Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis of randomized trials Axfors, Cathrine Saeed Khan, Khalid We wish to express our heartfelt gratitude to all patients volunteering for the trials involved. We furthermore thank Wenyan Ma and Benjamin Kasenda (University Hospital Basel, University of Basel) for kindly translating the emails to Chinese investigators. For valuable contributions to individual trials in this collaborative group, we sincerely thank: Hannah Jin, Monica Feeley, Bruce Bausk, Jessica Cauley, Jane Kleinjan, Jon Gothing, Naeema Bangash, Heather Wroe, Claire Bigogne, Christelle Castell, Annelies Mottart, Lisette Cortenraad, Judith Medema-Muller, Katia Handelberg, Khalid Benhammou, Shaheen Kumar, Sophie Gribomont, Kim Kuehne, Cathia Markina, Julien Labeirie, Julie Pencole, Eva Crispyn, Cecile Le Breton, Kelli Horn, Tina Patel, Benjamin Harrois, Isabelle Collin, Vetheeswar Manivannan, Irma Slomp, Frederick Becue, Isabelle Godefroy, Lynne Guo, Lene Kollmorgen, Toluwalope Cole, Catherine Chene, Praveena Deenumsetti, Anne Doisy, Ariane Vialfont, Melissa Charbit, Christine Shu, Stephane Kirkesseli, Howard Surks, Magalie De Meyer, Edel Hendrickx, and Paul Deutsch (Sanofi trial); Ellie Carmody, Martin Backer, Jaishvi Eapen, Jack A. DeHovitz, Prithiv J. Prasad, Yi Li, Camila Delgado, Morris Jrada, Gabriel A. Robbins, Brooklyn Henderson,Alexander Hrycko, Dinuli Delpachitra, Vanessa Raabe, Jonathan S. Austrian, and Yanina Dubrovskaya (TEACH trial); Farah Al-Beidh, Djillali Annane, Kenneth Baillie, Abigail Beane, Richard Beasley, Zahra Bhimani, Marc Bonten, Charlotte Bradbury, Frank Brunkhorst, Meredith Buxton, Allen Cheng, Menno de Jong, Eamon Duffy, Lise Estcourt, Rob Fowler, Timothy Girard, Herman Goossens, Cameron Green, Rashan Haniffa, Christopher Horvat, David Huang, Francois Lamontagne, Patrick Lawler, Kelsey Linstrum, Edward Litton, John Marshall, Daniel McAuley, Shay McGuinness, Stephanie Montgomery, Paul Mouncey, Katrina Orr, Rachael Parke, Jane Parker, Asad Patanwala, Kathryn Rowan, Marlene Santos, Christopher Seymour, Steven Tong, Anne Turner, Timothy Uyeki, Wilma van Bentum-Puijk, Frank van de Veerdonk, and Ryan Zarychanski (REMAP-CAP trial); Jan-Erik Berdal, Arne Eskesen, Dag Kvale, Inge Christoffer Olsen, Corina Silvia Rueegg, Anbjorg Rangberg, Christine Monceyron Jonassen, and Torbjorn Omland (NO COVID-19 trial). Support for title page creation and format was provided by AuthorArranger, a tool developed at the National Cancer Institute. This collaborative meta-analysis was supported by the Swiss National Science Foundation and Laura and John Arnold Foundation (grant supporting the postdoctoral fellowship at the Meta-Research Innovation Center at Stanford (METRICS), Stanford University). Funding also includes postdoctoral grants from Uppsala University, the Swedish Society of Medicine, the Blanceflor Foundation, and the Sweden-America Foundation (C.A.). The funders had no role in the design of this collaborative metaanalysis; in the collection, analysis, and interpretation of data; or in the report writing. The corresponding author had full access to all study data and final responsibility for the decision to submit for publication. Substantial COVID-19 research investment has been allocated to randomized clinical trials (RCTs) on hydroxychloroquine/chloroquine, which currently face recruitment challenges or early discontinuation. We aim to estimate the effects of hydroxychloroquine and chloroquine on survival in COVID-19 from all currently available RCT evidence, published and unpublished. We present a rapid meta-analysis of ongoing, completed, or discontinued RCTs on hydroxychloroquine or chloroquine treatment for any COVID-19 patients (protocol: https:// osf.io/QESV4/). We systematically identified unpublished RCTs (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, Cochrane COVID-registry up to June 11, 2020), and published RCTs (PubMed, medRxiv and bioRxiv up to October 16, 2020). All-cause mortality has been extracted (publications/preprints) or requested from investigators and combined in random-effects meta-analyses, calculating odds ratios (ORs) with 95% confidence intervals (CIs), separately for hydroxychloroquine and chloroquine. Prespecified subgroup analyses include patient setting, diagnostic confirmation, control type, and publication status. Sixty-three trials were potentially eligible. We included 14 unpublished trials (1308 patients) and 14 publications/preprints (9011 patients). Results for hydroxychloroquine are dominated by RECOVERY and WHO SOLIDARITY, two highly pragmatic trials, which employed relatively high doses and included 4716 and 1853 patients, respectively (67% of the total sample size). The combined OR on all-cause mortality for hydroxychloroquine is 1.11 (95% CI: 1.02, 1.20; I² = 0%; 26 trials; 10,012 patients) and for chloroquine 1.77 (95%CI: 0.15, 21.13, I² = 0%; 4 trials; 307 patients). We identified no subgroup effects. We found that treatment with hydroxychloroquine is associated with increased mortality in COVID-19 patients, and there is no benefit of chloroquine. Findings have unclear generalizability to outpatients, children, pregnant women, and people with comorbidities. 2021-05-26T10:39:51Z 2021-05-26T10:39:51Z 2021-04-15 info:eu-repo/semantics/article Axfors, C., Schmitt, A.M., Janiaud, P. et al. Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis of randomized trials. Nat Commun 12, 2349 (2021). [https://doi.org/10.1038/s41467-021-22446-z] http://hdl.handle.net/10481/68746 10.1038/s41467-021-22446-z eng http://creativecommons.org/licenses/by/3.0/es/ info:eu-repo/semantics/openAccess Atribución 3.0 España Nature