20% reduction in deaths reported in meta-analysis of 7 randomized trials

Treatment with corticosteroids was associated with a 20% reduction in deaths among hospitalized, critically ill patients with Covid-19 in a pooled analysis of seven studies.

Critically ill Covid-19 patients who were treated with systemic corticosteroids had lower 28-day mortality with no significant increase in adverse events in a meta-analysis of the randomized trials involving just over 1,700 patients recruited from five continents.

The meta-analysis and three of the Covid-19 randomized trials contributing data – REMAP-CAP, CoDEX, and CAPE – were published online September 2 in JAMA.

All three trials were halted early after results from a fourth trial, RECOVERY, were announced in a press release in mid-June, showing a one-third reduction in mortality associated with dexamethasone treatment among Covid-19 patients with acute respiratory distress syndrome (ARDS) on mechanical ventilation. Peer-reviewed trial findings were published in NEJM in mid-July.

The meta-analysis, conducted by the World Health Organization Rapid Evidence Appraisal for Covid-19 Therapies (REACT) Working Group, included patients recruited through June 9. Reviewers reasoned that clinical management of patients enrolled after this date would have been influenced by the RECOVERY findings.

In a press briefing held Wednesday morning, Jonathan Stern, PhD, who led the meta-analysis, said patients treated with corticosteroids in the trials represented the sickest patients with Covid-19 — patients who had an expected mortality of around 40% in the absence of treatment with corticosteroids.

He said treatment with corticosteroids was found to reduce this expected mortality to 32%, or a 20% relative reduction in mortality.

“Another way to think about it is that out of every 100 patients treated with corticosteroids, eight will not die,” he said, adding that “for every 12 critically ill patients treated, one life would be saved.”

“That is really the bottom line from these results,” he said.

Based on the pooled study findings, the World Health Organization announced that it is revising its treatment guidelines for Covid-19.

The guidelines now call for corticosteroids to be used in patients with severe or critical Covid-19 (strong recommendation; moderate certainty evidence), and the guidelines recommend against the use of corticosteroids for patients with mild Covid-19 due to concerns that the treatment could potentially increase deaths in these patients.

Janet Diez, MD, of the WHO Health Emergencies Programme, said the organization was able to make the guideline changes quickly because researchers shared their data in real time, before their publication in JAMA.

Critical care specialist Todd W. Rice, MD, of Vanderbilt University, Nashville, said corticosteroids appear to work in the most critically ill patients with Covid-19 because they address the runaway inflammation that characterizes more severe disease.

“I think it is becoming more and more clear that a later phase of this disease is dominated by an inflammatory component and hyperinflammation,” he said. “Steroids are very good at reducing that inflammatory component and reducing the effects of hyperinflammation in the body, and I think that is probably the mechanism.”

In an editorial published with the studies, Rice and critical care specialists Haillie Prescott, MD, of the University of Michigan, Ann Arbor, wrote that the three studies and meta-analysis “represent an important step forward in the treatment of patients with Covid-19.”

“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,” they wrote. “These trials and the meta-analysis have strengthened confidence, further defined the benefit, and shifted usual care of Covid-19 related ARDS to include corticosteroids.”

The analysis included 678 patients randomized to receive corticosteroids and 1,025 patients randomized to usual care or placebo. A total of 59% of the patients were from the RECOVERY trial.

The 28-day all-cause mortality was lower in patients treated with steroids, with 222 deaths occurring among 678, compared to 425 deaths among the 1,025 usual care group (summary odds ratio, 0.66, 95% CI to −0.82; P<0.001), with little heterogeneity across the studies).

Dexamethasone- and hydrocortisone-treated patients had showed similar mortality reduction, suggesting a class effect for the corticosteroids.

The fixed-effect summary odds ratio for the association with mortality was 0.64 (95% CI, 0.50-0.82; P<0.001) 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=0.13) 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).

The REMAP-CAP trial, conducted to determine whether hydrocortisone improves severe Covid-19 outcomes, included 384 patients randomized to a fixed 7-day course of intravenous hydrocortisone (50 mg or 100 mg every 6 hours (n=137), shock-dependent (50 mg every 6 hours when shock was evident) hydrocortisone (n=146), or no hydrocortisone (n=101). A total of 379 (99%) completed the study and were included in the analysis.

Among 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.

The researchers concluded that both hydrocortisone regimens were likely superior to no hydrocortisone, but the data were insufficient to confirm the optimal regimen.

The CoDEX trial included 299 patients treated in 41 ICUs in Brazil with moderate to severe ARDS and Covid-19 treated with open-label, high-dose dexamethasone (20 mg/d for five days, followed by 10 mg/d for 5 days) or no dexamethasone.

Patients in the dexamethasone arm had fewer ventilator-free days through day 28 (6.6 versus 4.0; P=0.04), which was the primary study outcome.

Two-thirds of the patients in the trial were being treated with vasopressors at the time of randomization, and just over a third (35%) of those randomized to usual care were treated with at least one dose of corticosteroids, which could have reduced the effect size in the trial.

No significant difference was seen in the two treatment groups in 28-day mortality(56.3% in the corticosteroid group versus 61.5% in the usual care group; P=0.83), but the researchers noted that stopping the study early due to the RECOVERY findings resulted in under-powering to evaluate the mortality outcome.

The CAPE COVID trial, which was the only one of the three studies that was blinded, included 149 Covid-19 patients with severe respiratory disease being treated in 9 ICUs in France.

The study’s primary outcome of 21-day treatment failure, defined as death, ongoing mechanical ventilation or high-flow oxygen, occurred in 42.1% of patients in the hydrocortisone group vs. 50.7% of patients in the placebo group (P=0.29).

The researchers concluded, however, that due to the early termination of the study it was probably under-powered to show a “statistically and clinically important difference in the primary outcome.”

In their editorial, Prescott and Rice wrote that despite many unanswered questions about the optimal use of corticosteroids in the treatment of Covid-19, “these studies provide evidence and some hope that an effective, inexpensive, and safe treatment has been identified.”

  1. Critically ill Covid-19 patients with treated with systemic corticosteroids had lower 28-day mortality with no significant increase in adverse events in a meta-analysis of the randomized trials involving just over 1,700 patients recruited from 5 continents.

  2. Treatment with corticosteroids was associated with a 20% reduction in deaths among hospitalized, critically ill patients with Covid-19 in a pooled analysis of 7 studies.

Salynn Boyles, Contributing Writer, BreakingMED™

The CAPE Covid Trial was funded by the French Ministry of Health PHRC. The REMAP-CAP trials was funded by the European Union and others. The CoDEX trial was funded by was funded and supported by the Coalition COVID-19 Brazil.

CoDEX lead researcher Bruno Tomazini reported receiving support from Aché pharmaceutical. Maia reported receiving nonfinancial support from Aché Laboratórios Farmacêuticos. Principal researcher Luciano C.P. Azeveda reported receiving grants from Aché Laboratórios and personal fees from Pfizer and Halex-Istar. Other researchers also reported receiving financial support from industry sources.

CAPE COVID lead researcher Pierre-Francios Dequin reported reported receiving grants from Abionic, Atox Bio, Sphingotec GMBH, Adrenomed, Medspace, Aridis, Merck, Combioxin, GlaxoSmithKline, MedImmune, Genentech INH, RevImmune, Faron, Kenta, and Tigenix. Principal researcher Luciano C. P. Azeveda reported receiving grants from Aché Laboratórios and personal fees from Pfizer and Halex-Istar. Other researchers also reported receiving financial support from industry sources.

REMAP-CAP investigator Derek C. Angus reported reported receiving personal fees from Ferring Pharmaceuticals Inc, Bristol-Myers Squibb, Bayer AG, and ALung Technologies Inc outside the submitted work; in addition, Dr Angus had a patent to selepressin—compounds, compositions, and methods for treating sepsis pending and a patent to proteomic biomarkers of sepsis in elderly patients pending. Other REMAP-CAP writing committee members also reported receiving financial support from industry sources.

Cat ID: 190

Topic ID: 79,190,254,930,791,932,570,190,926,192,927,151,928,925,934