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of hydroxychloroquine and chloroquine on survival in COVID-19 from all currently available RCT evidence, published and unpublished.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 We systematically identified unpublished RCTs (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, Cochrane COVID-registry up to June 11, 2020), and published RCTs (PubMed,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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