Background

COVID-19 is a viral prothrombotic respiratory infection. Heparins exert antithrombotic and anti-inflammatory effects, and might have antiviral properties. We aimed to investigate whether thromboprophylaxis with enoxaparin would prevent untoward hospitalisation and death in symptomatic, but clinically stable outpatients with COVID-19.

Methods

OVID was a randomised, open-label, parallel-group, investigator-initiated, phase 3 trial and was done at eight centres in Switzerland and Germany. Outpatients aged 50 years or older with acute COVID-19 were eligible if they presented with respiratory symptoms or body temperature higher than 37·5°C. Eligible participants underwent block-stratified randomisation (by age group 50–70 vs >70 years and by study centre) in a 1:1 ratio to receive either subcutaneous enoxaparin 40 mg once daily for 14 days versus standard of care (no thromboprophylaxis). The primary outcome was a composite of any untoward hospitalisation and all-cause death within 30 days of randomisation. Analysis of the efficacy outcomes was done in the intention-to-treat population. The primary safety outcome was major bleeding. The study was registered in ClinicalTrials.gov (NCT04400799) and has been completed.

Findings

At the predefined formal interim analysis for efficacy (50% of total study population), the independent Data Safety Monitoring Board recommended early termination of the trial on the basis of predefined statistical criteria having considered the very low probability of showing superiority of thromboprophylaxis with enoxaparin for the primary outcome under the initial study design assumptions. Between Aug 15, 2020, and Jan 14, 2022, from 3319 participants prescreened, 472 were included in the intention-to-treat population and randomly assigned to receive enoxaparin (n=234) or standard of care (n=238). The median age was 57 years (IQR 53–62) and 217 (46%) were women. The 30-day risk of the primary outcome was similar in participants allocated to receive enoxaparin and in controls (8 [3%] of 234 vs 8 [3%] of 238; adjusted relative risk 0·98; 95% CI 0·37–2·56; p=0·96). All hospitalisations were related to COVID-19. No deaths were reported during the study. No major bleeding events were recorded. Eight serious adverse events were recorded in the enoxaparin group versus nine in the control group.

Interpretation

These findings suggest thromboprophylaxis with enoxaparin does not reduce early hospitalisations and deaths among outpatients with symptomatic COVID-19. Futility of the treatment under the initial study design assumptions could not be conclusively assessed owing to under-representation of older patients and consequent low event rates.

Funding

SNSF (National Research Programme COVID-19 NRP78: 198352), University Hospital Zurich, University of Zurich, Dr-Ing Georg Pollert (Berlin), Johanna Dürmüller-Bol Foundation.

中文翻译：

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依诺肝素用于 COVID-19 (OVID) 有症状门诊患者的初级血栓预防：一项随机、开放标签、平行组、多中心、3 期试验

背景

COVID-19 是一种病毒性促血栓性呼吸道感染。肝素具有抗血栓形成和抗炎作用，并可能具有抗病毒特性。我们的目的是调查依诺肝素的血栓预防能否防止有症状但临床稳定的 COVID-19 门诊患者的意外住院和死亡。

方法

OVID 是一项随机、开放标签、平行组、研究者发起的 3 期试验，在瑞士和德国的八个中心进行。50 岁或以上的急性 COVID-19 门诊患者如果出现呼吸道症状或体温高于 37·5°C，则符合条件。符合条件的参与者进行了块分层随机化（按年龄组 50-70与>70 岁和研究中心）以 1:1 的比例接受皮下注射依诺肝素 40 mg，每天一次，持续 14 天，而标准治疗（无血栓预防）。主要结果是随机分组后 30 天内任何意外住院和全因死亡的复合结果。在意向治疗人群中进行了疗效结果分析。主要安全性结局是大出血。该研究已在 ClinicalTrials.gov (NCT04400799) 注册并已完成。

发现

在预先确定的正式中期疗效分析中（占研究总人数的 50%），独立数据安全监测委员会建议根据预先确定的统计标准提前终止试验，考虑到显示依诺肝素预防血栓的优势的可能性非常低初始研究设计假设下的主要结果。在 2020 年 8 月 15 日至 2022 年 1 月 14 日期间，从预筛选的 3319 名参与者中，有 472 名被纳入意向治疗人群，并随机分配接受依诺肝素 (n=234) 或标准护理 (n=238)。中位年龄为 57 岁（IQR 53-62），217 人（46%）为女性。分配接受依诺肝素的参与者和对照组的主要结局的 30 天风险相似（8 [3%] of 234 vs238 个中的 8 个 [3%]；调整后的相对风险 0·98；95% CI 0·37–2·56；p=0·96)。所有住院均与 COVID-19 有关。研究期间没有死亡报告。没有记录到大出血事件。依诺肝素组记录了 8 例严重不良事件，对照组记录了 9 例。

解释

这些发现表明，依诺肝素预防血栓并不能减少有症状的 COVID-19 门诊患者的早期住院和死亡。由于老年患者的代表性不足以及随之而来的低事件率，无法最终评估在初始研究设计假设下治疗的无效性。

资金

SNSF（国家研究计划 COVID-19 NRP78：198352），苏黎世大学医院，苏黎世大学，Ing Georg Pollert 博士（柏林），Johanna Dürmüller-Bol 基金会。