article Open Access (bronze) EN 2021-10-10

Efficacy and Safety of Therapeutic-Dose Heparin vs Standard Prophylactic or Intermediate-Dose Heparins for Thromboprophylaxis in High-risk Hospitalized Patients With COVID-19

Alex C. Spyropoulos, Mark Goldin, Dimitrios Giannis, Wassim Diab, Janice Wang, Sameer Khanijo, Andrea Mignatti, Eugenia Gianos, Marc Cohen, Gulru Sharifova, J Lund, Alfonso Tafur, Paul A. Lewis, Kevin P. Cohoon, Husneara Rahman, Cristina Sison, Martin Lesser, Kanta Ochani, Nirav Agrawal, Judith Hsia, Victoria E. Anderson, Marc P. Bonaca, Jonathan L. Halperin, Jeffrey I. Weitz, HEP-COVID Investigators, Lori Ohanesian, Michelle Glater, Christopher C.K. Ho, Annamaria Iakovou, Daniel Ying, Manile Dastagir, Alex Convissar, Seerat Aujla, Elizabeth Mathew, Vani Thiyagarajan, Tricia Lewis, Luis Gruberg, Paul Maccaro, Dana Kuziw, Bhumi Pandhi, George Surguladze, Ashley M. Eapen, A. Pantea, PHYLLIS SUEN, John P. Flynt, Michael Krzyzak, Kamal Sharma, Amanda Steadham, Sherry McLean, Karen Herring, Karen Maroney, Kambiz Zorriasateyn, Bernardo Vargas‐Leitón, Marisa Durante, Ujala Bhokary, Linda Pierchala, Elizabeth A. Fisher, Debi L. Oxenberg, Alison Sabados, Omair A. Chaudhary, Shelley Schultz, S. Cotey, Connie N. Hess, Hope Cruse, Daniel Uy, Sunita Sharma, Kevin Molina, Daliya Jagat, Bandyopadhyay Dehali

JAMA Internal Medicine, Vol. 181, Issue 12, pp. 1612–1612 (2021)

Northwell Health, Feinstein Institute for Medical Research, Sechenov University, Donald & Barbara Zucker School of Medicine at Hofstra/Northwell, Lenox Hill Hospital, Newark Beth Israel Medical Center, WellSpan York Hospital, Endeavor Health, University of Chicago, BayCare Health System, Froedtert Hospital, Medical College of Wisconsin, University of Colorado Anschutz, University of Colorado Denver, Mount Sinai Medical Center, Thrombosis and Atherosclerosis Research Institute, McMaster University

DOI: 10.1001/jamainternmed.2021.6203 PMID: 34617959

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Abstract

Importance: Hospitalized patients with COVID-19 are at risk for venous and arterial thromboembolism and death. Optimal thromboprophylaxis dosing in high-risk patients is unknown. Objective: To evaluate the effects of therapeutic-dose low-molecular-weight heparin (LMWH) vs institutional standard prophylactic or intermediate-dose heparins for thromboprophylaxis in high-risk hospitalized patients with COVID-19. Design, Setting, and Participants: The HEP-COVID multicenter randomized clinical trial recruited hospitalized adult patients with COVID-19 with D-dimer levels more than 4 times the upper limit of normal or sepsis-induced coagulopathy score of 4 or greater from May 8, 2020, through May 14, 2021, at 12 academic centers in the US. Interventions: Patients were randomized to institutional standard prophylactic or intermediate-dose LMWH or unfractionated heparin vs therapeutic-dose enoxaparin, 1 mg/kg subcutaneous, twice daily if creatinine clearance was 30 mL/min/1.73 m2 or greater (0.5 mg/kg twice daily if creatinine clearance was 15-29 mL/min/1.73 m2) throughout hospitalization. Patients were stratified at the time of randomization based on intensive care unit (ICU) or non-ICU status. Main Outcomes and Measures: The primary efficacy outcome was venous thromboembolism (VTE), arterial thromboembolism (ATE), or death from any cause, and the principal safety outcome was major bleeding at 30 ± 2 days. Data were collected and adjudicated locally by blinded investigators via imaging, laboratory, and health record data. Results: Of 257 patients randomized, 253 were included in the analysis (mean [SD] age, 66.7 [14.0] years; men, 136 [53.8%]; women, 117 [46.2%]); 249 patients (98.4%) met inclusion criteria based on D-dimer elevation and 83 patients (32.8%) were stratified as ICU-level care. There were 124 patients (49%) in the standard-dose vs 129 patients (51%) in the therapeutic-dose group. The primary efficacy outcome was met in 52 of 124 patients (41.9%) (28.2% VTE, 3.2% ATE, 25.0% death) with standard-dose heparins vs 37 of 129 patients (28.7%) (11.7% VTE, 3.2% ATE, 19.4% death) with therapeutic-dose LMWH (relative risk [RR], 0.68; 95% CI, 0.49-0.96; P = .03), including a reduction in thromboembolism (29.0% vs 10.9%; RR, 0.37; 95% CI, 0.21-0.66; P < .001). The incidence of major bleeding was 1.6% with standard-dose vs 4.7% with therapeutic-dose heparins (RR, 2.88; 95% CI, 0.59-14.02; P = .17). The primary efficacy outcome was reduced in non-ICU patients (36.1% vs 16.7%; RR, 0.46; 95% CI, 0.27-0.81; P = .004) but not ICU patients (55.3% vs 51.1%; RR, 0.92; 95% CI, 0.62-1.39; P = .71). Conclusions and Relevance: In this randomized clinical trial, therapeutic-dose LMWH reduced major thromboembolism and death compared with institutional standard heparin thromboprophylaxis among inpatients with COVID-19 with very elevated D-dimer levels. The treatment effect was not seen in ICU patients. Trial Registration: ClinicalTrials.gov Identifier: NCT04401293.

Topics

COVID-19 Clinical Research Studies 0.50 Heparin-Induced Thrombocytopenia and Thrombosis 0.22 Venous Thromboembolism Diagnosis and Management 0.17

Field: Medicine · Subfield: Infectious Diseases

Keywords

Medicine,Heparin,Coronavirus disease 2019 (COVID-19),2019-20 coronavirus outbreak,Intensive care medicine,Internal medicine,Virology

MeSH Terms

COVID-19COVID-19COVID-19COVID-19COVID-19COVID-19COVID-19COVID-19

UN Sustainable Development Goals

Good health and well-being (0.75)

All Available Versions

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Citations by Year

2026	2025	2024	2023	2022	2021
11	39	77	119	219	22

APA

Alex C. Spyropoulos, Mark Goldin, Dimitrios Giannis, Wassim Diab, Janice Wang, Sameer Khanijo, Andrea Mignatti, Eugenia Gianos, Marc Cohen, Gulru Sharifova, J Lund, Alfonso Tafur, Paul A. Lewis, Kevin P. Cohoon, Husneara Rahman, Cristina Sison, Martin Lesser, Kanta Ochani, Nirav Agrawal, Judith Hsia, Victoria E. Anderson, Marc P. Bonaca, Jonathan L. Halperin, Jeffrey I. Weitz, HEP-COVID Investigators, Lori Ohanesian, Michelle Glater, Christopher C.K. Ho, Annamaria Iakovou, Daniel Ying, Manile Dastagir, Alex Convissar, Seerat Aujla, Elizabeth Mathew, Vani Thiyagarajan, Tricia Lewis, Luis Gruberg, Paul Maccaro, Dana Kuziw, Bhumi Pandhi, George Surguladze, Ashley M. Eapen, A. Pantea, PHYLLIS SUEN, John P. Flynt, Michael Krzyzak, Kamal Sharma, Amanda Steadham, Sherry McLean, Karen Herring, Karen Maroney, Kambiz Zorriasateyn, Bernardo Vargas‐Leitón, Marisa Durante, Ujala Bhokary, Linda Pierchala, Elizabeth A. Fisher, Debi L. Oxenberg, Alison Sabados, Omair A. Chaudhary, Shelley Schultz, S. Cotey, Connie N. Hess, Hope Cruse, Daniel Uy, Sunita Sharma, Kevin Molina, Daliya Jagat, Bandyopadhyay Dehali (2021). Efficacy and Safety of Therapeutic-Dose Heparin vs Standard Prophylactic or Intermediate-Dose Heparins for Thromboprophylaxis in High-risk Hospitalized Patients With COVID-19. JAMA Internal Medicine, 181(12), 1612–1612. https://doi.org/10.1001/jamainternmed.2021.6203

MLA

Alex C. Spyropoulos, et al. "Efficacy and Safety of Therapeutic-Dose Heparin vs Standard Prophylactic or Intermediate-Dose Heparins for Thromboprophylaxis in High-risk Hospitalized Patients With COVID-19." JAMA Internal Medicine, vol. 181, no. 12, 2021, pp. 1612–1612. https://doi.org/10.1001/jamainternmed.2021.6203

Chicago

Alex C. Spyropoulos, Mark Goldin, Dimitrios Giannis, Wassim Diab, Janice Wang, Sameer Khanijo, Andrea Mignatti, Eugenia Gianos, Marc Cohen, Gulru Sharifova, J Lund, Alfonso Tafur, Paul A. Lewis, Kevin P. Cohoon, Husneara Rahman, Cristina Sison, Martin Lesser, Kanta Ochani, Nirav Agrawal, Judith Hsia, Victoria E. Anderson, Marc P. Bonaca, Jonathan L. Halperin, Jeffrey I. Weitz, HEP-COVID Investigators, Lori Ohanesian, Michelle Glater, Christopher C.K. Ho, Annamaria Iakovou, Daniel Ying, Manile Dastagir, Alex Convissar, Seerat Aujla, Elizabeth Mathew, Vani Thiyagarajan, Tricia Lewis, Luis Gruberg, Paul Maccaro, Dana Kuziw, Bhumi Pandhi, George Surguladze, Ashley M. Eapen, A. Pantea, PHYLLIS SUEN, John P. Flynt, Michael Krzyzak, Kamal Sharma, Amanda Steadham, Sherry McLean, Karen Herring, Karen Maroney, Kambiz Zorriasateyn, Bernardo Vargas‐Leitón, Marisa Durante, Ujala Bhokary, Linda Pierchala, Elizabeth A. Fisher, Debi L. Oxenberg, Alison Sabados, Omair A. Chaudhary, Shelley Schultz, S. Cotey, Connie N. Hess, Hope Cruse, Daniel Uy, Sunita Sharma, Kevin Molina, Daliya Jagat, Bandyopadhyay Dehali. "Efficacy and Safety of Therapeutic-Dose Heparin vs Standard Prophylactic or Intermediate-Dose Heparins for Thromboprophylaxis in High-risk Hospitalized Patients With COVID-19." JAMA Internal Medicine 181, no. 12 (2021): 1612–1612. https://doi.org/10.1001/jamainternmed.2021.6203

BibTeX

@article{spyropoulos2021,
  title = { Efficacy and Safety of Therapeutic-Dose Heparin vs Standard Prophylactic or Intermediate-Dose Heparins for Thromboprophylaxis in High-risk Hospitalized Patients With COVID-19 },
  author = { Alex C. Spyropoulos and Mark Goldin and Dimitrios Giannis and Wassim Diab and Janice Wang and Sameer Khanijo and Andrea Mignatti and Eugenia Gianos and Marc Cohen and Gulru Sharifova and J Lund and Alfonso Tafur and Paul A. Lewis and Kevin P. Cohoon and Husneara Rahman and Cristina Sison and Martin Lesser and Kanta Ochani and Nirav Agrawal and Judith Hsia and Victoria E. Anderson and Marc P. Bonaca and Jonathan L. Halperin and Jeffrey I. Weitz and HEP-COVID Investigators and Lori Ohanesian and Michelle Glater and Christopher C.K. Ho and Annamaria Iakovou and Daniel Ying and Manile Dastagir and Alex Convissar and Seerat Aujla and Elizabeth Mathew and Vani Thiyagarajan and Tricia Lewis and Luis Gruberg and Paul Maccaro and Dana Kuziw and Bhumi Pandhi and George Surguladze and Ashley M. Eapen and A. Pantea and PHYLLIS SUEN and John P. Flynt and Michael Krzyzak and Kamal Sharma and Amanda Steadham and Sherry McLean and Karen Herring and Karen Maroney and Kambiz Zorriasateyn and Bernardo Vargas‐Leitón and Marisa Durante and Ujala Bhokary and Linda Pierchala and Elizabeth A. Fisher and Debi L. Oxenberg and Alison Sabados and Omair A. Chaudhary and Shelley Schultz and S. Cotey and Connie N. Hess and Hope Cruse and Daniel Uy and Sunita Sharma and Kevin Molina and Daliya Jagat and Bandyopadhyay Dehali },
  journal = { JAMA Internal Medicine },
  year = { 2021 },
  volume = { 181 },
  number = { 12 },
  pages = { 1612--1612 },
  doi = { 10.1001/jamainternmed.2021.6203 }
}

RIS

TY  - JOUR
TI  - Efficacy and Safety of Therapeutic-Dose Heparin vs Standard Prophylactic or Intermediate-Dose Heparins for Thromboprophylaxis in High-risk Hospitalized Patients With COVID-19
AU  - Alex C. Spyropoulos
AU  - Mark Goldin
AU  - Dimitrios Giannis
AU  - Wassim Diab
AU  - Janice Wang
AU  - Sameer Khanijo
AU  - Andrea Mignatti
AU  - Eugenia Gianos
AU  - Marc Cohen
AU  - Gulru Sharifova
AU  - J Lund
AU  - Alfonso Tafur
AU  - Paul A. Lewis
AU  - Kevin P. Cohoon
AU  - Husneara Rahman
AU  - Cristina Sison
AU  - Martin Lesser
AU  - Kanta Ochani
AU  - Nirav Agrawal
AU  - Judith Hsia
AU  - Victoria E. Anderson
AU  - Marc P. Bonaca
AU  - Jonathan L. Halperin
AU  - Jeffrey I. Weitz
AU  - HEP-COVID Investigators
AU  - Lori Ohanesian
AU  - Michelle Glater
AU  - Christopher C.K. Ho
AU  - Annamaria Iakovou
AU  - Daniel Ying
AU  - Manile Dastagir
AU  - Alex Convissar
AU  - Seerat Aujla
AU  - Elizabeth Mathew
AU  - Vani Thiyagarajan
AU  - Tricia Lewis
AU  - Luis Gruberg
AU  - Paul Maccaro
AU  - Dana Kuziw
AU  - Bhumi Pandhi
AU  - George Surguladze
AU  - Ashley M. Eapen
AU  - A. Pantea
AU  - PHYLLIS SUEN
AU  - John P. Flynt
AU  - Michael Krzyzak
AU  - Kamal Sharma
AU  - Amanda Steadham
AU  - Sherry McLean
AU  - Karen Herring
AU  - Karen Maroney
AU  - Kambiz Zorriasateyn
AU  - Bernardo Vargas‐Leitón
AU  - Marisa Durante
AU  - Ujala Bhokary
AU  - Linda Pierchala
AU  - Elizabeth A. Fisher
AU  - Debi L. Oxenberg
AU  - Alison Sabados
AU  - Omair A. Chaudhary
AU  - Shelley Schultz
AU  - S. Cotey
AU  - Connie N. Hess
AU  - Hope Cruse
AU  - Daniel Uy
AU  - Sunita Sharma
AU  - Kevin Molina
AU  - Daliya Jagat
AU  - Bandyopadhyay Dehali
JO  - JAMA Internal Medicine
PY  - 2021
VL  - 181
IS  - 12
SP  - 1612
EP  - 1612
DO  - 10.1001/jamainternmed.2021.6203
ER  -

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