Alex C Spyropoulos1,2,3, Mark Goldin1,2, Dimitrios Giannis1, Wassim Diab2, Janice Wang1,2, Sameer Khanijo2, Andrea Mignatti2,4, Eugenia Gianos2,4, Marc Cohen5, Gulru Sharifova2, Jeet M Lund6, Alfonso Tafur7,8, Paul A Lewis9, Kevin P Cohoon10, Husneara Rahman1,11, Cristina P Sison1,2,11, Martin L Lesser1,2,11, Kanta Ochani1, Nirav Agrawal1, Judith Hsia12,13, Victoria E Anderson12, Marc Bonaca12,13, Jonathan L Halperin14, Jeffrey I Weitz15,16,17. 1. Institute of Health System Science, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, New York. 2. Department of Medicine, Donald and Barbara Zucker School of Medicine at Hofstra/Northwell, Hempstead, New York. 3. Department of Obstetrics and Gynecology, I.M. Sechenov First Moscow State Medical University, Moscow, Russia. 4. Department of Cardiology, Lenox Hill Hospital, Northwell Health, New York, New York. 5. Department of Medicine, Newark Beth Israel Medical Center, Newark, New Jersey. 6. WellSpan York Hospital, York, Pennsylvania. 7. Department of Medicine, Cardiovascular Institute, NorthShore University HealthSystem, Evanston, Illinois. 8. Division of Cardiology, Pritzker School of Medicine, University of Chicago, Chicago, Illinois. 9. BayCare Health System, Inc, Clearwater, Florida. 10. Division of Cardiovascular Medicine, Department of Medicine, Froedtert & the Medical College of Wisconsin, Milwaukee. 11. Biostatistics Unit, Feinstein Institutes for Medical Research, Northwell Health, Manhasset, New York. 12. Colorado Prevention Center (CPC) Clinical Research, Aurora. 13. Division of Cardiology, University of Colorado School of Medicine, University of Colorado, Aurora. 14. Zena and Michael A. Wiener Cardiovascular Institute, Mount Sinai Medical Center, New York, New York. 15. Department of Medicine, McMaster University, Hamilton, Ontario, Canada. 16. Department of Biochemistry and Biomedical Sciences, McMaster University, Hamilton, Ontario, Canada. 17. Thrombosis and Atherosclerosis Research Institute, Hamilton, Ontario, Canada.
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.
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.
Authors: Zainab Al Duhailib; Simon Oczkowski; Kamil Polok; Jakub Fronczek; Wojciech Szczeklik; Joshua Piticaru; Manoj J Mammen; Fayez Alshamsi; John Eikelboom; Emilie Belley-Cote; Waleed Alhazzani Journal: J Infect Public Health Date: 2022-05-14 Impact factor: 7.537
Authors: Kathleen M Andersen; Corey S Joseph; Hemalkumar B Mehta; Michael B Streiff; Joshua F Betz; Robert C Bollinger; Arielle M Fisher; Amita Gupta; Charles F LeMaistre; Matthew L Robinson; Yanxun Xu; Derek K Ng; G Caleb Alexander; Brian T Garibaldi Journal: Res Pract Thromb Haemost Date: 2022-07-15