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

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.

Conflict of interest statement

Conflict of Interest Disclosures: Dr Spyropoulos reported receiving grants from Janssen and personal fees from Bayer, Bristol Myers Squibb, Boehringer Ingelheim, and The ATLAS Group outside the submitted work. Dr Goldin reported receiving grants and personal fees from Janssen outside the submitted work. Dr Giannis reported receiving funding from Broxmeyer Fellowship in Clinical Thrombosis during the conduct of the study. Dr Cohen reported receiving personal fees for serving on a speakers bureau from Sanofi outside the submitted work. Dr Tafur reported receiving educational grants and consulting from Janssen, consulting from Recovery Force, and research support from Idorsia and DOASENSE during the conduct of the study. Dr Hsia reported grants from CPC Clinical Research during the conduct of the study; stock ownership from AstraZeneca and grants from Janssen and Arca outside the submitted work. Dr Anderson reported receiving grants from Northwell Health during the conduct of the study. Dr Bonaca reported receiving grant support to CPC from Northwell for trial activities during the conduct of the study; and receiving grant support to CPC from ARCA, Amgen, AstraZeneca, Bayer, Janssen, Merck, Anthos, and Pfizer outside the submitted work. Dr Weitz reported receiving personal fees (consulting and honoraria) from Bayer, Boehringer Ingelheim, Bristol Myers Squibb, Daiichi Sankyo, Ionis, Janssen, Merck, Novartis, and Pfizer outside the submitted work. No other disclosures were reported.

Figures

Figure.. CONSORT Study Flow Diagram

SIC indicates sepsis-induced coagulopathy.