Among critically ill patients with COVID-19, treatment with an interleukin-6 (IL-6) receptor antagonist or with an antiplatelet agent was associated with improved 180-day mortality, according to the study results published in JAMA.
Investigators conducted a secondary analysis of the ongoing Randomized Embedded Multifactorial Adaptive Platform for Community Acquire Pneumonia (REMAP-CAP) platform trial (ClinicalTrials.gov identifier: NCT02735707) to determine long-term outcomes associated with multiple interventions used for critically ill patients with COVID-19. This prespecified secondary analysis, designed to test interventions within multiple therapeutic domains, included 4791 critically ill patients with COVID-19 who were enrolled in the REMAP-CAP trial between March 9, 2020, and June 22, 2021. The participants were from 197 sites in 14 different countries. March 2, 2022, was the date of the final 180-day follow-up.
The main outcome measure was survival through day 180, which was evaluated with the use of a Bayesian piecewise exponential model. All participants were randomly assigned to receive at least 1 interventions within the following 6 treatment domains: (1) immune modulators (n=2274); (2) convalescent plasma (n=2011); (3) antiplatelet therapy (n=1557); (4) anticoagulation (n=1033); (5) antivirals (n=726); and (6) corticosteroids (n=401). Participants were also randomly assigned to 19 sites that took part in the 90-day follow-up (n=473), including sites in Nepal, India, and in the US, or to sites that participated in the 180-day follow-up (n=4318).
Among the 4318 participants with 180-day follow-up, 180-day mortality status was available for 95.1% (4107 of 4318) of patients, showing that 63.1% (2590 of 4107) of participants were alive at day 180. Treatment with IL-6 receptor antagonists was associated with a more than 99.9% probability of improving 6-month survival (adjusted hazard ratio [aHR], 0.74; 95% credible interval [CrI], 0.61-0.90), whereas treatment with antiplatelet agents was linked to a 95.0% probability of improving 6-month survival (aHR, 0.85; 95% CrI, 0.71-1.03), compared with the control group.
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). In contrast, the probabilities of harm from hydroxychloroquine (HCQ; 96.9%; HR, 1.51; 95% CrI, 0.98-2.29) and the combination of lopinavir-ritonavir plus HCQ (96.8%; HR, 1.61; 95% CrI, 0.97-2.67) were high. The corticosteroid domain was discontinued early prior to achieving a predefined statistical trigger, with a 57.1% to 61.6% probability of improving 6-month survival reported across various hydrocortisone dosing strategies.
Limitations of the trial include use an open-label design, although the mortality outcome is at a lower risk for bias. Moreover, because health-related quality of life and disability scores could not be collected at baseline, the trial was unable to guarantee balance across groups or to assess change in scores over time. Additionally, collection of outcomes beyond 90 days was not mandated; however, 6-month survival status was nonetheless available for 85.7% of the participants.
Study authors concluded that “there was a greater than 99.9% probability that IL-6 receptor antagonists and a 95.0% probability that antiplatelet agents improved survival through 6 months. In contrast, survival was not improved with therapeutic anticoagulation, convalescent plasma, or lopinavir-ritonavir, and the probability that survival was worsened with hydroxychloroquine alone or in combination with lopinavir-ritonavir was 96.8%.”
Disclosure: Some of the study authors have declared affiliations with biotech, pharmaceutical, and/or device companies. Please see the original reference for a full list of authors’ disclosures.
Higgins AM, Berry LR, Lorenzi E, et al; 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. 2023;329(1):39-51. doi:10.1001/jama.2022.23257