Therapeutic versus prophylactic anticoagulation for patients admitted to hospital with COVID-19 and elevated D-dimer concentration (ACTION): an open-label, multicentre, randomised, controlled trial

被引：384

作者：

Lopes, Renato D. ^{[1
,2
]}

de Barros E Silva, Pedro Gabriel Melo ^{[2
,3
,4
]}

Furtado, Remo H. M. ^{[5
,6
]}

Scarlatelli Macedo, Ariane Vieira ^{[2
]}

Bronhara, Bruna ^{[2
]}

Damiani, Lucas Petri ^{[2
,3
]}

Barbosa, Lilian Mazza ^{[2
]}

Morata, Julia de Aveiro ^{[2
]}

Ramacciotti, Eduardo ^{[2
,8
,9
]}

Martins, Priscilla de Aquino ^{[10
]}

de Oliveira, Aryadne Lyrio ^{[10
]}

Nunes, Vinicius Santana ^{[10
]}

Fonteles Ritt, Luiz Eduardo ^{[11
,12
]}

Rocha, Ana Thereza ^{[11
,12
,13
]}

Tramujas, Lucas ^{[3
]}

Santos, Sueli, V ^{[3
]}

Abregu Diaz, Dario Rafael ^{[5
]}

Viana, Lorena Souza ^{[5
,7
]}

Garcia Melro, Livia Maria ^{[4
]}

de Alcantara Chaud, Mariana Silveira ^{[4
]}

Figueiredo, Estevao Lanna ^{[14
]}

Neuenschwander, Fernando Carvalho ^{[14
]}

Andrade Dracoulakis, Marianna Deway ^{[15
]}

Souza Dourado Lima, Rodolfo Godinho ^{[15
]}

de Souza Dantas, Vicente Ces ^{[16
]}

Silva Fernandes, Anne Cristine ^{[16
]}

Eluf Gebara, Otavio Celso ^{[17
]}

Hernandes, Mauro Esteves ^{[18
]}

Rios Queiroz, Diego Aparecido ^{[19
]}

Veiga, Viviane C. ^{[20
,21
]}

Canesin, Manoel Fernandes ^{[22
]}

de Faria, Leonardo Meira ^{[23
]}

Feitosa-Filho, Gilson Soares ^{[12
,24
,25
]}

Gazzana, Marcelo Basso ^{[26
]}

Liporace, Idelzuita Leandro ^{[27
]}

Twardowsky, Aline de Oliveira ^{[28
]}

Maia, Lilia Nigro ^{[29
]}

Machado, Flavia Ribeiro ^{[20
,30
]}

Soeiro, Alexandre de Matos ^{[6
]}

Conceicao-Souza, Germano Emilio ^{[31
]}

Armaganijan, Luciana ^{[2
]}

Guimaraes, Patricia O. ^{[2
]}

Rosa, Regis G. ^{[20
,26
]}

Azevedo, Luciano C. P. ^{[20
,32
]}

Alexander, John H. ^{[1
]}

Avezum, Alvaro ^{[33
]}

Cavalcanti, Alexandre B. ^{[3
,20
]}

Berwanger, Otavio ^{[5
]}

机构：

[1] Duke Univ, Duke Clin Res Inst, Med Ctr, Durham, NC 27701 USA

[2] Clin Res Inst, Sao Paulo, Brazil

[3] HCor Res Inst, Sao Paulo, Brazil

[4] Hosp Samaritano Paulista, Sao Paulo, Brazil

[5] Hosp Israelita Albert Einstein, Acad Res Org, Sao Paulo, Brazil

[6] Univ Sao Paulo, Hosp Clin, Fac Med, Inst Coracao, Sao Paulo, Brazil

[7] Univ Sao Paulo, Hosp Clin, Fac Med, Inst Canc Estado Sao Paulo, Sao Paulo, Brazil

[8] Sci Valley Res Inst, Sao Paulo, Brazil

[9] Loyola Univ Med Ctr, Hemostasis & Thrombosis Res Labs, Maywood, IL 60153 USA

[10] Hosp Estadual Dr Jayme Santos Neves, Serra, Brazil

[11] Hosp Cardio Pulm, Salvador, BA, Brazil

[12] Escola Bahiana Med, Salvador, BA, Brazil

[13] Univ Fed Bahia, Salvador, BA, Brazil

[14] Hosp Vera Cruz, Belo Horizonte, MG, Brazil

[15] Hosp Bahia, Salvador, BA, Brazil

[16] Hosp Naval Marcilio Dias, Rio De Janeiro, Brazil

[17] Hosp Santa Paula, Sao Paulo, Brazil

[18] Santa Casa Misericordia Votuporanga, Votuporanga, Brazil

[19] Hosp Clin Fac Med Botucatu, Botucatu, SP, Brazil

[20] Brazilian Res Intens Care Network, Sao Paulo, Brazil

[21] BP, Sao Paulo, Brazil

[22] Univ Estadual Londrina, Hosp Univ, Londrina, Parana, Brazil

[23] Hosp Felicio Rocho, Belo Horizonte, MG, Brazil

[24] Santa Casa Misericordia Bahia Hosp Santa Izahel, Salvador, BA, Brazil

[25] Ctr Univ Fac Tecnol & Ciencias, Salvador, BA, Brazil

[26] Hosp Moinhos de Vento, Porto Alegre, RS, Brazil

[27] Inst Dante Pazzanese Cardiol, Sao Paulo, Brazil

[28] Hosp Amor Barretos Pio XII, Barretos, Brazil

[29] Hosp Base Sao Jose do Rio Preto, Sao Jose Do Rio Preto, Brazil

[30] Univ Fed Sao Paulo, Anesthesiol Pain & Intens Care Dept, Sao Paulo, Brazil

[31] Inst Socrates Guanaes, Sao Paulo, Brazil

[32] Hosp Sirio Libanes Res & Educ Inst, Sao Paulo, Brazil

[33] Hosp Alemao Oswaldo Cruz, Int Res Ctr, Sao Paulo, Brazil

来源：

LANCET | 2021年 / 397卷 / 10291期

关键词：

ATRIAL-FIBRILLATION; CLINICAL-TRIALS; RIVAROXABAN;

D O I：

10.1016/S0140-6736(21)01203-4

中图分类号：

R5 [内科学];

学科分类号：

1002 ; 100201 ;

摘要：

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. Copyright (C) 2021 Elsevier Ltd. All rights reserved.

引用

页码：2253 / 2263

页数：11

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