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

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.

Inclusion criteria

for Anticoagulation Hypothesis

• 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 .
• Estimated survival of at least 24 hours at the discretion of enrolling physician

Exclusion criteria

for Anticoagulation Hypothesis

• Weight <40 Kilogram (kg)
• Overt bleeding at the day of enrollment
• Known major bleeding within 30 days (according to the Bleeding Academic Research Consortium (BARC) definition, Appendix A)
• Platelet count <50,000/Fl
• Pregnancy (as confirmed by Beta human chorionic gonadotropin (HCG) testing among female patients <50 years)
• Patients on Extracorporeal Membrane Oxygenation (ECMO)
• History of heparin induced thrombocytopenia or immune thrombocytopenia
• Ischemic stroke within the past 2 weeks
• Craniotomy/major neurosurgery within the past 3 months
• Major head or spinal trauma in the past 30 days
• Known brain metastases or vascular malformations (aneurysm)
• Presence of an epidural, spinal or pericardial catheter
• Major surgery other than neurosurgery within 14 days prior to enrollment
• 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)
• Allergic reaction to study medications
• Lack or withdrawal of informed consent

Inclusion criteria

for the Statin Randomization

• Patients enrolled for the anticoagulation randomization
• Willingness to participation in the study and providing informed consent

Exclusions Criteria for the Statin Randomization

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