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 Shehzad; 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

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 ChengChien-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 Shehzad, 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

Infektionsmedicinsk Afdeling

219 Citationer (Scopus)

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.

Originalsprog	Engelsk
Artikelnummer	2349
Tidsskrift	Nature Communications
Vol/bind	12
Udgave nummer	1
Sider (fra-til)	1-13
Antal sider	13
DOI	https://doi.org/10.1038/s41467-021-22446-z
Status	Udgivet - 15 apr. 2021

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Axfors, C., Schmitt, A. M., Janiaud, P., Van't Hooft, J., Abd-Elsalam, S., Abdo, E. F., Abella, B. S., Akram, J., Amaravadi, R. K., Angus, D. C., Arabi, Y. M., Azhar, S., Baden, L. R., Baker, A. W., Belkhir, L., Benfield, T., Berrevoets, M. A. H., Chen, C.-P., Chen, T.-C., ... Hemkens, L. G. (2021). Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis of randomized trials. Nature Communications, 12(1), 1-13. Artikel 2349. https://doi.org/10.1038/s41467-021-22446-z

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, C-P, Chen, T-C, Cheng, S-H, Cheng, C-Y, Chung, W-S, 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, Y-W, Igau, B, Jin, R, Jurado-Camacho, F, Khan, KS, Kremsner, PG, Kreuels, B, Kuo, C-Y, Le, T, Lin, Y-C, Lin, W-P, Lin, T-H, 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, Shehzad, M, Soliman, S, Stout, JE, Thirion-Romero, I, Troxel, AB, Tseng, T-Y, Turner, NA, Ulrich, RJ, Walsh, SR, Webb, SA, Weehuizen, JM, Velinova, M, Wong, H-L, Wrenn, R, Zampieri, FG, Zhong, W, Moher, D, Goodman, SN, Ioannidis, JPA & Hemkens, LG 2021, 'Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis of randomized trials', Nature Communications, bind 12, nr. 1, 2349, s. 1-13. https://doi.org/10.1038/s41467-021-22446-z

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

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.",

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year = "2021",

month = apr,

day = "15",

doi = "10.1038/s41467-021-22446-z",

language = "English",

volume = "12",

pages = "1--13",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

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TY - JOUR

T1 - Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis of randomized trials

AU - Axfors, Cathrine

AU - Schmitt, Andreas M

AU - Janiaud, Perrine

AU - Van't Hooft, Janneke

AU - Abd-Elsalam, Sherief

AU - Abdo, Ehab F

AU - Abella, Benjamin S

AU - Akram, Javed

AU - Amaravadi, Ravi K

AU - Angus, Derek C

AU - Arabi, Yaseen M

AU - Azhar, Shehnoor

AU - Baden, Lindsey R

AU - Baker, Arthur W

AU - Belkhir, Leila

AU - Benfield, Thomas

AU - Berrevoets, Marvin A H

AU - Chen, Cheng-Pin

AU - Chen, Tsung-Chia

AU - Cheng, Shu-Hsing

AU - Cheng, Chien-Yu

AU - Chung, Wei-Sheng

AU - Cohen, Yehuda Z

AU - Cowan, Lisa N

AU - Dalgard, Olav

AU - de Almeida E Val, Fernando F

AU - de Lacerda, Marcus V G

AU - de Melo, Gisely C

AU - Derde, Lennie

AU - Dubee, Vincent

AU - Elfakir, Anissa

AU - Gordon, Anthony C

AU - Hernandez-Cardenas, Carmen M

AU - Hills, Thomas

AU - Hoepelman, Andy I M

AU - Huang, Yi-Wen

AU - Igau, Bruno

AU - Jin, Ronghua

AU - Jurado-Camacho, Felipe

AU - Khan, Khalid S

AU - Kremsner, Peter G

AU - Kreuels, Benno

AU - Kuo, Cheng-Yu

AU - Le, Thuy

AU - Lin, Yi-Chun

AU - Lin, Wu-Pu

AU - Lin, Tse-Hung

AU - Lyngbakken, Magnus Nakrem

AU - McArthur, Colin

AU - McVerry, Bryan J

AU - Meza-Meneses, Patricia

AU - Monteiro, Wuelton M

AU - Morpeth, Susan C

AU - Mourad, Ahmad

AU - Mulligan, Mark J

AU - Murthy, Srinivas

AU - Naggie, Susanna

AU - Narayanasamy, Shanti

AU - Nichol, Alistair

AU - Novack, Lewis A

AU - O'Brien, Sean M

AU - Okeke, Nwora Lance

AU - Perez, Léna

AU - Perez-Padilla, Rogelio

AU - Perrin, Laurent

AU - Remigio-Luna, Arantxa

AU - Rivera-Martinez, Norma E

AU - Rockhold, Frank W

AU - Rodriguez-Llamazares, Sebastian

AU - Rolfe, Robert

AU - Rosa, Rossana

AU - Røsjø, Helge

AU - Sampaio, Vanderson S

AU - Seto, Todd B

AU - Shehzad, Muhammad

AU - Soliman, Shaimaa

AU - Stout, Jason E

AU - Thirion-Romero, Ireri

AU - Troxel, Andrea B

AU - Tseng, Ting-Yu

AU - Turner, Nicholas A

AU - Ulrich, Robert J

AU - Walsh, Stephen R

AU - Webb, Steve A

AU - Weehuizen, Jesper M

AU - Velinova, Maria

AU - Wong, Hon-Lai

AU - Wrenn, Rebekah

AU - Zampieri, Fernando G

AU - Zhong, Wu

AU - Moher, David

AU - Goodman, Steven N

AU - Ioannidis, John P A

AU - Hemkens, Lars G

PY - 2021/4/15

Y1 - 2021/4/15

N2 - 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.

AB - 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.

KW - Adult

KW - COVID-19/complications

KW - Child

KW - Chloroquine/administration & dosage

KW - Combined Modality Therapy/adverse effects

KW - Comorbidity

KW - Female

KW - Humans

KW - Hydroxychloroquine/administration & dosage

KW - International Cooperation

KW - Odds Ratio

KW - Patient Participation/statistics & numerical data

KW - Pregnancy

KW - Pregnancy Complications, Infectious/drug therapy

KW - Randomized Controlled Trials as Topic/statistics & numerical data

KW - SARS-CoV-2

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U2 - 10.1038/s41467-021-22446-z

DO - 10.1038/s41467-021-22446-z

M3 - Journal article

C2 - 33859192

SN - 2041-1723

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JO - Nature Communications

JF - Nature Communications

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ER -

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

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