Full Dose Heparin Vs. Prophylactic Or Intermediate Dose Heparin in High Risk COVID-19 Patients
NCT ID: NCT04401293
Last Updated: 2021-11-22
Study Results
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View full resultsBasic Information
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COMPLETED
PHASE3
257 participants
INTERVENTIONAL
2020-04-26
2021-05-14
Brief Summary
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Detailed Description
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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.
Conditions
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Keywords
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Study Design
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RANDOMIZED
PARALLEL
TREATMENT
TRIPLE
Study Groups
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Full Dose LMWH anticoagulation therapy
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.
Enoxaparin
Full Dose LMWH anticoagulation therapy
Prophylactic/Intermediate Dose LMWH or UFH therapy
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.
Prophylactic/Intermediate Dose Enoxaparin
Prophylactic/Intermediate Dose LMWH or UFH therapy
Interventions
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Enoxaparin
Full Dose LMWH anticoagulation therapy
Prophylactic/Intermediate Dose Enoxaparin
Prophylactic/Intermediate Dose LMWH or UFH therapy
Other Intervention Names
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Eligibility Criteria
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Inclusion Criteria
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
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
18 Years
ALL
No
Sponsors
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Northwell Health
OTHER
Responsible Party
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Alex Spyropoulos
System Director - Anticoagulation and Clinical Thrombosis Services Northwell Health at Lenox Hill Hospital
Principal Investigators
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Alex C Spyropoulos, MD
Role: PRINCIPAL_INVESTIGATOR
Northwell Health
Locations
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Beth Israel Newark
Newark, New Jersey, United States
Southside Hospital
Bay Shore, New York, United States
Huntington Hospital
Huntington, New York, United States
Lenox Hill Hospital
New York, New York, United States
Long Island Jewish Medical Center
Queens, New York, United States
Staten Island University Hospital
Staten Island, New York, United States
Countries
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References
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Santos BC, Flumignan RL, Civile VT, Atallah AN, Nakano LC. Prophylactic anticoagulants for non-hospitalised people with COVID-19. Cochrane Database Syst Rev. 2023 Aug 16;8(8):CD015102. doi: 10.1002/14651858.CD015102.pub2.
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.
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.
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.
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.
Provided Documents
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Document Type: Study Protocol and Statistical Analysis Plan
Document Type: Informed Consent Form
Related Links
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Cardiovascular Considerations for Patients, Health Care Workers, and Health Systems During the Coronavirus Disease 2019 (COVID-19) Pandemic
Empirical systemic anticoagulation is associated with decreased venous thromboembolism in critically ill influenza A H1N1 acute respiratory distress syndrome patients
Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia
Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy
Prevalence of venous thromboembolism in patients with severe novel coronavirus pneumonia
Tissue Plasminogen Activator (tPA) Treatment for COVID-19 Associated Acute Respiratory Distress Syndrome (ARDS): A Case Series
Pharmacology of Heparin and Related Drugs
Incidence of thrombotic complications in critically ill ICU patients with COVID-19
Bivalirudin or Heparin in Patients Undergoing Invasive Management of Acute Coronary Syndromes
Emergence of Institutional Antithrombotic Protocols for Coronavirus 2019
Other Identifiers
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20-0340
Identifier Type: -
Identifier Source: org_study_id