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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From: The Lancet(Vol. 397, Issue 10291)
Publisher: Elsevier B.V.
Document Type: Article
Length: 1,085 words

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on behalf of the ACTION Coalition COVID-19 Brazil IV Investigators Summary 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 [greater than or equal to]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. Author Affiliation: (a) Duke Clinical Research Institute, Duke University Medical Center, Durham, NC, USA (b) Brazilian Clinical Research Institute, São Paulo, Brazil (c) HCor Research Institute, São Paulo, Brazil (d) Hospital Samaritano Paulista, São Paulo, Brazil (e) Academic Research Organization, Hospital Israelita Albert Einstein, São Paulo, Brazil (f) Instituto do Coração, Universidade de São Paulo, São Paulo, Brazil (g) Instituto do Câncer do Estado de São Paulo, Hospital das Clínicas da Faculdade de Medicina, Universidade de São Paulo, São Paulo, Brazil (h) Science Valley Research Institute, São Paulo, Brazil (i) Hemostasis & Thrombosis Research Laboratories at Loyola University Medical Center, Maywood, IL, USA (j) Hospital Estadual Dr Jayme Santos Neves, Serra, Brazil (k) Hospital Cárdio Pulmonar, Salvador, Brazil (l) Escola Bahiana de Medicina, Salvador, Brazil (m) Universidade Federal da Bahia, Salvador, Brazil (n) Hospital Vera Cruz, Belo Horizonte, Brazil (o) Hospital Da Bahia, Salvador, Brazil (p) Hospital Naval Marcílio Dias, Rio de Janeiro, Brazil (q) Hospital Santa Paula, São Paulo, Brazil (r) Santa Casa de Misericórdia de Votuporanga, Votuporanga, Brazil (s) Hospital das Clínicas da Faculdade de Medicina de Botucatu, Botucatu, Brazil (t) Brazilian Research in Intensive Care Network, São Paulo, Brazil (u) BP--A Beneficência Portuguesa de São Paulo, São Paulo, Brazil (v) Hospital Universitário da Universidade Estadual de Londrina, Londrina, Brazil (w) Hospital Felício Rocho, Belo Horizonte, Brazil (x) Santa Casa de Misericórdia da Bahia--Hospital Santa Izabel, Salvador, Brazil (y) Centro Universitário Faculdade de Tecnologia e Ciências, Salvador, Brazil (z) Hospital Moinhos de Vento, Porto Alegre, Brazil (aa) Instituto Dante Pazzanese de Cardiologia, São Paulo, Brazil (ab) Hospital de Amor de Barretos (Pio XII), Barretos, Brazil (ac) Hospital de Base de São José do Rio Preto, São José do Rio Preto, Brazil (ad) Anesthesiology, Pain and Intensive Care Department, Federal University of São Paulo, São Paulo, Brazil (ae) Instituto Socrates Guanaes, São Paulo, Brazil (af) Hospital Sírio Libanês Research and Education Institute, São Paulo, Brazil (ag) International Research Center, Hospital Alemão Oswaldo Cruz, São Paulo, Brazil * Correspondence to: Prof Renato D Lopes, Duke Clinical Research Institute, Duke University Medical Center, Durham, NC 27701 Byline: Prof Renato D Lopes, MD [USArenato.lopes@duke.edu] (a,b), Pedro Gabriel Melo de Barros e Silva, MD (b,c,d), Remo H M Furtado, MD (e,f), Ariane Vieira Scarlatelli Macedo, MD (b), Bruna Bronhara, PhD (b), Lucas Petri Damiani, MS (b,c), Lilian Mazza Barbosa, FT (b), Júlia de Aveiro Morata, BSc (b), Prof Eduardo Ramacciotti, MD (b,h,i), Priscilla de Aquino Martins, MD (j), Aryadne Lyrio de Oliveira, BSc (j), Vinicius Santana Nunes, PhD (j), Luiz Eduardo Fonteles Ritt, MD (k,l), Ana Thereza Rocha, MD (k,l,m), Lucas Tramujas, MD (c), Sueli V Santos, MD (c), Dario Rafael Abregu Diaz, MD (e), Lorena Souza Viana, MD (e,g), Lívia Maria Garcia Melro, MD (d), Mariana Silveira de Alcântara Chaud, MD (d), Estêvão Lanna Figueiredo, MD (n), Fernando Carvalho Neuenschwander, MD (n), Marianna Deway Andrade Dracoulakis, MD (o), Rodolfo Godinho Souza Dourado Lima, MD (o), Vicente Cés de Souza Dantas, MD (p), Anne Cristine Silva Fernandes, PhD (p), Otávio Celso Eluf Gebara, MD (q), Mauro Esteves Hernandes, MD (r), Diego Aparecido Rios Queiroz, MD (s), Viviane C Veiga, MD (t,u), Prof Manoel Fernandes Canesin, MD (v), Leonardo Meira de Faria, MD (w), Prof Gilson Soares Feitosa-Filho, MD (l,x,y), Marcelo Basso Gazzana, MD (z), Idelzuíta Leandro Liporace, MD (aa), Aline de Oliveira Twardowsky, MD (ab), Prof Lilia Nigro Maia, MD (ac), Prof Flávia Ribeiro Machado, MD (t,ad), Alexandre de Matos Soeiro, MD (f), Germano Emílio Conceição-Souza, MD (ae), Luciana Armaganijan, MD (b), Patrícia O Guimarães, MD (b), Regis G Rosa, MD (t,z), Prof Luciano C P Azevedo, MD (t,af), Prof John H Alexander, MD (a), Prof Alvaro Avezum, MD (ag), Prof Alexandre B Cavalcanti, MD (c,t), Prof Otavio Berwanger, MD (e)

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Gale Document Number: GALE|A664848914