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

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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.

Original language	English
Article number	2349
Number of pages	13
Journal	Nature Communications
Volume	12
Issue number	1
DOIs	https://doi.org/10.1038/s41467-021-22446-z
Publication status	Published - Dec 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), Article 2349. 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.",

author = "Cathrine Axfors and Schmitt, {Andreas M.} and Perrine Janiaud and {van{\textquoteright}t Hooft}, Janneke and Sherief Abd-Elsalam and Abdo, {Ehab F.} and Abella, {Benjamin S.} and Javed Akram and Amaravadi, {Ravi K.} and Angus, {Derek C.} and Arabi, {Yaseen M.} and Shehnoor Azhar and Baden, {Lindsey R.} and Baker, {Arthur W.} and Leila Belkhir and Thomas Benfield and Berrevoets, {Marvin A.H.} and Chen, {Cheng Pin} and Chen, {Tsung Chia} and Cheng, {Shu Hsing} and Cheng, {Chien Yu} and Chung, {Wei Sheng} and Cohen, {Yehuda Z.} and Cowan, {Lisa N.} and Olav Dalgard and {de Almeida e Val}, {Fernando F.} and {de Lacerda}, {Marcus V.G.} and {de Melo}, {Gisely C.} and Lennie Derde and Vincent Dubee and Anissa Elfakir and Gordon, {Anthony C.} and Hernandez-Cardenas, {Carmen M.} and Thomas Hills and Hoepelman, {Andy I.M.} and Huang, {Yi Wen} and Bruno Igau and Ronghua Jin and Felipe Jurado-Camacho and Khan, {Khalid S.} and Kremsner, {Peter G.} and Benno Kreuels and Kuo, {Cheng Yu} and Thuy Le and Lin, {Yi Chun} and Lin, {Wu Pu} and Lin, {Tse Hung} and Lyngbakken, {Magnus Nakrem} and Colin McArthur and McVerry, {Bryan J.} and Patricia Meza-Meneses and Monteiro, {Wuelton M.} and Morpeth, {Susan C.} and Ahmad Mourad and Mulligan, {Mark J.} and Srinivas Murthy and Susanna Naggie and Shanti Narayanasamy and Alistair Nichol and Novack, {Lewis A.} and O{\textquoteright}Brien, {Sean M.} and Okeke, {Nwora Lance} and L{\'e}na Perez and Rogelio Perez-Padilla and Laurent Perrin and Arantxa Remigio-Luna and Rivera-Martinez, {Norma E.} and Rockhold, {Frank W.} and Sebastian Rodriguez-Llamazares and Robert Rolfe and Rossana Rosa and Helge R{\o}sj{\o} and Sampaio, {Vanderson S.} and Seto, {Todd B.} and Muhammad Shehzad and Shaimaa Soliman and Stout, {Jason E.} and Ireri Thirion-Romero and Troxel, {Andrea B.} and Tseng, {Ting Yu} and Turner, {Nicholas A.} and Ulrich, {Robert J.} and Walsh, {Stephen R.} and Webb, {Steve A.} and Weehuizen, {Jesper M.} and Maria Velinova and Wong, {Hon Lai} and Rebekah Wrenn and Zampieri, {Fernando G.} and Wu Zhong and David Moher and Goodman, {Steven N.} and Ioannidis, {John P.A.} and Hemkens, {Lars G.}",

year = "2021",

month = dec,

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

language = "English",

volume = "12",

journal = "Nature Communications",

issn = "2041-1723",

publisher = "Nature Publishing Group",

number = "1",

}

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, Shehzad, 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 2021, 'Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis of randomized trials', Nature Communications, vol. 12, no. 1, 2349. https://doi.org/10.1038/s41467-021-22446-z

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 - 2021/12

Y1 - 2021/12

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.

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U2 - 10.1038/s41467-021-22446-z

DO - 10.1038/s41467-021-22446-z

M3 - Article

C2 - 33859192

AN - SCOPUS:85104110050

SN - 2041-1723

VL - 12

JO - Nature Communications

JF - Nature Communications

IS - 1

M1 - 2349

ER -

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

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Author Correction: Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis of randomized trials(Nature Communications, (2021), 12, (1), 10.1038/s41467-021-22446-z)

Author Correction: Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis of randomized trials (Nature Communications, (2021), 12, 1, (2349), 10.1038/s41467-021-22446-z)

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