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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

 

  • References

  • 1 Novel Coronavirus. (2019-nCoV) situation reports [Internet]. [cited 2020 Dec 28]. Accessed April 18, 2021 at: https://www.who.int/emergencies/diseases/novel-coronavirus-2019/situation-reports
    Google Scholar
  • 2 Klok FA, Kruip MJHA, van der Meer NJM. et al. Confirmation of the high cumulative incidence of thrombotic complications in critically ill ICU patients with COVID-19: An updated analysis. Thromb Res 2020; 191: 148-150
    CrossrefPubMedGoogle Scholar
  • 3 Hanif A, Khan S, Mantri N. et al. Thrombotic complications and anticoagulation in COVID-19 pneumonia: a New York City hospital experience. Ann Hematol 2020; 99 (10) 2323-2328
    CrossrefPubMedGoogle Scholar
  • 4 Bilaloglu S, Aphinyanaphongs Y, Jones S, Iturrate E, Hochman J, Berger JS. Thrombosis in hospitalized patients with COVID-19 in a New York City health system. JAMA 2020; 324 (08) 799-801
    CrossrefPubMedGoogle Scholar
  • 5 Spyropoulos AC, Weitz JI. Hospitalized COVID-19 patients and venous thromboembolism: a perfect storm. Circulation 2020; 142 (02) 129-132
    CrossrefPubMedGoogle Scholar
  • 6 Bikdeli B, Madhavan MV, Gupta A. et al; Global COVID-19 Thrombosis Collaborative Group. Pharmacological agents targeting thromboinflammation in COVID-19: review and implications for future research. Thromb Haemost 2020; 120 (07) 1004-1024
    Article in Thieme ConnectPubMedGoogle Scholar
  • 7 Bikdeli B, Madhavan MV, Jimenez D. et al; Global COVID-19 Thrombosis Collaborative Group, Endorsed by the ISTH, NATF, ESVM, and the IUA, Supported by the ESC Working Group on Pulmonary Circulation and Right Ventricular Function. COVID-19 and thrombotic or thromboembolic disease: implications for prevention, antithrombotic therapy, and follow-up: JACC state-of-the-art review. J Am Coll Cardiol 2020; 75 (23) 2950-2973
    CrossrefPubMedGoogle Scholar
  • 8 Manne BK, Denorme F, Middleton EA. et al. Platelet gene expression and function in patients with COVID-19. Blood 2020; 136 (11) 1317-1329
    CrossrefPubMedGoogle Scholar
  • 9 Giannis D, Ziogas IA, Gianni P. Coagulation disorders in coronavirus infected patients: COVID-19, SARS-CoV-1, MERS-CoV and lessons from the past. J Clin Virol 2020; 127: 104362
    CrossrefPubMedGoogle Scholar
  • 10 Tang N, Bai H, Chen X, Gong J, Li D, Sun Z. Anticoagulant treatment is associated with decreased mortality in severe coronavirus disease 2019 patients with coagulopathy. J Thromb Haemost 2020; 18 (05) 1094-1099
    CrossrefPubMedGoogle Scholar
  • 11 Wichmann D, Sperhake J-P, Lütgehetmann M. et al. Autopsy findings and venous thromboembolism in patients with COVID-19: a prospective cohort study. Ann Intern Med 2020; 173 (04) 268-277
    CrossrefPubMedGoogle Scholar
  • 12 Lax SF, Skok K, Zechner P. et al. Pulmonary arterial thrombosis in COVID-19 with fatal outcome: results from a prospective, single-center, clinicopathologic case series. Ann Intern Med 2020; 173 (05) 350-361
    CrossrefPubMedGoogle Scholar
  • 13 Helms J, Tacquard C, Severac F. et al; CRICS TRIGGERSEP Group (Clinical Research in Intensive Care and Sepsis Trial Group for Global Evaluation and Research in Sepsis). High risk of thrombosis in patients with severe SARS-CoV-2 infection: a multicenter prospective cohort study. Intensive Care Med 2020; 46 (06) 1089-1098
    CrossrefPubMedGoogle Scholar
  • 14 Tang N, Li D, Wang X, Sun Z. Abnormal coagulation parameters are associated with poor prognosis in patients with novel coronavirus pneumonia. J Thromb Haemost 2020; 18 (04) 844-847
    CrossrefPubMedGoogle Scholar
  • 15 Paranjpe I, Fuster V, Lala A. et al. Association of treatment dose anticoagulation with in-hospital survival among hospitalized patients with COVID-19. J Am Coll Cardiol 2020; 76 (01) 122-124
    CrossrefPubMedGoogle Scholar
  • 16 Stessel B, Vanvuchelen C, Bruckers L. et al. Impact of implementation of an individualised thromboprophylaxis protocol in critically ill ICU patients with COVID-19: a longitudinal controlled before-after study. Thromb Res 2020; 194: 209-215
    CrossrefPubMedGoogle Scholar
  • 17 Nadkarni GN, Lala A, Bagiella E. et al. Anticoagulation, bleeding, mortality, and pathology in hospitalized patients with COVID-19. J Am Coll Cardiol 2020; 76 (16) 1815-1826
    CrossrefPubMedGoogle Scholar
  • 18 Spyropoulos AC, Levy JH, Ageno W. et al; Subcommittee on Perioperative, Critical Care Thrombosis, Haemostasis of the Scientific, Standardization Committee of the International Society on Thrombosis and Haemostasis. Scientific and Standardization Committee communication: clinical guidance on the diagnosis, prevention, and treatment of venous thromboembolism in hospitalized patients with COVID-19. J Thromb Haemost 2020; 18 (08) 1859-1865
    CrossrefPubMedGoogle Scholar
  • 19 Moores LK, Tritschler T, Brosnahan S. et al. Prevention, diagnosis, and treatment of VTE in patients with coronavirus disease 2019: CHEST guideline and expert panel report. Chest 2020; 158 (03) 1143-1163
    CrossrefPubMedGoogle Scholar
  • 20 Fernández-Capitán C, Barba R, Díaz-Pedroche MDC. et al. Presenting characteristics, treatment patterns, and outcomes among patients with venous thromboembolism during hospitalization for COVID-19. Semin Thromb Hemost 2021; 47 (04) 351-361
    Article in Thieme ConnectPubMedGoogle Scholar
  • 21 Merli G, Spiro TE, Olsson CG. et al; Enoxaparin Clinical Trial Group. Subcutaneous enoxaparin once or twice daily compared with intravenous unfractionated heparin for treatment of venous thromboembolic disease. Ann Intern Med 2001; 134 (03) 191-202
    CrossrefPubMedGoogle Scholar
  • 22 Gargiulo G, Carrara G, Frigoli E. et al. Bivalirudin or heparin in patients undergoing invasive management of acute coronary syndromes. J Am Coll Cardiol 2018; 71 (11) 1231-1242
    CrossrefPubMedGoogle Scholar
  • 23 Cohoon KP, Mahé G, Tafur AJ, Spyropoulos AC. Emergence of institutional antithrombotic protocols for coronavirus 2019. Res Pract Thromb Haemost 2020; 4 (04) 510-517
    CrossrefPubMedGoogle Scholar
  • 24 Cuker A, Arepally GM, Chong BH. et al. American Society of Hematology 2018 guidelines for management of venous thromboembolism: heparin-induced thrombocytopenia. Blood Adv 2018; 2 (22) 3360-3392
    CrossrefPubMedGoogle Scholar
  • 25 Raskob GE, Spyropoulos AC, Cohen AT. et al. Association between asymptomatic proximal deep vein thrombosis and mortality in acutely ill medical patients. J Am Heart Assoc 2021; 10 (05) e019459
    CrossrefPubMedGoogle Scholar
  • 26 Emerson SS, Fleming TR. Symmetric group sequential test designs. Biometrics 1989; 45 (03) 905-923
    CrossrefPubMedGoogle Scholar
  • 27 Poissy J, Goutay J, Caplan M. et al; Lille ICU Haemostasis COVID-19 Group. Pulmonary embolism in patients with COVID-19: awareness of an increased prevalence. Circulation 2020; 142 (02) 184-186
    CrossrefPubMedGoogle Scholar
  • 28 Cohen SL, Gianos E, Barish MA. et al; Northwell Health COVID-19 Research Consortium. Prevalence and predictors of venous thromboembolism or mortality in hospitalized COVID-19 patients. Thromb Haemost 2021; 121 (08) 1043-1053
    Article in Thieme ConnectPubMedGoogle Scholar
  • 29 Spyropoulos AC, Weitz JI. Hospitalized COVID-19 patients and venous thromboembolism: a perfect storm. Circulation 2020; 142 (02) 129-132
    CrossrefPubMedGoogle Scholar
  • 30 Lemos ACB, do Espírito Santo DA, Salvetti MC. et al. Therapeutic versus prophylactic anticoagulation for severe COVID-19: a randomized phase II clinical trial (HESACOVID). Thromb Res 2020; 196: 359-366
    CrossrefPubMedGoogle Scholar
  • 31 Motta JK, Ogunnaike RO, Shah R. et al. Clinical outcomes with the use of prophylactic versus therapeutic anticoagulation in COVID-19. medRxiv [Internet] Cold Spring Harbor Laboratory Press; 2020 [cited 2020 Sep 14]. Accessed April 18, 2021 at: https://www.medrxiv.org/content/10.1101/2020.07.20.20147769v1
    Google Scholar
  • 32 Loo J, Spittle DA, Newnham M. COVID-19, immunothrombosis and venous thromboembolism: biological mechanisms. Thorax 2021; 76: 412-420
    CrossrefPubMedGoogle Scholar
  • 33 Tritschler T, Mathieu M-E, Skeith L. et al; International Network of VENous Thromboembolism Clinical Research Networks INVENT-VTE. Anticoagulant interventions in hospitalized patients with COVID-19: a scoping review of randomized controlled trials and call for international collaboration. J Thromb Haemost 2020; 18 (11) 2958-2967
    CrossrefPubMedGoogle Scholar
  • 34 National Institutes of Health.. NIH ACTIV Trial of blood thinners pauses enrollment of critically ill COVID-19 patients [Internet]. Natl. Inst. Health NIH. 2020 [cited 2021 Jan 15]. Accessed April 18, 2021 at: https://www.nih.gov/news-events/news-releases/nih-activ-trial-blood-thinners-pauses-enrollment-critically-ill-covid-19-patients
    Google Scholar