抗IL-6阻害薬は重症COVIDの180日死亡率を改善?!

今日見かけたツイート、重要なことのような気がして備忘録

IL-6(インターロイキン-6)って何やねん?でググると、
「多彩な生理作用を有するサイトカインと呼ばれる物質の一種で、免疫応答や炎症反応の調節において重要な役割を果たしています。その役割は生体の恒常性(安定した状態)の維持にとても重要ですが、長期にわたって過剰に産生し続けると、さまざまな病態を引き起こすことが知られています。」
「炎症性サイトカインの一種で、感染症、外傷および自己免疫性疾患などで上昇します。全身のさまざまな部位における免疫応答を活性化させ、過剰に産生されるとサイトカインス
トームを生じ、多臓器障害を誘発します。」
などなど・・・
積読したままの免疫学の教科書を放置するな!という御神託かな

 

Long-term (180-Day) Outcomes in Critically Ill Patients With COVID-19 in the REMAP-CAP Randomized Clinical Trial【JAMA Network 2022年12月16日】

Key Points

Question What is the effect of treatment for critically ill patients with COVID-19 on longer-term mortality, disability, and health-related quality of life?

Findings In this bayesian adaptive randomized clinical platform trial that included 4869 critically ill patients with COVID-19, the probability was high that IL-6 receptor antagonists and antiplatelet agents improved survival at 6 months (posterior probabilities of superiority of >99.9% and 95.0%, respectively). Long-term outcomes were not improved with therapeutic anticoagulation (11.5%), convalescent plasma (54.7%), or lopinavir-ritonavir (31.9%) and were worsened with hydroxychloroquine (posterior probability of harm, 96.8%). Corticosteroids did not improve long-term outcomes, although enrollment had been terminated early in response to external evidence.

Meaning Among critically ill patients with COVID-19 randomized to receive 1 or more therapeutic interventions, there was a high likelihood of improved 180-day mortality among patients treated with IL-6 receptor antagonists and antiplatelet agents.

Abstract

Importance The longer-term effects of therapies for the treatment of critically ill patients with COVID-19 are unknown.

Objective To determine the effect of multiple interventions for critically ill adults with COVID-19 on longer-term outcomes.

Design, Setting, and Participants Prespecified secondary analysis of an ongoing adaptive platform trial (REMAP-CAP) testing interventions within multiple therapeutic domains in which 4869 critically ill adult patients with COVID-19 were enrolled between March 9, 2020, and June 22, 2021, from 197 sites in 14 countries. The final 180-day follow-up was completed on March 2, 2022.

Interventions Patients were randomized to receive 1 or more interventions within 6 treatment domains: immune modulators (n = 2274), convalescent plasma (n = 2011), antiplatelet therapy (n = 1557), anticoagulation (n = 1033), antivirals (n = 726), and corticosteroids (n = 401).

Main Outcomes and Measures The main outcome was survival through day 180, analyzed using a bayesian piecewise exponential model. A hazard ratio (HR) less than 1 represented improved survival (superiority), while an HR greater than 1 represented worsened survival (harm); futility was represented by a relative improvement less than 20% in outcome, shown by an HR greater than 0.83.

Results Among 4869 randomized patients (mean age, 59.3 years; 1537 [32.1%] women), 4107 (84.3%) had known vital status and 2590 (63.1%) were alive at day 180. IL-6 receptor antagonists had a greater than 99.9% probability of improving 6-month survival (adjusted HR, 0.74 [95% credible interval {CrI}, 0.61-0.90]) and antiplatelet agents had a 95% probability of improving 6-month survival (adjusted HR, 0.85 [95% CrI, 0.71-1.03]) compared with the control, while the probability of trial-defined statistical futility (HR >0.83) was high for therapeutic anticoagulation (99.9%; HR, 1.13 [95% CrI, 0.93-1.42]), convalescent plasma (99.2%; HR, 0.99 [95% CrI, 0.86-1.14]), and lopinavir-ritonavir (96.6%; HR, 1.06 [95% CrI, 0.82-1.38]) and the probabilities of harm from hydroxychloroquine (96.9%; HR, 1.51 [95% CrI, 0.98-2.29]) and the combination of lopinavir-ritonavir and hydroxychloroquine (96.8%; HR, 1.61 [95% CrI, 0.97-2.67]) were high. 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.

Conclusions and Relevance Among critically ill patients with COVID-19 randomized to receive 1 or more therapeutic interventions, treatment with an IL-6 receptor antagonist had a greater than 99.9% probability of improved 180-day mortality compared with patients randomized to the control, and treatment with an antiplatelet had a 95.0% probability of improved 180-day mortality compared with patients randomized to the control. Overall, when considered with previously reported short-term results, the findings indicate that initial in-hospital treatment effects were consistent for most therapies through 6 months.

Introduction

Randomized clinical trials in critically ill patients, including those with COVID-19, typically assess short-term outcomes, such as organ failure or 28-day mortality, with fewer published trials assessing whether treatments affect long-term survival and patient-centered outcomes, such as disability and health-related quality of life (HRQoL). Longer-term survival free of major disability with an acceptable HRQoL may be more important to patients than short-term survival. The World Health Organization and others have called for additional research on the effect of initial therapeutic interventions on longer-term outcomes.

The Randomized Embedded Multifactorial Adaptive Platform for Community Acquired Pneumonia (REMAP-CAP) trial is an ongoing international, multicenter, randomized platform trial evaluating multiple treatments for patients with severe pneumonia in both pandemic and nonpandemic settings (NCT02735707) (Supplement 1).4 To date, the trial has reported results for 6 treatment domains for patients with COVID-19: corticosteroids, antiviral agents, immune modulators, immunoglobulin, anticoagulation, and antiplatelet therapy. The trial primary outcome for patients with COVID-19 is the composite of hospital survival and organ support provision up to 21 days. The trial reported benefit on this primary outcome for IL-6 receptor antagonists (immune modulators), but not for antiviral agents, anakinra (immune modulator), convalescent plasma (immunoglobulin), therapeutic anticoagulation (in critically ill patients), or antiplatelet therapies. The corticosteroid domain was closed early on the basis of external evidence, but a moderate probability of benefit was observed. Whether these initial treatment effects translate into effects on longer-term survival, disability, and HRQoL is unknown. The objective of this study was to report on the effects of these treatments on prespecified longer-term outcomes, including mortality, disability, and HRQoL, at 6 months for patients randomized to receive 1 or more treatments in the reported domains in the trial.