Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19: 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. , 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. 
Published: September 2020

Background

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of hydroxychloroquine and chloroquine on survival in COVID-19 from all currently available RCT evidence, published and unpublished. Methods: 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 published and unpublished RCTs by September 14, 2020 (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, PubMed, Cochrane COVID-19 registry). 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/chloroquine. Prespecified subgroup analyses included patient setting, diagnostic confirmation, control type, and publication status.

Results

Sixty-two trials were potentially eligible. We included 16 unpublished trials (1596 patients) and 10 publications/preprints (6317 patients). The combined summary OR on all-cause mortality for hydroxychloroquine was 1.08 (95%CI: 0.99, 1.18; I2=0%; 24 trials; 7659 patients) and for chloroquine 1.77 (95%CI: 0.15, 21.13, I2=0%; 4 trials; 307 patients). We identified no subgroup effects.

Conclusions

We found no benefit of hydroxychloroquine or chloroquine on the survival of COVID-19 patients. For hydroxychloroquine, the confidence interval is compatible with increased mortality (OR 1.18) or negligibly reduced mortality (OR 0.99). Findings have unclear generalizability to outpatients, children, pregnant women, and people with comorbidities.