IL-6 receptor antagonists and antiplatelet agents improve survival among critically ill COVID-19 patients

Patients who are critically ill with COVID-19 infection had a 99.9% probability of improved 180-day mortality compared to placebo when treated with IL-6 receptor antagonist and a 95.0% probability of improved 180-day mortality when on antiplatelets compared to control. The trial results of the REMAP-CAP Randomized Clinical Trial were published in the journal JAMA Network. 

Randomized clinical trials in critically ill patients, even those with COVID-19, typically assess only short-term outcomes like organ failure or 28-day mortality. Still, there is uncertainty regarding the longer-term effects of therapies used for the treatment of critically ill patients with COVID-19. Hence researchers conducted a secondary analysis of an ongoing adaptive platform trial (REMAP-CAP) to determine the effect of multiple interventions for critically ill adults with COVID-19 on longer-term outcomes between March 9, 2020, and June 22, 2021. 

Nearly 4869 critically ill adult patients with COVID-19 with a mean age of 59.3 years (1537 [32.1%] women) were enrolled for testing interventions within multiple therapeutic domains. Patients were randomized to receive 1 or more interventions within 6 treatment domains like the immune modulators (n = 2274), convalescent plasma (n = 2011), antiplatelet therapy (n = 1557), anticoagulation (n = 1033), antivirals (n = 726), and corticosteroids (n = 401). A Bayesian outcome was survival through day 180. Bayesian piecewise exponential model was used to analyze this. Survival was measured by Hazard ratio where <1 meant improved survival (superiority) and > 1 meant worsened survival (harm). A relative improvement of less than 20% in outcome, shown by an HR greater than 0.83 represented futility. 

Findings of the trial: 

Among 4869 randomized patients 4107 (84.3%) had known vital status and 2590 (63.1%) were alive at day 180.

When compared with the control, IL-6 receptor antagonists had a greater than 99.9% probability of improving 6-month survival and antiplatelet agents had a 95% probability of improving 6-month survival. 

Therapeutic anticoagulation, convalescent plasma, and lopinavir-ritonavir had the highest probability of trial-defined statistical futility (HR >0.83). 

Hydroxychloroquine and the combination of lopinavir-ritonavir and hydroxychloroquine showed the highest probabilities of harm. 

The corticosteroid domain was stopped early prior to reaching a predefined statistical trigger; there was a 57.1% to 61.6% probability of improving 6-month survival across varying hydrocortisone dosing strategies. 

Thus, this prespecified secondary analysis of a bayesian adaptive randomized clinical platform trial was the largest trial that reported on the effect of treatments for COVID-19 on longer-term mortality, HRQoL, and disability in critically ill patients. 

Further reading: Writing Committee for the REMAP-CAP Investigators. Long-term (180-Day) Outcomes in Critically Ill Patients With COVID-19 in the REMAP-CAP Randomized Clinical Trial. JAMA. Published online December 16, 2022. doi: 10.1001/jama.2022.23257