Full Dose Heparin Vs. Prophylactic Or Intermediate Dose Heparin in High Risk COVID-19 Patients

Phase 3

Completed

Conditions: Sars-CoV2
COVID

Interventions: Drug: Enoxaparin
Drug: Prophylactic/Intermediate Dose Enoxaparin

Registration Number: NCT04401293

Lead Sponsor: Northwell Health

Brief Summary: The aim of this study is to test the hypothesis that prophylaxis of severe COVID-19 patients with treatment dose LMWH leads to better thromboembolic-free outcomes and associated complications during hospitalization than prophylaxis with institutional standard of care with prophylactic to intermediate-doses of UFH or LMWH

Detailed Description: There are clinical data to support the observation that hospitalized acutely ill medical patients with severe viral pneumonitis/Acute Respiratory Distress Syndrome (ARDS), such as those with influenza H1N1 infection, have an over 23-fold increased risk for venous thromboembolism (VTE) - especially pulmonary embolism (PE) - with an overall 44% incidence of VTE in ARDS associated with H1N1 pneumonia. Multicenter studies from China report that key markers of inflammation and/or coagulopathy are associated with morbidity and increased mortality in COVID-19 patients. Elevated D-dimer levels (that are sometime greater than 4 or 6 times the upper limit of normal \[ULN\]) are strongly associated with mortality in patients with severe COVID-19 illness. Recent data also shows that mortality among COVID-19 patients is markedly higher in patients with elevated Troponin-T (TnT) levels than in patients with normal TnT levels. Recently a cohort of 81 patients retrospectively evaluated diagnosed with severe COVID-19 pneumonia and reported a lower extremity VTE incidence of 25% (20/81) and a mortality of 40% (8/20) in the presence of VTE. Reported a case of bilateral pulmonary embolism in a 75 year old woman diagnosed with severe COVID-19, in the absence of predisposing risk factors and a negative lower extremity US. Lastly the investigated use of Tissue Plasminogen Activator (tPA) in the treatment of COVID-19 associated ARDS and reported promising, but transient, results in terms of pulmonary function improvement. It appears that either the SARS-CoV2 infection itself induces a hypercoagulable state, possibly by hypofibrinolytic mechanisms, or the cytokine storm in COVID-19 patients with severe disease induces a prothrombotic state, which leads to clinical deterioration, hypoxia and hemodynamic instability secondary to thromboembolic phenomena and potentially cardiac ischemia. Preliminary data from Northwell Health System, which has one of the largest populations of hospitalized COVID-19 patients in the US, reveals a positivity rate for deep vein thrombosis (DVT) of 40% of those COVID-19 patients screened by Doppler compression ultrasonography of the lower extremities.

Heparin has been shown to have anti-inflammatory and immunomodulatory properties in addition to its anticoagulation effect, which could play a beneficial role in sepsis. In addition, there is in vitro evidence that the large negatively charged sulfated glycosaminoglycans of unfractionated heparin may act as an alternate ligand for the SARS-CoV2 receptor irrespective of ACE2. Whether this in vitro evidence supports the role of a protective or deleterious mechanism in COVID-19 infection is not known. However, an early report with empiric use of treatment dose unfractionated heparin (UFH) in ARDS from a different viral family, influenza H1N1, revealed that H1N1 ARDS patients under systemic anticoagulation had 33-fold fewer VTE events than those treated given prophylactic doses of UFH/low-molecular weight heparin (LMWH) thromboprophylaxis. Very recent evidence suggests that therapy with prophylactic to intermediate doses of the LMWH enoxaparin (30mg to 60mg QD) in severe hospitalized COVID-19 patents with a SIC score ≥ 4 or D-dimer (Dd) \> 6 X ULN improves outcomes and prognosis. All-cause mortality at 28 days was reduced from 64.2% to 40.0% in those patients with a SIC score ≥ 4 (p=0.029), and from 52.4% to 32.8% in those patients with an elevated Dd \> 6 x ULN (P=0.017). Notably, Klok and colleagues investigated 184 ICU patients infected with COVID-19 and reported a 13% mortality rate, a relatively high incidence of CTPA- or ultrasonography-confirmed VTE rate (27%), and arterial thrombotic events (3.7%) despite the use of standard dose thromboprophylaxis. Postulated mechanisms for the improved prognosis with the use of treatment doses of LMWH in the sick COVID-19 population include the decrease in the risk of microthrombi, especially in the pulmonary vasculature, which can lead to hypoxemia, pulmonary vasoconstriction and right ventricular dysfunction as well as the decrease in the risk of progression to disseminated intravascular coagulopathy as a contributor to the high mortality seen in these patients.

The optimal dose of heparin (either LMWH or UFH) in hospitalized COVID-19 patients is unknown, as patients on conventional prophylactic dose heparin (UFH or LMWH) as supported by international guidance statements on hospitalized COVID-19 patients appear to remain at risk for thromboembolic events. There is data to support improved efficacy with treatment doses of twice daily enoxaparin versus once-daily weight-adjusted enoxaparin for the management of VTE, especially with large thrombus burden. There is also long-standing data to support that treatment-dose heparin can reduce major cardiovascular events. Our current standard of care in our 24 hospital Northwell Health System, which has a very large hospitalized COVID-19 patient population, is to use Lovenox 40mg SQ QD for patients with a BMI \< 30 and Creatinine Clearance (CrCl) \> 15ml/min, Lovenox 40mg SQ BID for patients with a BMI \> 30 and CrCl \> 15ml/min, and UFH 5000U SQ BID or TID in patients with a CrCl \< 15ml/min and BMI \< 30 and UFH 7500U SQ BID or TID with a CrCl \< 15ml/min and BMI \> 30. Large healthcare institutions in the US and elsewhere have protocols for in-patient thromboprophylaxis ranging from prophylactic-to-intermediate dose UFH or LMWH for the management of patients with COVID-19 associated coagulopathy. The aim of this study is to test the hypothesis that prophylaxis of severe COVID-19 patients with treatment dose LMWH leads to better thromboembolic-free outcomes and associated complications during hospitalization than prophylaxis with institutional standard of care with prophylactic to intermediate-doses of UFH or LMWH.

Recruitment & Eligibility

Status: COMPLETED

Sex: All

Target Recruitment: 257

Inclusion Criteria

Subject (or legally authorized representative) provides written informed consent prior to initiation of any study procedures.
Understands and agrees to comply with planned study procedures.
Male or non-pregnant female adult ≥18 years of age at time of enrollment.
Subject consents to randomization within 72 hours of hospital admission or transfer from another facility within 72 hours of index presentation.
Subjects with a positive COVID-19 diagnosis by nasal swab or serologic testing.
Hospitalized with a requirement for supplemental oxygen.
Have:
- Either a D- Dimer > 4.0 X ULN, OR
- Sepsis-induced coagulopathy (SIC) score of ≥4

Exclusion Criteria

Indications for therapeutic anticoagulation
Absolute contraindication to anticoagulation including:
1. active bleeding,
2. recent (within 1 month) history of bleed,
3. dual (but not single) antiplatelet therapy,
4. active gastrointestinal and intracranial cancer,
5. a history of bronchiectasis or pulmonary cavitation,
6. Hepatic failure with a baseline INR > 1.5,
7. CrCl < 15ml/min,
8. a platelet count < 25,000,
9. a history of heparin-induced thrombocytopenia (HIT) within the past 100 days or in the presence of circulating antibodies,
10. contraindications to enoxaparin including a hypersensitivity to enoxaparin sodium, hypersensitivity to heparin or pork products, hypersensitivity to benzyl alcohol,
11. pregnant female,
12. inability to give or designate to give informed consent,
13. participation in another blinded trial of investigational drug therapy for COVID-19

Study & Design

Study Type: INTERVENTIONAL

Study Design: PARALLEL

Arm && Interventions

Group	Intervention	Description
Full Dose LMWH anticoagulation therapy	Enoxaparin	Subjects in this study arm will be treated with therapeutic doses of subcutaneous low-molecular-weight heparin (enoxaparin). Enoxaparin 1mg/kg SQ BID for CrCl ≥ 30ml/min (or Enoxaparin 0.5mg/kg SQ BID for CrCl ≥ 15ml/min and \< 30ml/min) during the course of their hospitalization.
Prophylactic/Intermediate Dose LMWH or UFH therapy	Prophylactic/Intermediate Dose Enoxaparin	Subjects in this study arm will be treated with Local institutional standard-of-care for prophylactic-dose or intermediate-dose UFH or LMWH. Regimens allowed are UFH up to 22,500 IU daily in BID or TID doses (i.e. UFH 5000 IU SQ BID/TID or 7500 IU BID/TID), enoxaparin 30mg and 40mg SQ QD or BID (the use of weight-based enoxaparin i.e. 0.5mg/kg SQ BID for this arm is acceptable but strongly discouraged), dalteparin 2500IU or 5000IU QD.

Primary Outcome Measures

Name	Time	Method
Composite Outcome of Arterial Thromboembolic Events, Venous Thromboembolic Events and All-cause Mortality at Day 30 ± 2 Days.	Day 30 ± 2 days	Risk of arterial thromboembolic events (including myocardial infarction, stroke, systemic embolism), venous thromboembolism (including symptomatic deep vein thrombosis (DVT) of the upper or lower extremity, asymptomatic proximal DVT of the lower extremity, non-fatal pulmonary embolism (PE)), and all-cause mortality at Day 30 ± 2 days.

Secondary Outcome Measures

Name	Time	Method
Major Bleeding	Day 30 ± 2 days	Risk of major bleeding defined using the International Society of Thrombosis and Haemostasis (ISTH) criteria
Composite Outcome of Arterial Thromboembolic Events, Venous Thromboembolic Events and All-cause Mortality at Hospital Day 10 + 4	Day 10 + 4	The composite of arterial thromboembolic events (including myocardial infarction, stroke, systemic embolism), venous thromboembolism (including symptomatic deep vein thrombosis (DVT) of the upper or lower extremity, asymptomatic proximal DVT of the lower extremity, non-fatal pulmonary embolism (PE)), and all-cause mortality at Hospital Day 10 + 4
Sepsis-induced Coagulopathy (SIC) Score	Day 30 ± 2 days.	Sepsis-induced coagulopathy (SIC) score predicts likelihood of sepsis-induced coagulopathy based on ISTH guidelines. The score uses the following domains: * Platelets, K/uL (thousands per microliter) * INR (International Normalized Ratio) * D-Dimer Level * Fibrinogen Platelet count \> 100 cells x 10\^9/L is 0 points, platelet count 50 to 100 cells x 10\^9/L is 1 point and Platelet count \< 50 cells x 10\^9/L is 2 points. INR \< 1.3 is 0 points, INR 1.3 to 1.7 is 1 point and INR \> 1.7 is 2 points. D-Dimer level \< 400 ng/mL is 0 points, D-Dimer level 400-4000 ng/mL is 2 points and D-Dimer level \> 4000 ng/mL is 3 points. Fibrinogen level \> 100 mg/dL is 0 points and fibrinogen level \< 100 mg/dL is 1 point. Calculated (SIC) scores yields a possible 0 to 6 points, where ≥4 predicts higher mortality rates within 30 days and greater risk of pulmonary embolism.
Progression to Acute Respiratory Distress Syndrome (ARDS)	Day 30 ± 2 days.	Progression to Acute Respiratory Distress Syndrome (ARDS) based on monitoring of patient conditions.
Need for Intubation	Day 30 ± 2 days.	Need for Intubation will be based on monitoring of patient conditions.
Re-hospitalization	Day 30 ± 2 days.	Need for Re-hospitalization will be based on monitoring of patient conditions.

Trial Locations

Locations (6): Lenox Hill Hospital
🇺🇸
New York, New York, United States
Beth Israel Newark
🇺🇸
Newark, New Jersey, United States
Staten Island University Hospital
🇺🇸
Staten Island, New York, United States
Southside Hospital
🇺🇸
Bay Shore, New York, United States
Huntington Hospital
🇺🇸
Huntington, New York, United States
Long Island Jewish Medical Center
🇺🇸
Queens, New York, United States