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.
【초록키워드】 COVID-19, Randomized controlled trial, coronavirus disease, Coronavirus disease 2019, immune response, therapy, anticoagulation, thrombosis, randomization, Prophylactic, Venous Thromboembolism, Randomized, reverse transcription polymerase chain reaction, polymerase chain reaction, extracorporeal membrane oxygenation, management, Myopathy, factorial design, non-inferiority, Patient, statin, Arterial thrombosis, Controlled trial, bleeding, death, Platelet, atorvastatin, Ventilator-free days, reverse transcription, thrombocytopenia, eligibility criteria, Thrombotic events, Platelet count, antithrombotic therapy, prophylactic anticoagulation, liver enzymes, Hypothesis, primary endpoint, Analysis, Odds ratio, Composite, manifestation, VTE, double-blind, liver enzyme, open, Chain Reaction, normal limit, subgroup, intensity, Standard dose, Enrollment, secondary endpoint, non-inferiority margin, open label, Exploratory analysis, all-cause mortality, help, cohorts, Exploratory analyses, inspiration, inferiority, intention-to-treat, hallmark, hallmarks, intermediate, Standard-dose, major bleeding, matching placebo, Stratified randomization, Prevent, limit, independent, thrombotic event, modified intention-to-treat, polymerase chain, Result, tested, performed, include, screened, undergo, question, hypothese, patients with COVID-19, per-protocol, safety endpoint, 【제목키워드】 therapy, anticoagulation, Prophylactic, Patient, Placebo, rationale, intermediate,