Mortality outcomes with hydroxychloroquine and chloroquine in COVID-19 from an international collaborative meta-analysis of randomized trials.
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.
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of hydroxychloroquine and chloroquine on survival in COVID-19 from all currently available RCT evidence, published and unpublished.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 We systematically identified unpublished RCTs (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, Cochrane COVID-registry up to June 11, 2020), and published RCTs (PubMed,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.