IL-6 receptor antagonists, antiplatelets show high probability of benefit for COVID-19

IL-6 receptor antagonists and antiplatelet agents improved chances for 6-month survival among patients with COVID-19, according to study results presented at Society of Critical Care Medicine’s Critical Care Congress and published in JAMA.

Lisa Higgins

“In our analysis of longer-term outcomes among critically ill patients with COVID-19 who participated in the Randomized Embedded Multifactorial Adaptive Platform for Community Acquired Pneumonia (REMAP-CAP) platform trial, we observed that the beneficial effects of interleukin-6 receptor antagonist treatment while in ICU persisted through 6 months in the form of improved long-term survival and quality of life,” Lisa Higgins, PhD, MPH, senior research fellow and lead of the health economics program at the Australian and New Zealand Intensive Care Research Centre, told Healio. “Overall, across most interventions studied in REMAP-CAP, hospital-based treatment effects were consistent with longer-term outcomes.”

In a secondary analysis of the REMAP-CAP trial, researchers evaluated 4,791 adults (median age, 60 years; interquartile range, 51-68; 32.1% women) with COVID-19 in the ICU from 197 sites in 14 countries between March 9, 2020, and June 22, 2021, to assess outcomes of multiple therapeutic interventions after 180 days.

Researchers randomly assigned patients to one or more treatment domains, each which comprised at least two interventions, including control: immune modulators (n = 2,274), convalescent plasma (n = 2,011), antiplatelet therapy (n = 1,557), anticoagulation (n = 1,033), antivirals (n = 726) and corticosteroids (n = 401).

Using a Bayesian piecewise exponential model, researchers assessed patient survival to day 180, the study’s primary outcome, for which a hazard ratio of less than one indicated a survival benefit.

Researchers also analyzed health-related quality of life and disability, which they measured through the 5-level EuroQol-5 Dimension (EQ-5D-5L) score, EQ VAS score and the 12-item WHO Disability Assessment Schedule (WHODAS) 2.0 at day 180.

Treatments, survival

According to researchers, known survival status by day 180 was available for 4,107 (95.1%) patients.

Overall, 1,517 (36.9%) patients died by day 180, and 6% of the deaths happened between discharge from the hospital and day 180.

Out of all the treatment domains, researchers found a greater than 99.9% probability of improved 6-month survival with pooled IL-6 receptor antagonists tocilizumab (Actemra, Genentech) and sarilumab (Kevzara; Sanofi, Regeneron; adjusted HR = 0.74; 95% credible interval [CrI], 0.61-0.9) and a 95% probability of improved 6-month survival with antiplatelet agents (aspirin or the P2Y12 inhibitors clopidogrel, prasugrel or ticagrelor; aHR = 0.85; 95% CrI, 0.71-1.03) compared with patients receiving the control for those domains.

This positive result related to antiplatelet agents differs from results of an earlier REMAP-CAP analysis that found that antiplatelet agents did not improve the number of organ support-free days at 21 days.

“The beneficial effect of antiplatelet agents in critically ill patients with COVID-19 has not previously been demonstrated,” Higgins told Healio. “The finding of improved survival and quality of life in patients treated with an antiplatelet agent in this secondary, prespecified analysis requires confirmation in subsequent studies.”

Researchers found high probabilities for futility among patients receiving therapeutic anticoagulation (99.9%; aHR = 1.13; 95% CrI, 0.93-1.42), convalescent plasma

(99.2%; aHR = 0.99; 95% CrI, 0.86-1.14) and lopinavir-ritonavir from the antiviral domain (96.6%; aHR = 1.06; 95% CrI, 0.82-1.38).

In terms of increased probabilities for worsened survival, hydroxychloroquine alone (96.8%; aHR = 1.51; 95% CrI, 0.98-2.29) and combined with lopinavir-ritonavir (96.8%; aHR = 1.61; 95% CrI, 0.97-2.67) showed high probabilities of harm.

Researchers had to end corticosteroid treatment before it could reach a predefined statistical trigger, so fixed-dose corticosteroids only had a 61.6% probability (aHR = 0.93; 95% CrI, 0.61-1.47) of improving survival, and shock-dependent corticosteroids had a 57.1% probability (aHR = 0.96; 95% CrI, 0.61-1.5) of improvement when evaluated against patients receiving no corticosteroids.

Researchers observed similar results when looking at 90-day mortality.

Quality of life, disability

Of the patients with an EQ VAS score (n = 1,009), an EQ-5D-5L score (n = 989) and a WHODAS score (n = 720), researchers observed broad variation in 6-month health-related quality-of-life and disability scores, with most survivors reporting favorable health-related quality of life and functional status. Still, approximately one in three patients had at least moderate disability that continued through the 180 days.

Specifically, researchers found that pooled IL-6 receptor antagonists had an 87% probability of improving quality of life and a 92.6% probability of reducing disability, and the pooled antiplatelet agents had a 97.4% probability of improving quality of life and an 81.6% probability of reducing disability. Conversely, lopinavir-ritonavir had a 97.4% probability of reducing quality of life and a 91.7% probability of worsening disability.

“Future studies should continue to evaluate whether antiplatelet agents confer benefit in critically ill patients with COVID-19,” Higgins told Healio. “REMAP-CAP has also shown the advantages of a Bayesian adaptive platform study design, and it was able to determine the effect of multiple interventions concurrently and rapidly during the pandemic. The number of studies using a similar design will likely increase in the future.”

Although the results of this study are limited by the fact that the omicron variant of COVID-19 is less likely to lead to pneumonia and, thus, ICU admission, the findings add knowledge to the literature surrounding long-term outcomes for various COVID-19 therapeutics, according to an accompanying editorial by Michael L. Barnett, MD, MS, associate professor of health policy and management at Harvard T.H. Chan School of Public Health, and Paul E. Sax, MD, clinical director of the infectious disease clinic at Brigham and Women’s Hospital.

“The evidence in this study remains valuable given that COVID-19 will continue to be a common cause of critical illness globally,” Barnett and Sax wrote. “However, the most effective strategy to reduce mortality and critical illness will be prevention through a global effort to expand COVID-19 vaccination.”

For more information:

Lisa Higgins, PhD, MPH, can be reached at lisa.higgins@monash.edu.

References:

• Barnett ML, et al. JAMA. 2023;doi:10.1001/jama.2022.23700.
• Writing Committee for the REMAP-CAP Investigators. JAMA. 2023;doi:10.1001/jama.2022.23257.