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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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of hydroxychloroquine and chloroquine on survival in COVID-19 from all currently available RCT evidence, published and unpublished.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RCTs on hydroxychloroquine or chloroquine treatment for any COVID-19 patients (protocol: We systematically identified unpublished RCTs (, WHO International Clinical Trials Registry Platform, Cochrane COVID-registry up to June 11, 2020), and published RCTs (PubMed, medRxiv and bioRxiv up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 languageEnglish
Article number2349
Number of pages13
JournalNature Communications
Issue number1
Publication statusPublished - Dec 2021
  • 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)

    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., Cheng, S. H., & 74 othersCheng, C. Y., Chung, W. S., Cohen, Y. Z., Cowan, L. N., Dalgard, O., de Almeida e Val, F. F., de Lacerda, M. V. G., de Melo, G. C., Derde, L., Dubee, V., Elfakir, A., Gordon, A. C., Hernandez-Cardenas, C. M., Hills, T., Hoepelman, A. I. M., Huang, Y. W., Igau, B., Jin, R., Jurado-Camacho, F., Khan, K. S., Kremsner, P. G., Kreuels, B., Kuo, C. Y., Le, T., Lin, Y. C., Lin, W. P., Lin, T. H., Lyngbakken, M. N., McArthur, C., McVerry, B. J., Meza-Meneses, P., Monteiro, W. M., Morpeth, S. C., Mourad, A., Mulligan, M. J., Murthy, S., Naggie, S., Narayanasamy, S., Nichol, A., Novack, L. A., O’Brien, S. M., Okeke, N. L., Perez, L., Perez-Padilla, R., Perrin, L., Remigio-Luna, A., Rivera-Martinez, N. E., Rockhold, F. W., Rodriguez-Llamazares, S., Rolfe, R., Rosa, R., Røsjø, H., Sampaio, V. S., Seto, T. B., Shahzad, M., Soliman, S., Stout, J. E., Thirion-Romero, I., Troxel, A. B., Tseng, T. Y., Turner, N. A., Ulrich, R. J., Walsh, S. R., Webb, S. A., Weehuizen, J. M., Velinova, M., Wong, H. L., Wrenn, R., Zampieri, F. G., Zhong, W., Moher, D., Goodman, S. N., Ioannidis, J. P. A. & Hemkens, L. G., Dec 2021, In: Nature Communications. 12, 1, 3001.

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    Open Access
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