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of hydroxychloroquine and chloroquine on survival in COVID-19 from all currently available RCT evidence, published and unpublished.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 We systematically identified unpublished RCTs (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, Cochrane COVID-registry up to June 11, 2020), and published RCTs (PubMed,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 We included 14 unpublished trials (1308 patients) and 14 publications/preprints (9011 patients).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.
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; Shahzad, 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
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