Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis of randomized trials
Authors: 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. , Shahzad 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. 
Published: April 2021

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of hydroxychloroquine and chloroquine on survival in COVID-19 from all currently available RCT evidence, published and unpublished.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.