Association between convalescent plasma treatment and mortality in COVID-19: a collaborative systematic review and meta-analysis of randomized clinical trials
Authors: Axfors Cathrine , Janiaud Perrine , Schmitt Andreas M. , van’t Hooft Janneke , Smith Emily R. , Haber Noah A. , Abayomi Akin , Abduljalil Manal , Abdulrahman Abdulkarim , Acosta-Ampudia Yeny , Aguilar-Guisado Manuela , Al-Beidh Farah , Alejandria Marissa M. , Alfonso Rachelle N. , Ali Mohammad , AlQahtani Manaf , AlZamrooni Alaa , Anaya Juan-Manuel , Ang Mark Angelo C. , Aomar Ismael F. , Argumanis Luis E. , Averyanov Alexander , Baklaushev Vladimir P. , Balionis Olga , Benfield Thomas , Berry Scott , Birocco Nadia , Bonifacio Lynn B. , Bowen Asha C. , Bown Abbie , Cabello-Gutierrez Carlos , Camacho Bernardo , Camacho-Ortiz Adrian , Campbell-Lee Sally , Cao Damon H. , Cardesa Ana , Carnate Jose M. , Castillo German Jr. J. , Cavallo Rossana , Chowdhury Fazle R. , Chowdhury Forhad U. H. , Ciccone Giovannino , Cingolani Antonella , Climacosa Fresthel Monica M. , Compernolle Veerle , Cortez Carlo Francisco N. , Costa Neto Abel , D’Antico Sergio , Daly James , Danielle Franca , Davis Joshua S. , De Rosa Francesco Giuseppe , Denholm Justin T. , Denkinger Claudia M. , Desmecht Daniel , Díaz-Coronado Juan C. , Díaz Ponce-Medrano Juan A. , Donneau Anne-Françoise , Dumagay Teresita E. , Dunachie Susanna , Dungog Cecile C. , Erinoso Olufemi , Escasa Ivy Mae S. , Estcourt Lise J. , Evans Amy , Evasan Agnes L. M. , Fareli Christian J. , Fernandez-Sanchez Veronica , Galassi Claudia , Gallo Juan E. , Garcia Patricia J. , Garcia Patricia L. , Garcia Jesus A. , Garigliany Mutien , Garza-Gonzalez Elvira , Gauiran Deonne Thaddeus V. , Gaviria García Paula A. , Giron-Gonzalez Jose-Antonio , Gómez-Almaguer David , Gordon Anthony C. , Gothot André , Grass Guaqueta Jeser Santiago , Green Cameron , Grimaldi David , Hammond Naomi E. , Harvala Heli , Heralde Francisco M. , Herrick Jesica , Higgins Alisa M. , Hills Thomas E. , Hines Jennifer , Holm Karin , Hoque Ashraful , Hoste Eric , Ignacio Jose M. , Ivanov Alexander V. , Janssen Maike , Jennings Jeffrey H. , Jha Vivekanand , King Ruby Anne N. , Kjeldsen-Kragh Jens , Klenerman Paul , Kotecha Aditya , Krapp Fiorella , Labanca Luciana , Laing Emma , Landin-Olsson Mona , Laterre Pierre-François , Lim Lyn-Li , Lim Jodor , Ljungquist Oskar , Llaca-Díaz Jorge M. , López-Robles Concepción , López-Cárdenas Salvador , Lopez-Plaza Ileana , Lucero Josephine Anne C. , Lundgren Maria , Macías Juan , Maganito Sandy C. , Malundo Anna Flor G. , Manrique Rubén D. , Manzini Paola M. , Marcos Miguel , Marquez Ignacio , Martínez-Marcos Francisco Javier , Mata Ana M. , McArthur Colin J. , McQuilten Zoe K. , McVerry Bryan J. , Menon David K. , Meyfroidt Geert , Mirasol Ma. Angelina L. , Misset Benoît , Molton James S. , Mondragon Alric V. , Monsalve Diana M. , Moradi Choghakabodi Parastoo , Morpeth Susan C. , Mouncey Paul R. , Moutschen Michel , Müller-Tidow Carsten , Murphy Erin , Najdovski Tome , Nichol Alistair D. , Nielsen Henrik , Novak Richard M. , O’Sullivan Matthew V. N. , Olalla Julian , Osibogun Akin , Osikomaiya Bodunrin , Oyonarte Salvador , Pardo-Oviedo Juan M. , Patel Mahesh C. , Paterson David L. , Peña-Perez Carlos A. , Perez-Calatayud Angel A. , Pérez-Alba Eduardo , Perkina Anastasia , Perry Naomi , Pouladzadeh Mandana , Poyato Inmaculada , Price David J. , Quero Anne Kristine H. , Rahman Md. M. , Rahman Md. S. , Ramesh Mayur , Ramírez-Santana Carolina , Rasmussen Magnus , Rees Megan A. , Rego Eduardo , Roberts Jason A. , Roberts David J. , Rodríguez Yhojan , Rodríguez-Baño Jesús , Rogers Benjamin A. , Rojas Manuel , Romero Alberto , Rowan Kathryn M. , Saccona Fabio , Safdarian Mehdi , Santos Maria Clariza M. , Sasadeusz Joe , Scozzari Gitana , Shankar-Hari Manu , Sharma Gorav , Snelling Thomas , Soto Alonso , Tagayuna Pedrito Y. , Tang Amy , Tatem Geneva , Teofili Luciana , Tong Steven Y. C. , Turgeon Alexis F. , Veloso Januario D. , Venkatesh Balasubramanian , Ventura-Enriquez Yanet , Webb Steve A. , Wiese Lothar , Wikén Christian , Wood Erica M. , Yusubalieva Gaukhar M. , Zacharowski Kai , Zarychanski Ryan , Khanna Nina , Moher David , Goodman Steven N. , Ioannidis John P. A. , Hemkens Lars G. 
Published: November 2021

Abstract
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.