Lopes Renato D, de Barros E Silva Pedro Gabriel Melo, Furtado Remo H M, Macedo Ariane Vieira Scarlatelli, Bronhara Bruna, Damiani Lucas Petri, Barbosa Lilian Mazza, de Aveiro Morata Júlia, Ramacciotti Eduardo, de Aquino Martins Priscilla, de Oliveira Aryadne Lyrio, Nunes Vinicius Santana, Ritt Luiz Eduardo Fonteles, Rocha Ana Thereza, Tramujas Lucas, Santos Sueli V, Diaz Dario Rafael Abregu, Viana Lorena Souza, Melro Lívia Maria Garcia, de Alcântara Chaud Mariana Silveira, Figueiredo Estêvão Lanna, Neuenschwander Fernando Carvalho, Dracoulakis Marianna Deway Andrade, Lima Rodolfo Godinho Souza Dourado, de Souza Dantas Vicente Cés, Fernandes Anne Cristine Silva, Gebara Otávio Celso Eluf, Hernandes Mauro Esteves, Queiroz Diego Aparecido Rios, Veiga Viviane C, Canesin Manoel Fernandes, de Faria Leonardo Meira, Feitosa-Filho Gilson Soares, Gazzana Marcelo Basso, Liporace Idelzuíta Leandro, de Oliveira Twardowsky Aline, Maia Lilia Nigro, Machado Flávia Ribeiro, de Matos Soeiro Alexandre, Conceição-Souza Germano Emílio, Armaganijan Luciana, Guimarães Patrícia O, Rosa Regis G, Azevedo Luciano C P, Alexander John H, Avezum Alvaro, Cavalcanti Alexandre B, Berwanger Otavio
Duke Clinical Research Institute, Duke University Medical Center, Durham, NC, USA; Brazilian Clinical Research Institute, São Paulo, Brazil.
Brazilian Clinical Research Institute, São Paulo, Brazil; HCor Research Institute, São Paulo, Brazil; Hospital Samaritano Paulista, São Paulo, Brazil.
Lancet. 2021 Jun 12;397(10291):2253-2263. doi: 10.1016/S0140-6736(21)01203-4. Epub 2021 Jun 4.
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.
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.
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.
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.
Coalition COVID-19 Brazil, Bayer SA.
新型冠状病毒肺炎（COVID-19）与血栓形成前状态相关，可导致不良临床结局。治疗性抗凝是否能改善COVID-19住院患者的结局尚不清楚。我们旨在比较该人群中治疗性抗凝与预防性抗凝的疗效和安全性。
我们在巴西的31个地点进行了一项实用、开放标签（裁决 blinded）、多中心、随机、对照试验。年龄≥18岁、因COVID-19住院且D-二聚体浓度升高、在随机分组前出现COVID-19症状达14天的患者被随机分配（1:1）接受治疗性或预防性抗凝。治疗性抗凝方案为，病情稳定的患者住院期间口服利伐沙班（每日20 mg或15 mg），临床不稳定的患者初始皮下注射依诺肝素（每日1 mg/kg，分两次）或静脉注射普通肝素（使抗Xa浓度达到0.3 - 0.7 IU/mL），随后至第30天口服利伐沙班。预防性抗凝采用医院常规的依诺肝素或普通肝素。主要疗效结局是对至死亡时间、住院时间或至第30天补充氧气时间进行分层分析，在意向性治疗人群中采用胜率法进行分析（比值>1表明治疗性抗凝组结局更好）。主要安全性结局是30天内的大出血或临床相关非大出血。本研究已在ClinicalTrials.gov注册（NCT04394377），且已完成。
从2020年6月24日至2021年2月26日，共筛选了3331例患者，615例被随机分配（治疗性抗凝组311例[50%]，预防性抗凝组304例[50%]）。576例（94%）临床稳定，39例（6%）临床不稳定。治疗组有1例患者因撤回同意而失访，未纳入主要分析。接受治疗性或预防性抗凝的患者之间主要疗效结局无差异，治疗组有28899次（34.8%）“获胜”，预防性抗凝组有34288次（41.3%）“获胜”（胜率0.86[95%CI 0.59 - 1.22]，p = 0.40）。临床稳定和临床不稳定患者的结果一致。接受治疗性抗凝的患者中，26例（8%）发生大出血或临床相关非大出血这一主要安全性结局，接受预防性抗凝的患者中有7例（2%）发生（相对风险3.64[95%CI 1.61 - 8.27]，p = 0.0010）。治疗性抗凝组有2例（1%）患者、预防性抗凝组有3例（1%）患者出现对研究药物的过敏反应。
对于因COVID-19住院且D-二聚体浓度升高的患者，与预防性抗凝相比，住院期间使用利伐沙班或依诺肝素进行治疗性抗凝，随后至第30天使用利伐沙班，并不能改善临床结局，反而增加了出血风险。因此，在没有口服抗凝的循证指征时，应避免在这些患者中使用治疗剂量的利伐沙班及其他直接口服抗凝剂。
巴西COVID-19联盟，拜耳公司。
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