Background

COVID-19 is associated with a prothrombotic state leading to adverse clinical outcomes. Whether therapeutic anticoagulation improves outcomes in patients hospitalised with COVID-19 is unknown. We aimed to compare the efficacy and safety of therapeutic versus prophylactic anticoagulation in this population.

Methods

We did a pragmatic, open-label (with blinded adjudication), multicentre, randomised, controlled trial, at 31 sites in Brazil. Patients (aged ≥18 years) hospitalised with COVID-19 and elevated D-dimer concentration, and who had COVID-19 symptoms for up to 14 days before randomisation, were randomly assigned (1:1) to receive either therapeutic or prophylactic anticoagulation. Therapeutic anticoagulation was in-hospital oral rivaroxaban (20 mg or 15 mg daily) for stable patients, or initial subcutaneous enoxaparin (1 mg/kg twice per day) or intravenous unfractionated heparin (to achieve a 0·3–0·7 IU/mL anti-Xa concentration) for clinically unstable patients, followed by rivaroxaban to day 30. Prophylactic anticoagulation was standard in-hospital enoxaparin or unfractionated heparin. The primary efficacy outcome was a hierarchical analysis of time to death, duration of hospitalisation, or duration of supplemental oxygen to day 30, analysed with the win ratio method (a ratio >1 reflects a better outcome in the therapeutic anticoagulation group) in the intention-to-treat population. The primary safety outcome was major or clinically relevant non-major bleeding through 30 days. This study is registered with ClinicalTrials.gov (NCT04394377) and is completed.

Findings

From June 24, 2020, to Feb 26, 2021, 3331 patients were screened and 615 were randomly allocated (311 [50%] to the therapeutic anticoagulation group and 304 [50%] to the prophylactic anticoagulation group). 576 (94%) were clinically stable and 39 (6%) clinically unstable. One patient, in the therapeutic group, was lost to follow-up because of withdrawal of consent and was not included in the primary analysis. The primary efficacy outcome was not different between patients assigned therapeutic or prophylactic anticoagulation, with 28 899 (34·8%) wins in the therapeutic group and 34 288 (41·3%) in the prophylactic group (win ratio 0·86 [95% CI 0·59–1·22], p=0·40). Consistent results were seen in clinically stable and clinically unstable patients. The primary safety outcome of major or clinically relevant non-major bleeding occurred in 26 (8%) patients assigned therapeutic anticoagulation and seven (2%) assigned prophylactic anticoagulation (relative risk 3·64 [95% CI 1·61–8·27], p=0·0010). Allergic reaction to the study medication occurred in two (1%) patients in the therapeutic anticoagulation group and three (1%) in the prophylactic anticoagulation group.

Interpretation

In patients hospitalised with COVID-19 and elevated D-dimer concentration, in-hospital therapeutic anticoagulation with rivaroxaban or enoxaparin followed by rivaroxaban to day 30 did not improve clinical outcomes and increased bleeding compared with prophylactic anticoagulation. Therefore, use of therapeutic-dose rivaroxaban, and other direct oral anticoagulants, should be avoided in these patients in the absence of an evidence-based indication for oral anticoagulation.

Funding

Coalition COVID-19 Brazil, Bayer SA.

中文翻译：

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因 COVID-19 和 D-二聚体浓度升高而入院的患者的治疗性与预防性抗凝治疗 (ACTION)：一项开放标签、多中心、随机、对照试验

背景

COVID-19 与导致不良临床结果的血栓形成前状态有关。抗凝治疗是否能改善 COVID-19 住院患者的预后尚不清楚。我们旨在比较该人群中治疗性和预防性抗凝治疗的疗效和安全性。

方法

我们在巴西的 31 个地点进行了一项实用的、开放标签（盲法裁决）、多中心、随机、对照试验。因 COVID-19 住院且 D-二聚体浓度升高且在随机分组前出现 COVID-19 症状长达 14 天的患者（年龄≥18 岁）被随机分配（1:1）接受治疗性或预防性抗凝治疗。对于稳定的患者，治疗性抗凝是在院内口服利伐沙班（每天 20 mg 或 15 mg），或初始皮下注射依诺肝素（1 mg/kg，每天两次）或静脉注射普通肝素（以达到 0·3–0·7 IU/ mL 抗 Xa 浓度）用于临床不稳定的患者，随后使用利伐沙班至第 30 天。预防性抗凝是标准的院内依诺肝素或普通肝素。主要疗效结果是死亡时间、住院时间或到第 30 天的补充氧气持续时间的分层分析，使用胜率法进行分析（比率 >1 表示治疗性抗凝组的结局更好） - 治疗人口。主要安全性结果是 30 天内的大出血或临床相关的非大出血。本研究已在 ClinicalTrials.gov (NCT04394377) 注册并已完成。

发现

从 2020 年 6 月 24 日到 2021 年 2 月 26 日，筛选了 3331 名患者，并随机分配了 615 名患者（311 名 [50%] 分配至治疗性抗凝组，304 名 [50%] 分配至预防性抗凝组）。576 例 (94%) 临床稳定，39 例 (6%) 临床不稳定。治疗组中的一名患者因撤回同意而失访，未纳入主要分析。主要疗效结果在分配治疗性或预防性抗凝治疗的患者之间没有差异，治疗组 28 899 (34·8%) 获胜，预防组 34 288 (41·3%)（获胜比 0·86 [95 % 置信区间 0·59–1·22]，p=0·40）。在临床稳定和临床不稳定的患者中观察到一致的结果。26 名 (8%) 分配治疗性抗凝治疗的患者和 7 名 (2%) 分配预防性抗凝治疗的患者发生大出血或临床相关非大出血的主要安全性结果（相对风险 3·64 [95% CI 1·61–8·27 ], p=0·0010)。治疗性抗凝组的两名 (1%) 患者和预防性抗凝组的三名 (1%) 患者发生了对研究药物的过敏反应。

解释

在因 COVID-19 和 D-二聚体浓度升高而住院的患者中，与预防性抗凝治疗相比，在院内使用利伐沙班或依诺肝素进行治疗性抗凝，随后使用利伐沙班进行抗凝治疗至第 30 天，并未改善临床结果并增加了出血。因此，在缺乏口服抗凝治疗的循证适应证的情况下，应避免在这些患者中使用治疗剂量的利伐沙班和其他直接口服抗凝剂。

资金

Coalition COVID-19 Brazil, Bayer SA。