Journal Article

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

Lyngbakken, Magnus Nakrem, Okeke, Nwora Lance, Tseng, Ting-Yu, Lin, Wu-Pu, Elfakir, Anissa, Chen, Cheng-Pin, Morpeth, Susan C., Khan, Khalid S., Rivera-Martinez, Norma E., Hemkens, Lars G., Hernandez-Cardenas, Carmen M., Novack, Lewis A., Ulrich, Robert J., Cohen, Yehuda Z., Perez, Léna, Amaravadi, Ravi K., Narayanasamy, Shanti, Rosa, Rossana, Troxel, Andrea B., Azhar, Shehnoor, Chen, Tsung-Chia, Zampieri, Fernando G., Webb, Steve A., Zhong, Wu, McVerry, Bryan J., Turner, Nicholas A., Soliman, Shaimaa, Stout, Jason E., Weehuizen, Jesper M., Moher, David, Berrevoets, Marvin A. H., Huang, Yi-Wen, Remigio-Luna, Arantxa, Walsh, Stephen R., Kremsner, Peter G., Le, Thuy, Meza-Meneses, Patricia, Rolfe, Robert, van’t Hooft, Janneke, Shahzad, Muhammad, Dubee, Vincent, Nichol, Alistair, Rodriguez-Llamazares, Sebastian, Thirion-Romero, Ireri, Benfield, Thomas, Arabi, Yaseen M., Abd-Elsalam, Sherief, McArthur, Colin, Velinova, Maria, Abdo, Ehab F., Angus, Derek C., Derde, Lennie, Belkhir, Leila, Hoepelman, Andy I. M., Lin, Yi-Chun, Perez-Padilla, Rogelio, de Lacerda, Marcus V. G., Seto, Todd B., Wrenn, Rebekah, I

2021

Overview

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of hydroxychloroquine and chloroquine on survival in COVID-19 from all currently available RCT evidence, published and unpublished.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 We systematically identified unpublished RCTs (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, Cochrane COVID-registry up to June 11, 2020), and published RCTs (PubMed,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. Hydroxychloroquine and chloroquine have been investigated as a potential treatment for Covid-19 in several clinical trials. Here the authors report a meta-analysis of published and unpublished trials, and show that treatment with hydroxychloroquine for patients with Covid-19 was associated with increased mortality, and there was no benefit from chloroquine.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 692/308/174 / 692/699/255/2514 / Adult / Child / Chloroquine / Chloroquine - administration & dosage / Chloroquine - adverse effects / Clinical trials / Combined Modality Therapy - adverse effects / Combined Modality Therapy - methods / Comorbidity / Confidence intervals / Coronaviruses / COVID-19 / COVID-19 - complications / COVID-19 - mortality / COVID-19 - virology / COVID-19 Drug Treatment / Documents / Female / Humanities and Social Sciences / Humans / Hydroxychloroquine / Hydroxychloroquine - administration & dosage / Hydroxychloroquine - adverse effects / International Cooperation / Meta-analysis / Mortality / multidisciplinary / Odds Ratio / Patient Participation - statistics & numerical data / Patients / Pregnancy / Pregnancy Complications, Infectious - drug therapy / Pregnancy Complications, Infectious - mortality / Pregnancy Complications, Infectious - virology / Randomized Controlled Trials as Topic - statistics & numerical data / SARS-CoV-2 / Science / Science (multidisciplinary) / Subgroups