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Intermediate Versus Standard-Dose Prophylactic Anticoagulation and Statin Therapy Versus Placebo in Critically-Ill Patients With Covid-19: Rationale and Design of the Inspiration/Inspiration-S Studies Publisher Pubmed



Bikdeli B1, 2, 3 ; Talasaz AH4 ; Rashidi F5 ; Sharifkashani B6, 7 ; Farrokhpour M8 ; Bakhshandeh H9 ; Sezavar H10 ; Dabbagh A11 ; Beigmohammadi MT12 ; Payandemehr P13 ; Yadollahzadeh M8 ; Riahi T10 ; Khalili H14 ; Jamalkhani S15, 23 Show All Authors
Authors
  1. Bikdeli B1, 2, 3
  2. Talasaz AH4
  3. Rashidi F5
  4. Sharifkashani B6, 7
  5. Farrokhpour M8
  6. Bakhshandeh H9
  7. Sezavar H10
  8. Dabbagh A11
  9. Beigmohammadi MT12
  10. Payandemehr P13
  11. Yadollahzadeh M8
  12. Riahi T10
  13. Khalili H14
  14. Jamalkhani S15, 23
  15. Rezaeifar P5
  16. Abedini A16
  17. Lookzadeh S16
  18. Shahmirzaei S13
  19. Tahamtan O5
  20. Matin S5
  21. Amin A9
  22. Parhizgar SE9
  23. Jimenez D17, 18, 19
  24. Gupta A3, 20
  25. Madhavan MV3, 20
  26. Parikh SA3, 20
  27. Monreal M21
  28. Hadavand N9
  29. Hajighasemi A4
  30. Maleki M9
  31. Sadeghian S4
  32. Mohebbi B9
  33. Piazza G1
  34. Kirtane AJ3, 20
  35. Lip GYH22, 23
  36. Krumholz HM2, 24, 25
  37. Goldhaber SZ1
  38. Sadeghipour P26, 27
Show Affiliations
Authors Affiliations
  1. 1. Cardiovascular Medicine Division, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, United States
  2. 2. Yale/YNHH Center for Outcomes Research & Evaluation, New Haven, CT, United States
  3. 3. Cardiovascular Research Foundation (CRF), New York, NY, United States
  4. 4. Tehran Heart Center, Tehran University of Medical Sciences, Tehran, Iran
  5. 5. Tuberclosis and Lung Diseases Research Center, Tabriz, Iran
  6. 6. Tobacoo Prevention and control Research center, National Research lnstitute of Tuberculosis and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
  7. 7. Lung Transplantion Research Center, Department of Cardiology, National Research Institute of Tuberculosls and Lung Diseases (NRITLD), Shahid Beheshti University of Medical Sciences, Tehran, Iran
  8. 8. Firouzgar Hospital, Department of Internal Medicine, Iran University of Medical Sciences, Tehran, Iran
  9. 9. Rajaie Cardiovascular Medical and Research Center, Iran university of Medical sciences, Tehran, Iran
  10. 10. Rasoul-e-Akram Hospital, Iran University of Medical Sciences, Tehran, Iran
  11. 11. Department of Anesthesiology, School of Medicine Anesthesiology Research Center Shahid Modarres Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
  12. 12. Anesthesiology and Intensive Care, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
  13. 13. Sina Hospital, Tehran University of Medical Sciences, Tehran, Iran
  14. 14. Department of Pharmacotherapy, Imam Khomeini Hospital Complex, Tehran University of Medical Sciences, Tehran, Iran
  15. 15. Student Research Committee, Iran University of Medical Sciences, Tehran, Iran
  16. 16. Chronic Respiratory Disease Research Center, Masih Daneshvari Hospital, Shahid Beheshti University of Medical Sciences, Tehran, Iran
  17. 17. Respiratory Department, Hospital Ramon y Cajal (IRYCIS), Madrid, Spain
  18. 18. Medicine Department, Universidad de Alcala (IRYCIS), Madrid, Spain
  19. 19. CIBER Enfermedades Respiratorias (CIBERES), Madrid, Spain
  20. 20. Division of Cardiology, Columbia University Irving Medical Center, New York, NY, United States
  21. 21. Department of Internal Medicine, Hospital Germans Trias i Pujol, Badalona, Barcelona, Universidad Catolica de Murcia, Murcia, Spain
  22. 22. Liverpool Centre for Cardiovascular Science, University of Liverpool and Liverpool Heart & Chest Hospital, Liverpool, United Kingdom
  23. 23. Aalborg University, Aalborg, Denmark
  24. 24. Section of Cardiovascular Medicine, Department of Internal Medicine, Yale School of Medicine, New Haven, CT, United States
  25. 25. Department of Health Policy and Adminitration, Yale School of Public Health, New Haven, CT, United States
  26. 26. Cardiovascular Intervention Research Center, Rajaie Cardiovascular, Medical, and Research Center, Iran University of Medical Sciences, Iran
  27. 27. Clinical Trial Center, Rajaie Cardiovascular, Medical, and Research Center, Iran University of Medical Sciences, Iran

Source: Thrombosis Research Published:2020


Abstract

Background: Microvascular 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. Methods: The 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. Conclusions: INSPIRATION and INSPIRATON-S studies will help address clinically-relevant questions for antithrombotic therapy and thromboinflammatory therapy in critically-ill patients with COVID-19. © 2020 Elsevier Ltd
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