IL-6 Inhibitors, Antiplatelets Improve Survival of Critically Ill COVID-19 Patients

Critically ill COVID-19 patients who were treated with interleukin-6 receptor antagonists had the greatest probability of survival at six months among people receiving one or more interventions in six treatment groups, a large international study found.

The study, published in JAMA, included 4869 critically ill adults with COVID-19 who were ennrolled at 197 sites in 14 countries between March 9, 2020, and June 22, 2021, as part of the Randomized Embedded Multifactorial Adaptive Platform for Community Acquired Pneumonia (REMAP-CAP) trial. REMAP-CAP was initiated before the emergence of SARS-CoV-2 to evaluate treatments for severe pneumonia in pandemic and nonpandemic settings.

Patients were randomized into six treatment groups, with 2274 receiving immune modulators, 2011 receiving convalescent plasma, 1557 receiving antiplatelet therapy, 1033 receiving anticoagulation, 726 receiving antivirals and 401 receiving corticosteroids. Each group includes at least two interventions, including a control.

The primary outcome was survival at 180 days, at which point 2590 patients, or 63.1%, were alive. Secondary outcomes were health-related quality of life and disability at 180 days.

“The interleukin-6 receptor antagonists (tocilizumab and sarilumab) reduce mortality in critically ill patients with COVID-19, and the improved survival is not associated with reduced quality of life or increased disability,” corresponding author Alisa M. Higgins, PhD, of the School of Public Health and Preventive Medicine at Monash University in Melbourne, Australia, told Contagion.

The IL-6 receptor antagonist and antiplatelet agent treatments were associated with the highest likelihood of survival, which was analyzed using a bayesian piecewise exponential model. The posterior probability of improving survival at six months was greater than 99.9% for IL-6 receptor antagonists and 95% for antiplatelet agents compared with the control.

Health-related quality of life was favorable for most patients in the study, but about a third reported at least moderate disability at six months. Probability of improved health-related quality of life at six months was 87% for those taking IL-6 receptor antagonists and 97.4% for antiplatelets.

Higgins counted the findings related to antiplatelets as a surprise.

“Antiplatelets improved survival and quality of life – antiplatelets are not currently standard of care for critically ill patients with COVID-19,” she said. “This was an analysis of secondary outcomes in the REMAP-CAP trial and as such, the results are hypothesis generating, but further research into the long-term benefits of treatment with antiplatelets for this patient group should be conducted.”

Investigators reported no improved long-term outcomes among therapeutic anticoagulation, convalescent plasma, or lopinavir-ritonavir.

Hydroxychloroquine was associated with worsened outcomes, with a posterior probability of harm of 96.9% for hydroxycholroquines and 96.8% for the combination of lopinavir-ritonavir and hydroxychloroquine.

Use of corticosteroids was stopped early, but the probability ofimproved survival was moderate. Hydrocortisone had a probability of improvement of survival ranging from 57.1% to 61.6%, depending on dosing.

“The investigators deserve the highest praise for executing an expansive, forward-thinking initiative that has produced a wealth of evidence under intense pressure,” Michael L. Barnett, MD, MS, and Paul E. Sax, MD, wrote in an associated editorial comment.

Limitations of the study included a substantial amount of missing data on health-related quality of life and disability outcomes, which weren’t collected at all sites, and couldn’t be collected at baseline as patients were critically ill. Also, the study was conducted when early variants of the virus were circulating and may not be generalizable to new phases of the pandemic.

Next steps include “ongoing analysis of the longer-term outcomes of other treatments under investigation for the management of COVID-19 in critically ill patients and further evaluation of the role of antiplatelets in the management of critically ill patients with COVID-19,” Higgins said.