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

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...

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Main Authors: 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, Nichol, A
Format: Journal article
Language:English
Published: Springer Nature 2021
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Summary: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of hydroxychloroquine and chloroquine on survival in COVID-19 from all currently available RCT evidence, published and unpublished.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 We systematically identified unpublished RCTs (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, Cochrane COVID-registry up to June 11, 2020), and published RCTs (PubMed,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.