Efficacy and Safety of Therapeutic-Dose Heparin vs Standard Prophylactic or Intermediate-Dose Heparins for Thromboprophylaxis in High-risk Hospitalized Patients With COVID-19
Authors: Alex C. Spyropoulos, Mark Goldin, Dimitrios Giannis, Wassim Diab, Janice Wang, Sameer Khanijo, Andrea Mignatti, Eugenia Gianos, Marc Cohen, Gulru Sharifova, Jeet M. Lund, Alfonso Tafur, Paul A. Lewis, Kevin P. Cohoon, Husneara Rahman, Cristina P. Sison, Martin L. Lesser, Kanta Ochani, Nirav Agrawal, Judith Hsia, Victoria E. Anderson, Marc Bonaca, Jonathan L. Halperin, Jeffrey I. Weitz, Lori Ohanesian, Michelle Glater, Christopher 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, Alexandra Pantea, Phyllis Suen, John Flynt, Michael Krzyzak, Kamal Sharma, Amanda Steadham, Sherry L. McLean, Karen Herring, Karen Maroney, Kambiz Zorriasateyn, Bernardo Vargas, Marisa Durante, Ujala Bhokary, Linda Pierchala, Elizabeth A. Fisher, Debi L. Oxenberg, Alison Sabados, Omair A. Chaudhary, Shelley Schultz, Sue Cotey, Connie Hess, Hope Cruse, Daniel Uy, Sunita Sharma, Kevin Molina, Daliya Jagat, Bandyopadhyay Dehali
Journal: JAMA Internal Medicine (2021)

<h3>Importance</h3> Hospitalized patients with COVID-19 are at risk for venous and arterial thromboembolism and death. Optimal thromboprophylaxis dosing in high-risk patients is unknown. <h3>Objective</h3> 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. <h3>Design, Setting, and Participants</h3> 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. <h3>Interventions</h3> 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 m<sup>2</sup>or greater (0.5 mg/kg twice daily if creatinine clearance was 15-29 mL/min/1.73 m<sup>2</sup>) throughout hospitalization. Patients were stratified at the time of randomization based on intensive care unit (ICU) or non-ICU status. <h3>Main Outcomes and Measures</h3> 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. <h3>Results</h3> 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;<i>P</i> = .03), including a reduction in thromboembolism (29.0% vs 10.9%; RR, 0.37; 95% CI, 0.21-0.66;<i>P</i> &lt; .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;<i>P</i> = .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;<i>P</i> = .004) but not ICU patients (55.3% vs 51.1%; RR, 0.92; 95% CI, 0.62-1.39;<i>P</i> = .71). <h3>Conclusions and Relevance</h3> 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. <h3>Trial Registration</h3> ClinicalTrials.gov Identifier:NCT04401293