CLEAR Methods Center, Division of Clinical Epidemiology, University Hospital Basel, Basel, Switzerland; Department of Clinical Research, University Hospital Basel, Basel, Switzerland.
CLEAR Methods Center, Division of Clinical Epidemiology, University Hospital Basel, Basel, Switzerland; Department of Clinical Research, University Hospital Basel, Basel, Switzerland.
Lancet Respir Med. 2023 May;11(5):453-464. doi: 10.1016/S2213-2600(22)00528-8. Epub 2023 Feb 21.
Interpretation of the evidence from randomised controlled trials (RCTs) of remdesivir in patients treated in hospital for COVID-19 is conflicting. We aimed to assess the benefits and harms of remdesivir compared with placebo or usual care in these patients, and whether treatment effects differed between prespecified patient subgroups.
For this systematic review and meta-analysis, we searched PubMed, Embase, the Cochrane COVID-19 trial registry, ClinicalTrials.gov, the International Clinical Trials Registry Platform, and preprint servers from Jan 1, 2020, until April 11, 2022, for RCTs of remdesivir in adult patients hospitalised with COVID-19, and contacted the authors of eligible trials to request individual patient data. The primary outcome was all-cause mortality at day 28 after randomisation. We used multivariable hierarchical regression-adjusting for respiratory support, age, and enrollment period-to investigate effect modifiers. This study was registered with PROSPERO, CRD42021257134.
Our search identified 857 records, yielding nine RCTs eligible for inclusion. Of these nine eligible RCTs, individual data were provided for eight, covering 10 480 patients hospitalised with COVID-19 (99% of such patients included in such RCTs worldwide) recruited between Feb 6, 2020, and April 1, 2021. Within 28 days of randomisation, 662 (12·5%) of 5317 patients assigned to remdesivir and 706 (14·1%) of 5005 patients assigned to no remdesivir died (adjusted odds ratio [aOR] 0·88, 95% CI 0·78-1·00, p=0·045). We found evidence for a credible subgroup effect according to respiratory support at baseline (p=0·019). Of patients who were ventilated-including those who received high-flow oxygen-253 (30·0%) of 844 patients assigned to remdesivir died compared with 241 (28·5%) of 846 patients assigned to no remdesivir (aOR 1·10 [0·88-1·38]; low-certainty evidence). Of patients who received no oxygen or low-flow oxygen, 409 (9·1%) of 4473 patients assigned to remdesivir died compared with 465 (11·2%) of 4159 patients assigned to no remdesivir (0·80 [0·70-0·93]; high-certainty evidence). No credible subgroup effect was found for time to start of remdesivir after symptom onset, age, presence of comorbidities, enrolment period, or corticosteroid use. Remdesivir did not increase the frequency of severe or serious adverse events.
This individual patient data meta-analysis showed that remdesivir reduced mortality in patients hospitalised with COVID-19 who required no or conventional oxygen support, but was underpowered to evaluate patients who were ventilated when receiving remdesivir. The effect size of remdesivir in patients with more respiratory support or acquired immunity and the cost-effectiveness of remdesivir remain to be further elucidated.
EU-RESPONSE.
对瑞德西韦治疗住院 COVID-19 患者的随机对照试验（RCT）的证据进行解释存在争议。我们旨在评估瑞德西韦与安慰剂或常规护理相比在这些患者中的益处和危害，以及治疗效果是否在预先指定的患者亚组中存在差异。
为了进行这项系统评价和荟萃分析，我们从 2020 年 1 月 1 日至 2022 年 4 月 11 日，在 PubMed、Embase、Cochrane COVID-19 试验注册中心、ClinicalTrials.gov、国际临床试验注册平台和预印本服务器上搜索了瑞德西韦治疗住院 COVID-19 患者的 RCT，并联系了合格试验的作者，以请求获取个体患者数据。主要结局是随机分组后第 28 天的全因死亡率。我们使用多变量分层回归（调整呼吸支持、年龄和入组期）来研究效应修饰因子。这项研究已在 PROSPERO、CRD42021257134 上注册。
我们的搜索共确定了 857 条记录，其中有 9 项 RCT 符合纳入标准。在这 9 项符合纳入标准的 RCT 中，有 8 项提供了个体数据，涵盖了 10480 名住院 COVID-19 患者（全世界此类 RCT 纳入的此类患者的 99%），招募时间为 2020 年 2 月 6 日至 2021 年 4 月 1 日。随机分组后 28 天内，5317 名接受瑞德西韦治疗的患者中有 662 名（12.5%）和 5005 名未接受瑞德西韦治疗的患者中有 706 名（14.1%）死亡（调整后的优势比[aOR]0.88，95%CI 0.78-1.00，p=0.045）。我们发现了证据表明，根据基线时的呼吸支持存在可信的亚组效应（p=0.019）。在接受机械通气的患者中（包括接受高流量氧疗的患者），844 名接受瑞德西韦治疗的患者中有 253 名（30.0%）死亡，而 846 名未接受瑞德西韦治疗的患者中有 241 名（28.5%）死亡（aOR 1.10 [0.88-1.38]；低质量证据）。在未接受或低流量氧疗的患者中，847 名接受瑞德西韦治疗的患者中有 409 名（9.1%）死亡，而 8159 名接受瑞德西韦治疗的患者中有 465 名（11.2%）死亡（0.80 [0.70-0.93]；高质量证据）。对于瑞德西韦开始治疗后症状出现的时间、年龄、合并症存在、入组期或皮质激素使用，我们未发现可信的亚组效应。瑞德西韦并未增加严重或严重不良事件的发生频率。
这项个体患者数据荟萃分析表明，瑞德西韦降低了需要无或常规氧疗的住院 COVID-19 患者的死亡率，但对接受瑞德西韦治疗时需要机械通气的患者的疗效评估能力有限。瑞德西韦在具有更多呼吸支持或获得性免疫的患者中的疗效大小和成本效益仍有待进一步阐明。
欧盟响应。
