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