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“Let us try to assume our fundamental ambiguity.”
-Simone de Beauvoir
When the pre-peer review RECOVERY trial was released in mid-June of this year, clinicians lost equipoise to enroll hospitalized patients receiving at least oxygen for COVID-19 into trials including a treatment arm without corticosteroids. This brought to an early-halt three randomized trials evaluating corticosteroids in hospitalized patients with COVID-19-associated lung injury. Two of these three trials studied hydrocortisone while the third evaluated dexamethasone at a higher dosing regimen than RECOVERY. Recall that studies up to and including RECOVERY suggested that corticosteroids most-benefited COVID-19 patients receiving mechanical ventilation. Accordingly, the three, halted randomized trials are briefly summarized below in rough order of COVID-19 severity at randomization, based on respiratory organ support. Critically, the definition of ‘severe’ COVID-19 is non-standardized. Nevertheless, based on the criteria delineated by Yuan et al. [which are nearly identical to the NIH criteria, found here], the patients enrolled in each of these randomized trials had ‘severe’ COVID-19 associated lung injury upon trial entry. Thus, we expect these patient populations to derive most benefit.
Finally, a meta-analysis is reported in the same issue of JAMA that includes RECOVERY, the additional three randomized trials and a few smaller investigations. In totality, the data strengthen the case for corticosteroids in hospitalized, COVID-19-associated lung injury needing respiratory organ support.
The Randomized, Embedded, Multifactorial Adaptive Platform Trial for Community-Acquired Pneumonia [REMAP-CAP] study included adult patients with presumed or confirmed, ‘severe’ SARS-CoV-2 infection. Patients required ICU admission for either respiratory or cardiovascular organ support. The former was defined as invasive or non-invasive mechanical ventilation or high-flow nasal cannula [>30 L/min, FiO2 > 0.4] while the latter as any inotrope or vasopressor infusion. In terms of respiratory organ support at baseline, the patients in the REMAP-CAP trial were the least sick of the three randomized trials summarized herein. The percentage of patients receiving invasive mechanical ventilation, non-invasive ventilation, and high-flow nasal cannula were between 50-64%, 24-34% and 12-16%, respectively. Duration of symptoms was not specifically reported.
Hydrocortisone dosing was of similar glucocorticoid equivalency to that used in RECOVERY [i.e. 6 mg of dexamethasone is approximatively equivalent to 160 mg of hydrocortisone]. Patients were randomized to receive the following within 36 hours of ICU admission:
- fixed dose of intravenous hydrocortisone, 50 mg, q6h for 7 days [n = 143];
- intravenous hydrocortisone, 50 mg q6h while in shock for up to 28 days [n = 152];
- no hydrocortisone [n = 108]
The shock-dependent strategy was studied with the hypothesis that restricting hydrocortisone to the period of overt shock would maximize the risk-benefit ratio. Patients were enrolled from 121 clinical sites in Australia, Canada, France, Ireland, the Netherlands, New Zealand, the United Kingdom, and the United States and the primary outcome was organ support-free days.
The study utilized a Bayesian cumulative logistic model as opposed to a ‘frequentist’ approach; the former allows quantification of posterior probabilities, which is arguably more meaningful than the latter approach which fails to reject the null hypothesis when statistical power is lacking [e.g. when a trial is ceased prematurely]. Accordingly, the odd ratios for the primary outcome were 1.43 and 1.22 for the fixed-dose and shock-dependent hydrocortisone groups compared with the no hydrocortisone group, yielding 93% and 80% probabilities of superiority over the no hydrocortisone group, respectively. Importantly, only about 50% of those randomized to shock-dependent dosing received any corticosteroids.
For those not intubated at baseline, the probabilities of superiority for hydrocortisone compared to no hydrocortisone for preventing progression to invasive mechanical ventilation were 99% and 70% for the fixed-dose and shock-dependent dosing, respectively. Lastly, in total, there were 10 serious adverse events, 9 of which occurred in the hydrocortisone groups and of those 9, only 2 were considered related to corticosteroids [i.e. myopathy and fungemia]. Nevertheless, because the trial was stopped early and no treatment strategy met pre-specified criteria for statistical superiority, definitive conclusions could not be made.
This investigation was embedded in the ongoing Community-Acquired Pneumonia: Evaluation of Corticosteroids [i.e. CAPE COD] trial. Adult patients were enrolled from 9 participating French ICUs for acute respiratory failure secondary to confirmed or suspected COVID-19.
One of the following severity criteria had to be present: 1. mechanical ventilation with PEEP of at least 5 cm H2O; 2. An arterial oxygen partial pressure [PaO2] to fraction of inspired oxygen [FiO2] less than 300 on high-flow oxygen therapy, or reservoir mask, with an FiO2 value of at least 50% [estimated from pre-specified charts for those on reservoir mask]; 3. Pulmonary Severity Index greater than 130. At baseline, about 80% of patients were receiving invasive ventilation, 3% non-invasive ventilation, 12-13% high flow oxygen therapy and 5-7% non-rebreathing mask with reservoir bag. Their SOFA scores were 6.0 and their symptom duration prior to enrollment was roughly 7 days.
Patients were randomized to receive the following within 24 hours of the onset of the first severity criterion above or within 48 hours for patients referred from another hospital:
- Continuous intravenous infusion of hydrocortisone 200 mg/day for seven days, 100 mg/day for four days and 50 mg/day for three days. If the patient’s general and respiratory status improved by day 4, a shorter course of 200 mg/day for four days, 100 mg/day for two days and then 50 mg/day for two days was allowed [n = 76].
- Placebo infusion [n = 73].
The primary outcome was treatment failure on day 21, defined as death or persistent dependency on mechanical ventilation or high-flow oxygen therapy. Treatment failure on day 21 occurred in 32 of 76 patients [42.1%] in the hydrocortisone group compared with 37 of 73 [50.7%] in the placebo group; while clinically-significant, it was not statistically-significant. As well, hydrocortisone did not significantly reduce the proportion of patients receiving mechanical ventilation on day 21 and did not increase in the rate of secondary infections. Nevertheless, like REMAP-CAP, the trial was likely underpowered because it stopped enrolling patients following the results of RECOVERY.
The COVID-19 Dexamethasone [CoDEX] trial evaluated the efficacy of intravenous dexamethasone in moderate-to-severe ARDS due to COVID-19. Adult patients from 41 ICUs in Brazil were enrolled. Given that moderate-to-severe ARDS was a pre-requisite for this trial, CoDEX patients were sicker than both REMAP-CAP and CAPE-COVID. All patients were mechanically-ventilated, their SOFA scores were 8-9 and their average symptoms duration was 9-10 days.
Patients were randomized to receive the following within 48 hours of the diagnosis of moderate-to-severe ARDS based on the Berlin criteria:
- Dexamethasone 20 mg intravenously once daily for 5 days, followed by 10 mg intravenously daily for 5 more days or until ICU discharge, whichever occurred first [n = 151].
- Standard care alone [n = 148].
The hypothesis was that dexamethasone would increase the number of days alive and free from mechanical ventilation during the first 28 days. This primary outcome was clinically and statistically significantly higher in the dexamethasone group than in the standard care group by 2.6 days. As well, the SOFA score at day 7 was significantly diminished by dexamethasone by 1.6 and there was a 5% absolute risk reduction in mortality favouring dexamethasone, though the mortality reduction was not statistically significant. There was no difference in adverse outcomes between the groups.
I found these trials surprisingly in-line with my expectations. Given the results of RECOVERY, Fadel and colleagues and retrospective analyses described previously, I anticipated the following:
- The trials would be under-powered to detect significant differences in mortality, but there would be clinically-suggestive trends favouring corticosteroids.
- In trials enrolling non-intubated patients, corticosteroids would prevent progression to mechanical ventilation.
- Corticosteroids would help resolve shock and probably get patients out of the ICU faster.
- Trials enrolling sicker patients at baseline would be the most likely to show a significant benefit for corticosteroids.
In both REMAP-CAP and CAPE-COVID, enrollment was stopped early because of the RECOVERY results, thus they were both under-powered to detect difference with statistical confidence. Nevertheless, treatment with corticosteroids trended towards lower mortality and both studies intimated that non-intubated patients randomized to corticosteroids were less likely to progress to invasive mechanical ventilation. Preventing invasive ventilation was also observed in the case series by Kolilekas and colleagues, the quasi-experimental study by Fadel et al. as well as the RECOVERY investigators. Hence, these findings are congruent with expectations. Further, REMAP-CAP alluded to shock reversal with steroids, while this data was not apparent from CAPE-COVID.
Finally, CoDEX, which enrolled moderate-to-severe ARDS patients, was the only trial of the three to show statistical benefit to steroids. Patients randomized to relatively high-dose dexamethasone were more likely to be alive and free from the ventilator at 28 days. While mortality was reduced by 5%, this metric was not statistically-significant.
Perhaps most interesting, to me at least, was that patients randomized to shock-dependent hydrocortisone in REMAP-CAP had a lower probability of superiority in contradistinction to fixed-dose hydrocortisone. This finding suggests, in conjunction with all of the other data, that the benefit of corticosteroids in COVID-19 is beyond that of cardiovascular support.
Lastly, in two studies, a clinically-significant proportion of patients randomized to ‘no corticosteroids’ actually received them [15% in REMAP-CAP; 35% in CoDEX] which would have washed away some of the suggested or observed benefit.
Part 2, here.