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Meta-Analysis
. 2021 Nov 20;21(1):1170.
doi: 10.1186/s12879-021-06829-7.

Association between convalescent plasma treatment and mortality in COVID-19: a collaborative systematic review and meta-analysis of randomized clinical trials

Cathrine Axfors  1   2 , Perrine Janiaud #  3 , Andreas M Schmitt  3   4 , Janneke Van't Hooft  5 , Emily R Smith  6 , Noah A Haber  1 , Akin Abayomi  7 , Manal Abduljalil  8 , Abdulkarim Abdulrahman  9   10 , Yeny Acosta-Ampudia  11 , Manuela Aguilar-Guisado  12 , Farah Al-Beidh  13 , Marissa M Alejandria  14 , Rachelle N Alfonso  15 , Mohammad Ali  16 , Manaf AlQahtani  9   17   18 , Alaa AlZamrooni  19 , Juan-Manuel Anaya  11 , Mark Angelo C Ang  20 , Ismael F Aomar  21 , Luis E Argumanis  22 , Alexander Averyanov  23   24 , Vladimir P Baklaushev  24   25 , Olga Balionis  23   26 , Thomas Benfield  27 , Scott Berry  28 , Nadia Birocco  29 , Lynn B Bonifacio  15 , Asha C Bowen  30   31   32 , Abbie Bown  33 , Carlos Cabello-Gutierrez  34 , Bernardo Camacho  35 , Adrian Camacho-Ortiz  36 , Sally Campbell-Lee  37 , Damon H Cao  38 , Ana Cardesa  39 , Jose M Carnate  40 , German Jr J Castillo  15 , Rossana Cavallo  41 , Fazle R Chowdhury  42 , Forhad U H Chowdhury  43 , Giovannino Ciccone  44 , Antonella Cingolani  45 , Fresthel Monica M Climacosa  46 , Veerle Compernolle  47   48 , Carlo Francisco N Cortez  15 , Abel Costa Neto  49 , Sergio D'Antico  50 , James Daly  51 , Franca Danielle  52 , Joshua S Davis  30 , Francesco Giuseppe De Rosa  53 , Justin T Denholm  54   55 , Claudia M Denkinger  56 , Daniel Desmecht  57 , Juan C Díaz-Coronado  58 , Juan A Díaz Ponce-Medrano  59 , Anne-Françoise Donneau  60 , Teresita E Dumagay  15 , Susanna Dunachie  16 , Cecile C Dungog  40 , Olufemi Erinoso  61 , Ivy Mae S Escasa  15 , Lise J Estcourt  62   63 , Amy Evans  64 , Agnes L M Evasan  14 , Christian J Fareli  65 , Veronica Fernandez-Sanchez  66 , Claudia Galassi  44 , Juan E Gallo  67 , Patricia J Garcia  68 , Patricia L Garcia  69 , Jesus A Garcia  70 , Mutien Garigliany  57 , Elvira Garza-Gonzalez  36 , Deonne Thaddeus V Gauiran  15 , Paula A Gaviria García  35 , Jose-Antonio Giron-Gonzalez  71 , David Gómez-Almaguer  72 , Anthony C Gordon  13   73 , André Gothot  74 , Jeser Santiago Grass Guaqueta  35 , Cameron Green  75 , David Grimaldi  76 , Naomi E Hammond  77 , Heli Harvala  78 , Francisco M Heralde  79 , Jesica Herrick  80 , Alisa M Higgins  75 , Thomas E Hills  81   82 , Jennifer Hines  83 , Karin Holm  84   85 , Ashraful Hoque  86 , Eric Hoste  87 , Jose M Ignacio  88 , Alexander V Ivanov  89 , Maike Janssen  90 , Jeffrey H Jennings  83 , Vivekanand Jha  91   92   93 , Ruby Anne N King  79 , Jens Kjeldsen-Kragh  94 , Paul Klenerman  16 , Aditya Kotecha  83 , Fiorella Krapp  95 , Luciana Labanca  52 , Emma Laing  64 , Mona Landin-Olsson  96   97 , Pierre-François Laterre  98 , Lyn-Li Lim  99 , Jodor Lim  14 , Oskar Ljungquist  100 , Jorge M Llaca-Díaz  101 , Concepción López-Robles  102 , Salvador López-Cárdenas  103 , Ileana Lopez-Plaza  104 , Josephine Anne C Lucero  15 , Maria Lundgren  94 , Juan Macías  105 , Sandy C Maganito  40 , Anna Flor G Malundo  14 , Rubén D Manrique  106 , Paola M Manzini  50 , Miguel Marcos  107 , Ignacio Marquez  108 , Francisco Javier Martínez-Marcos  109 , Ana M Mata  110 , Colin J McArthur  111 , Zoe K McQuilten  112   113 , Bryan J McVerry  114 , David K Menon  115 , Geert Meyfroidt  116 , Ma Angelina L Mirasol  15 , Benoît Misset  117 , James S Molton  118 , Alric V Mondragon  119 , Diana M Monsalve  11 , Parastoo Moradi Choghakabodi  120   121 , Susan C Morpeth  122 , Paul R Mouncey  123 , Michel Moutschen  117 , Carsten Müller-Tidow  90 , Erin Murphy  83 , Tome Najdovski  124 , Alistair D Nichol  125   126   127 , Henrik Nielsen  128 , Richard M Novak  80 , Matthew V N O'Sullivan  129   130   131 , Julian Olalla  132 , Akin Osibogun  133 , Bodunrin Osikomaiya  7 , Salvador Oyonarte  134 , Juan M Pardo-Oviedo  135 , Mahesh C Patel  80 , David L Paterson  136 , Carlos A Peña-Perez  137 , Angel A Perez-Calatayud  138 , Eduardo Pérez-Alba  36 , Anastasia Perkina  23   26 , Naomi Perry  55 , Mandana Pouladzadeh  139 , Inmaculada Poyato  140 , David J Price  141   142 , Anne Kristine H Quero  15 , Md M Rahman  43 , Md S Rahman  143 , Mayur Ramesh  144 , Carolina Ramírez-Santana  11 , Magnus Rasmussen  84   85 , Megan A Rees  145   146 , Eduardo Rego  49 , Jason A Roberts  135   147   148 , David J Roberts  63   149 , Yhojan Rodríguez  11   150 , Jesús Rodríguez-Baño  151   152 , Benjamin A Rogers  153   154 , Manuel Rojas  11 , Alberto Romero  155 , Kathryn M Rowan  156 , Fabio Saccona  44 , Mehdi Safdarian  157 , Maria Clariza M Santos  15 , Joe Sasadeusz  54   55 , Gitana Scozzari  158 , Manu Shankar-Hari  159   160 , Gorav Sharma  83 , Thomas Snelling  30   31   161   162 , Alonso Soto  163   164 , Pedrito Y Tagayuna  40 , Amy Tang  165 , Geneva Tatem  83 , Luciana Teofili  166 , Steven Y C Tong  167   168 , Alexis F Turgeon  169 , Januario D Veloso  15 , Balasubramanian Venkatesh  77   170   171 , Yanet Ventura-Enriquez  172 , Steve A Webb  125   173 , Lothar Wiese  174 , Christian Wikén  85 , Erica M Wood  175 , Gaukhar M Yusubalieva  25 , Kai Zacharowski  176 , Ryan Zarychanski  177 , Nina Khanna  178 , David Moher  179 , Steven N Goodman  1   180   181 , John P A Ioannidis  1   181   182   183   184 , Lars G Hemkens  185   186   187
Affiliations
Meta-Analysis

Association between convalescent plasma treatment and mortality in COVID-19: a collaborative systematic review and meta-analysis of randomized clinical trials

Cathrine Axfors et al. BMC Infect Dis. .

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.

Keywords: COVID-19; Convalescent plasma; Meta-analysis; SARS-CoV-2.

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Conflict of interest statement

During the conduct of the study, the following is reported: Dr. Berry reports being employee with ownership role at Berry Consultants (receives payments for statistical modeling and design of REMAP-CAP). Dr. Castillo reports grants from DOST PCHRD. Dr. Daly reports grants from Medical Research Future Fund (Australian Govt) and RBWH. Dr. Denkinger reports grants from German Ministry for Education and Research. Dr. Dumagay reports grants from Philippine Council for Health Research and Development. Dr. Dunachie reports grants from UK Department of Health and Social Care, grants from UK National Institute of Health Research. Dr. Gauiran reports grants from Department of Science and Technology—Philippine Council for Health Research and Development. Dr. Gordon reports grants from NIHR, grants from NIHR Research Professorship (RP-2015-06-18), and non-financial support from NIHR Clinical Research Network. Dr. Higgins reports grants from NHMRC and from the Minderoo Foundation. Dr. Hills reports grants from Health Research Council of New Zealand. Dr. Holm reports grants from Swedish Government Funds for Clinical Research (ALF). Dr. Janssen and Dr. Müller-Tidow report grants from the Federal Ministry of Education and Research in Germany (BMBF) to the RECOVER clinical trial. Dr. Krapp reports grants from Department of Foreign Affairs, Trade, and Development of Canada, grants from Fundación Telefónica del Perú. Dr. J. Lim reports grants from the Department of Science and Technology, Philippine Council for Health Research and Development. Dr. Lucero reports grants from Philippine Council for Health Research and Development. Dr Manrique reports economic support from Grupo ISA Intercolombia for the project development of trial NCT04332835. Drs. McQuilten and Wood report grants from Medical Research Future Fund. Dr. McVerry reports grants from The Pittsburgh Foundation, Translational Breast Cancer Research Consortium, and from UPMC Learning While Doing Program. Mr. Mouncey reports grants from National Institute for Health Research and from the European Union FP7: PREPARE. Dr. Najdovski reports payment from KUL Leuven to Belgian Red Cross for supply of convalescent plasma. Dr. Nichol reports grants from Health Research Board of Ireland. Dr. D. Roberts reports grants from the National Institute for Health (UKRIDHSC COVID-19 Rapid Response Rolling Call—Grant Reference Number COV19-RECPLAS) and the European Commission (SUPPORT-E #101015756). Dr. Rowan reports grants from the European Commission and from the UK National Institute for Health Research. Dr. Shankar-Hari reports grants from National Institute for Health Research UK, grants from UKRI-National Institute for Health Research UK. Dr. Turgeon reports grants from Canadian Institutes of Health Research. Dr. Venkatesh reports grants from Baxter. Dr. Webb reports grants from National Health and Medical Research Council, grants from Minderoo Foundation. Dr. Zacharowski reports grants from EU Horizon 2020. The ASCOT trial team (Drs Bowen, Daly, Davis, Denholm, Hammond, Jha, L. Lim, McQuilten, Molton, Morpeth, O’Sullivan, Paterson, Perry, Price, Rees, Roberts, Rogers, Sasadeusz, Snelling, Tong, Venkatesh, Wood) is funded by grants from from Royal Brisbane and Women’s Hospital Foundation, Pratt Foundation, Minderoo Foundation, BHP Foundation, Hospital Research Foundation, Macquarie Group Foundation, Health Research Council of New Zealand, Australian Partnership for Preparedness Research on Infectious Disease Emergencies (APPRISE), and the collection and supply of convalescent plasma was conducted within Lifeblood’s funding arrangements. The CONFIDENT trial is funded by the Belgian KCE (blood establishments received payment for the convalescent plasma supplied in the clinical trial). REMAP-CAP was supported in part by funding from UKRIDHSC COVID-19 Rapid Response Rolling Call (Grant Reference Number COV19-RECPLAS). Collection of convalescent plasma for REMAP-CAP was funded by the Department of Health and Social Care, UK. The IRCT20200310046736N1 trial was supported by the Ahvaz Jundishapur University of Medical Sciences (Grant No. R.AJUMS.REC.1399.003, Dr. Pouladzadeh). The PC-COVID-19 Group is supported by the Universidad del Rosario, IDCBIS, ISA Group and Suramericana (Colombia). Outside the submitted work, the following is reported: Dr. Axfors reports postdoctoral grants from the Knut and Alice Wallenberg Foundation, Uppsala University, the Swedish Society of Medicine, the Blanceflor Foundation, and the Sweden-America Foundation. Dr. Aomar reports personal fees from SOBI, GEDEON RICHTER, and GSK. Dr. Benfield reports grants from Novo Nordisk Foundation, Simonsen Foundation, Lundbeck Foundation, Kai Hansen Foundation, Erik and Susanna Olesen’s Charitable Fund; grants and personal fees from GSK, Pfizer, Gilead; and personal fees from Boehringer Ingelheim, MSD, and Pentabase ApS. Dr. Estcourt reports being an investigator on the RECOVERY trial. Dr. Gordon reports personal fees from GlaxoSmithKline, Bristol Myers Squibb, and 30 Respiratory. Dr. Jha reports grants and personal fees from Baxter Healthcare, personal fees from Astra Zeneca, grants from NephroPlus. Dr. Laterre reports personal fees from Adrenomed. Dr. McVerry reports grants from NIH/NHLBI and Bayer Pharmaceuticals, Inc. Dr. Mondragon reports financial activities outside the submitted work (employment at Johnson & Johnson). Dr. Perry reports partner being employed at CSL and owning shares in CSL. Dr. Paterson reports involvement with ALLIANCE trial of COVID-19 treatments. Dr. J. Roberts reports other COVID-19 related trials (in different patient groups): tocilizumab in ICU patients; hydroxychloroquine dosing in ICU patients; planned study of remdesivir pharmacokinetics in patients during expanded access program; and in silico evaluation of ivermectin dosing. Dr Sasadeusz reports grants from various Pharma companies including Gilead Sciences, Abvvie, Merck, and Takeda. Dr. Zacharowski reports personal fees from Biotest AG, CSL Behring, GE Heathcare, and is President of the ESAIC.

Figures

Fig. 1
Fig. 1
Flowchart of the data collection process. aOf 102 potentially eligible trials, 7 had publications available, and investigators of trials unpublished at the time of our initial search by September 28, 2020 or at an update on March 1, 2021, with a valid email address were contacted (n = 90); of these, 51 responded. All trials that were potentially eligible but not included are described in Additional file 4. bTrials excluded as “withdrawn” are trials labelled as such on the registries (such trials will never be conducted)
Fig. 2
Fig. 2
Random effects meta-analysis on the association between convalescent plasma treatment compared to placebo or no treatment and all-cause mortality in patients with COVID-19, stratified by publication status. CI confidence interval, RR risk ratio. NCT04403477 compares two different volumes of plasma a 400 mL and b 200 mL versus standard of care. To avoid double counting the control arm, the number of patients and number of events were split equally between the two comparisons
Fig. 3
Fig. 3
Subgroup analyses. CI confidence interval, ICU intensive care unit, RR risk ratio. Subgroup analyses include only trials with at least one event in one arm (i.e. trials with zero events in both arms were excluded). Number of comparisons differ from number of trials as two trials had more than one comparison. We defined high-titer as S-protein receptor binding domain (RBD)-specific IgG antibody titer of 1:640 or higher, or serum neutralization titer of 1:40 or higher. For studies using the Ortho VITROS SARS-CoV-2 IgG test, which reports a signal-to-cutoff (S/C) value, we defined high titer as S/C > 12 (corresponding to the initial United States Food and Drug Administration emergency use authorization) as prespecified. We complemented the high-titer definition with additional information made available in the March 2021 version emergency use authorization, e.g., EUROIMMUN (ratio ≥ 3.5) and Abbott ARCHITECT (S/C ≥ 4.5)
Fig. 4
Fig. 4
Accumulation of evidence over time (Cumulative meta-analysis). CI confidence interval, RR risk ratio. Published trials are ordered by their date of publication. For the PLACID trial we used the date when it was first posted as a preprint (September 10th, 2020) before being published in a peer reviewed journal (October 22nd, 2020). Similarly, NCT04479163 was first posted as a preprint (November 21st, 2020) before being published a peer reviewed journal (February 18th, 2021) and RECOVERY Trial was first posted as a preprint (March 10th, 2021) before being published in a peer reviewed journal (May 14th, 2021)
See this image and copyright information in PMC

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