Safety and Efficacy of Therapeutic Anticoagulation on Clinical Outcomes in Hospitalized Patients With COVID-19

Study Overview
=================
Brief Summary
-----------------
The coronavirus disease 2019 (COVID-19) global pandemic caused by the severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) has caused considerable morbidity and mortality in over 170 countries. Increasing age and burden of cardiovascular comorbidities are associated with a worse prognosis among patients with COVID-19. In addition, serologic markers of more severe disease including coagulation abnormalities and thrombocytopenia, are not uncommon among patients hospitalized with severe COVID-19 infection and are more common in patients who died in-hospital. As the COVID-19 pandemic continues to grow, there is a pressing need to identify safe, effective, and widely available therapies that can be scaled and rapidly incorporated into clinical practice. Understanding the putative mechanism of increased mortality risk associated with abnormal coagulation function and cardiac injury is critical to guide studies of promising therapeutic interventions. Published and anecdotal reports indicate that endothelial dysfunction and thrombosis are common in critically ill patients with COVID-19, including reports of diffuse microvascular thrombosis in the lungs, heart, liver, and kidneys. Patients with cardiovascular disease (CVD) and CVD risk factors are known to have endothelial dysfunction and a heightened risk of thrombosis. A recent study of COVID-19 inpatients from Wuhan, China observed that an elevated D-dimer level greater than 1 ug/mL was associated with an 18 times higher risk of in-hospital death, underscoring the importance of increased coagulation activity as a potential modifiable risk marker that may drive end-organ injury. Given the established link between endothelial dysfunction and thrombosis in patients with cardiovascular disease, and the association between coagulopathy and adverse outcomes in patients with sepsis, the association between increased coagulation activity, end-organ injury, and mortality risk may represent a modifiable risk factor among COVID-19 patients with critical illness. Therefore, we propose to conduct a randomized, open-label trial of therapeutic anticoagulation in COVID-19 patients with an elevated D-dimer to evaluate the efficacy and safety.

Detailed Description
-----------------
Patients identified as eligible through discussions with the primary care team and review of the electronic medical record will be approached and consented as described above in Subject Enrollment and Procedures for obtaining consent. For research purposes, 20mL of blood will be drawn and stored for biobanking at the following timepoints: at baseline (i.e., after enrollment and before randomization), 5-7 days post-randomization, and on the day of discharge. After enrollment and blood collection, patients will then be randomized to therapeutic anticoagulation (LMWH for most subjects but UFH for those with morbid obesity or moderate to severe renal dysfunction as noted below) or standard of care. Based on the MGH COVID-19 Treatment Guidance document, the risk stratification recommends daily complete blood count (CBC), comprehensive metabolic panel (CMP), creatine kinase (CPK), ferritin, C-reactive protein (CRP), and erythrocyte sedimentation rate (ESR). In addition, PT, PTT, fibrinogen, and D-dimer are recommended to be checked every other day if in the ICU or daily if elevated. Given that by virtue of the inclusion criteria of our study (i.e., a D-dimer >1ug/mL), all of our patients will be within Category 3 and all of the above markers will be obtained for clinical purposes and thus will also be documented for research purposes. For clinical risk stratification, LDH is to be checked daily if elevated and troponin to be checked q2-3d if elevated. If clinically indicated, procalcitonin will be measured and IL-6 obtained in patients in Category 2 or 3 disease severity. If measured for clinical purposes, LDH, troponin, procalcitonin, and IL-6 will be recorded for research purposes.

Official Title
-----------------
A Randomized, Open-Label Trial of Therapeutic Anticoagulation in COVID-19 Patients With an Elevated D-Dimer

Conditions
-----------------
Cardiovascular Diseases, COVID-19

Intervention / Treatment
-----------------
* Drug: Enoxaparin


Participation Criteria
=================
Eligibility Criteria
-----------------
Inclusion: COVID-19 positive on admission or during hospitalization (having been tested within the past 5 days) with symptoms consistent with COVID-19 including fever (≥ 38C, 100.4F), pneumonia, symptoms of lower respiratory illness (e.g., cough, difficulty breathing), loss of smell or taste, myalgias, pharyngitis, or diarrhea Admitted to the regular medical floor or intensive care unit (ICU) without severe ARDS (P/F ratio<100) Elevated D-dimer (>1.5g/mL) Age>18 years and not older than 90 Fibrinogen >100 Platelets >50,000 No prior intracranial hemorrhage or recent ischemic stroke or TIA within 6 months D-dimer > 1500 ng/ml No other clinical indication for therapeutic anticoagulation (e.g., deep vein thrombosis [DVT], pulmonary embolism [PE], atrial fibrillation, acute coronary syndromes, or extracorporeal membrane oxygenation) Exclusion: Disseminated intravascular coagulation (DIC) according to the International Society on Thrombosis and Hemostasis overt DIC definition Hemoglobin (Hgb) <8 g/dl Hypersensitivity to heparin or heparin formulation including heparin-induced thrombocytopenia Thrombocytopenia: platelets<50,000 platelets/ul Uncontrolled or active/recent bleeding including intracranial hemorrhage, signs of active bleeding (e.g., blood transfusion within 30 days), any GI bleed within the past 6 months, or internal bleeding within the past 1 month High bleeding risk: significant closed-head or facial trauma within 3 months, traumatic or prolonged CPR (>10min), or use of dual anti-platelet therapy Known or suspected pregnancy Recent (<48 hours) or planned spinal or epidural anesthesia or puncture If the patient is on other anticoagulants, antihistamines, nonsteroidal anti-inflammatory drugs (i.e. aspirin) or hydroxychloroquine Uncontrolled hypertension

Ages Eligible for Study
-----------------
Minimum Age: 18 Years

Sexes Eligible for Study
-----------------
All

Accepts Healthy Volunteers
-----------------
No

Study Plan
=================
How is the study designed?
-----------------

Design Details

Primary Purpose: Treatment
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: randomized 1:1
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Therapeutic Anticoagulation Group<br>Patients identified as eligible through discussions with the primary care team and review of the electronic medical record will be approached and consented as described above in Subject Enrollment and Procedures for obtaining consent. For research purposes, 20ml of blood will be drawn and stored for biobanking at the following timepoints: at baseline (i.e., after enrollment and before randomization), 5-7 days post-randomization, and on the day of discharge. The blood sample taken at baseline will also be used to conduct a pregnancy test for women of childbearing age. After enrollment and blood collection, patients will then be randomized to therapeutic anticoagulation (LMWH for most subjects but UFH for those with morbid obesity or moderate to severe renal dysfunction as noted below) or standard of care anticoagulation. Those assigned to the therapeutic anticoagulation group will receive a higher dose of heparin. | Drug: Enoxaparin<br>* Given the established link between endothelial dysfunction and thrombosis in patients with cardiovascular disease9, 10 and the association between coagulopathy and adverse outcomes in patients with sepsis11, the association between increased coagulation activity, end-organ injury, and mortality risk may represent a modifiable risk factor among COVID-19 patients with critical illness. Therefore, we propose to conduct a randomized, open-label trial of therapeutic anticoagulation in COVID-19 patients with an elevated D-dimer to evaluate the efficacy. Most patients will receive low molecular weight heparin however, unfractionated heparin (UFH) will be administered for those with morbid obesity or moderate to severe renal dysfunction.<br>* Other names: Low molecular weight heparin;|
| Active Comparator: Standard of Care Anticoagulation Group<br>Patients identified as eligible through discussions with the primary care team and review of the electronic medical record will be approached and consented as described above in Subject Enrollment and Procedures for obtaining consent. For research purposes, 20ml of blood will be drawn and stored for biobanking at the following timepoints: at baseline (i.e., after enrollment and before randomization), 5-7 days post-randomization, and on the day of discharge. The blood sample taken at baseline will also be used to conduct a pregnancy test for women of childbearing age. After enrollment and blood collection, patients will then be randomized to therapeutic anticoagulation or standard of care anticoagulation. Those assigned to the standard of care anticoagulation group will receive the normal dose of heparin as per the Mass General guidelines. | Drug: Enoxaparin<br>* Given the established link between endothelial dysfunction and thrombosis in patients with cardiovascular disease9, 10 and the association between coagulopathy and adverse outcomes in patients with sepsis11, the association between increased coagulation activity, end-organ injury, and mortality risk may represent a modifiable risk factor among COVID-19 patients with critical illness. Therefore, we propose to conduct a randomized, open-label trial of therapeutic anticoagulation in COVID-19 patients with an elevated D-dimer to evaluate the efficacy. Most patients will receive low molecular weight heparin however, unfractionated heparin (UFH) will be administered for those with morbid obesity or moderate to severe renal dysfunction.<br>* Other names: Low molecular weight heparin;|

What is the study measuring?
-----------------
Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Number of patients with the composite efficacy endpoint of death, cardiac arrest, symptomatic deep venous thrombosis, pulmonary embolism, arterial thromboembolism, myocardial infarction, or hemodynamic shock. | Aim 1 - Risk of death, cardiac arrest, symptomatic deep venous thrombosis, pulmonary embolism, arterial thromboembolism, myocardial infarction, or hemodynamic shock. | 12 weeks | 
| Number of patients with a major bleeding event according to the International Society on Thrombosis and Haemostasis (ISTH) definition. | Aim 2 - Risk of major bleeding event according to the International Society on Thrombosis and Haemostasis (ISTH) definition. | 12 weeks |