Nature Communications (Apr 2021)
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,
- Lars G. Hemkens
Affiliations
- Cathrine Axfors
- Meta-Research Innovation Center at Stanford (METRICS), Stanford University
- Andreas M. Schmitt
- Department of Clinical Research, University Hospital Basel, University of Basel
- Perrine Janiaud
- Department of Clinical Research, University Hospital Basel, University of Basel
- Janneke van’t Hooft
- Meta-Research Innovation Center at Stanford (METRICS), Stanford University
- Sherief Abd-Elsalam
- Tropical Medicine and Infectious Diseases Department, Faculty of Medicine, Tanta University
- Ehab F. Abdo
- Tropical Medicine and Gastroenterology Department, Faculty of Medicine, Assiut University
- Benjamin S. Abella
- Department of Emergency Medicine, University of Pennsylvania
- Javed Akram
- Department of Internal Medicine, Vice Chancellor, University of Health Sciences
- Ravi K. Amaravadi
- Abramson Cancer Center and Department of Medicine, University of Pennsylvania
- Derek C. Angus
- Department of Critical Care Medicine, The Clinical Research Investigation and Systems Modeling of Acute Illness (CRISMA) Center, University of Pittsburgh
- Yaseen M. Arabi
- Intensive Care Department, King Saud Bin Abdulaziz University for Health Sciences and King Abdullah International Medical Research Center
- Shehnoor Azhar
- Department of Public Health, University of Health Sciences
- Lindsey R. Baden
- Division of Infectious Diseases, Brigham and Women’s Hospital
- Arthur W. Baker
- Department of Medicine, Division of Infectious Diseases and International Health, Duke University Medical Center
- Leila Belkhir
- Infectious Diseases Department, Cliniques universitaires Saint-Luc, Université Catholique de Louvain
- Thomas Benfield
- Center of Research & Disruption of Infectious Diseases, Department of Infectious Diseases, Copenhagen University Hospital, Amager and Hvidovre
- Marvin A. H. Berrevoets
- Department of Internal Medicine, Elisabeth-Tweesteden hospital
- Cheng-Pin Chen
- Department of Infectious Diseases, Taoyuan General Hospital, Ministry of Health and Welfare
- Tsung-Chia Chen
- Department of Internal Medicine, Taichung Hospital, Ministry of Health and Welfare
- Shu-Hsing Cheng
- Department of Infectious Diseases, Taoyuan General Hospital, Ministry of Health and Welfare
- Chien-Yu Cheng
- Department of Infectious Diseases, Taoyuan General Hospital, Ministry of Health and Welfare
- Wei-Sheng Chung
- Department of Internal Medicine, Taichung Hospital, Ministry of Health and Welfare
- Yehuda Z. Cohen
- Sanofi
- Lisa N. Cowan
- Sanofi
- Olav Dalgard
- Department of Infectious Diseases, Division of Medicine, 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
- Julius Center for Health Sciences and Primary Care, University Medical Center Utrecht
- Vincent Dubee
- Infectious and Tropical Diseases Department, Angers University Hospital
- Anissa Elfakir
- Ividata Life Sciences
- Anthony C. Gordon
- Department of Surgery and Cancer, Anaesthetics, Pain Medicine, and Intensive Care Medicine, Imperial College London and Imperial College Healthcare NHS Trust
- Carmen M. Hernandez-Cardenas
- Critical Care Department, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas
- Thomas Hills
- Medical Research Institute of New Zealand
- Andy I. M. Hoepelman
- Department of Infectious Diseases, University Medical Center Utrecht
- Yi-Wen Huang
- Department of Internal Medicine, Chang Hua Hospital, Ministry of Health and Welfare
- Bruno Igau
- Sanofi
- Ronghua Jin
- Beijing Youan Hospital, Capital Medical University
- Felipe Jurado-Camacho
- Critical Care Department, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas
- Khalid S. Khan
- Department of Preventive Medicine & Public Health, University of Granada, Hospital Real, Avenida del Hospicio, Granada
- Peter G. Kremsner
- Institute of Tropical Medicine, University of Tübingen
- Benno Kreuels
- Department of Medicine, Division of Tropical Medicine and Division of Infectious Diseases, University Medical Center Hamburg-Eppendorf
- Cheng-Yu Kuo
- Department of Internal Medicine, Pingtung Hospital, Ministry of Health and Welfare
- Thuy Le
- Department of Medicine, Division of Infectious Diseases and International Health, Duke University Medical Center
- Yi-Chun Lin
- Department of Infectious Diseases, Taoyuan General Hospital, Ministry of Health and Welfare
- Wu-Pu Lin
- Department of Internal Medicine, Taipei Hospital, Ministry of Health and Welfare
- Tse-Hung Lin
- Department of Internal Medicine, Chang Hua Hospital, Ministry of Health and Welfare
- Magnus Nakrem Lyngbakken
- Institute of Clinical Medicine, Faculty of Medicine, University of Oslo
- Colin McArthur
- Medical Research Institute of New Zealand
- Bryan J. McVerry
- Department of Medicine, 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
- Department of Medicine, Duke University Medical Center
- Mark J. Mulligan
- Department of Microbiology, NYU Grossman School of Medicine
- Srinivas Murthy
- University of British Columbia School of Medicine
- Susanna Naggie
- Department of Medicine, Division of Infectious Diseases and International Health, Duke University Medical Center
- Shanti Narayanasamy
- Department of Medicine, Division of Infectious Diseases and International Health, Duke University Medical Center
- Alistair Nichol
- School of Epidemiology and Preventive Medicine, Australian and New Zealand Intensive Care Research Centre, Monash University
- Lewis A. Novack
- Division of Infectious Diseases, Brigham and Women’s Hospital, Harvard Medical School
- Sean M. O’Brien
- Department of Biostatistics and Bioinformatics, Duke University Medical Center and Duke Clinical Research Institute
- Nwora Lance Okeke
- Department of Medicine, Division of Infectious Diseases and International Health, Duke University Medical Center
- Léna Perez
- Excelya
- Rogelio Perez-Padilla
- Department of Smoking and COPD, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas
- Laurent Perrin
- Sanofi
- Arantxa Remigio-Luna
- Department of Smoking and COPD, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas
- Norma E. Rivera-Martinez
- Hospital Regional de Alta especialidad de Oaxaca
- Frank W. Rockhold
- Department of Biostatistics and Bioinformatics, Duke University Medical Center and Duke Clinical Research Institute
- Sebastian Rodriguez-Llamazares
- Department of Smoking and COPD, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas
- Robert Rolfe
- Department of Medicine, Division of Infectious Diseases and International Health, Duke University Medical Center
- Rossana Rosa
- UnityPoint Health
- Helge Røsjø
- Institute of Clinical Medicine, Faculty of Medicine, 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
- Department of Pharmacology, University of Health Sciences
- Shaimaa Soliman
- Public Health and Community Medicine, Menoufia University
- Jason E. Stout
- Department of Medicine, Division of Infectious Diseases and International Health, Duke University Medical Center
- Ireri Thirion-Romero
- Department of Smoking and COPD, Instituto Nacional de Enfermedades Respiratorias Ismael Cosío Villegas
- Andrea B. Troxel
- Division of Biostatistics, Department of Population Health, NYU Grossman School of Medicine
- Ting-Yu Tseng
- Department of Internal Medicine, Taichung Hospital, Ministry of Health and Welfare
- Nicholas A. Turner
- Department of Medicine, Division of Infectious Diseases and International Health, Duke University Medical Center
- Robert J. Ulrich
- Department of Medicine, Division of Infectious Diseases and Immunology, NYU Grossman School of Medicine
- Stephen R. Walsh
- Division of Infectious Diseases, Brigham and Women’s Hospital
- Steve A. Webb
- School of Epidemiology and Preventive Medicine, Australian and New Zealand Intensive Care Research Centre, Monash University
- Jesper M. Weehuizen
- Department of Infectious Diseases, University Medical Center Utrecht
- Maria Velinova
- PRA Health Science
- Hon-Lai Wong
- Department of Internal Medicine, Keelung Hospital, Ministry of Health and Welfare
- Rebekah Wrenn
- Department of Medicine, Division of Infectious Diseases and International Health, Duke University Medical Center
- Fernando G. Zampieri
- Research Institute, HCor-Hospital do Coração
- Wu Zhong
- National Engineering Research Center for the Emergency Drug, Beijing Institute of Pharmacology and Toxicology
- David Moher
- Centre for Journalology, Clinical Epidemiology Program, Ottawa Hospital Research Institute
- Steven N. Goodman
- Meta-Research Innovation Center at Stanford (METRICS), Stanford University
- John P. A. Ioannidis
- Meta-Research Innovation Center at Stanford (METRICS), Stanford University
- Lars G. Hemkens
- Meta-Research Innovation Center at Stanford (METRICS), Stanford University
- DOI
- https://doi.org/10.1038/s41467-021-22446-z
- Journal volume & issue
-
Vol. 12,
no. 1
pp. 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.
