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

Bikdeli, Behnood; Talasaz, Azita H.; Rashidi, Farid; Sharif-Kashani, Babak; Farrokhpour, Mohsen; Bakhshandeh, Hooman; Sezavar, Hashem; Dabbagh, Ali; Beigmohammadi, Mohammad Taghi; Payandemehr, Pooya; Yadollahzadeh, Mahdi; Riahi, Taghi; Khalili, Hossein; Jamalkhani, Sepehr; Rezaeifar, Parisa; Abedini, Atefeh; Lookzadeh, Somayeh; Shahmirzaei, Shaghayegh; Tahamtan, Ouria; Matin, Samira; Amin, Ahmad; Parhizgar, Seyed Ehsan; Jimenez, David; Gupta, Aakriti; Madhavan, Mahesh V.; Parikh, Sahil A.; Monreal, Manuel; Hadavand, Naser; Hajighasemi, Alireza; Maleki, Majid; Sadeghian, Saeed; Mohebbi, Bahram; Piazza, Gregory; Kirtane, Ajay J.; Lip, Gregory Y.H.; Krumholz, Harlan M.; Goldhaber, Samuel Z.; Sadeghipour, Parham

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 control 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.