Is convalescent plasma futile in COVID-19? A Bayesian re-analysis of the RECOVERY randomized controlled trial

F.W Hamilton,Todd Lee,D.T Arnold,R Lilford,K Hemming

doi:10.1016/j.ijid.2021.06.034

Abstract

BackgroundRandomized trials are generally performed from a frequentist perspective, which can conflate absence of evidence with evidence of absence. The RECOVERY trial evaluated convalescent plasma for patients hospitalized with coronavirus disease 2019 (COVID-19) and concluded that there was no evidence of an effect. Re-analysis from a Bayesian perspective is warranted. MethodsOutcome data were extracted from the RECOVERY trial by serostatus and time of presentation. A Bayesian re-analysis with a wide variety of priors (vague, optimistic, sceptical, and pessimistic) was performed, calculating the posterior probability for: any benefit, an absolute risk difference of 0.5% (small benefit, number needed to treat 200), and an absolute risk difference of one percentage point (modest benefit, number needed to treat 100). ResultsAcross all patients, when analysed with a vague prior, the likelihood of any benefit or a modest benefit with convalescent plasma was estimated to be 64% and 18%, respectively. The estimated chance of any benefit was 95% if presenting within 7 days of symptoms, or 17% if presenting after this. In patients without a detectable antibody response at presentation, the chance of any benefit was 85%. However, it was only 20% in patients with a detectable antibody response at presentation. ConclusionsBayesian re-analysis suggests that convalescent plasma reduces mortality by at least one percentage point among the 39% of patients who present within 7 days of symptoms, and that there is a 67% chance of the same mortality reduction in the 38% who are seronegative at the time of presentation. This is in contrast to the results in people who already have antibodies when they present. This biologically plausible finding bears witness to the advantage of Bayesian analyses over misuse of hypothesis tests to inform decisions.

Highlights

Convalescent plasma (CP) – blood components from patients who have recovered from an infection – has been used for more than a century to treat infections, with widespread use in the 1920s and 1930s for pneumococcal infections and scarlet fever, before falling out of favour with the development of antibiotics (The Lancet Haematology, 2020)
In the United Kingdom, the data have been taken by the regulator as strong evidence of a null effect, leading the Medicines Health Regulatory Authority (MHRA (CAS-ViewAlert 2021); the UK medicines regulator) to recommend against the use of CP in patients hospitalized with COVID-19, effectively removing the therapy in the National Health Service (NHS), with many editorials agreeing with the authors that this proves no effect (Liu and Aberg, 2021)
The estimated chance of a risk difference of >1% was high, and varied little between prior assumptions. This contrasts with the seropositive arm, where the estimated chance of any benefit was only 20%, and with a very small (3%) chance of a modest benefit (NNT ≤100)

Summary

Introduction

Convalescent plasma (CP) – blood components from patients who have recovered from an infection – has been used for more than a century to treat infections, with widespread use in the 1920s and 1930s for pneumococcal infections and scarlet fever, before falling out of favour with the development of antibiotics (The Lancet Haematology, 2020). Conclusions: Bayesian re-analysis suggests that convalescent plasma reduces mortality by at least one percentage point among the 39% of patients who present within 7 days of symptoms, and that there is a 67% chance of the same mortality reduction in the 38% who are seronegative at the time of presentation. This is in contrast to the results in people who already have antibodies when they present.

Methods

Results

Conclusion