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. 2020 Dec;196:382-394. doi: 10.1016/j.thromres.2020.09.027. Epub 2020 Sep 24.

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.

Publication types

  • Clinical Trial Protocol

MeSH terms

  • Anticoagulants / administration & dosage*
  • Anticoagulants / adverse effects
  • Atorvastatin / administration & dosage*
  • Atorvastatin / adverse effects
  • COVID-19 / complications
  • COVID-19 / diagnosis
  • COVID-19 / drug therapy*
  • Critical Illness
  • Double-Blind Method
  • Enoxaparin / administration & dosage*
  • Enoxaparin / adverse effects
  • Humans
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / administration & dosage*
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors / adverse effects
  • Iran
  • Multicenter Studies as Topic
  • Randomized Controlled Trials as Topic
  • Thrombosis / diagnosis
  • Thrombosis / etiology
  • Thrombosis / prevention & control*
  • Time Factors
  • Treatment Outcome
  • Venous Thromboembolism / diagnosis
  • Venous Thromboembolism / etiology
  • Venous Thromboembolism / prevention & control*

Substances

  • Anticoagulants
  • Enoxaparin
  • Hydroxymethylglutaryl-CoA Reductase Inhibitors
  • Atorvastatin

Supplementary concepts

  • COVID-19 drug treatment