Abstract
BackgroundConvalescent plasma has been widely used to treat COVID-19 and is under investigation in numerous randomized clinical trials, but results are publicly available only for a small number of trials. The objective of this study was to assess the benefits of convalescent plasma treatment compared to placebo or no treatment and all-cause mortality in patients with COVID-19, using data from all available randomized clinical trials, including unpublished and ongoing trials (Open Science Framework, https://doi.org/10.17605/OSF.IO/GEHFX).MethodsIn this collaborative systematic review and meta-analysis, clinical trial registries (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform), the Cochrane COVID-19 register, the LOVE database, and PubMed were searched until April 8, 2021. Investigators of trials registered by March 1, 2021, without published results were contacted via email. Eligible were ongoing, discontinued and completed randomized clinical trials that compared convalescent plasma with placebo or no treatment in COVID-19 patients, regardless of setting or treatment schedule. Aggregated mortality data were extracted from publications or provided by investigators of unpublished trials and combined using the Hartung–Knapp–Sidik–Jonkman random effects model. We investigated the contribution of unpublished trials to the overall evidence.ResultsA total of 16,477 patients were included in 33 trials (20 unpublished with 3190 patients, 13 published with 13,287 patients). 32 trials enrolled only hospitalized patients (including 3 with only intensive care unit patients). Risk of bias was low for 29/33 trials. Of 8495 patients who received convalescent plasma, 1997 died (23%), and of 7982 control patients, 1952 died (24%). The combined risk ratio for all-cause mortality was 0.97 (95% confidence interval: 0.92; 1.02) with between-study heterogeneity not beyond chance (I2 = 0%). The RECOVERY trial had 69.8% and the unpublished evidence 25.3% of the weight in the meta-analysis.ConclusionsConvalescent plasma treatment of patients with COVID-19 did not reduce all-cause mortality. These results provide strong evidence that convalescent plasma treatment for patients with COVID-19 should not be used outside of randomized trials. Evidence synthesis from collaborations among trial investigators can inform both evidence generation and evidence application in patient care.
Highlights
The transfer of plasma from a patient who recovered and is convalescent from coronavirus disease 2019 (COVID19) to a person currently suffering from the disease aims to create transient passive immunity to combat the active infection
We describe the accumulation of publicly available evidence in a cumulative non-prespecified meta-analysis using the HKSJ random-effects model with Paule and Mandel (PM) tausquared, with published trials ordered by their date of publication or preprint posting, and the unpublished trials added to the model last as one summarized treatment estimate
The RECOVERY Trial has been published in a peer-review journal [41] and the IRCT20200310046736N trial has been published [42]; resulting in 13 published trials (6 preprints and 7 publications) and 20 unpublished trials included
Summary
The transfer of plasma from a patient who recovered and is convalescent from coronavirus disease 2019 (COVID19) to a person currently suffering from the disease aims to create transient passive immunity to combat the active infection. Non-randomized studies indicated a beneficial effect on mortality in COVID-19 [5]. As stated by the US Food and Drug Administration (FDA) in March, 2020, “ promising, convalescent plasma has not been shown to be effective in every disease studied” [6]. Thousands of patients with COVID-19 worldwide have received convalescent plasma outside of clinical trials. Convalescent plasma has been widely used to treat COVID-19 and is under investigation in numerous randomized clinical trials, but results are publicly available only for a small number of trials. The objective of this study was to assess the benefits of convalescent plasma treatment compared to placebo or no treatment and all-cause mortality in patients with COVID-19, using data from all available randomized clinical trials, including unpublished and ongoing trials (Open Science Framework, https://doi.org/10.17605/OSF.IO/GEHFX)
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