From the Journals

Which treatments improve long-term outcomes of critical COVID illness?



Treatment with interleukin-6 receptor antagonists or antiplatelet agents improves survival and outcomes at 6 months for critically ill patients with COVID-19, according to new data.

However, survival wasn’t improved with therapeutic anticoagulation, convalescent plasma, or lopinavir-ritonavir, and survival was worsened with hydroxychloroquine.

“After critically ill patients leave the hospital, there’s a high risk of readmission, death after discharge, or exacerbations of chronic illness,” study author Patrick Lawler, MD, a clinician-scientist at the Peter Munk Cardiac Centre at University Health Network and an assistant professor of medicine at the University of Toronto, said in an interview.

“When looking at the impact of treatment, we don’t want to improve short-term outcomes yet worsen long-term disability,” he said. “That long-term, 6-month horizon is what matters most to patients.”

The study was published online in JAMA.

Investigating treatments

The investigators analyzed data from an ongoing platform trial called Randomized Embedded Multifactorial Adaptive Platform for Community Acquired Pneumonia (REMAP-CAP). The trial is evaluating treatments for patients with severe pneumonia in pandemic and nonpandemic settings.

In the trial, patients are randomly assigned to receive one or more interventions within the following six treatment domains: immune modulators, convalescent plasma, antiplatelet therapy, anticoagulation, antivirals, and corticosteroids. The trial’s primary outcome for patients with COVID-19 is hospital survival and organ support–free days up to 21 days. Researchers previously observed improvement after treatment with IL-6 receptor antagonists (which are immune modulators).

For this study, the research team analyzed data for 4,869 critically ill adult patients with COVID-19 who were enrolled between March 2020 and June 2021 at 197 sites in 14 countries. A 180-day follow-up was completed in March 2022. The critically ill patients had been admitted to an intensive care unit and had received respiratory or cardiovascular organ support.

The researchers examined survival through day 180. A hazard ratio of less than 1 represented improved survival, and an HR greater than 1 represented harm. Futility was represented by a relative improvement in outcome of less than 20%, which was shown by an HR greater than 0.83.

Among the 4,869 patients, 4,107 patients had a known mortality status, and 2,590 were alive at day 180. Among the 1,517 patients who died by day 180, 91 deaths (6%) occurred between hospital discharge and day 180.

Overall, use of IL-6 receptor antagonists (either tocilizumab or sarilumab) had a greater than 99.9% probability of improving 6-month survival, and use of antiplatelet agents (aspirin or a P2Y12 inhibitor such as clopidogrel, prasugrel, or ticagrelor) had a 95% probability of improving 6-month survival, compared with control therapies.

In contrast, long-term survival wasn’t improved with therapeutic anticoagulation (11.5%), convalescent plasma (54.7%), or lopinavir-ritonavir (31.9%). The probability of trial-defined statistical futility was high for anticoagulation (99.9%), convalescent plasma (99.2%), and lopinavir-ritonavir (96.6%).

Long-term survival was worsened with hydroxychloroquine, with a posterior probability of harm of 96.9%. In addition, the combination of lopinavir-ritonavir and hydroxychloroquine had a 96.8% probability of harm.

Corticosteroids didn’t improve long-term outcomes, although enrollment in the treatment domain was terminated early in response to external evidence. The probability of improving 6-month survival ranged from 57.1% to 61.6% for various hydrocortisone dosing strategies.


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