Effect of Hydrocortisone on Mortality and Organ Support in Patients With Severe COVID-19: The REMAP-CAP COVID-19 Corticosteroid Domain Randomized Clinical Trial

SPS commentary:

Trial reported that treatment with a 7-day fixed-dose course of hydrocortisone (HC) or shock-dependent dosing of HC, vs. no HC, resulted in 93% and 80% probabilities of superiority, respectively, with regard to odds of improvement in organ support–free days within 21 days. Median adjusted odds ratio and bayesian probability of superiority were 1.43 (95% CI, 0.91-2.27) and 93% for fixed-dose HC, respectively, and 1.22 (0.76-1.94) and 80% for shock-dependent HC vs. no HC.

 

This trial was published in JAMA along with 2 other randomised trials of corticosteroids and a meta-analysis:

 

• Pooled data from 7 RCTs (n=1703) found administration of systemic corticosteroids, compared with usual care or placebo, was associated with lower 28-day all-cause mortality (222/678 [32.7%] died vs. 425/1025 [41.5%], OR, 0.66; 95% CI, 0.53-0.82; p <0 .001).

 

• CoDEX trial found that number of days alive and free from mechanical ventilation during first 28 days was significantly higher among patients treated with dexamethasone plus standard care vs. standard care alone (6.6 days vs 4.0 days; p = 0.04).

 

• CAPE COD trial reported that low-dose hydrocortisone did not significantly reduce treatment failure in patients with COVID-19–related acute respiratory failure; however as trial was terminated early, it was likely underpowered.

 

According to an editorial, these data represent an important step forward in the treatment of patients with COVID-19. It notes that while the RECOVERY results were embraced because they provided hope in the treatment of this catastrophic disease, numerous study limitations prevented complete confidence in using corticosteroids in hospitalized patients with COVID-19. It adds that these trials and the meta-analysis have strengthened confidence, further defined the benefit, and shifted usual care of COVID-19–related acute respiratory distress syndrome. (ARDS) to include corticosteroids.

 

It warns however that many clinically important questions remain.

 

1. Do the benefit and optimal dosing of corticosteroids differ between different ARDS subphenotypes?
2. Should corticosteroid administration be individualized, with initiation, dosing, and duration guided by clinical response or biomarkers, such as C-reactive protein? Does inflammation rebound after cessation of corticosteroids in some patients and would tapering them improve outcomes?
3. What are the true incidence and optimal management of adverse effects, given that most of the randomized trials are open-label pragmatic designs with minimal reporting of adverse effects?
4. Should less severely ill or nonhospitalized patients be treated with corticosteroids?
5. What is the threshold of illness severity at which corticosteroids are now indicated?
6. Do corticosteroids delay clearance of SARS-CoV-2, especially in less ill patients not hospitalized, and if so, does this affect clinical outcomes?
7. Should remdesivir or other potentially active therapeutics be administered with corticosteroids?

 

While much work remains on the exact details of implementation into clinical practice, it concludes for now that the consistent findings of benefit in these studies provide definitive data that corticosteroids should be first-line treatment for critically ill patients with COVID-19.

 

Following publication of the REMAP-CAP trial and this meta-analysis, the World Health Organization has issued new interim guidance recommending the use of systemic corticosteroids in severe and critical COVID-19 disease as follows:

 

1. Strong recommendation for systemic (intravenous or oral) corticosteroid therapy in patients with severe and critical COVID-19, and
2. Conditional recommendation not to use corticosteroid therapy in patients with non-severe  COVID-19.