, 12(1): 2349. December 2021.\n
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@article{axfors_mortality_2021,\n\ttitle = {Mortality outcomes with hydroxychloroquine and chloroquine in {COVID}-19 from an international collaborative meta-analysis of randomized trials},\n\tvolume = {12},\n\tissn = {2041-1723},\n\turl = {http://www.nature.com/articles/s41467-021-22446-z},\n\tdoi = {10.1038/s41467-021-22446-z},\n\tabstract = {Abstract\n \n 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of hydroxychloroquine and chloroquine on survival in COVID-19 from all currently available RCT evidence, published and unpublished.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:\n https://osf.io/QESV4/\n ). We systematically identified unpublished RCTs (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, Cochrane COVID-registry up to June 11, 2020), and published RCTs (PubMed,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 We included 14 unpublished trials (1308 patients) and 14 publications/preprints (9011 patients).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.},\n\tlanguage = {en},\n\tnumber = {1},\n\turldate = {2021-04-28},\n\tjournal = {Nature Communications},\n\tauthor = {Axfors, Cathrine and Schmitt, Andreas M. and Janiaud, Perrine and van’t Hooft, Janneke and Abd-Elsalam, Sherief and Abdo, Ehab F. and Abella, Benjamin S. and Akram, Javed and Amaravadi, Ravi K. and Angus, Derek C. and Arabi, Yaseen M. and Azhar, Shehnoor and Baden, Lindsey R. and Baker, Arthur W. and Belkhir, Leila and Benfield, Thomas and Berrevoets, Marvin A. H. and Chen, Cheng-Pin and Chen, Tsung-Chia and Cheng, Shu-Hsing and Cheng, Chien-Yu and Chung, Wei-Sheng and Cohen, Yehuda Z. and Cowan, Lisa N. and Dalgard, Olav and de Almeida e Val, Fernando F. and de Lacerda, Marcus V. G. and de Melo, Gisely C. and Derde, Lennie and Dubee, Vincent and Elfakir, Anissa and Gordon, Anthony C. and Hernandez-Cardenas, Carmen M. and Hills, Thomas and Hoepelman, Andy I. M. and Huang, Yi-Wen and Igau, Bruno and Jin, Ronghua and Jurado-Camacho, Felipe and Khan, Khalid S. and Kremsner, Peter G. and Kreuels, Benno and Kuo, Cheng-Yu and Le, Thuy and Lin, Yi-Chun and Lin, Wu-Pu and Lin, Tse-Hung and Lyngbakken, Magnus Nakrem and McArthur, Colin and McVerry, Bryan J. and Meza-Meneses, Patricia and Monteiro, Wuelton M. and Morpeth, Susan C. and Mourad, Ahmad and Mulligan, Mark J. and Murthy, Srinivas and Naggie, Susanna and Narayanasamy, Shanti and Nichol, Alistair and Novack, Lewis A. and O’Brien, Sean M. and Okeke, Nwora Lance and Perez, Léna and Perez-Padilla, Rogelio and Perrin, Laurent and Remigio-Luna, Arantxa and Rivera-Martinez, Norma E. and Rockhold, Frank W. and Rodriguez-Llamazares, Sebastian and Rolfe, Robert and Rosa, Rossana and Røsjø, Helge and Sampaio, Vanderson S. and Seto, Todd B. and Shehzad, Muhammad and Soliman, Shaimaa and Stout, Jason E. and Thirion-Romero, Ireri and Troxel, Andrea B. and Tseng, Ting-Yu and Turner, Nicholas A. and Ulrich, Robert J. and Walsh, Stephen R. and Webb, Steve A. and Weehuizen, Jesper M. and Velinova, Maria and Wong, Hon-Lai and Wrenn, Rebekah and Zampieri, Fernando G. and Zhong, Wu and Moher, David and Goodman, Steven N. and Ioannidis, John P. A. and Hemkens, Lars G.},\n\tmonth = dec,\n\tyear = {2021},\n\tpages = {2349},\n}\n\n
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\n Abstract 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.\n