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Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19: an international collaborative meta-analysis of randomized trials

By Cathrine Axfors, Andreas M. Schmitt, Perrine Janiaud, Janneke van ’t Hooft, Sherief Abd-Elsalam, Ehab F. Abdo, Benjamin S. Abella, Shehla 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 D 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 Shehzad, 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

Posted 18 Sep 2020
medRxiv DOI: 10.1101/2020.09.16.20194571

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 aimed to estimate the effects of hydroxychloroquine and chloroquine on survival in COVID-19 from all currently available RCT evidence, published and unpublished. We conducted 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 We systematically identified unpublished RCTs (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, Cochrane COVID-registry up to June 11, 2020), and published RCTs (PubMed,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 was 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 included 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 was 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 was associated with increased mortality in COVID-19 patients, and there was no benefit of chloroquine. Findings have unclear generalizability to outpatients, children, pregnant women, and people with comorbidities.

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