Covid19
Conditions
Keywords
anticoagulation, statin
Brief summary
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.
Detailed 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.
Interventions
DRUGintermediate dose Enoxaparin/ unfractionated heparin
Intermediate dose anticoagulation according to creatinine clearance and weight
DRUGstandard prophylactic dose Enoxaparin/ unfractionated heparin
Standard prophylaxis anticoagulation according to creatinine clearance and weight
DRUGAtorvastatin 20mg
Statin
DRUGMatched placebo
Matched placebo to atorvastatin 20 mg
Sponsors
Brigham and Women's Hospital
Tehran Heart Center
Masih Daneshvari Hospital
Hazrat Rasool Hospital
Modarres Hospital
Firuzgar hospital affiliated to Iran University of Medical Sciences
Imam Khomeini Hospital
Sina Hospital, Iran
Tabriz University of Medical Sciences
Shariati Hospital
Imam Ali Hospital
Labbafinejhad Hospital
Rajaie Cardiovascular Medical and Research Center
Study design
Allocation
RANDOMIZED
Intervention model
FACTORIAL
Primary purpose
TREATMENT
Masking
SINGLE (Outcomes Assessor)
Masking description
For the first hypothesis, allocation sequence concealment and blinded endpoint adjudication. For the second hypothesis, allocation sequence concealment, double-blind medication administration, and blinded endpoint adjudication.
Intervention model description
1:1 multicenter open-label 2x2 factorial design randomized controlled trial with allocation sequence concealment and blinded endpoint adjudication.
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
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
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| a composite of acute VTE, arterial thrombosis, treatment with ECMO, or all-cause mortality | 30 days from enrollment | composite of adjudicated 30-day acute VTE, arterial thrombosis, treatment with extracorporeal membrane oxygenation (ECMO), or all-cause mortality. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Rate of objectively-confirmed VTE | 30 days from enrollment | Distal or proximal deep vein thrombosis which has been confirmed by ultrasonography or venography/ PE confirmed by at least one CTPA or lung scan |
| Ventilator free days | 30 days from enrollment | Difference between days of ICU stay and days on invasive mechanical ventilation |
| Rate of major bleeding | 30 days from enrollment | According to the Bleeding Academic Research Consortium (BARC 3 or 5 bleeding) |
| Rate of clinically-relevant non-major bleeding | 30 days from enrollment | Clinically-significant bleeding, not fulfilling criteria for major bleeding) |
| Rate of severe thrombocytopenia | 30 days from enrollment | Platelet count \<20.000 |
| Rate of rise in liver enzymes | 30 days from enrollment | Increase liver function tests 3 times greater than upper limit of normal |
| Clinically-diagnosed myopathy | 30 days from enrollment | Assessed by clinical and biomarker tests according to the treating physicians. |
| Objectively-confirmed arterial thrombosis | 30 days from enrollment | Imaging confirmed acute arterial thrombosis (by ultrasonography, CT, MRI, or invasive angiography) |
| Rate of all-cause mortality | 30 days from enrollment | Patient status regarding to being alive or dead at the end of 30-day follow up |
Other
| Measure | Time frame | Description |
|---|---|---|
| Rate of objectively clinically-diagnosed type I acute myocardial infarction | 30 days from enrollment | According to the fourth universal definition of myocardial infraction and confirmed by coronary angiography, intravascular imaging or autopsy |
| Rate of objectively clinically -diagnosed stroke | 30 days from enrollment | Any stroke episode which has been confirmed with appropriate diagnostic imaging (brain CT and/or brain MRI) |
| Rate of objectively clinically -diagnosed acute peripheral arterial thrombosis | 30 days from enrollment | Imaging confirmed acute peripheral arterial thrombosis (by ultrasonography, CT, MRI, or invasive angiography) |
| Median ICU length of stay | 30 days from enrollment | Number of days that a patient has stayed in the ICU |
| ICU discharge status | 30 days from enrollment | Status of patients regarding to mortality (alive/dead) at the time of discharge from ICU |
| Incident atrial fibrillation | 30 days from enrollment | Any AF episode which has been confirmed by at least one ECG or telemetry monitoring, in patients without prior history of AF |
| Rate of need for renal replacement therapy | 30 days from enrollment | Use hemodialysis or veno-venous hemofiltration or peritoneal dialysis for a patient during the hospitalization period, due to acute kidney injury |
| Post-COVID-19 Functional Status | 60 and 90 -day | Based on Post-COVID-19 Functional Status questionnaire, which varies fro score 0 to 4, and higher scores mean worse outcome. |
Countries
Iran
Outcome results
None listed