A new statistical analysis of an existing meta-analysis reaffirms a finding that hospitalized patients with COVID-19 who are on simple oxygen or noninvasive ventilation can benefit from treatment with the arthritis drug tocilizumab (Actemra) in conjunction with corticosteroids. But the report also casts doubt on the effectiveness of tocilizumab in patients who are on ventilators.
“Clinicians should prescribe steroids and tocilizumab for hospitalized patients needing simple oxygen or noninvasive ventilation,” said epidemiologist and study co-author James (Jay) Brophy, MD, PhD, of Montreal’s McGill University, in an interview. “Further research is required to answer the question of whether tocilizumab is beneficial in patients requiring invasive ventilation, and consideration of participation in further tocilizumab studies seems reasonable.”
The new analysis was published February 28 in JAMA Network Open.
The initial meta-analysis, published last summer in the Journal of the American Medical Association, was conducted by the WHO Rapid Evidence Appraisal for COVID-19 Therapies (REACT) Working Group. It analyzed the results of 27 randomized trials that explored the use of IL-6 antagonists, including tocilizumab, and found that “28-day all-cause mortality was lower among patients who received IL-6 antagonists compared with those who received usual care or placebo (summary odds ratio, 0.86). The summary odds ratios for the association of IL-6 antagonist treatment with 28-day all-cause mortality were 0.78 with concomitant administration of corticosteroids vs 1.09 without administration of corticosteroids.”
For the new report, researchers conducted a Bayesian statistical analysis of 15 studies within the meta-analysis that specifically examined the use of the rheumatoid arthritis drug tocilizumab. “Bayesian analysis allows one to make direct probability statements regarding the exact magnitude and the certainty of any benefit,” Brophy said. “This provides clinicians with the information they require to make well-informed decisions.”
The analysis estimated that the probability of a “clinically meaningful association” (absolute mortality risk difference > 1%) due to use of tocilizumab was higher than 95% in patients receiving simple oxygen and higher than 90% in those receiving noninvasive ventilation. But the probability was only about 67% higher in those receiving invasive mechanical ventilation.
Also, the researchers estimated that about 72% of future tocilizumab studies in patients on invasive mechanical ventilation would show a benefit.
The new analysis findings don’t add much to existing knowledge, said Harvard Medical School nephrologist David E. Leaf, MD, MMSc, who’s studied tocilizumab in COVID-19.
“The signal seems to be consistent that there is a greater benefit of tocilizumab in less ill patients than those who are more ill — eg, those who are receiving invasive mechanical ventilation,” Leaf said in an interview. “This is interesting because in clinical practice the opposite approach is often undertaken, with tocilizumab use only being used in the sickest patients, even though the patients most likely to benefit seem to be those who are less ill.”
Clinically, he said, “hospitalized patients with COVID-19 should receive tocilizumab unless they have a clear contraindication and assuming it can be administered relatively early in their disease course. Earlier administration, before the onset of irreversible organ injury, is likely to have greater benefit.”
Leaf also noted it’s unknown whether the drug is helpful in several groups — patients presenting later in the course of COVID-19 illness, patients with additional infections, and immunocompromised patients.
It’s also not clear if tocilizumab benefits patients with lower levels of C-reactive protein, said Shruti Gupta, MD, MPH, a Brigham and Women’s Hospital nephrologist, in an interview. The RECOVERY trial, for example, limited subjects to those with CRP ≥ 75 mg/L, she said.
Leaf and Gupta co-authored a 2021 cohort study analyzing mortality rates in patients with COVID-19 who were treated with tocilizumab vs those who were not.
No study funding was reported. Brophy, Leaf, and Gupta have disclosed no relevant financial relationships. One study author reported participating in one of the randomized clinical trials included in the analysis.
JAMA Netw Open. 2022;5:e220548. Full text
Randy Dotinga is a journalist who specializes in covering medicine.
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