By Marie Rosenthal, MS

 

As a result, the World Health Organization issued a new guideline recommending systemic corticosteroids for the treatment of patients with severe and critical COVID-19. However, the guideline suggested that corticosteroids not be used for those with mild disease. The WHO said treatment in mild COVID-19 cases brought no benefits, and could even prove harmful.

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Steroids appear to work by calming the inflammatory response, which occurs when the body’s immune system overreacts, damaging the lungs and surrounding tissue in seriously ill COVID-19 patients. “There is now strong evidence to suggest that the blockade of inflammation in COVID-19 is effective in severely ill patients,” said C. Michael White, PharmD, FCP, FCCP, the department head and a professor of pharmacy practice at the University of Connecticut School of Pharmacy, in Storrs. Dr. White was not part of the studies but has conducted systematic reviews into other treatment options for COVID-19 and was asked to comment.

The meta-analysis reviewed seven randomized clinical trials from 12 countries with a total of 1,703 critically ill patients with COVID-19 comparing corticosteroids with the standard of care. The trials studied three different corticosteroids—dexamethasone, hydrocortisone and methylprednisolone—and the authors analyzed the results of the RECOVERY, REMAP-CAP, CoDEX, CAPE COVID and three additional trials. The primary end point was risk for death after 28 days. Fewer people receiving any type of systemic steroid died (222/678; 33%) than those who did not receive steroids (425/1,025; 41%) (JAMA 2020 Sep 2. [Epub ahead of print]). Dexamethasone had the largest populations studied and was the only steroid with significant survival benefits in a subgroup analysis (36% reduction in odds), but hydrocortisone had almost the same reductions in odds (31%) and just missed significant findings. Methylprednisolone was only assessed in a single small trial and the odds reduction was a nonsignificant 9%, but with a very large confidence interval.

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The meta-analysis helped to clarify whether the benefit from steroids seen in the earlier RECOVERY trial was due to dexamethasone or was a class effect, but this pooling of data seems to point to a class effect, according to Steven J. Martin, PharmD, BCPS, FCCP, FCCM, the dean and a professor of Ohio Northern University Rudolph H. Raabe College of Pharmacy, in Ada. Dr. Martin did not participate in the studies.

“I believe the RECOVERY trial’s use of dexamethasone led to the early speculation that that drug may be preferred, but the other two trials with hydrocortisone and methylprednisolone also demonstrated positive benefits. Thus, at this point, one would conclude that this is a class effect,” Dr. Martin explained.

The CoDEX trial supporting the use of dexamethasone was performed in Brazil. This open-label, multicenter, randomized clinical trial of 299 patients with COVID-19 and moderate or severe acute respiratory distress syndrome compared IV dexamethasone plus standard of care with standard of care alone. They saw a statistically significant increase in the number of days patients were alive and free from mechanical ventilation. The dexamethasone group had a mean of 6.6 days off the ventilator (95% CI, 5.0-8.2) versus four days in the standard of care group (95% CI, 0.2-4.38; P=0.04), but there was no mortality difference between both groups (JAMA 2020 Sep 2. [Epub ahead of print]).

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An international group in the REMAP-CAP trial looked at whether hydrocortisone also had promising effects on critically ill patients with COVID-19 (JAMA 2020 Sep 2. [Epub ahead of print]). In the randomized hydrocortisone study, 403 patients with suspected or confirmed COVID-19 who required respiratory or cardiovascular organ support, such as mechanical ventilation or drugs to support their blood pressure, were enrolled between March and June 2020. The cohort included patients of mixed ethnicities in the United Kingdom, Ireland, Australia, the United States, the Netherlands, New Zealand, Canada and France. One group was treated with a fixed dose of 50 mg of hydrocortisone four times per day for seven days; another group was treated with hydrocortisone only if their blood pressure dropped; and a third group received no hydrocortisone.

The results showed that using the fixed dose of hydrocortisone led to a 93% chance of a better outcome—greater chance of survival and less need for organ support—than not using hydrocortisone. If the hydrocortisone was given only when the blood pressure was low, the chance of a better outcome was 80%. (This study stopped recruiting patients early after the RECOVERY trial published data in early June, suggesting dexamethasone boosted recovery (N Engl J Med 2020 Jul 17. [Epub ahead of print]. doi: 10.1056/NEJMoa2021436).

“The data seemed clearest for dexamethasone, but in totality they all worked,” said Shmuel Shoham, MD, an associate professor of medicine at the Johns Hopkins University School of Medicine, in Baltimore. Dr. Shoham was not part of the studies but has been involved other treatment studies for COVID-19 and sits on the COVID-19 treatment guideline panel of the Infectious Diseases Society of America.

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“That does not mean it is better than the other ones,” he said. “If available, it might still make sense to use dexamethasone as a first option, but it looks like it is the class effect rather than individual corticosteroids that is important.” 

Hydrocortisone has mineralocorticoid effects that produce a positive sodium balance and higher serum sodium concentrations, increased extracellular fluid volume, hypokalemia and alkalosis, Dr. Martin explained. “Expanded extracellular fluid is generally a good thing in shock, but alkalosis can worsen oxygenation if the pH becomes too high. Hypokalemia can cause heart rhythm disturbances if too low. Dexamethasone doesn't have mineralocorticoid activities, and I can't tell whether that was a good thing or bad thing in these studies. 

“There are potency differences, but the dosing of the drugs was adjusted to account for those differences,” he said. “At this point, one would conclude this is a class effect.”

Dr. White agreed: “While dexamethasone has the strongest data set showing benefit, hydrocortisone is a very reasonable alternative. Methylprednisolone had too small a trial to make a meaningful determination of its efficacy; the 95% confidence interval was very wide. But in equipotent doses, there is reason to believe from other inflammatory diseases that methylprednisolone could also be an alternative if dexamethasone and hydrocortisone were unavailable.”

This is an important consideration because “dexamethasone was one of the drugs on back order and shortage since the initial RECOVERY trial results came out, so being able to diversify to other corticosteroids would help meet demand,” Dr. White explained. 

Dosing seems to be an important consideration, according to Drs. White and Martin, and lower doses appear to be as effective as higher ones. 

“I have to believe dose is important,” Dr. Martin said. “The dosing for the trials in the meta-analysis was varied. In trials that administered low doses of corticosteroids, the overall fixed-effect OR [odds ratio] was 0.61, and the corresponding absolute risk was 29% for low-dose corticosteroids versus an assumed risk of 40% for usual care or placebo. In trials that administered high doses of corticosteroids, the fixed-effect OR was 0.83, and the corresponding absolute risk was 36% for high-dose corticosteroids versus an assumed risk of 40% for usual care or placebo.”

Even the authors of the meta-analysis concluded that higher doses were not more beneficial than lower ones. Using lower doses could also help reserve the medication for more patients, according to Dr. White.

It’s important to advise patients that all of the patients in these studies were critically ill and required some type of oxygenation, typically ventilator support, all three experts said. 

There is little to support widespread use by mildly ill patients. “We have learned in other disease states that steroids have a clearly demarcated role in managing systemic inflammation without worsening the underlying condition,” Dr. Martin said. “Too much steroid can cause problems of its own.”

The WHO recommended against the use of steroids outside of critical patients in its COVID-19 treatment recommendations.

“At the beginning of the year, at times, it felt almost hopeless, knowing that we had no specific treatments. It was a very worrying time. Yet less than six months later, we’ve found clear, reliable evidence in high-quality clinical trials of how we can tackle this devastating disease,” said Anthony Gordon, MD, FFICM, FRCA, the chair of anesthesia and critical care at the Imperial College London, who participated in the REMAP-CAP study.

—Dr Gordon reported receiving grants from the NIHR and the NIHR Research Professorship. Drs. Martin, Shoham and White reported no relevant financial disclosures.