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

Axfors, Cathrine; Schmitt, Andreas M.; Janiaud, Perrine; van’t Hooft, Janneke; Abd-Elsalam, Sherief; Abdo, Ehab F.; Abella, Benjamin S.; Akram, Javed; Amaravadi, Ravi K.; Angus, Derek C.; Arabi, Yaseen M.; Azhar, Shehnoor; Baden, Lindsey R.; Baker, Arthur W.; Belkhir, Leila; Benfield, Thomas; Berrevoets, Marvin A. H.; Chen, Cheng-Pin; Chen, Tsung-Chia; Cheng, Shu-Hsing; Cheng, Chien-Yu; Chung, Wei-Sheng; Cohen, Yehuda Z.; Cowan, Lisa N.; Dalgard, Olav; de Almeida e Val, Fernando F.; de Lacerda, Marcus V. G.; de Melo, Gisely C.; Derde, Lennie; Dubee, Vincent; Elfakir, Anissa; Gordon, Anthony C.; Hernandez-Cardenas, Carmen M.; Hills, Thomas; Hoepelman, Andy I. M.; Huang, Yi-Wen; Igau, Bruno; Jin, Ronghua; Jurado-Camacho, Felipe; Khan, Khalid S.; Kremsner, Peter G.; Kreuels, Benno; Kuo, Cheng-Yu; Le, Thuy; Lin, Yi-Chun; Lin, Wu-Pu; Lin, Tse-Hung; Lyngbakken, Magnus Nakrem; McArthur, Colin; McVerry, Bryan J.; Meza-Meneses, Patricia; Monteiro, Wuelton M.; Morpeth, Susan C.; Mourad, Ahmad; Mulligan, Mark J.; Murthy, Srinivas; Naggie, Susanna; Narayanasamy, Shanti; Nichol, Alistair; Novack, Lewis A.; O’Brien, Sean M.; Okeke, Nwora Lance; Perez, Léna; Perez-Padilla, Rogelio; Perrin, Laurent; Remigio-Luna, Arantxa; Rivera-Martinez, Norma E.; Rockhold, Frank W.; Rodriguez-Llamazares, Sebastian; Rolfe, Robert; Rosa, Rossana; Røsjø, Helge; Sampaio, Vanderson S.; Seto, Todd B.; Shehzad, Muhammad; Soliman, Shaimaa; Stout, Jason E.; Thirion-Romero, Ireri; Troxel, Andrea B.; Tseng, Ting-Yu; Turner, Nicholas A.; Ulrich, Robert J.; Walsh, Stephen R.; Webb, Steve A.; Weehuizen, Jesper M.; Velinova, Maria; Wong, Hon-Lai; Wrenn, Rebekah; Zampieri, Fernando G.; Zhong, Wu; Moher, David; Goodman, Steven N.; Ioannidis, John P. A.; Hemkens, Lars G.

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of hydroxychloroquine and chloroquine on survival in COVID-19 from all currently available RCT evidence, published and unpublished.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 We systematically identified unpublished RCTs (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, Cochrane COVID-registry up to June 11, 2020), and published RCTs (PubMed,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