Objective To determine whether hydrocortisone improves outcome for patients with severe COVID-19.
Design, Setting, and Participants An ongoing adaptive platform trial testing multiple interventions within multiple therapeutic domains, for example, antiviral agents, corticosteroids, or immunoglobulin. Between March 9 and June 17, 2020, 614 adult patients with suspected or confirmed COVID-19 were enrolled and randomized within at least 1 domain following admission to an intensive care unit (ICU) for respiratory or cardiovascular organ support at 121 sites in 8 countries. Of these, 403 were randomized to open-label interventions within the corticosteroid domain. The domain was halted after results from another trial were released. Follow-up ended August 12, 2020.
Interventions The corticosteroid domain randomized participants to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours) (n = 143), a shock-dependent course (50 mg every 6 hours when shock was clinically evident) (n = 152), or no hydrocortisone (n = 108).
Main Outcomes and Measures The primary end point was organ support–free days (days alive and free of ICU-based respiratory or cardiovascular support) within 21 days, where patients who died were assigned –1 day. The primary analysis was a bayesian cumulative logistic model that included all patients enrolled with severe COVID-19, adjusting for age, sex, site, region, time, assignment to interventions within other domains, and domain and intervention eligibility. Superiority was defined as the posterior probability of an odds ratio greater than 1 (threshold for trial conclusion of superiority >99%).
Results After excluding 19 participants who withdrew consent, there were 384 patients (mean age, 60 years; 29% female) randomized to the fixed-dose (n = 137), shock-dependent (n = 146), and no (n = 101) hydrocortisone groups; 379 (99%) completed the study and were included in the analysis. The mean age for the 3 groups ranged between 59.5 and 60.4 years; most patients were male (range, 70.6%-71.5%); mean body mass index ranged between 29.7 and 30.9; and patients receiving mechanical ventilation ranged between 50.0% and 63.5%. For the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively, the median organ support–free days were 0 (IQR, –1 to 15), 0 (IQR, –1 to 13), and 0 (–1 to 11) days (composed of 30%, 26%, and 33% mortality rates and 11.5, 9.5, and 6 median organ support–free days among survivors). The median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% credible interval, 0.91-2.27) and 93% for fixed-dose hydrocortisone, respectively, and were 1.22 (95% credible interval, 0.76-1.94) and 80% for shock-dependent hydrocortisone compared with no hydrocortisone. Serious adverse events were reported in 4 (3%), 5 (3%), and 1 (1%) patients in the fixed-dose, shock-dependent, and no hydrocortisone groups, respectively.
Conclusions and Relevance Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support–free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions.
The principal findings from this study were a 93% probability of benefit of a fixed-duration dosing of hydrocortisone and an 80% probability of benefit of a shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, with regard to the odds of improvement in organ support–free days within 21 days. However, the study was stopped early, the probability of benefit with hydrocortisone did not meet the prespecified statistical trigger for a trial conclusion of superiority, and no strategy was determined to be optimal.
REMAP-CAP is designed to test numerous interventions for pandemic and nonpandemic pneumonia over time. The design has internal statistical triggers for stopping particular study questions, but external factors, such as lack of equipoise following new evidence, can also trigger termination of a portion of the trial. This analysis was prompted by the loss of equipoise following announcement that dexamethasone reduced mortality in the RECOVERY trial.18 Coincidentally, this analysis was also the first interim analysis of the severe COVID-19 cohort: had any internal threshold been triggered, the results would have been released regardless of RECOVERY. However, had RECOVERY not prompted cessation, the internal action would simply be to generate updated randomization proportions and continue enrollment.
Given the findings from contemporaneous trials, the findings might generally be considered supportive of corticosteroid use in this patient population.For example, the benefit reported in RECOVERY was in patients similar to those enrolled in this trial using a corticosteroid, dexamethasone, with a similar glucocorticoid effect to that of the fixed-dose hydrocortisone course in this trial. As such, it seems reasonable that either dexamethasone or hydrocortisone might be beneficial. In turn, it is plausible that the primary benefit is exerted through glucocorticoid, rather than mineralocorticoid effects, given dexamethasone’s lack of mineralocorticoid activity. Systemic corticosteroids have well-described adverse effects. In this open-label trial, serious adverse events were rare, precluding statistical inference. However, they were reported more commonly in the 2 hydrocortisone groups.
The findings regarding the shock-dependent hydrocortisone group are less clear, with an 80% probability of benefit. In this group, physicians only administered hydrocortisone when the patient was in shock. Thus, if corticosteroids are beneficial for COVID-19 through mechanisms other than mitigation of shock, this group was effectively undertreated, and one would anticipate less average benefit. In contrast, if the benefits of corticosteroids largely accrue to those in shock, avoidance of unnecessary corticosteroid therapy in those not in shock might improve the safety profile of corticosteroid therapy. This question remains unresolved.
Strengths of the study include the pragmatic and international design, rendering findings likely generalizable at least to other resource-rich settings around the world. In addition, all analyses were specified prior to unblinding results, results were robust to sensitivity analyses, and findings of multiple secondary outcomes demonstrated similar probabilities of benefit of hydrocortisone. An advantage of using a bayesian approach is that any data, including data following unplanned cessation in enrollment, can be analyzed and quantified as posterior probabilities, which is arguably more useful and is more quantitative than a frequentist finding of failure to reject a null hypothesis possibly because of lack of power.The platform trial design allows efficient enrollment into multiple therapeutic domains simultaneously. One concern could have been potential confounding because of treatment-by-treatment interactions. However, the results were similar with and without adjustment for other treatment assignments.
The study has several limitations. First, the results are presented before reaching any prespecified internal trigger. Nonetheless, to our knowledge, this trial represents the largest randomized data on hydrocortisone in this patient population. Second, the study used an open-label design, although clinician and patient awareness of study assignment likely had minimal effect on the primary outcome. Third, 15% of the no hydrocortisone group received systemic corticosteroids, although typically only for a short period. This usage is similar to that in RECOVERY18 and may often have been unavoidable (eg, to treat postextubation stridor). Nonetheless, it could have biased the results toward smaller effect sizes than would have been observed had corticosteroid use been lower in the no hydrocortisone group.
Among patients with severe COVID-19, treatment with a 7-day fixed-dose course of hydrocortisone or shock-dependent dosing of hydrocortisone, compared with no hydrocortisone, resulted in 93% and 80% probabilities of superiority with regard to the odds of improvement in organ support–free days within 21 days. However, the trial was stopped early and no treatment strategy met prespecified criteria for statistical superiority, precluding definitive conclusions.
Reference & Source information: https://jamanetwork.com/
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