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 F. Abdo, Benjamin S. Abella, Javed Akram, Ravi K. Amaravadi, Derek C. Angus, Yaseen M. Arabi, Shehnoor Azhar, Lindsey R. Baden, Arthur W. Baker, Leila 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 Dalgard, Fernando F. de Almeida e Val, Marcus V. G. de Lacerda, Gisely C. de Melo, Lennie Derde, Vincent Dubee, Anissa Elfakir, Anthony C. Gordon, Carmen M. Hernandez-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 M. 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 Perez-Padilla, Laurent Perrin, Arantxa Remigio-Luna, Norma E. Rivera-Martinez, Frank W. Rockhold, Sebastian Rodriguez-Llamazares, Robert Rolfe, Rossana Rosa, Helge Røsjø, Vanderson S. Sampaio, Todd B. Seto, Muhammad Shahzad, Shaimaa Soliman, Jason E. Stout, Ireri Thirion-Romero, Andrea B. Troxel, Ting-Yu Tseng, Nicholas A. Turner, Robert J. Ulrich, Stephen R. Walsh, Steve A. 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 and Lars G. Hemkens ()
Additional contact information
Cathrine Axfors: Stanford University
Andreas M. Schmitt: University of Basel
Perrine Janiaud: University of Basel
Janneke van’t Hooft: Stanford University
Sherief Abd-Elsalam: Tanta University
Ehab F. Abdo: Assiut University
Benjamin S. Abella: University of Pennsylvania
Javed Akram: University of Health Sciences
Ravi K. Amaravadi: University of Pennsylvania
Derek C. Angus: University of Pittsburgh
Yaseen M. Arabi: King Saud Bin Abdulaziz University for Health Sciences and King Abdullah International Medical Research Center
Shehnoor Azhar: University of Health Sciences
Lindsey R. Baden: Brigham and Women’s Hospital
Arthur W. Baker: Duke University Medical Center
Leila Belkhir: Université Catholique de Louvain
Thomas Benfield: Amager and Hvidovre
Marvin A. H. Berrevoets: Elisabeth-Tweesteden hospital
Cheng-Pin Chen: Ministry of Health and Welfare
Tsung-Chia Chen: Ministry of Health and Welfare
Shu-Hsing Cheng: Ministry of Health and Welfare
Chien-Yu Cheng: Ministry of Health and Welfare
Wei-Sheng Chung: Ministry of Health and Welfare
Yehuda Z. Cohen: Sanofi
Lisa N. Cowan: Sanofi
Olav Dalgard: Akershus University Hospital
Fernando F. de Almeida e Val: Fundação de Medicina Tropical Dr. Heitor Vieira Dourado
Marcus V. G. de Lacerda: Fundação de Medicina Tropical Dr. Heitor Vieira Dourado
Gisely C. de Melo: Fundação de Medicina Tropical Dr. Heitor Vieira Dourado
Lennie Derde: University Medical Center Utrecht
Vincent Dubee: Angers University Hospital
Anissa Elfakir: Ividata Life Sciences
Anthony C. Gordon: Imperial College London and Imperial College Healthcare NHS Trust
Carmen M. Hernandez-Cardenas: Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas
Thomas Hills: Medical Research Institute of New Zealand
Andy I. M. Hoepelman: University Medical Center Utrecht
Yi-Wen Huang: Chang Hua Hospital, Ministry of Health and Welfare
Bruno Igau: Sanofi
Ronghua Jin: Capital Medical University
Felipe Jurado-Camacho: Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas
Khalid S. Khan: University of Granada, Hospital Real, Avenida del Hospicio, Granada
Peter G. Kremsner: University of Tübingen
Benno Kreuels: University Medical Center Hamburg-Eppendorf
Cheng-Yu Kuo: Ministry of Health and Welfare
Thuy Le: Duke University Medical Center
Yi-Chun Lin: Ministry of Health and Welfare
Wu-Pu Lin: Taipei Hospital, Ministry of Health and Welfare
Tse-Hung Lin: Chang Hua Hospital, Ministry of Health and Welfare
Magnus Nakrem Lyngbakken: University of Oslo
Colin McArthur: Medical Research Institute of New Zealand
Bryan J. McVerry: University of Pittsburgh
Patricia Meza-Meneses: Hospital Regional de Alta especialidad de Ixtapaluca
Wuelton M. Monteiro: Fundação de Medicina Tropical Dr. Heitor Vieira Dourado
Susan C. Morpeth: Middlemore Hospital
Ahmad Mourad: Duke University Medical Center
Mark J. Mulligan: NYU Grossman School of Medicine
Srinivas Murthy: University of British Columbia School of Medicine
Susanna Naggie: Duke University Medical Center
Shanti Narayanasamy: Duke University Medical Center
Alistair Nichol: Monash University
Lewis A. Novack: Harvard Medical School
Sean M. O’Brien: Duke University Medical Center and Duke Clinical Research Institute
Nwora Lance Okeke: Duke University Medical Center
Léna Perez: Excelya
Rogelio Perez-Padilla: Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas
Laurent Perrin: Sanofi
Arantxa Remigio-Luna: Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas
Norma E. Rivera-Martinez: Hospital Regional de Alta especialidad de Oaxaca
Frank W. Rockhold: Duke University Medical Center and Duke Clinical Research Institute
Sebastian Rodriguez-Llamazares: Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas
Robert Rolfe: Duke University Medical Center
Rossana Rosa: UnityPoint Health
Helge Røsjø: University of Oslo
Vanderson S. Sampaio: Fundação de Medicina Tropical Dr. Heitor Vieira Dourado
Todd B. Seto: University of Hawaii John A. Burns School of Medicine
Muhammad Shahzad: University of Health Sciences
Shaimaa Soliman: Menoufia University
Jason E. Stout: Duke University Medical Center
Ireri Thirion-Romero: Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas
Andrea B. Troxel: NYU Grossman School of Medicine
Ting-Yu Tseng: Ministry of Health and Welfare
Nicholas A. Turner: Duke University Medical Center
Robert J. Ulrich: NYU Grossman School of Medicine
Stephen R. Walsh: Brigham and Women’s Hospital
Steve A. Webb: Monash University
Jesper M. Weehuizen: University Medical Center Utrecht
Maria Velinova: PRA Health Science
Hon-Lai Wong: Ministry of Health and Welfare
Rebekah Wrenn: Duke University Medical Center
Fernando G. Zampieri: HCor-Hospital do Coração
Wu Zhong: Beijing Institute of Pharmacology and Toxicology
David Moher: Ottawa Hospital Research Institute
Steven N. Goodman: Stanford University
John P. A. Ioannidis: Stanford University
Lars G. Hemkens: Stanford University

Nature Communications, 2021, vol. 12, issue 1, 1-13

Abstract: 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.

Date: 2021
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DOI: 10.1038/s41467-021-22446-z

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