Parham Sadeghipour1,2, Azita H Talasaz3, Farid Rashidi4, Babak Sharif-Kashani5,6, Mohammad Taghi Beigmohammadi7, Mohsen Farrokhpour8, Seyed Hashem Sezavar9, Pooya Payandemehr10, Ali Dabbagh11, Keivan Gohari Moghadam12, Sepehr Jamalkhani13, Hossein Khalili14, Mahdi Yadollahzadeh8, Taghi Riahi15, Parisa Rezaeifar4, Ouria Tahamtan4, Samira Matin4, Atefeh Abedini16, Somayeh Lookzadeh16, Hamid Rahmani17, Elnaz Zoghi18, Keyhan Mohammadi18, Pardis Sadeghipour8, Homa Abri8, Sanaz Tabrizi15, Seyed Masoud Mousavian15, Shaghayegh Shahmirzaei10, Hooman Bakhshandeh2,19, Ahmad Amin19, Farnaz Rafiee19, Elahe Baghizadeh19, Bahram Mohebbi1, Seyed Ehsan Parhizgar19, Rasoul Aliannejad20,21, Vahid Eslami22, Alireza Kashefizadeh23, Hessam Kakavand18, Seyed Hossein Hosseini18, Shadi Shafaghi6, Samrand Fattah Ghazi7, Atabak Najafi10, David Jimenez24,25,26, Aakriti Gupta27,28,29, Mahesh V Madhavan27,28, Sanjum S Sethi27,28, Sahil A Parikh27,28, Manuel Monreal30, Naser Hadavand19, Alireza Hajighasemi3, Majid Maleki19, Saeed Sadeghian3, Gregory Piazza31, Ajay J Kirtane27,28, Benjamin W Van Tassell32,33, Paul P Dobesh34, Gregg W Stone27,35, Gregory Y H Lip36,37, Harlan M Krumholz29,38,39, Samuel Z Goldhaber31, Behnood Bikdeli27,29,31. 1. Cardiovascular Intervention Research Center, Rajaie Cardiovascular, Medical, and Research Center, Iran University of Medical Sciences, Tehran, Iran. 2. Clinical Trial Center, Rajaie Cardiovascular, Medical, and Research Center, Iran University of Medical Sciences, Tehran, Iran. 3. Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran. 4. Tuberculosis and Lung Diseases Research Center, Tabriz University of Medical Sciences, Tabriz, Iran. 5. Tobacoo Prevention and control Research center, National Research institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran. 6. Lung Transplantation Research Center, Department of Cardiology, National Research Institute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran. 7. Anesthesiology and Intensive Care, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran. 8. Firouzgar hospital, Department of internal medicine, Iran University of Medical Sciences, Tehran, Iran. 9. Research Center for Prevention of Cardiovascular Disease, Institute of Endocrinology & Metabolism, Iran University of Medical Sciences, Tehran, Iran. 10. Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran. 11. Department of Anesthesiology, School of Medicine Anesthesiology Research Center Shahid Modarres Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 12. School of Medicine, Department of Internal Medicine, Shariati Hospital, Tehran, Iran. 13. Student Research Committee, Iran University of Medical Sciences, Tehran, Iran. 14. Department of Pharmacotherapy, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran. 15. Rasoul-e-Akram Hospital, Iran University of Medical Sciences, Tehran, Iran. 16. Chronic Respiratory Disease Research Center, Masih Daneshvari Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 17. Department of Pharmacotherapy, Faculty of Pharmacy, Kermanshah University of Medical Sciences, Kermanshah, Iran. 18. School of Pharmacy, Tehran University of Medical Sciences, Tehran, Iran. 19. Rajaie Cardiovascular Medical and Research Center, Iran university of Medical sciences, Tehran, Iran. 20. School of Medicine, Department of Pulmonary and Critical Care, Shariati Hospital, Tehran, Iran. 21. Advanced Thoracic Research Center, Tehran University of Medical Sciences, Tehran, Iran. 22. Cardiovascular Research Center, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 23. Shahid Dr Labbafinejad Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran. 24. Respiratory Department, Hospital Ramón y Cajal (IRYCIS), Madrid, Spain. 25. Medicine Department, Universidad de Alcalá (IRYCIS), Madrid, Spain. 26. CIBER Enfermedades Respiratorias (CIBERES), Madrid, Spain. 27. Cardiovascular Research Foundation (CRF), New York, New York. 28. Division of Cardiology, Columbia University Irving Medical Center/NewYork-Presbyterian Hospital, New York, New York. 29. Yale/YNHH Center for Outcomes Research & Evaluation, New Haven, Connecticut. 30. Department of Internal Medicine, Hospital Germans Trias i Pujol, Badalona, Barcelona, Universidad Católica de Murcia, Murcia, Spain. 31. Cardiovascular Medicine Division, Brigham and Women's Hospital, Harvard Medical School, Boston, Massachusetts. 32. School of Pharmacy, Department of Pharmacotherapy and Outcome Science, Virginia Commonwealth University, Richmond, Virginia. 33. School of Pharmacy, Pauley Heart Center, Division of Cardiology, Department of Internal Medicine, Virginia Commonwealth University, Richmond, Virginia. 34. College of Pharmacy, University of Nebraska Medical Center, Omaha. 35. The Zena and Michael A. Wiener Cardiovascular Institute, Icahn School of Medicine at Mount Sinai, New York, New York. 36. Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool Heart & Chest Hospital, Liverpool, United Kingdom. 37. Aalborg University, Aalborg, Denmark. 38. Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, Connecticut. 39. Department of Health Policy and Administration, Yale School of Public Health, New Haven, Connecticut.
Abstract
Importance: Thrombotic events are commonly reported in critically ill patients with COVID-19. Limited data exist to guide the intensity of antithrombotic prophylaxis. Objective: To evaluate the effects of intermediate-dose vs standard-dose prophylactic anticoagulation among patients with COVID-19 admitted to the intensive care unit (ICU). Design, Setting, and Participants: Multicenter randomized trial with a 2 × 2 factorial design performed in 10 academic centers in Iran comparingintermediate-dose vs standard-dose prophylactic anticoagulation (first hypothesis) and statin therapy vs matching placebo (second hypothesis; not reported in this article) among adult patients admitted to the ICU with COVID-19. Patients were recruited between July 29, 2020, and November 19, 2020. The final follow-up date for the 30-day primary outcome was December 19, 2020. Interventions: Intermediate-dose (enoxaparin, 1 mg/kg daily) (n = 276) vs standard prophylactic anticoagulation (enoxaparin, 40 mg daily) (n = 286), with modification according to body weight and creatinine clearance. The assigned treatments were planned to be continued until completion of 30-day follow-up. Main Outcomes and Measures: The primary efficacy outcome was a composite of venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days, assessed in randomized patients who met the eligibility criteria and received at least 1 dose of the assigned treatment. Prespecified safety outcomes included major bleeding according to the Bleeding Academic Research Consortium (type 3 or 5 definition), powered for noninferiority (a noninferiority margin of 1.8 based on odds ratio), and severe thrombocytopenia (platelet count <20 ×103/µL). All outcomes were blindly adjudicated. Results: Among 600 randomized patients, 562 (93.7%) were included in the primary analysis (median [interquartile range] age, 62 [50-71] years; 237 [42.2%] women). The primary efficacy outcome occurred in 126 patients (45.7%) in the intermediate-dose group and 126 patients (44.1%) in the standard-dose prophylaxis group (absolute risk difference, 1.5% [95% CI, -6.6% to 9.8%]; odds ratio, 1.06 [95% CI, 0.76-1.48]; P = .70). Major bleeding occurred in 7 patients (2.5%) in the intermediate-dose group and 4 patients (1.4%) in the standard-dose prophylaxis group (risk difference, 1.1% [1-sided 97.5% CI, -∞ to 3.4%]; odds ratio, 1.83 [1-sided 97.5% CI, 0.00-5.93]), not meeting the noninferiority criteria (P for noninferiority >.99). Severe thrombocytopenia occurred only in patients assigned to the intermediate-dose group (6 vs 0 patients; risk difference, 2.2% [95% CI, 0.4%-3.8%]; P = .01). Conclusions and Relevance: Among patients admitted to the ICU with COVID-19, intermediate-dose prophylactic anticoagulation, compared with standard-dose prophylactic anticoagulation, did not result in a significant difference in the primary outcome of a composite of adjudicated venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days. These results do not support the routine empirical use of intermediate-dose prophylactic anticoagulation in unselected patients admitted to the ICU with COVID-19. Trial Registration: ClinicalTrials.gov Identifier: NCT04486508.
RCT Entities:
Importance: Thrombotic events are commonly reported in critically illpatients with COVID-19. Limited data exist to guide the intensity of antithrombotic prophylaxis. Objective: To evaluate the effects of intermediate-dose vs standard-dose prophylactic anticoagulation among patients with COVID-19 admitted to the intensive care unit (ICU). Design, Setting, and Participants: Multicenter randomized trial with a 2 × 2 factorial design performed in 10 academic centers in Iran comparing intermediate-dose vs standard-dose prophylactic anticoagulation (first hypothesis) and statin therapy vs matching placebo (second hypothesis; not reported in this article) among adult patients admitted to the ICU with COVID-19. Patients were recruited between July 29, 2020, and November 19, 2020. The final follow-up date for the 30-day primary outcome was December 19, 2020. Interventions: Intermediate-dose (enoxaparin, 1 mg/kg daily) (n = 276) vs standard prophylactic anticoagulation (enoxaparin, 40 mg daily) (n = 286), with modification according to body weight and creatinine clearance. The assigned treatments were planned to be continued until completion of 30-day follow-up. Main Outcomes and Measures: The primary efficacy outcome was a composite of venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days, assessed in randomized patients who met the eligibility criteria and received at least 1 dose of the assigned treatment. Prespecified safety outcomes included major bleeding according to the Bleeding Academic Research Consortium (type 3 or 5 definition), powered for noninferiority (a noninferiority margin of 1.8 based on odds ratio), and severe thrombocytopenia (platelet count <20 ×103/µL). All outcomes were blindly adjudicated. Results: Among 600 randomized patients, 562 (93.7%) were included in the primary analysis (median [interquartile range] age, 62 [50-71] years; 237 [42.2%] women). The primary efficacy outcome occurred in 126 patients (45.7%) in the intermediate-dose group and 126 patients (44.1%) in the standard-dose prophylaxis group (absolute risk difference, 1.5% [95% CI, -6.6% to 9.8%]; odds ratio, 1.06 [95% CI, 0.76-1.48]; P = .70). Major bleeding occurred in 7 patients (2.5%) in the intermediate-dose group and 4 patients (1.4%) in the standard-dose prophylaxis group (risk difference, 1.1% [1-sided 97.5% CI, -∞ to 3.4%]; odds ratio, 1.83 [1-sided 97.5% CI, 0.00-5.93]), not meeting the noninferiority criteria (P for noninferiority >.99). Severe thrombocytopenia occurred only in patients assigned to the intermediate-dose group (6 vs 0 patients; risk difference, 2.2% [95% CI, 0.4%-3.8%]; P = .01). Conclusions and Relevance: Among patients admitted to the ICU with COVID-19, intermediate-dose prophylactic anticoagulation, compared with standard-dose prophylactic anticoagulation, did not result in a significant difference in the primary outcome of a composite of adjudicated venous or arterial thrombosis, treatment with extracorporeal membrane oxygenation, or mortality within 30 days. These results do not support the routine empirical use of intermediate-dose prophylactic anticoagulation in unselected patients admitted to the ICU with COVID-19. Trial Registration: ClinicalTrials.gov Identifier: NCT04486508.
Authors: Jason Roh; Robert Kitchen; J Sawalla Guseh; Jenna McNeill; Malika Aid; Amanda Martinot; Andy Yu; Colin Platt; James Rhee; Brittany Weber; Lena Trager; Margaret Hastings; Sarah Ducat; Peng Xia; Claire Castro; Bjarni Atlason; Timothy Churchill; Marcelo Di Carli; Patrick Ellinor; Dan Barouch; Jennifer Ho; Anthony Rosenzweig Journal: Res Sq Date: 2021-06-08
Authors: 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 Journal: Lancet Date: 2021-06-04 Impact factor: 79.321