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Convalescent plasma fails to improve outcomes in critically ill COVID-19 patients

Convalescent plasma didn’t help adults with critical COVID-19 have better outcomes, according to a randomised trial published in JAMA.

The 2,011-person study was rolled out at sites in the United Kingdom (115), Canada (9), Australia (4), and the United States (1, the only location that offered delayed convalescent plasma to 11 patients). The median age was 61 years, and 32.3% were women.

Almost 1,050 people received two units of high-titer, ABO-compatible convalescent plasma an average of 42.7 hours after hospital admission and 17.7 hours after ICU admission; 916 didn’t receive anything beyond the standard of care. The median number of organ support-free days within the first 21 days was zero in the treatment group and three in the control group (odds ratio, 0.97). Overall mortality was lower in the treatment group (37.3% vs 38.4%), but serious adverse events were more common (3.0% vs 1.3%). The posterior probability of futility was 99.4% across the primary outcome of being organ support-free within 21 days.

“We speculate that [the futility] could be a combination of too few high-quality antibodies in the plasma and these patients being too far along in their illness with a run-away inflammatory immune response for those antibodies to turn the tide,” said co-senior author Dr Derek Angus, University of Pittsburgh. “It is still possible that convalescent plasma helps people in earlier stages of illness, though it is likely not efficient to use given that monoclonal antibodies … are such an effective treatment for early COVID-19.”

While the study was stopped on 15 January for futility, the researchers noted that convalescent plasma appeared to help the 126 immunocompromised patients (posterior probability of superiority, 89.8%), unless it was given more than seven days into their hospitalisation (posterior probability of harm, 90.3%).
However, the sample size was too small to draw any conclusions.

Study details
Effect of Convalescent Plasma on Organ Support–Free Days in Critically Ill Patients With COVID-19: A Randomized Clinical Trial

Writing Committee for the REMAP-CAP Investigators

Published in JAMA on 4 October 2021

Key Points

Question Does 2 units of ABO-compatible, high-titer convalescent plasma, administered to critically ill patients with COVID-19, improve organ support–free days up to day 21 (a composite end point of in-hospital mortality and the duration of intensive care unit–based respiratory or cardiovascular support)?
Findings This international bayesian randomised clinical trial that included 2011 participants treated with 2 units of high-titer convalescent plasma, compared with no convalescent plasma, resulted in a posterior probability of futility of 99.4% for the primary outcome of organ support–free days up to day 21.
Meaning Among critically ill adults with confirmed COVID-19, treatment with convalescent plasma had a low likelihood of providing improvement in organ support–free days.

Abstract

Importance The evidence for benefit of convalescent plasma for critically ill patients with COVID-19 is inconclusive.
Objective To determine whether convalescent plasma would improve outcomes for critically ill adults with COVID-19.
Design, Setting, and Participants The ongoing Randomised, Embedded, Multifactorial, Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP) enrolled and randomised 4763 adults with suspected or confirmed COVID-19 between 9 March 2020, and 18 January 2021, within at least one domain; 2011 critically ill adults were randomized to open-label interventions in the immunoglobulin domain at 129 sites in four countries. Follow-up ended on 19 April 2021.
Interventions The immunoglobulin domain randomised participants to receive 2 units of high-titer, ABO-compatible convalescent plasma (total volume of 550 mL ± 150 mL) within 48 hours of randomization (n = 1084) or no convalescent plasma (n = 916).

Main Outcomes and Measures
The primary ordinal end point was organ support–free days (days alive and free of intensive care unit–based organ support) up to day 21 (range, −1 to 21 days; patients who died were assigned –1 day). The primary analysis was an adjusted bayesian cumulative logistic model. Superiority was defined as the posterior probability of an odds ratio (OR) greater than 1 (threshold for trial conclusion of superiority >99%). Futility was defined as the posterior probability of an OR less than 1.2 (threshold for trial conclusion of futility >95%). An OR greater than 1 represented improved survival, more organ support–free days, or both.

The prespecified secondary outcomes included in-hospital survival; 28-day survival; 90-day survival; respiratory support–free days; cardiovascular support–free days; progression to invasive mechanical ventilation, extracorporeal mechanical oxygenation, or death; intensive care unit length of stay; hospital length of stay; World Health Organization ordinal scale score at day 14; venous thromboembolic events at 90 days; and serious adverse events.

Results
Among the 2011 participants who were randomised (median age, 61 [IQR, 52 to 70] years and 645/1998 [32.3%] women), 1990 (99%) completed the trial. The convalescent plasma intervention was stopped after the prespecified criterion for futility was met. The median number of organ support–free days was 0 (IQR, –1 to 16) in the convalescent plasma group and 3 (IQR, –1 to 16) in the no convalescent plasma group. The in-hospital mortality rate was 37.3% (401/1075) for the convalescent plasma group and 38.4% (347/904) for the no convalescent plasma group and the median number of days alive and free of organ support was 14 (IQR, 3 to 18) and 14 (IQR, 7 to 18), respectively. The median-adjusted OR was 0.97 (95% credible interval, 0.83 to 1.15) and the posterior probability of futility (OR <1.2) was 99.4% for the convalescent plasma group compared with the no convalescent plasma group. The treatment effects were consistent across the primary outcome and the 11 secondary outcomes. Serious adverse events were reported in 3.0% (32/1075) of participants in the convalescent plasma group and in 1.3% (12/905) of participants in the no convalescent plasma group.

Conclusions and Relevance
Among critically ill adults with confirmed COVID-19, treatment with 2 units of high-titer, ABO-compatible convalescent plasma had a low likelihood of providing improvement in the number of organ support–free days.

 

JAMA article – Effect of Convalescent Plasma on Organ Support–Free Days in Critically Ill Patients With COVID-19: A Randomized Clinical Trial (Open access)

 

See more from MedicalBrief archives:

 

Early convalescent plasma for high-risk outpatients with COVID-19 — Trial stopped

 

Drop in convalescent plasma use in US hospitals linked to higher COVID-19 mortality

 

Convalescent plasma may improve survival with severe COVID-19 — US/Brazil trial

 

 

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