Clinical trial NCT04401293: Full Dose Heparin Vs. Prophylactic Or Intermediate Dose Heparin in High Risk COVID-19 Patients
Official title: Systemic Anticoagulation With Full Dose Low Molecular Weight Heparin (LMWH) Vs. Prophylactic or Intermediate Dose LMWH in High Risk COVID-19 Patients (HEP-COVID Trial)
Study type: INTERVENTIONAL
Overall status: COMPLETED
Phase: PHASE3
Conditions: Sars-CoV2
COVID
Keywords: COVID-19
Anticoagulation
Heparin
Coronavirus
Thrombosis
Lead sponsor: Northwell Health
Sponsor class: OTHER
First posted: 2020-05-26
Enrollment: 257
Sex: ALL
Minimum age (years): 18
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: PARALLEL
Primary purpose: TREATMENT

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.

Eligibility criteria: Inclusion Criteria:

1. Subject (or legally authorized representative) provides written informed consent prior to initiation of any study procedures.
2. Understands and agrees to comply with planned study procedures.
3. Male or non-pregnant female adult ≥18 years of age at time of enrollment.
4. Subject consents to randomization within 72 hours of hospital admission or transfer from another facility within 72 hours of index presentation.
5. Subjects with a positive COVID-19 diagnosis by nasal swab or serologic testing.
6. Hospitalized with a requirement for supplemental oxygen.
7. Have:

   * Either a D- Dimer \> 4.0 X ULN, OR
   * Sepsis-induced coagulopathy (SIC) score of ≥4

Exclusion Criteria:

1. Indications for therapeutic anticoagulation
2. 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

Primary outcomes:
measure: Composite Outcome of Arterial Thromboembolic Events, Venous Thromboembolic Events and All-cause Mortality at Day 30 ± 2 Days.
timeFrame: Day 30 ± 2 days
Secondary outcomes:
measure: Major Bleeding
timeFrame: Day 30 ± 2 days
measure: Composite Outcome of Arterial Thromboembolic Events, Venous Thromboembolic Events and All-cause Mortality at Hospital Day 10 + 4
timeFrame: Day 10 + 4
measure: Sepsis-induced Coagulopathy (SIC) Score
timeFrame: Day 30 ± 2 days.
measure: Progression to Acute Respiratory Distress Syndrome (ARDS)
timeFrame: Day 30 ± 2 days.
measure: Need for Intubation
timeFrame: Day 30 ± 2 days.
measure: Re-hospitalization
timeFrame: Day 30 ± 2 days.
Other outcomes:
Locations:
city: Newark
country: United States
facility: Beth Israel Newark
state: New Jersey
city: Bay Shore
country: United States
facility: Southside Hospital
state: New York
city: Huntington
country: United States
facility: Huntington Hospital
state: New York
city: New York
country: United States
facility: Lenox Hill Hospital
state: New York
city: Queens
country: United States
facility: Long Island Jewish Medical Center
state: New York
city: Staten Island
country: United States
facility: Staten Island University Hospital
state: New York
Study officials:
affiliation: Northwell Health
name: Alex C Spyropoulos, MD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Flumignan RL, Civile VT, Tinoco JDS, Pascoal PI, Areias LL, Matar CF, Tendal B, Trevisani VF, Atallah AN, Nakano LC. Anticoagulants for people hospitalised with COVID-19. Cochrane Database Syst Rev. 2022 Mar 4;3(3):CD013739. doi: 10.1002/14651858.CD013739.pub2.
citation: Spyropoulos AC, Goldin M, Giannis D, Diab W, Wang J, Khanijo S, Mignatti A, Gianos E, Cohen M, Sharifova G, Lund JM, Tafur A, Lewis PA, Cohoon KP, Rahman H, Sison CP, Lesser ML, Ochani K, Agrawal N, Hsia J, Anderson VE, Bonaca M, Halperin JL, Weitz JI; HEP-COVID Investigators. Efficacy and Safety of Therapeutic-Dose Heparin vs Standard Prophylactic or Intermediate-Dose Heparins for Thromboprophylaxis in High-risk Hospitalized Patients With COVID-19: The HEP-COVID Randomized Clinical Trial. JAMA Intern Med. 2021 Dec 1;181(12):1612-1620. doi: 10.1001/jamainternmed.2021.6203.
citation: Short SAP, Gupta S, Brenner SK, Hayek SS, Srivastava A, Shaefi S, Singh H, Wu B, Bagchi A, Al-Samkari H, Dy R, Wilkinson K, Zakai NA, Leaf DE; STOP-COVID Investigators. d-dimer and Death in Critically Ill Patients With Coronavirus Disease 2019. Crit Care Med. 2021 May 1;49(5):e500-e511. doi: 10.1097/CCM.0000000000004917.
citation: Flumignan RL, Tinoco JDS, Pascoal PI, Areias LL, Cossi MS, Fernandes MI, Costa IK, Souza L, Matar CF, Tendal B, Trevisani VF, Atallah AN, Nakano LC. Prophylactic anticoagulants for people hospitalised with COVID-19. Cochrane Database Syst Rev. 2020 Oct 2;10(10):CD013739. doi: 10.1002/14651858.CD013739.