Intermediate-dose vs Standard Prophylactic Anticoagulation and Statin vs Placebo in ICU Patients With COVID-19 (INSPIRATION)

Rajaie Cardiovascular Medical and Research Center

Status and phase: Completed; Phase 3

Conditions: Covid19

Treatments: Drug: Atorvastatin 20mg; Drug: Matched placebo; Drug: standard prophylactic dose Enoxaparin/ unfractionated heparin; Drug: intermediate dose Enoxaparin/ unfractionated heparin

Study type: Interventional

Funder types: Other

Identifiers

NCT04486508

99060

Details and patient eligibility

About

In a 2x2 factorial design randomized controlled trial, the investigators aim to elaborate the safety and efficacy of two pharmacological regimens on outcomes of critically-ill patients with COVID-19. The first randomization entails open-label assignment to intermediate versus standard dose prophylactic anticoagulation. The investigators hypothesize that intermediate dose compared with standard prophylactic dose anticoagulation will have a superior efficacy with respect to a composite of venous thromboembolism (VTE), requirement for extracorporeal membrane oxygenation (ECMO), or all-cause mortality. The second randomization will be double-blind assignment of the included patients to atorvastatin 20mg daily versus matching placebo. The hypothesis is that statin therapy, compared with placebo, will reduce the composite of VTE, need for ECMO, or all-cause mortality.

Full description

Coronavirus disease-2019 (COVID-19) -- a viral illness caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) -- has important manifestations outside the pulmonary parenchyma, including microthrombosis and macrothrombosis, with venous thrombosis being the most common form of thrombotic involvement. Existing studies, depending on the type of outcome assessment and type and dose of prophylaxis, have reported thrombotic events in 7-85% of patients with COVID-19.

However, the optimal antithrombotic regimen in these patients remains uncertain. Although many clinicians continue to consider standard-dose prophylactic anticoagulation, other believe that more intense anticoagulation may reduce the thrombotic events, and improve outcomes. However, limited high-quality data exist to inform clinical practice and the existing guidelines recommendations are mostly based on expert opinion and consensus.

In addition, exuberant inflammatory response is known to play a role in the pathophysiology of acute respiratory distress syndrome (ARDS) and COVID-19. It is possible that the pleiotropic effects of statins, which include anti-inflammatory and antithrombotic effects, prove beneficial in patients with severe COVID-19.

This study plans to investigate the safety and efficacy of two pharmacological regimens on outcomes of critically-ill patients with COVID-19 using a 2x2 factorial design.

First, patients will be assessed for the eligibility criteria for the anticoagulation hypothesis. Those meeting the criteria, will be assigned to intermediate versus standard dose prophylactic anticoagulation. These patients will subsequently be assessed for eligibility for the second randomization, and if meeting the criteria, will be assigned to atorvastatin 20mg/d or matching placebo.

Enrollment: 600 patients

Sex: All

Ages: 18+ years old

Volunteers: No Healthy Volunteers

Inclusion and exclusion criteria

Inclusion Criteria for Anticoagulation Hypothesis

1. Adult patients (≥18 years), with polymerase chain reaction (PCR)-confirmed COVID-19 admitted to ICU within 7 days of initial hospitalization , who do not have another firm indication for anticoagulation (such as mechanical valve, high-risk atrial fibrillation (AF), VTE, or left ventricle (LV) thrombus),who are not enrolled in another blinded randomized trial, and are willing to participate in the study and provide informed consent .
2. Estimated survival of at least 24 hours at the discretion of enrolling physician

Exclusion Criteria for Anticoagulation Hypothesis

1. Weight <40 Kilogram (kg)
2. Overt bleeding at the day of enrollment
3. Known major bleeding within 30 days (according to the Bleeding Academic Research Consortium (BARC) definition, Appendix A)
4. Platelet count <50,000/Fl
5. Pregnancy (as confirmed by Beta human chorionic gonadotropin (HCG) testing among female patients <50 years)
6. Patients on Extracorporeal Membrane Oxygenation (ECMO)
7. History of heparin induced thrombocytopenia or immune thrombocytopenia
8. Ischemic stroke within the past 2 weeks
9. Craniotomy/major neurosurgery within the past 3 months
10. Major head or spinal trauma in the past 30 days
11. Known brain metastases or vascular malformations (aneurysm)
12. Presence of an epidural, spinal or pericardial catheter
13. Major surgery other than neurosurgery within 14 days prior to enrollment
14. Coexistence of severe obesity (weight >120 kg or BMI>35 kg/m2 along with severe renal insufficiency defined as creatinine clearance (CrCl) <30 mL/sec)
15. Allergic reaction to study medications
16. Lack or withdrawal of informed consent

Inclusion Criteria for the Statin Randomization

1. Patients enrolled for the anticoagulation randomization
2. Willingness to participation in the study and providing informed consent

Exclusions Criteria for the Statin Randomization

1. Baseline liver function tests> 3 times upper normal limits (ULN) or creatine kinase (CK) >500 U/L
2. Active liver disease (LFT>3 ULN plus histologic finding including cirrhosis or inflammation or necrosis)
3. Routine use of statins prior to the index hospitalization
4. Previous documented statin intolerance

Trial design

Primary purpose: Treatment

Allocation: Randomized

Interventional model: Factorial Assignment

Masking: Single Blind

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600 participants in 4 patient groups, including a placebo group

Intermediate dose anticoagulation

Experimental group

Description:

Intermediate dose anticoagulation will be the the tested regimen. The anticoagulation regimen will be modified according to weight/ body mass index, and creatinine clearance level (Cl Cr). Enoxaparin will be the primary agent for anticoagulation, with unfractionated heparin reserved only for patients with creatinine clearance of ≤15 mL/min according to Cockcroft-Gault Formula.

Treatment:

Drug: intermediate dose Enoxaparin/ unfractionated heparin

Standard Prophylaxis

Active Comparator group

Description:

Standard prophylaxis dose anticoagulation will be the anticoagulation of choice in the control arm. Enoxaparin will be the primary agent for anticoagulation, with unfractionated heparin reserved only for patients with creatinine clearance of ≤15 mL/min according Cockcroft-Gault Formula.

Treatment:

Drug: standard prophylactic dose Enoxaparin/ unfractionated heparin

Atorvastatin 20

Experimental group

Description:

Atorvastatin 20 mg daily will be the statin therapy of choice in the intervention arm

Treatment:

Drug: Atorvastatin 20mg

Atorvastatin 20 mg Matched placebo

Placebo Comparator group

Description:

Matching placebo will be used for the control arm

Treatment:

Drug: Matched placebo