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

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dc.contributor.authorLopes, Renato D
dc.contributor.authorde Barros e Silva, Pedro Gabriel Melo
dc.contributor.authorFurtado, Remo H M
dc.contributor.authorMacedo, Ariane Vieira Scarlatelli
dc.contributor.authorBronhara, Bruna
dc.contributor.authorDamiani, Lucas Petri
dc.contributor.authorBarbosa, Lilian Mazza
dc.contributor.authorde Aveiro Morata, Júlia
dc.contributor.authorRamacciotti, Eduardo
dc.contributor.authorde Aquino Martins, Priscilla
dc.contributor.authorde Oliveira, Aryadne Lyrio
dc.contributor.authorNunes, Vinicius Santana
dc.contributor.authorRitt, Luiz Eduardo Fonteles
dc.contributor.authorRocha, Ana Thereza
dc.contributor.authorTramujas, Lucas
dc.contributor.authorSantos, Sueli V
dc.contributor.authorDiaz, Dario Rafael Abregu
dc.contributor.authorViana, Lorena Souza
dc.contributor.authorMelro, Lívia Maria Garcia
dc.contributor.authorde Alcântara Chaud, Mariana Silveira
dc.contributor.authorFigueiredo, Estêvão Lanna
dc.contributor.authorNeuenschwander, Fernando Carvalho
dc.contributor.authorDracoulakis, Marianna Deway Andrade
dc.contributor.authorLima, Rodolfo Godinho Souza Dourado
dc.contributor.authorde Souza Dantas, Vicente Cés
dc.contributor.authorFernandes, Anne Cristine Silva
dc.contributor.authorGebara, Otávio Celso Eluf
dc.contributor.authorHernandes, Mauro Esteves
dc.contributor.authorQueiroz, Diego Aparecido Rios [UNESP]
dc.contributor.authorVeiga, Viviane C
dc.contributor.authorCanesin, Manoel Fernandes
dc.contributor.authorde Faria, Leonardo Meira
dc.contributor.authorFeitosa-Filho, Gilson Soares
dc.contributor.authorGazzana, Marcelo Basso
dc.contributor.authorLiporace, Idelzuíta Leandro
dc.contributor.authorde Oliveira Twardowsky, Aline
dc.contributor.authorMaia, Lilia Nigro
dc.contributor.authorMachado, Flávia Ribeiro
dc.contributor.authorde Matos Soeiro, Alexandre
dc.contributor.authorConceição-Souza, Germano Emílio
dc.contributor.authorArmaganijan, Luciana
dc.contributor.authorGuimarães, Patrícia O
dc.contributor.authorRosa, Regis G
dc.contributor.authorAzevedo, Luciano C P
dc.contributor.authorAlexander, John H
dc.contributor.authorAvezum, Alvaro
dc.contributor.authorCavalcanti, Alexandre B
dc.contributor.authorBerwanger, Otavio
dc.contributor.institutionDuke University Medical Center
dc.contributor.institutionBrazilian Clinical Research Institute
dc.contributor.institutionHCor Research Institute
dc.contributor.institutionHospital Samaritano Paulista
dc.contributor.institutionHospital Israelita Albert Einstein
dc.contributor.institutionUniversidade de São Paulo (USP)
dc.contributor.institutionScience Valley Research Institute
dc.contributor.institutionHemostasis & Thrombosis Research Laboratories at Loyola University Medical Center
dc.contributor.institutionHospital Estadual Dr Jayme Santos Neves
dc.contributor.institutionHospital Cárdio Pulmonar
dc.contributor.institutionEscola Bahiana de Medicina
dc.contributor.institutionUniversidade Federal da Bahia (UFBA)
dc.contributor.institutionHospital Vera Cruz
dc.contributor.institutionHospital Da Bahia
dc.contributor.institutionHospital Naval Marcílio Dias
dc.contributor.institutionHospital Santa Paula
dc.contributor.institutionSanta Casa de Misericórdia de Votuporanga
dc.contributor.institutionUniversidade Estadual Paulista (UNESP)
dc.contributor.institutionBrazilian Research in Intensive Care Network
dc.contributor.institutionBP—A Beneficência Portuguesa de São Paulo
dc.contributor.institutionUniversidade Estadual de Londrina (UEL)
dc.contributor.institutionHospital Felício Rocho
dc.contributor.institutionSanta Casa de Misericórdia da Bahia–Hospital Santa Izabel
dc.contributor.institutionCentro Universitário Faculdade de Tecnologia e Ciências
dc.contributor.institutionHospital Moinhos de Vento
dc.contributor.institutionInstituto Dante Pazzanese de Cardiologia
dc.contributor.institutionHospital de Amor de Barretos (Pio XII)
dc.contributor.institutionHospital de Base de São José do Rio Preto
dc.contributor.institutionInstituto Socrates Guanaes
dc.contributor.institutionHospital Sírio Libanês Research and Education Institute
dc.contributor.institutionHospital Alemão Oswaldo Cruz
dc.date.accessioned2022-04-29T08:29:34Z
dc.date.available2022-04-29T08:29:34Z
dc.date.issued2021-06-12
dc.description.abstractBackground: 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.en
dc.description.affiliationDuke Clinical Research Institute Duke University Medical Center
dc.description.affiliationBrazilian Clinical Research Institute
dc.description.affiliationHCor Research Institute
dc.description.affiliationHospital Samaritano Paulista
dc.description.affiliationAcademic Research Organization Hospital Israelita Albert Einstein
dc.description.affiliationInstituto do Coração Universidade de São Paulo
dc.description.affiliationInstituto do Câncer do Estado de São Paulo Hospital das Clínicas da Faculdade de Medicina Universidade de São Paulo
dc.description.affiliationScience Valley Research Institute
dc.description.affiliationHemostasis & Thrombosis Research Laboratories at Loyola University Medical Center
dc.description.affiliationHospital Estadual Dr Jayme Santos Neves
dc.description.affiliationHospital Cárdio Pulmonar
dc.description.affiliationEscola Bahiana de Medicina
dc.description.affiliationUniversidade Federal da Bahia
dc.description.affiliationHospital Vera Cruz
dc.description.affiliationHospital Da Bahia
dc.description.affiliationHospital Naval Marcílio Dias
dc.description.affiliationHospital Santa Paula
dc.description.affiliationSanta Casa de Misericórdia de Votuporanga
dc.description.affiliationHospital das Clínicas da Faculdade de Medicina de Botucatu
dc.description.affiliationBrazilian Research in Intensive Care Network
dc.description.affiliationBP—A Beneficência Portuguesa de São Paulo
dc.description.affiliationHospital Universitário da Universidade Estadual de Londrina
dc.description.affiliationHospital Felício Rocho
dc.description.affiliationSanta Casa de Misericórdia da Bahia–Hospital Santa Izabel
dc.description.affiliationCentro Universitário Faculdade de Tecnologia e Ciências
dc.description.affiliationHospital Moinhos de Vento
dc.description.affiliationInstituto Dante Pazzanese de Cardiologia
dc.description.affiliationHospital de Amor de Barretos (Pio XII)
dc.description.affiliationHospital de Base de São José do Rio Preto
dc.description.affiliationAnesthesiology Pain and Intensive Care Department Federal University of São Paulo
dc.description.affiliationInstituto Socrates Guanaes
dc.description.affiliationHospital Sírio Libanês Research and Education Institute
dc.description.affiliationInternational Research Center Hospital Alemão Oswaldo Cruz
dc.description.affiliationUnespHospital das Clínicas da Faculdade de Medicina de Botucatu
dc.format.extent2253-2263
dc.identifierhttp://dx.doi.org/10.1016/S0140-6736(21)01203-4
dc.identifier.citationThe Lancet, v. 397, n. 10291, p. 2253-2263, 2021.
dc.identifier.doi10.1016/S0140-6736(21)01203-4
dc.identifier.issn1474-547X
dc.identifier.issn0140-6736
dc.identifier.scopus2-s2.0-85107673912
dc.identifier.urihttp://hdl.handle.net/11449/228961
dc.language.isoeng
dc.relation.ispartofThe Lancet
dc.sourceScopus
dc.titleTherapeutic versus prophylactic anticoagulation for patients admitted to hospital with COVID-19 and elevated D-dimer concentration (ACTION): an open-label, multicentre, randomised, controlled trialen
dc.typeArtigo

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