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Thromb Haemost 2021; 121(12): 1684-1695
DOI: 10.1055/a-1475-2351
Trial Protocol Design Paper

Treatment-Dose LMWH versus Prophylactic/Intermediate Dose Heparins in High-Risk COVID-19 Inpatients: Rationale and Design of the HEP-COVID Trial

Mark Goldin
1   Institute of Health Innovations and Outcomes Research, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, New York, United States
2   Department of Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, United States
,
Dimitrios Giannis
1   Institute of Health Innovations and Outcomes Research, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, New York, United States
,
Wassim Diab
2   Department of Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, United States
,
Janice Wang
1   Institute of Health Innovations and Outcomes Research, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, New York, United States
2   Department of Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, United States
,
Sameer Khanijo
2   Department of Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, United States
,
Gulru Sharifova
2   Department of Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, United States
,
Marc Cohen
3   Department of Medicine, Newark Beth Israel Medical Center, Newark, New Jersey, United States
,
Jeet M. Lund
4   Wellspan York Hospital, York, Pennsylvania, United States
,
Andrea Mignatti
2   Department of Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, United States
5   Department of Cardiology, Lenox Hill Hospital, Northwell Health, New York, New York, United States
,
Eugenia Gianos
2   Department of Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, United States
5   Department of Cardiology, Lenox Hill Hospital, Northwell Health, New York, New York, United States
,
Alfonso Tafur
6   Department of Medicine and Vascular Medicine, NorthShore University Health System, Evanston, Illinois, United States
7   Division of Cardiology, University of Chicago, Pritzker School of Medicine, Chicago, Illinois, United States
,
Paul A. Lewis
8   Evidence Based Medicine, Baycare Health System, Clearwater, Florida, United States
,
Kevin Cohoon
9   Division of Cardiovascular Medicine, Department of Medicine, Froedtert and Medical College of Wisconsin, Milwaukee, Wisconsin, United States
,
John M. Kittelson
10   Department of Biostatistics and Informatics, Colorado School of Public Health, University of Colorado Anschutz Medical Campus, Aurora, Colorado, United States
,
Martin L. Lesser
1   Institute of Health Innovations and Outcomes Research, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, New York, United States
2   Department of Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, United States
,
Cristina P. Sison
1   Institute of Health Innovations and Outcomes Research, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, New York, United States
2   Department of Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, United States
,
Husneara Rahman
1   Institute of Health Innovations and Outcomes Research, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, New York, United States
,
Kanta Ochani
1   Institute of Health Innovations and Outcomes Research, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, New York, United States
,
William R. Hiatt   †
11   Biostatistics, Colorado Prevention Center (CPC) Clinical Research, Aurora, Colorado, United States
12   Division of Cardiology, University of Colorado, School of Medicine, Aurora, Colorado, United States
,
Rita A. Dale
11   Biostatistics, Colorado Prevention Center (CPC) Clinical Research, Aurora, Colorado, United States
,
Victoria E. Anderson
11   Biostatistics, Colorado Prevention Center (CPC) Clinical Research, Aurora, Colorado, United States
,
Marc Bonaca
11   Biostatistics, Colorado Prevention Center (CPC) Clinical Research, Aurora, Colorado, United States
12   Division of Cardiology, University of Colorado, School of Medicine, Aurora, Colorado, United States
,
Jonathan L. Halperin
13   Department of Cardiovascular Medicine, The Cardiovascular Institute, Mount Sinai Medical Center, New York, New York, United States
,
Jeffrey I. Weitz
14   Department of Medicine, McMaster University, Hamilton, Ontario, Canada
15   Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada
16   Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada
,
Alex C. Spyropoulos
1   Institute of Health Innovations and Outcomes Research, The Feinstein Institutes for Medical Research, Northwell Health, Manhasset, New York, United States
2   Department of Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York, United States
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Abstract

Coronavirus disease-2019 (COVID-19) has been associated with significant risk of venous thromboembolism (VTE), arterial thromboembolism (ATE), and mortality particularly among hospitalized patients with critical illness and elevated D-dimer (Dd) levels. Conflicting data have yet to elucidate optimal thromboprophylaxis dosing. HEP-COVID (NCT04401293) is a phase 3, multicenter, pragmatic, prospective, randomized, pseudo-blinded, active control trial to evaluate efficacy and safety of therapeutic-dose low-molecular-weight heparin (LMWH) versus prophylactic-/intermediate-dose LMWH or unfractionated heparin (UFH) for prevention of a primary efficacy composite outcome of VTE, ATE, and all-cause mortality 30 ± 2 days post-enrollment. Eligible patients have COVID-19 diagnosis by nasal swab or serologic testing, requirement for supplemental oxygen per investigator judgment, and Dd >4 × upper limit of normal (ULN) or sepsis-induced coagulopathy score ≥4. Subjects are randomized to enoxaparin 1 mg/kg subcutaneous (SQ)/two times a day (BID) (creatinine clearance [CrCl] ≥ 30 mL/min) or 0.5 mg/kg (CrCl 15–30 mL/min) versus local institutional prophylactic regimens including (1) UFH up to 22,500 IU (international unit) daily (divided BID or three times a day), (2) enoxaparin 30 and 40 mg SQ QD (once daily) or BID, or (3) dalteparin 2,500 IU or 5,000 IU QD. The principal safety outcome is major bleeding. Events are adjudicated locally. Based on expected 40% relative risk reduction with treatment-dose compared with prophylactic-dose prophylaxis, 308 subjects will be enrolled (assuming 20% drop-out) to achieve 80% power. Distinguishing design features include an enriched population for the composite endpoint anchored on Dd >4 × ULN, stratification by intensive care unit (ICU) versus non-ICU, and the ability to capture asymptomatic proximal deep venous thrombosis via screening ultrasonography prior to discharge.

Keywords

coronavirus disease-2019 - venous thromboembolism - arterial thromboembolism - thromboprophylaxis - D-dimer

† Deceased.




Publication History

Received: 22 January 2021

Accepted: 01 April 2021

Accepted Manuscript online:
06 April 2021

Article published online:
28 May 2021

© 2021. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

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