Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis of randomized trials
Cathrine Axfors, Andreas M Schmitt, Perrine Janiaud, Janneke Van’t Hooft, Sherief Abd-Elsalam, Ehab F Abdo, Benjamin S Abella, Javed Akram, Ravi K Amaravadi, Derek C Angus, Yaseen M Arabi, Shehnoor Azhar, Lindsey R Baden, Arthur W Baker, Leila Belkhir, Thomas Benfield, Marvin A H Berrevoets, Cheng-Pin Chen, Tsung-Chia Chen, Shu-Hsing Cheng, Chien-Yu Cheng, Wei-Sheng Chung, Yehuda Z Cohen, Lisa N Cowan, Olav Dalgard, Fernando F De Almeida E Val, Marcus V G De Lacerda, Gisely C De Melo, Lennie Derde, Vincent Dubee, Anissa Elfakir, Anthony C Gordon, Carmen M Hernandez-Cardenas, Thomas Hills, Andy I M Hoepelman, Yi-Wen Huang, Bruno Igau, Ronghua Jin, Felipe Jurado-Camacho, Khalid S Khan, Peter G Kremsner, Benno Kreuels, Cheng-Yu Kuo, Thuy Le, Yi-Chun Lin, Wu-Pu Lin, Tse-Hung Lin, Magnus Nakrem Lyngbakken, Colin Mcarthur, Bryan J Mcverry, Patricia Meza-Meneses, Wuelton M Monteiro, Susan C Morpeth, Ahmad Mourad, Mark J Mulligan, Srinivas Murthy, Susanna Naggie, Shanti Narayanasamy, Alistair Nichol, Lewis A Novack, Sean M O’brien, Nwora Lance Okeke, Léna Perez, Rogelio Perez-Padilla, Laurent Perrin, Arantxa Remigio-Luna, Norma E Rivera-Martinez, Frank W Rockhold, Sebastian Rodriguez-Llamazares, Robert Rolfe, Rossana Rosa, Helge Røsjø, Vanderson S Sampaio, Todd B Seto, Muhammad Shahzad, Shaimaa Soliman, Jason E Stout, Ireri Thirion-Romero, Andrea B Troxel, Ting-Yu Tseng, Nicholas A Turner, Robert J Ulrich, Stephen R Walsh, Steve A Webb, Jesper M Weehuizen, Maria Velinova, Hon-Lai Wong, Rebekah Wrenn, Fernando G Zampieri, Wu Zhong, David Moher, Steven N Goodman, John P A Ioannidis, Lars G Hemkens
Nature Communications, doi:10.1038/s41467-021-22446-z
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of hydroxychloroquine and chloroquine on survival in COVID-19 from all currently available RCT evidence, published and unpublished.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 We systematically identified unpublished RCTs (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, Cochrane COVID-registry up to June 11, 2020), and published RCTs (PubMed,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.
Reporting summary. Further information on research design is available in the Nature Research Reporting Summary linked to this article.
Author contributions L.G.H., C.A., and A.M.S. had full access to all data in this study and take responsibility for the integrity of the data and the accuracy of the data analysis. Concept and design: L.G.H., J.P.A.I., C.A., A.M.S., S.N.G., and D.M. Acquisition, analysis, or interpretation of data: all authors. Drafting of the manuscript: C.A., A.M.S., and L.G.H. Critical revision of the manuscript for important intellectual content: all authors. Statistical analysis: A.M.S., L.G.H., J.P.A.I., S.N.G., and P.J. Approval of the final manuscript: all authors. Obtained funding: L.G.H., C.A., and J.P.A.I. Administrative, technical, or material support: C.A., A.M.S., L.G.H., P.J., and J.v.H. Supervision: L.G.H.
Competing interests
Additional information
Supplementary information The online version contains supplementary material available at https://doi.org/10.1038/s41467-021-22446-z. Correspondence and requests for materials should be addressed to L.G.H. Peer review information Nature Communications thanks the anonymous reviewer(s) for their contribution to the peer review of this work. Peer reviewer reports are available. Reprints and permission information is available at http://www.nature.com/reprints Publisher's note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
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{ 'value': 'https://doi.org/10.1038/s41467-024-45360-6',
'URL': 'https://doi.org/10.1038/s41467-024-45360-6',
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{ 'value': '14 May 2021',
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{ 'value': 'Correction',
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{ 'value': 'https://doi.org/10.1038/s41467-021-23559-1',
'URL': 'https://doi.org/10.1038/s41467-021-23559-1',
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{ 'value': 'B.S.A. and R.K.A. are the primary investigators of the Prevention and Treatment '
'of COVID19 with Hydroxychloroquine (PATCH) trial, funded by a philanthropic '
'gift. R.K.A reports being founder with equity of Pinpoint Therapeutics and '
'Immunacell, and personal fees from Sprint Biosciences and Deciphera, outside '
'the submitted work. D.C.A. reports personal fees from Ferring Pharmaceuticals, '
'Inc., Bristol-Myers Squibb, and Bayer AG, other from Alung Technologies, Inc., '
'outside the submitted work; in addition, D.C.A. has pending patents for '
'Selepressin—compounds, compositions, and methods for treating sepsis to '
'Ferring, B.V., and Proteomic biomarkers of sepsis in elderly patients pending '
'to University of Pittsburgh. Y.M.A. reports that he is the principal '
'investigator on a clinical trial of lopinavir–ritonavir and interferon for '
'Middle East respiratory syndrome (MERS) and that he was a nonpaid consultant on '
'therapeutics for MERS-coronavirus (CoV) for Gilead Sciences and SAB '
'Biotherapeutics. He is a coinvestigator on the Randomized, Embedded, '
'Multi-factorial Adaptive Platform Trial for Community-Acquired Pneumonia '
'(REMAP-CAP), a board member of the International Severe Acute Respiratory and '
'Emerging Infection Consortium (ISARIC), and the Lead-Co Chair of the Think20 '
'(T20) Taskforce for COVID-19. Brigham and Women’s Hospital, PRA Health Science, '
'and Cliniques universitaires Saint-Luc received funds from Sanofi. T.B. reports '
'grants from Pfizer, Novo Nordisk Foundation, Simonsen Foundation, Lundbeck '
'Foundation, and Kai Hansen Foundation; grants and personal fees from GSK, '
'Pfizer, Boehringer Ingelheim, and Gilead; and personal fees from MSD, all '
'outside the submitted work. Y.Z.C., L.N.C., B.I., and L.P. are employees of '
'Sanofi. The COV-HCQ and COMIHY trials were supported by the German Federal '
'Ministry of Education and Research (EudraCT number 2020-001224-33) and the '
'German Federal Ministry of Health (EudraCT number 2020-001512-26). L.D. reports '
'grants from EU FP7-HEALTH-2013-INNOVATION-1, grant number 602525, grants from '
'H2020 RECOVER, grant agreement no. 101003589, during the conduct of the study; '
'and is a member of the COVID-19 guideline committee SCCM/ESICM/SSC, member of '
'the ESICM COVID-19 taskforce, and chair of the Dutch intensivists (NVIC) '
'taskforce infectious threats. V.D. reports nonfinancial support from MSD France '
'and from Sanofi Aventis France, outside the submitted work. A.E. is an employee '
'of Ividata Life Sciences and works as an external contractor for Sanofi. A.C.G. '
'received grant funding from an NIHR Research Professorship (RP-2015-06-18), '
'support from the NIHR Imperial Biomedical Research Centre, and consulting fees '
'paid to his institution from GlaxoSmithKline and Bristol-Myers Squibb. T.H. '
'reports grants from the Health Research Council of New Zealand, during the '
'conduct of the study. A.I.M.H. reports grants from ZonMw, Netherlands '
'organisation for Health Research and Development, during the conduct of the '
'study. HYDRA trial was an investigator-initiated study supported by Sanofi, '
'CONACYT (National Council of Science and Technology of Mexico) and by the '
'participating centers. Thuy Le reports grants from Gilead Sciences, outside the '
'submitted work. B.J.M. reports grants from NIH/NHLBI, and from Bayer '
'Pharmaceuticals, Inc., outside the submitted work. S.M. receives funding as the '
'Innovative Medicines Canada Chair in Pandemic Preparedness. C.M. reports grants '
'from the Health Research Council of New Zealand. M.J.M. reports having received '
'the HCQ drug from the New York State government, during the conduct of the '
'study; grants from Lilly, Pfizer, Sanofi, and personal fees from Meissa, '
'outside the submitted work; in addition, M.J.M. has a patent anti-Zika '
'monoclonal ab/ Emory Univ pending. A.N. is supported by a Health Research Board '
'of Ireland Clinical Trial Network Award (HRB-CTH-2014-012). L.P. is an employee '
'of Excelya and works as an external contractor for Sanofi. F.W.R. reports '
'personal fees from Merck Research Labs, Novartis, Lilly, Sanofi, NovoNordisk, '
'KLSMC, Tolerion, Rhythm, UCB, AstraZeneca, Janssen, Merck KGaA, Sarepta, Eidos, '
'Amgen, Phathom, outside the submitted work; and having equity interest in '
'GlaxoSmithkline, Athira Pharma, DataVant, Spencer Healthcare. S.R.W. reports '
'receiving a grant from Sanofi during the conduct of the study and grants from '
'NIH-NIAID outside the submitted work, and having conducted vaccine (HIV, Zika) '
'clinical trials funded by Janssen. S.A.W. reports grants from National Health '
'and Medical Research Council (Australia), grants from Minderoo Foundation, from '
'Health Research Council (New Zealand), and from Medical Research Future Fund '
'(Australia), during the conduct of the study. J.M.W. reports grants from ZonMw, '
'Netherlands organisation for Health Research and Development, during the '
'conduct of the study. F.G.Z. was part of the Coalition 1 trial partially '
'supported by EMS Pharmaceuticals, has received previous grants from Bactiguard, '
'Sweden, outside the submitted work, and support from Baxter LA for another '
'clinical trial in critically ill patients. None of the other authors have any '
'competing interests to declare.',
'order': 1,
'name': 'Ethics',
'group': {'name': 'EthicsHeading', 'label': 'Competing interests'}}],
'article-number': '2349'}
