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.
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.
Drug: intermediate dose Enoxaparin/ unfractionated heparin
Intermediate dose anticoagulation according to creatinine clearance and weight
Other Name: Intermediate dose anticoagulation
Drug: standard prophylactic dose Enoxaparin/ unfractionated heparin
Standard prophylaxis anticoagulation according to creatinine clearance and weight
Other Name: Standard dose prophylaxis anticoagulation
Drug: Atorvastatin 20mg
Statin
Other Name: Statin
Drug: Matched placebo
Matched placebo to atorvastatin 20 mg
Other Name: Statin
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
Masih Daneshvari Hospital
Tehran, Iran, Islamic Republic of