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

doi:10.1038/s41467-021-22446-z

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

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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, …

Nature communications, Vol.12(1), pp.2349-2349

15/04/2021

DOI: https://doi.org/10.1038/s41467-021-22446-z

PMID: 33859192

Abstract

Adult

Child

Chloroquine - administration & dosage

Chloroquine - adverse effects

Combined Modality Therapy - adverse effects

Combined Modality Therapy - methods

Comorbidity

COVID-19 - complications

COVID-19 - drug therapy

COVID-19 - mortality

COVID-19 - virology

Female

Humans

Hydroxychloroquine - administration & dosage

Hydroxychloroquine - adverse effects

International Cooperation

Odds Ratio

Patient Participation - statistics & numerical data

Pregnancy

Pregnancy Complications, Infectious - drug therapy

Pregnancy Complications, Infectious - mortality

Pregnancy Complications, Infectious - virology

Randomized Controlled Trials as Topic - statistics & numerical data

SARS-CoV-2

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.

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Title: Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis of randomized trials
Creators - without role: Cathrine Axfors - Stanford University
Andreas M Schmitt - University Hospital of Basel
Perrine Janiaud - University Hospital of Basel
Janneke Van't Hooft - University of Amsterdam
Sherief Abd-Elsalam - Tanta University
Ehab F Abdo - Assiut University
Benjamin S Abella - University of Pennsylvania
Javed Akram - University of Health Sciences Lahore
Ravi K Amaravadi - University of Pennsylvania
Derek C Angus - University of Pittsburgh
Yaseen M Arabi - King Saud bin Abdulaziz University for Health Sciences
Shehnoor Azhar - University of Health Sciences Lahore
Lindsey R Baden - Brigham and Women's Hospital
Arthur W Baker - Duke Medical Center
Leila Belkhir - Cliniques Universitaires Saint-Luc
Thomas Benfield - Copenhagen University Hospital
Marvin A H Berrevoets - Elisabeth-TweeSteden Ziekenhuis
Cheng-Pin Chen - Ministry of Health and Welfare
Tsung-Chia Chen - Taichung Hospital
Shu-Hsing Cheng - Ministry of Health and Welfare
Chien-Yu Cheng - Ministry of Health and Welfare
Wei-Sheng Chung - Taichung Hospital
Yehuda Z Cohen - Sanofi
Lisa N Cowan - Sanofi, Bridgewater, NJ, USA
Olav Dalgard - Akershus University Hospital
Fernando F de Almeida E Val - Fundação de Medicina Tropical
Marcus V G de Lacerda - Instituto Leonidas e Maria Deane - ILMD, FIOCRUZ-AM, Manaus, AM, Brazil
Gisely C de Melo - Universidade do Estado do Amazonas, Manaus, AM, Brazil
Lennie Derde - University Medical Center Utrecht
Vincent Dubee - Université d'Angers
Anissa Elfakir - Arysta LifeScience
Anthony C Gordon - Imperial College Healthcare NHS Trust
Carmen M Hernandez-Cardenas - Instituto Nacional de Enfermedades Respiratorias
Thomas Hills - Medical Research Institute of New Zealand
Andy I M Hoepelman - University Medical Center Utrecht
Yi-Wen Huang - Chang Hua Hospital
Bruno Igau - Sanofi
Ronghua Jin - Beijing YouAn Hospital
Felipe Jurado-Camacho - Instituto Nacional de Enfermedades Respiratorias
Khalid S Khan - Universidad de Granada
Peter G Kremsner - University of Tübingen
Benno Kreuels - University Medical Center Hamburg-Eppendorf
Cheng-Yu Kuo - Pingtung Hospital
Thuy Le - Duke Medical Center
Yi-Chun Lin - Ministry of Health and Welfare
Wu-Pu Lin - Ministry of Health and Welfare
Tse-Hung Lin - Chang Hua Hospital
Magnus Nakrem Lyngbakken - University of Oslo
Colin McArthur - Auckland City Hospital
Bryan J McVerry - University of Pittsburgh
Patricia Meza-Meneses - Universidad México Contemporáneo
Wuelton M Monteiro - Fundação de Medicina Tropical
Susan C Morpeth - Middlemore Hospital
Ahmad Mourad - Duke Medical Center
Mark J Mulligan - New York University
Srinivas Murthy - University of British Columbia
Susanna Naggie - Duke Medical Center
Shanti Narayanasamy - Duke Medical Center
Alistair Nichol - Alfred Health
Lewis A Novack - Brigham and Women's Hospital
Sean M O'Brien - Department of Biostatistics and Bioinformatics, Duke University Medical Center and Duke Clinical Research Institute, Durham, NC, USA
Nwora Lance Okeke - Duke Medical Center
Léna Perez - Excelya, Montpellier, France
Rogelio Perez-Padilla - Instituto Nacional de Enfermedades Respiratorias
Laurent Perrin - Sanofi
Arantxa Remigio-Luna - Instituto Nacional de Enfermedades Respiratorias
Norma E Rivera-Martinez - Hospitales Regionales de Alta Especialidad
Frank W Rockhold - Duke University
Sebastian Rodriguez-Llamazares - Instituto Nacional de Enfermedades Respiratorias
Robert Rolfe - Duke Medical Center
Rossana Rosa - UnityPoint Health
Helge Røsjø - University of Oslo
Vanderson S Sampaio - Fundação de Vigilância em Saúde do Amazonas, Manaus, AM, Brazil
Todd B Seto - University of Hawaiʻi at Mānoa
Muhammad Shahzad - University of Health Sciences Lahore
Shaimaa Soliman - Menoufia University
Jason E Stout - Duke Medical Center
Ireri Thirion-Romero - Instituto Nacional de Enfermedades Respiratorias
Andrea B Troxel - New York University
Ting-Yu Tseng - Taichung Hospital
Nicholas A Turner - Department of Medicine, Division of Infectious Diseases and International Health, Duke University Medical Center, Durham, NC, USA
Robert J Ulrich - Department of Medicine, Division of Infectious Diseases and Immunology, NYU Grossman School of Medicine, New York, NY, USA
Stephen R Walsh - Brigham and Women's Hospital
Steve A Webb - Australian and New Zealand Intensive Care Society
Jesper M Weehuizen - University Medical Center Utrecht
Maria Velinova - Dialyse Centrum Groningen
Hon-Lai Wong - Ministry of Health and Welfare
Rebekah Wrenn - Duke Medical Center
Fernando G Zampieri - Hospital do Coração
Wu Zhong - Institute of Pharmacology
David Moher - Ottawa Hospital
Steven N Goodman - Protein Metrics
John P A Ioannidis - Stanford University
Lars G Hemkens - Protein Metrics
Publication Details: Nature communications, Vol.12(1), pp.2349-2349
Identifiers: 9921878108331
Academic Unit: King Abdulaziz University; King Saud Bin Abdulaziz University for Health Sciences
Language: English
Resource Type: Journal article