Thromb Res . 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

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Thromb Res


. 2020 Sep 24;196:382-394.
doi: 10.1016/j.thromres.2020.09.027. Online ahead of print.
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


Behnood Bikdeli ¹ , Azita H Talasaz ² , Farid Rashidi ³ , Babak Sharif-Kashani ⁴ , Mohsen Farrokhpour ⁵ , Hooman Bakhshandeh ⁶ , Hashem Sezavar ⁷ , Ali Dabbagh ⁸ , Mohammad Taghi Beigmohammadi ⁹ , Pooya Payandemehr ¹⁰ , Mahdi Yadollahzadeh ⁵ , Taghi Riahi ⁷ , Hossein Khalili ¹¹ , Sepehr Jamalkhani ¹² , Parisa Rezaeifar ³ , Atefeh Abedini ¹³ , Somayeh Lookzadeh ¹³ , Shaghayegh Shahmirzaei ¹⁰ , Ouria Tahamtan ³ , Samira Matin ³ , Ahmad Amin ⁶ , Seyed Ehsan Parhizgar ⁶ , David Jimenez ¹⁴ , Aakriti Gupta ¹⁵ , Mahesh V Madhavan ¹⁵ , Sahil A Parikh ¹⁵ , Manuel Monreal ¹⁶ , Naser Hadavand ⁶ , Alireza Hajighasemi ² , Majid Maleki ⁶ , Saeed Sadeghian ² , Bahram Mohebbi ⁶ , Gregory Piazza ¹⁷ , Ajay J Kirtane ¹⁵ , Gregory Y H Lip ¹⁸ , Harlan M Krumholz ¹⁹ , Samuel Z Goldhaber ¹⁷ , Parham Sadeghipour ²⁰



Affiliations

• PMID: 32992075
• PMCID: PMC7513771
• DOI: 10.1016/j.thromres.2020.09.027

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.