64) was similar to the odds ratio for hydrocortisone (0.69). Dr Iftikhar is making the common error of interpreting two associations that are and are not statistically significant as being different. This could be the case even if the estimated associations were identical, because statistical significance depends both on the magnitude of the association and the precision with which it was estimated. See (2) for quantification of the problems arising from this misinterpretation of subgroup differences

    REFERENCES

    1. https://www.bmj.com/content/322/7280/226.1
    2. https://pubmed.ncbi.nlm.nih.gov/15066682/ 
    CONFLICT OF INTEREST: I received grants from the UK National Institute for Health Research (NIHR)
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    Inadvertent Underdosing of Dexamethasone - Alert
    Andrea Vila, MD, Infectious Diseases | Hospital Dr. Ramón Carrillo. Las Heras. Mendoza. Argentina
    When considering the use of a drug, it is essential to know its chemical characteristics, as well as the formulations available on the market; to ensure that the patient gets the necessary and appropriate dose. Dosing recommendations for dexamethasone are made in milligrams of dexamethasone base, which is the pure active substance. The differences between the presentations of dexamethasone between countries is a potential source of dosing errors when interpreting clinical studies.

    In the RECOVERY trial, dexamethasone was prescribed as an UK product containing dexamethasone active substance (dexamethasone base: C22H29FO5).

    Nevertheless, there are two more dexamethasone
    presentations for injection: dexamethasone phosphate (C22H30FO8P), which is the 21-O-phospho derivative of dexamethasone; and dexamethasone sodium phosphate (C22H28FNa2O8P), which is a sodium salt form of dexamethasone phosphate.

    Each milliliter of solution of dexamethasone base contains 3.3 mg, which is equivalent to 4 mg dexamethasone phosphate or 4.3 mg dexamethasone sodium phosphate.

    Thus, equivalences per mililiter of parenteral solutions are: dexamethasone base 3.3mg = dexamethasone phosphate 4mg = dexamethasone sodium phosphate 4,3 mg.

    Each country should analyze their available commercial presentations of dexamethasone for injection, in order to avoid confusion resulting in underdosing. This could be especially relevant in obese adults weighing, since no adjustment is made per kilogram of weight in adults.

    In countries where dexamethasone is available as dexamethasone sodium phosphate, it is necessary to use 7.82 mg of this compound in order to reach the dose used in the RECOVERY study (6 mg of dexamethasone base). Since available commercial presentations contain 8 mg total dexamethasone sodium phosphate in 2 ml, for practical purposes a complete ampoule should be used (it is impractical to fractionate to 7.82 mg), to obtain 6 mg dexamethasone base.

    REFERENCES

    1. Effect of Dexamethasone in Hospitalized Patients with COVID-19 – Preliminary Report SUPPLEMENTARY APPENDIX PROTOCOL AND STATISTICAL ANALYSIS PLAN RECOVERY Collaborative Group. https://www.nejm.org/doi/suppl/10.1056/NEJMoa2021436/suppl_file/nejmoa2021436_protocol.pdf
    2. DRUG GUIDELINE NSW Therapeutic Advisory Group. Dexamethasone in COVID-19. 11 August 2020. Version 1. Use of dexamethasone for COVID-19 in hospitalized adults, adolescents and children. http://www.nswtag.org.au/resources-for-experimental-medicines-for-the-treatment-of-covid-19
    3. Scottish Palliative Care Guidelines – Dexamethasone https://www.palliativecareguidelines.scot.nhs.uk/media/71370/20-2019-dexamethasone.pdf
    4. PubmedChem. Compound summary. Dexamethasone. https://pubchem.ncbi.nlm.nih.gov/compound/Dexamethasone
    5. PubmedChem. Compound summary. Dexamethasone phosphate. https://pubchem.ncbi.nlm.nih.gov/compound/dexamethasone%20phosphate.
    6. PubmedChem. Compound summary. Dexamethasone sodium phosphate. https://pubchem.ncbi.nlm.nih.gov/compound/16961
    10. Electronic Medicines Compendium. Dexamethasone 3.3 mg/ml solution for injection https://www.medicines.org.uk/emc/medicine/24697#gref
    12. Package leaflet: Information for the user Dexamethasone 3.3 mg/ml Solution for Injection (3.3 mg/1 ml ampoules). https://www.medicines.org.uk/emc/files/
    CONFLICT OF INTEREST: None Reported
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    Original Investigation
    Caring for the Critically Ill Patient
    September 2, 2020

    Association Between Administration of Systemic Corticosteroids and Mortality Among Critically Ill Patients With COVID-19: A Meta-analysis

    The WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group
    JAMA. 2020;324(13):1330-1341. doi:10.1001/jama.2020.17023
    Key Points

    Question  Is administration of systemic corticosteroids associated with reduced 28-day mortality in critically ill patients with coronavirus disease 2019 (COVID-19)?

    Findings  In this prospective meta-analysis of 7 randomized trials that included 1703 patients of whom 647 died, 28-day all-cause mortality was lower among patients who received corticosteroids compared with those who received usual care or placebo (summary odds ratio, 0.66).

    Meaning  Administration of systemic corticosteroids, compared with usual care or placebo, was associated with lower 28-day all-cause mortality in critically ill patients with COVID-19.

    Abstract

    Importance  Effective therapies for patients with coronavirus disease 2019 (COVID-19) are needed, and clinical trial data have demonstrated that low-dose dexamethasone reduced mortality in hospitalized patients with COVID-19 who required respiratory support.

    Objective  To estimate the association between administration of corticosteroids compared with usual care or placebo and 28-day all-cause mortality.

    Design, Setting, and Participants  Prospective meta-analysis that pooled data from 7 randomized clinical trials that evaluated the efficacy of corticosteroids in 1703 critically ill patients with COVID-19. The trials were conducted in 12 countries from February 26, 2020, to June 9, 2020, and the date of final follow-up was July 6, 2020. Pooled data were aggregated from the individual trials, overall, and in predefined subgroups. Risk of bias was assessed using the Cochrane Risk of Bias Assessment Tool. Inconsistency among trial results was assessed using the I2 statistic. The primary analysis was an inverse variance–weighted fixed-effect meta-analysis of overall mortality, with the association between the intervention and mortality quantified using odds ratios (ORs). Random-effects meta-analyses also were conducted (with the Paule-Mandel estimate of heterogeneity and the Hartung-Knapp adjustment) and an inverse variance–weighted fixed-effect analysis using risk ratios.

    Exposures  Patients had been randomized to receive systemic dexamethasone, hydrocortisone, or methylprednisolone (678 patients) or to receive usual care or placebo (1025 patients).

    Main Outcomes and Measures  The primary outcome measure was all-cause mortality at 28 days after randomization. A secondary outcome was investigator-defined serious adverse events.

    Results  A total of 1703 patients (median age, 60 years [interquartile range, 52-68 years]; 488 [29%] women) were included in the analysis. Risk of bias was assessed as “low” for 6 of the 7 mortality results and as “some concerns” in 1 trial because of the randomization method. Five trials reported mortality at 28 days, 1 trial at 21 days, and 1 trial at 30 days. There were 222 deaths among the 678 patients randomized to corticosteroids and 425 deaths among the 1025 patients randomized to usual care or placebo (summary OR, 0.66 [95% CI, 0.53-0.82]; P < .001 based on a fixed-effect meta-analysis). There was little inconsistency between the trial results (I2 = 15.6%; P = .31 for heterogeneity) and the summary OR was 0.70 (95% CI, 0.48-1.01; P = .053) based on the random-effects meta-analysis. The fixed-effect summary OR for the association with mortality was 0.64 (95% CI, 0.50-0.82; P < .001) for dexamethasone compared with usual care or placebo (3 trials, 1282 patients, and 527 deaths), the OR was 0.69 (95% CI, 0.43-1.12; P = .13) for hydrocortisone (3 trials, 374 patients, and 94 deaths), and the OR was 0.91 (95% CI, 0.29-2.87; P = .87) for methylprednisolone (1 trial, 47 patients, and 26 deaths). Among the 6 trials that reported serious adverse events, 64 events occurred among 354 patients randomized to corticosteroids and 80 events occurred among 342 patients randomized to usual care or placebo.

    Conclusions and Relevance  In this prospective meta-analysis of clinical trials of critically ill patients with COVID-19, administration of systemic corticosteroids, compared with usual care or placebo, was associated with lower 28-day all-cause mortality.

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