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.
Thromb Res
; 196: 382-394, 2020 12.
Article
in English
| MEDLINE | ID: covidwho-791550
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.
Full text:
Available
Collection:
International databases
Database:
MEDLINE
Main subject:
Thrombosis
/
Enoxaparin
/
Hydroxymethylglutaryl-CoA Reductase Inhibitors
/
Venous Thromboembolism
/
Atorvastatin
/
COVID-19 Drug Treatment
/
Anticoagulants
Type of study:
Cohort study
/
Diagnostic study
/
Experimental Studies
/
Observational study
/
Prognostic study
/
Randomized controlled trials
Topics:
Long Covid
Limits:
Humans
Country/Region as subject:
Asia
Language:
English
Journal:
Thromb Res
Year:
2020
Document Type:
Article
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