Skip to main page content
U.S. flag

An official website of the United States government

Dot gov

The .gov means it’s official.
Federal government websites often end in .gov or .mil. Before sharing sensitive information, make sure you’re on a federal government site.

Https

The site is secure.
The https:// ensures that you are connecting to the official website and that any information you provide is encrypted and transmitted securely.

Access keys NCBI Homepage MyNCBI Homepage Main Content Main Navigation
Meta-Analysis
. 2021 Apr 15;12(1):2349.
doi: 10.1038/s41467-021-22446-z.

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

Cathrine Axfors #  1   2 , Andreas M Schmitt #  3   4 , Perrine Janiaud  3 , Janneke Van't Hooft  1   5 , Sherief Abd-Elsalam  6 , Ehab F Abdo  7 , Benjamin S Abella  8 , Javed Akram  9 , Ravi K Amaravadi  10 , Derek C Angus  11   12 , Yaseen M Arabi  13 , Shehnoor Azhar  14 , Lindsey R Baden  15 , Arthur W Baker  16 , Leila Belkhir  17 , Thomas Benfield  18 , Marvin A H Berrevoets  19 , Cheng-Pin Chen  20 , Tsung-Chia Chen  21 , Shu-Hsing Cheng  20 , Chien-Yu Cheng  20 , Wei-Sheng Chung  21 , Yehuda Z Cohen  22 , Lisa N Cowan  22 , Olav Dalgard  23   24 , Fernando F de Almeida E Val  25 , Marcus V G de Lacerda  25   26 , Gisely C de Melo  25   27 , Lennie Derde  28   29 , Vincent Dubee  30 , Anissa Elfakir  31 , Anthony C Gordon  32 , Carmen M Hernandez-Cardenas  33 , Thomas Hills  34   35 , Andy I M Hoepelman  36 , Yi-Wen Huang  37 , Bruno Igau  22 , Ronghua Jin  38 , Felipe Jurado-Camacho  33 , Khalid S Khan  39 , Peter G Kremsner  40   41   42 , Benno Kreuels  43   44 , Cheng-Yu Kuo  45 , Thuy Le  16 , Yi-Chun Lin  20 , Wu-Pu Lin  46 , Tse-Hung Lin  37 , Magnus Nakrem Lyngbakken  24   47 , Colin McArthur  34   35   48 , Bryan J McVerry  49 , Patricia Meza-Meneses  50 , Wuelton M Monteiro  25   27 , Susan C Morpeth  51 , Ahmad Mourad  52 , Mark J Mulligan  53   54 , Srinivas Murthy  55 , Susanna Naggie  16 , Shanti Narayanasamy  16 , Alistair Nichol  48   56   57   58 , Lewis A Novack  59 , Sean M O'Brien  60 , Nwora Lance Okeke  16 , Léna Perez  61 , Rogelio Perez-Padilla  62 , Laurent Perrin  63 , Arantxa Remigio-Luna  62 , Norma E Rivera-Martinez  64 , Frank W Rockhold  60 , Sebastian Rodriguez-Llamazares  62 , Robert Rolfe  16 , Rossana Rosa  65 , Helge Røsjø  24   66 , Vanderson S Sampaio  25   67 , Todd B Seto  68   69 , Muhammad Shahzad  70 , Shaimaa Soliman  71 , Jason E Stout  16 , Ireri Thirion-Romero  62 , Andrea B Troxel  72 , Ting-Yu Tseng  21 , Nicholas A Turner  16 , Robert J Ulrich  73 , Stephen R Walsh  15 , Steve A Webb  48   74 , Jesper M Weehuizen  36 , Maria Velinova  75 , Hon-Lai Wong  76 , Rebekah Wrenn  16 , Fernando G Zampieri  77   78   79 , Wu Zhong  80 , David Moher  81 , Steven N Goodman  1   82   83 , John P A Ioannidis  1   82   83   84   85 , Lars G Hemkens  86   87   88
Affiliations
Meta-Analysis

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

Cathrine Axfors et al. Nat Commun. .

Erratum in

  • Author Correction: Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis of randomized trials.
    Axfors C, Schmitt AM, Janiaud P, Van't Hooft J, Abd-Elsalam S, Abdo EF, Abella BS, Akram J, Amaravadi RK, Angus DC, Arabi YM, Azhar S, Baden LR, Baker AW, Belkhir L, Benfield T, Berrevoets MAH, Chen CP, Chen TC, Cheng SH, Cheng CY, Chung WS, Cohen YZ, Cowan LN, Dalgard O, de Almeida E Val FF, de Lacerda MVG, de Melo GC, Derde L, Dubee V, Elfakir A, Gordon AC, Hernandez-Cardenas CM, Hills T, Hoepelman AIM, Huang YW, Igau B, Jin R, Jurado-Camacho F, Khan KS, Kremsner PG, Kreuels B, Kuo CY, Le T, Lin YC, Lin WP, Lin TH, Lyngbakken MN, McArthur C, McVerry BJ, Meza-Meneses P, Monteiro WM, Morpeth SC, Mourad A, Mulligan MJ, Murthy S, Naggie S, Narayanasamy S, Nichol A, Novack LA, O'Brien SM, Okeke NL, Perez L, Perez-Padilla R, Perrin L, Remigio-Luna A, Rivera-Martinez NE, Rockhold FW, Rodriguez-Llamazares S, Rolfe R, Rosa R, Røsjø H, Sampaio VS, Seto TB, Shahzad M, Soliman S, Stout JE, Thirion-Romero I, Troxel AB, Tseng TY, Turner NA, Ulrich RJ, Walsh SR, Webb SA, Weehuizen JM, Velinova M, Wong HL, Wrenn R, Zampieri FG, Zhong W, Moher D, Goodman SN, Ioannidis JPA, Hemkens LG. Axfors C, et al. Nat Commun. 2021 May 14;12(1):3001. doi: 10.1038/s41467-021-23559-1. Nat Commun. 2021. PMID: 33990619 Free PMC article. No abstract available.
  • Author Correction: Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis of randomized trials.
    Axfors C, Schmitt AM, Janiaud P, Van't Hooft J, Abd-Elsalam S, Abdo EF, Abella BS, Akram J, Amaravadi RK, Angus DC, Arabi YM, Azhar S, Baden LR, Baker AW, Belkhir L, Benfield T, Berrevoets MAH, Chen CP, Chen TC, Cheng SH, Cheng CY, Chung WS, Cohen YZ, Cowan LN, Dalgard O, de Almeida E Val FF, de Lacerda MVG, de Melo GC, Derde L, Dubee V, Elfakir A, Gordon AC, Hernandez-Cardenas CM, Hills T, Hoepelman AIM, Huang YW, Igau B, Jin R, Jurado-Camacho F, Khan KS, Kremsner PG, Kreuels B, Kuo CY, Le T, Lin YC, Lin WP, Lin TH, Lyngbakken MN, McArthur C, McVerry BJ, Meza-Meneses P, Monteiro WM, Morpeth SC, Mourad A, Mulligan MJ, Murthy S, Naggie S, Narayanasamy S, Nichol A, Novack LA, O'Brien SM, Okeke NL, Perez L, Perez-Padilla R, Perrin L, Remigio-Luna A, Rivera-Martinez NE, Rockhold FW, Rodriguez-Llamazares S, Rolfe R, Rosa R, Røsjø H, Sampaio VS, Seto TB, Shahzad M, Soliman S, Stout JE, Thirion-Romero I, Troxel AB, Tseng TY, Turner NA, Ulrich RJ, Walsh SR, Webb SA, Weehuizen JM, Velinova M, Wong HL, Wrenn R, Zampieri FG, Zhong W, Moher D, Goodman SN, Ioannidis JPA, Hemkens LG. Axfors C, et al. Nat Commun. 2024 Feb 5;15(1):1075. doi: 10.1038/s41467-024-45360-6. Nat Commun. 2024. PMID: 38316844 Free PMC article. No abstract available.

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.

PubMed Disclaimer

Conflict of interest statement

B.S.A. and R.K.A. are the primary investigators of the Prevention and Treatment of COVID19 with Hydroxychloroquine (PATCH) trial, funded by a philanthropic gift. R.K.A reports being founder with equity of Pinpoint Therapeutics and Immunacell, and personal fees from Sprint Biosciences and Deciphera, outside the submitted work. D.C.A. reports personal fees from Ferring Pharmaceuticals, Inc., Bristol-Myers Squibb, and Bayer AG, other from Alung Technologies, Inc., outside the submitted work; in addition, D.C.A. has pending patents for Selepressin—compounds, compositions, and methods for treating sepsis to Ferring, B.V., and Proteomic biomarkers of sepsis in elderly patients pending to University of Pittsburgh. Y.M.A. reports that he is the principal investigator on a clinical trial of lopinavir–ritonavir and interferon for Middle East respiratory syndrome (MERS) and that he was a nonpaid consultant on therapeutics for MERS-coronavirus (CoV) for Gilead Sciences and SAB Biotherapeutics. He is a coinvestigator on the Randomized, Embedded, Multi-factorial Adaptive Platform Trial for Community-Acquired Pneumonia (REMAP-CAP), a board member of the International Severe Acute Respiratory and Emerging Infection Consortium (ISARIC), and the Lead-Co Chair of the Think20 (T20) Taskforce for COVID-19. Brigham and Women’s Hospital, PRA Health Science, and Cliniques universitaires Saint-Luc received funds from Sanofi. T.B. reports grants from Pfizer, Novo Nordisk Foundation, Simonsen Foundation, Lundbeck Foundation, and Kai Hansen Foundation; grants and personal fees from GSK, Pfizer, Boehringer Ingelheim, and Gilead; and personal fees from MSD, all outside the submitted work. Y.Z.C., L.N.C., B.I., and L.P. are employees of Sanofi. The COV-HCQ and COMIHY trials were supported by the German Federal Ministry of Education and Research (EudraCT number 2020-001224-33) and the German Federal Ministry of Health (EudraCT number 2020-001512-26). L.D. reports grants from EU FP7-HEALTH-2013-INNOVATION-1, grant number 602525, grants from H2020 RECOVER, grant agreement no. 101003589, during the conduct of the study; and is a member of the COVID-19 guideline committee SCCM/ESICM/SSC, member of the ESICM COVID-19 taskforce, and chair of the Dutch intensivists (NVIC) taskforce infectious threats. V.D. reports nonfinancial support from MSD France and from Sanofi Aventis France, outside the submitted work. A.E. is an employee of Ividata Life Sciences and works as an external contractor for Sanofi. A.C.G. received grant funding from an NIHR Research Professorship (RP-2015-06-18), support from the NIHR Imperial Biomedical Research Centre, and consulting fees paid to his institution from GlaxoSmithKline and Bristol-Myers Squibb. T.H. reports grants from the Health Research Council of New Zealand, during the conduct of the study. A.I.M.H. reports grants from ZonMw, Netherlands organisation for Health Research and Development, during the conduct of the study. HYDRA trial was an investigator-initiated study supported by Sanofi, CONACYT (National Council of Science and Technology of Mexico) and by the participating centers. Thuy Le reports grants from Gilead Sciences, outside the submitted work. B.J.M. reports grants from NIH/NHLBI, and from Bayer Pharmaceuticals, Inc., outside the submitted work. S.M. receives funding as the Innovative Medicines Canada Chair in Pandemic Preparedness. C.M. reports grants from the Health Research Council of New Zealand. M.J.M. reports having received the HCQ drug from the New York State government, during the conduct of the study; grants from Lilly, Pfizer, Sanofi, and personal fees from Meissa, outside the submitted work; in addition, M.J.M. has a patent anti-Zika monoclonal ab/ Emory Univ pending. A.N. is supported by a Health Research Board of Ireland Clinical Trial Network Award (HRB-CTH-2014-012). L.P. is an employee of Excelya and works as an external contractor for Sanofi. F.W.R. reports personal fees from Merck Research Labs, Novartis, Lilly, Sanofi, NovoNordisk, KLSMC, Tolerion, Rhythm, UCB, AstraZeneca, Janssen, Merck KGaA, Sarepta, Eidos, Amgen, Phathom, outside the submitted work; and having equity interest in GlaxoSmithkline, Athira Pharma, DataVant, Spencer Healthcare. S.R.W. reports receiving a grant from Sanofi during the conduct of the study and grants from NIH-NIAID outside the submitted work, and having conducted vaccine (HIV, Zika) clinical trials funded by Janssen. S.A.W. reports grants from National Health and Medical Research Council (Australia), grants from Minderoo Foundation, from Health Research Council (New Zealand), and from Medical Research Future Fund (Australia), during the conduct of the study. J.M.W. reports grants from ZonMw, Netherlands organisation for Health Research and Development, during the conduct of the study. F.G.Z. was part of the Coalition 1 trial partially supported by EMS Pharmaceuticals, has received previous grants from Bactiguard, Sweden, outside the submitted work, and support from Baxter LA for another clinical trial in critically ill patients. None of the other authors have any competing interests to declare.

Figures

Fig. 1
Fig. 1. Flowchart of included randomized clinical trials.
Sources searched up to June 11, 2020 (PubMed, ClinicalTrials.gov, WHO ICTRP, Cochrane COVID Register) or April 9 (WHO Literature database, bioRxiv, medRxiv, SwissEthics). 1Trials for which we received no answer were presumed to be eligible unless withdrawn. 2One publication and two preprints were identified in a later search update. 3Published peer-reviewed articles or posted preprints. CQ chloroquine, HCQ hydroxychloroquine, ICTRP International Clinical Trials Registry Platform, WHO World Health Organization.
Fig. 2
Fig. 2. Random effects meta-analysis for mortality for treatment of COVID-19, trials are stratified by publication status.
A Random-effects meta-analysis for mortality for treatment of COVID-19 with Hydroxychloroquine, trials are stratified by publication status. The dashed vertical line denotes an odds ratio of 1.0, which represents no difference in risk between hydroxychloroquine and the control. The black horizontal bars represent 95% confidence intervals (CIs). Random-effects model of the Hartung–Knapp–Sidik–Jonkman approach was performed to obtain a pooled estimate of the odds ratio. The estimate of heterogeneity (τ2) was obtained using the Paule and Mandel (PM) estimator. We describe the between-trial heterogeneity using the I2 statistic. The results of the statistical tests for the overall effect and corresponding p values are presented. All tests were two-tailed. *Published as peer-reviewed articles or posted preprints. B Random-effects meta-analysis for mortality for treatment of COVID-19 with chloroquine. The dashed vertical line denotes an odds ratio of 1.0, which represents no difference in risk between chloroquine and the control. The black horizontal bars represent 95% confidence intervals (CIs). Random-effects model of the Hartung–Knapp–Sidik–Jonkman approach was performed to obtain a pooled estimate of the odds ratio. The estimate of heterogeneity (τ2) was obtained using the Paule and Mandel (PM) estimator. We describe the between-trial heterogeneity using the I2 statistic. The results of the statistical tests for the overall effect and corresponding p values are presented. All tests were two-tailed. The x-axis scales differ for reasons of readability. Source data are provided as a Source Data file.
Fig. 3
Fig. 3. Cumulative meta-analysis for mortality for treatment of COVID-19 with Hydroxychloroquine.
A Cumulative meta-analysis for mortality for treatment of COVID-19 with hydroxychloroquine. HCQ was evaluated in 26 trials with 10,012 patients. Four thousand three hundred and sixteen patients were treated with hydroxychloroquine, of whom 606 died. Five thousand six hundred and ninety-six patients were allocated to the control group, of whom 960 died. The dashed vertical line denotes an odds ratio of 1.0, which represents no difference in risk between hydroxychloroquine and the control. The black horizontal bars represent 95% confidence intervals (CIs). Random-effects model of the Hartung–Knapp–Sidik–Jonkman approach was performed to obtain a pooled estimate of the odds ratio. The estimate of heterogeneity (τ2) was obtained using the Paule and Mandel (PM) estimator. We describe the between-trial heterogeneity using the I2 statistic. The results of the statistical tests for the overall effect and corresponding p values are presented. All tests were two-tailed. B Cumulative meta-analysis for mortality for treatment of COVID-19 with hydroxychloroquine (publications and preprints only). HCQ was evaluated in 14 published trials with 8981 patients. Three thousand eight hundred and nine patients were treated with hydroxychloroquine, of whom 547 died. Five thousand one hundred and seventy-two patients were allocated to the control group, of whom 893 died.The dashed vertical line denotes an odds ratio of 1.0, which represents no difference in risk between hydroxychloroquine and the control. The black horizontal bars represent 95% confidence intervals (CI). Random-effects model of the Hartung–Knapp–Sidik–Jonkman approach was performed to obtain a pooled estimate of the odds ratio. The estimate of heterogeneity (τ2) was obtained using the Paule and Mandel (PM) estimator. We describe the between-trial heterogeneity using the I2 statistic. The results of the statistical tests for the overall effect and corresponding p values are presented. All tests were two-tailed. C Cumulative meta-analysis for mortality for treatment of COVID-19 with hydroxychloroquine (unpublished data only). HCQ was evaluated in 12 unpublished trials with 1031 patients. Five hundred and seven patients were treated with hydroxychloroquine, of whom 59 died. Five hundred and twenty-four patients were allocated to the control group, of whom 67 died. The dashed vertical line denotes an odds ratio of 1.0, which represents no difference in risk between hydroxychloroquine and the control. The black horizontal bars represent 95% confidence intervals (CIs). Random-effects model of the Hartung–Knapp–Sidik–Jonkman approach was performed to obtain a pooled estimate of the odds ratio. The estimate of heterogeneity (τ2) was obtained using the Paule and Mandel (PM) estimator. We describe the between-trial heterogeneity using the I2 statistic. The results of the statistical tests for the overall effect and corresponding p values are presented. All tests were two-tailed. The x-axis scales differ for reasons of readability. Source data are provided as a Source Data file.
See this image and copyright information in PMC

References

    1. Berlin, D. A., Gulick, R. M. & Martinez, F. J. Severe Covid-19. N. Engl. J. Med.10.1056/NEJMcp2009575 (2020). - PubMed
    1. Johns Hopkins Coronavirus Resource Center. COVID-19 Map. https://coronavirus.jhu.edu/map.html (2020).
    1. RECOVERY Collaborative Group et al. Dexamethasone in hospitalized Patients with Covid-19 - preliminary report. N. Engl. J. Med.10.1056/NEJMoa2021436 (2020).
    1. Janiaud, P. et al. The worldwide clinical trial research response to the COVID-19 pandemic - the first 100 days. F1000Res.9, 1193 (2020). - PMC - PubMed
    1. Fantini, J., Di Scala, C., Chahinian, H. & Yahi, N. Structural and molecular modelling studies reveal a new mechanism of action of chloroquine and hydroxychloroquine against SARS-CoV-2 infection. Int. J. Antimicrob. Agents55, 105960 (2020). - PMC - PubMed

Publication types

MeSH terms