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

Background: 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 aimed to estimate the effects of hydroxychloroquine and chloroquine on survival in COVID-19 from all currently available RCT evidence, published and unpublished. Methods: 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 We systematically identified published and unpublished RCTs by September 14, 2020 (ClinicalTrials.gov, WHO International Clinical Trials Registry Platform, PubMed, Cochrane COVID-19 registry). All-cause mortality was 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/chloroquine. Prespecified subgroup analyses included patient setting, diagnostic confirmation, control type, and publication status. Results: Sixty-two trials were potentially eligible. We included 16 unpublished trials (1596 patients) and 10 publications/preprints (6317 patients). The combined summary OR on all-cause mortality for hydroxychloroquine was 1.08 (95%CI: 0.99, 1.18; I-square=0%; 24 trials; 7659 patients) and for chloroquine 1.77 (95%CI: 0.15, 21.13, I-square=0%; 4 trials; 307 patients). We identified no subgroup effects. Conclusions: We found no benefit of hydroxychloroquine or chloroquine on the survival of COVID-19 patients. For hydroxychloroquine, the confidence interval is compatible with increased mortality (OR 1.18) or negligibly reduced mortality (OR 0.99). Findings have unclear generalizability to outpatients, children, pregnant women, and people with comorbidities.

背景：大量新冠病毒（COVID - 19）研究资金已投入到羟氯喹/氯喹的随机临床试验（RCT）中，这些试验目前面临招募困难或提前终止的问题。我们旨在从所有现有的已发表和未发表的随机对照试验证据中评估羟氯喹和氯喹对COVID - 19患者生存率的影响。 方法：对正在进行的、已完成的或已终止的关于羟氯喹或氯喹治疗任何COVID - 19患者的随机对照试验进行快速荟萃分析（方案：https://osf.io/QESV4/）。我们在2020年9月14日前系统地检索了已发表和未发表的随机对照试验（ClinicalTrials.gov、世界卫生组织国际临床试验注册平台、PubMed、Cochrane COVID - 19注册库）。提取全因死亡率（来自出版物/预印本）或向研究人员索取，并在随机效应荟萃分析中进行合并，分别计算羟氯喹/氯喹的比值比（OR）及95%置信区间（CI）。预先设定的亚组分析包括患者情况、诊断确认、对照类型和发表状态。 结果：62项试验可能符合条件。我们纳入了16项未发表的试验（1596名患者）和10篇出版物/预印本（6317名患者）。羟氯喹全因死亡率的综合汇总比值比为1.08（95%CI：0.99，1.18；I² = 0%；24项试验；7659名患者），氯喹为1.77（95%CI：0.15，21.13，I² = 0%；4项试验；307名患者）。我们未发现亚组效应。 结论：我们发现羟氯喹或氯喹对COVID - 19患者的生存率没有益处。对于羟氯喹，置信区间与死亡率增加（OR为1.18）或死亡率略微降低（OR为0.99）均相符。研究结果对于门诊患者、儿童、孕妇和合并症患者的普遍性尚不明确。