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

Renato D Lopes, Pedro Gabriel Melo de Barros E Silva, Remo H M Furtado, Ariane Vieira Scarlatelli Macedo, Bruna Bronhara, Lucas Petri Damiani, Lilian Mazza Barbosa, Júlia de Aveiro Morata, Eduardo Ramacciotti, Priscilla de Aquino Martins, Aryadne Lyrio de Oliveira, Vinicius Santana Nunes, Luiz Eduardo Fonteles Ritt, Ana Thereza Rocha, Lucas Tramujas, Sueli V Santos, Dario Rafael Abregu Diaz, Lorena Souza Viana, Lívia Maria Garcia Melro, Mariana Silveira de Alcântara Chaud, Estêvão Lanna Figueiredo, Fernando Carvalho Neuenschwander, Marianna Deway Andrade Dracoulakis, Rodolfo Godinho Souza Dourado Lima, Vicente Cés de Souza Dantas, Anne Cristine Silva Fernandes, Otávio Celso Eluf Gebara, Mauro Esteves Hernandes, Diego Aparecido Rios Queiroz, Viviane C Veiga, Manoel Fernandes Canesin, Leonardo Meira de Faria, Gilson Soares Feitosa-Filho, Marcelo Basso Gazzana, Idelzuíta Leandro Liporace, Aline de Oliveira Twardowsky, Lilia Nigro Maia, Flávia Ribeiro Machado, Alexandre de Matos Soeiro, Germano Emílio Conceição-Souza, Luciana Armaganijan, Patrícia O Guimarães, Regis G Rosa, Luciano C P Azevedo, John H Alexander, Alvaro Avezum, Alexandre B Cavalcanti, Otavio Berwanger
Lancet 2021 June 4

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 (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.

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