• Behnood Bikdeli, Azita H Talasaz, Farid Rashidi, Babak Sharif-Kashani, Mohsen Farrokhpour, Hooman Bakhshandeh, Hashem Sezavar, Ali Dabbagh, Mohammad Taghi Beigmohammadi, Pooya Payandemehr, Mahdi Yadollahzadeh, Taghi Riahi, Hossein Khalili, Sepehr Jamalkhani, Parisa Rezaeifar, Atefeh Abedini, Somayeh Lookzadeh, Shaghayegh Shahmirzaei, Ouria Tahamtan, Samira Matin, Ahmad Amin, Seyed Ehsan Parhizgar, David Jimenez, Aakriti Gupta, Mahesh V Madhavan, Sahil A Parikh, Manuel Monreal, Naser Hadavand, Alireza Hajighasemi, Majid Maleki, Saeed Sadeghian, Bahram Mohebbi, Gregory Piazza, Ajay J Kirtane, Lip Gregory Y H GYH Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool Heart & Chest Hospital, Liverpool, United Kingdom; Aalborg Universi, Harlan M Krumholz, Samuel Z Goldhaber, and Parham Sadeghipour.
• Cardiovascular Medicine Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA; Yale/YNHH Center for Outcomes Research & Evaluation, New Haven, CT, USA; Cardiovascular Research Foundation (CRF), New York, NY, USA. Electronic address: bbikdeli@bwh.harvard.edu.
• Thromb. Res. 2020 Dec 1; 196: 382-394.

BackgroundMicrovascular and macrovascular thrombotic events are among the hallmarks of coronavirus disease 2019 (COVID-19). Furthermore, the exuberant immune response is considered an important driver of pulmonary and extrapulmonary manifestations of COVID-19. The optimal management strategy to prevent thrombosis in critically-ill patients with COVID-19 remains unknown.MethodsThe Intermediate versus Standard-dose Prophylactic anticoagulation In cRitically-ill pATIents with COVID-19: An opeN label randomized controlled trial (INSPIRATION) and INSPIRATION-statin (INSPIRATION-S) studies test two independent hypotheses within a randomized controlled trial with 2 × 2 factorial design. Hospitalized critically-ill patients with reverse transcription polymerase chain reaction confirmed COVID-19 will be randomized to intermediate-dose versus standard dose prophylactic anticoagulation. The 600 patients undergoing this randomization will be screened and if meeting the eligibility criteria, will undergo an additional double-blind stratified randomization to atorvastatin 20 mg daily versus matching placebo. The primary endpoint, for both hypotheses will be tested for superiority and includes a composite of adjudicated acute arterial thrombosis, venous thromboembolism (VTE), use of extracorporeal membrane oxygenation, or all-cause death within 30 days from enrollment. Key secondary endpoints include all-cause mortality, adjudicated VTE, and ventilator-free days. Key safety endpoints include major bleeding according to the Bleeding Academic Research Consortium definition and severe thrombocytopenia (platelet count <20,000/fL) for the anticoagulation hypothesis. In a prespecified secondary analysis for non-inferiority, the study will test for the non-inferiority of intermediate intensity versus standard dose anticoagulation for major bleeding, considering a non-inferiority margin of 1.8 based on odds ratio. Key safety endpoints for the statin hypothesis include rise in liver enzymes >3 times upper normal limit and clinically-diagnosed myopathy. The primary analyses will be performed in the modified intention-to-treat population. Results will be tested in exploratory analyses across key subgroups and in the intention-to-treat and per-protocol cohorts.ConclusionsINSPIRATION and INSPIRATON-S studies will help address clinically-relevant questions for antithrombotic therapy and thromboinflammatory therapy in critically-ill patients with COVID-19.Copyright © 2020 Elsevier Ltd. All rights reserved.

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