Association between convalescent plasma treatment and mortality in COVID-19: a collaborative systematic review and meta-analysis of randomized clinical trials.
Axfors C., Janiaud P., Schmitt AM., Van't Hooft J., Smith ER., Haber NA., Abayomi A., Abduljalil M., Abdulrahman A., Acosta-Ampudia Y., Aguilar-Guisado M., Al-Beidh F., Alejandria MM., Alfonso RN., Ali M., AlQahtani M., AlZamrooni A., Anaya J-M., Ang MAC., Aomar IF., Argumanis LE., Averyanov A., Baklaushev VP., Balionis O., Benfield T., Berry S., Birocco N., Bonifacio LB., Bowen AC., Bown A., Cabello-Gutierrez C., Camacho B., Camacho-Ortiz A., Campbell-Lee S., Cao DH., Cardesa A., Carnate JM., Castillo GJJ., Cavallo R., Chowdhury FR., Chowdhury FUH., Ciccone G., Cingolani A., Climacosa FMM., Compernolle V., Cortez CFN., Costa Neto A., D'Antico S., Daly J., Danielle F., Davis JS., De Rosa FG., Denholm JT., Denkinger CM., Desmecht D., Díaz-Coronado JC., Díaz Ponce-Medrano JA., Donneau A-F., Dumagay TE., Dunachie S., Dungog CC., Erinoso O., Escasa IMS., Estcourt LJ., Evans A., Evasan ALM., Fareli CJ., Fernandez-Sanchez V., Galassi C., Gallo JE., Garcia PJ., Garcia PL., Garcia JA., Garigliany M., Garza-Gonzalez E., Gauiran DTV., Gaviria García PA., Giron-Gonzalez J-A., Gómez-Almaguer D., Gordon AC., Gothot A., Grass Guaqueta JS., Green C., Grimaldi D., Hammond NE., Harvala H., Heralde FM., Herrick J., Higgins AM., Hills TE., Hines J., Holm K., Hoque A., Hoste E., Ignacio JM., Ivanov AV., Janssen M., Jennings JH., Jha V., King RAN., Kjeldsen-Kragh J., Klenerman P., Kotecha A., Krapp F., Labanca L., Laing E., Landin-Olsson M., Laterre P-F., Lim L-L., Lim J., Ljungquist O., Llaca-Díaz JM., López-Robles C., López-Cárdenas S., Lopez-Plaza I., Lucero JAC., Lundgren M., Macías J., Maganito SC., Malundo AFG., Manrique RD., Manzini PM., Marcos M., Marquez I., Martínez-Marcos FJ., Mata AM., McArthur CJ., McQuilten ZK., McVerry BJ., Menon DK., Meyfroidt G., Mirasol MAL., Misset B., Molton JS., Mondragon AV., Monsalve DM., Moradi Choghakabodi P., Morpeth SC., Mouncey PR., Moutschen M., Müller-Tidow C., Murphy E., Najdovski T., Nichol AD., Nielsen H., Novak RM., O'Sullivan MVN., Olalla J., Osibogun A., Osikomaiya B., Oyonarte S., Pardo-Oviedo JM., Patel MC., Paterson DL., Peña-Perez CA., Perez-Calatayud AA., Pérez-Alba E., Perkina A., Perry N., Pouladzadeh M., Poyato I., Price DJ., Quero AKH., Rahman MM., Rahman MS., Ramesh M., Ramírez-Santana C., Rasmussen M., Rees MA., Rego E., Roberts JA., Roberts DJ., Rodríguez Y., Rodríguez-Baño J., Rogers BA., Rojas M., Romero A., Rowan KM., Saccona F., Safdarian M., Santos MCM., Sasadeusz J., Scozzari G., Shankar-Hari M., Sharma G., Snelling T., Soto A., Tagayuna PY., Tang A., Tatem G., Teofili L., Tong SYC., Turgeon AF., Veloso JD., Venkatesh B., Ventura-Enriquez Y., Webb SA., Wiese L., Wikén C., Wood EM., Yusubalieva GM., Zacharowski K., Zarychanski R., Khanna N., Moher D., Goodman SN., Ioannidis JPA., Hemkens LG.
BACKGROUND: 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 ). METHODS: In 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. RESULTS: A 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. CONCLUSIONS: Convalescent 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.