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 Fawzy Abdo, Benjamin S. Abella, Javed Akram, Ravi K. Amaravadi, Derek C. Angus, Yaseen M. Arabi, Shehnoor Azhar, Lindsey R. Baden, Arthur W. Baker, Leïla 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 Dalgård, Fernando Val, Marcus Lacerda, Gisely Cardoso de Melo, Lennie Derde, Vincent Dubée, Anissa Elfakir, Anthony Gordon, Carmen Margarita Hernández‐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 Marcelo 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 Pérez‐Padilla, Laurent Perrin, Arantxa Remigio-Luna, Norma E. Rivera-Martínez, Frank W. Rockhold, Sebastián Rodríguez‐Llamazares, Robert Rolfe, Rossana Rosa, Helge Røsjø, Vanderson de Souza Sampaio, Todd B. Seto, Muhammad Shahzad, Shaimaa Soliman, Jason E. Stout, Ireri Thirión-Romero, Andrea B. Troxel, Ting-Yu Tseng, Nicholas Turner, Robert J. Ulrich, Stephen R. Walsh, Steve 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
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of hydroxychloroquine and chloroquine on survival in COVID-19 from all currently available RCT evidence, published and unpublished.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 We systematically identified unpublished RCTs (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, Cochrane COVID-registry up to June 11, 2020), and published RCTs (PubMed,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.