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

Abstract

IMPORTANCEHospitalized 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 PARTICIPANTSThe 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 m 2 or greater (0.5 mg/kg twice daily if creatinine clearance was 15-29 mL/min/1.73 m 2 ) throughout hospitalization. Patients were stratified at the time of randomization based on intensive care unit (ICU) or non-ICU status. MAIN OUTCOMES AND MEASURESThe 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. RESULTSOf 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 RELEVANCEIn 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.

The effect of higher-intensity dosing of anticoagulation on the clinical outcomes in hospitalized patients with COVID-19: A meta-analysis of randomized controlled trials

“…Our systematic literature search retrieved 1881 hits, of which 1045 were unique (titles retrieved after removing duplications). After screening against inclusion and exclusion criteria, eight randomized controlled trials [ [5] , [6] , [7] , [8] , [9] , [10] , [11] , [12] ] were included ( Fig. 1 ), with a total of 5405 patients (2746 patients randomized to the intermediate or therapeutic anticoagulation group, and 2659 patients randomized to the prophylactic anticoagulation group).…”

“…1 ), with a total of 5405 patients (2746 patients randomized to the intermediate or therapeutic anticoagulation group, and 2659 patients randomized to the prophylactic anticoagulation group). Four of the included randomized trials in this systematic review and meta-analysis were from Iran (n = 1) [ 7 ], the United States (n = 2) [ 8 , 12 ], and Brazil (n = 2) [ 5 , 9 ], respectively, and one of the included randomized trial [ 11 ] was a global trial performed in six countries. In contrast, the remaining two randomized trials [ 6 , 10 ] were international multiplatform randomized controlled trials.…”

Studying the coagulopathy of COVID-19

“…We should step back and reflect on primary principles in studying thrombotic mechanisms of COVID-19. The reason why the HEP-COVID trial 12 yielded a clear result despite its modest size in answering the trial hypothesis was that it used a traditional antithrombotic clinical trial design. 12 HEP-COVID used an agent with established efficacy in thromboembolic disease at an optimal dose (therapeutic low molecular weight heparin), selected a highly enriched population using a validated strategy (elevated D dimers), and used an endpoint that was specific to the mechanism of intervention (a composite of major thromboembolism and mortality).…”

“…The reason why the HEP-COVID trial 12 yielded a clear result despite its modest size in answering the trial hypothesis was that it used a traditional antithrombotic clinical trial design. 12 HEP-COVID used an agent with established efficacy in thromboembolic disease at an optimal dose (therapeutic low molecular weight heparin), selected a highly enriched population using a validated strategy (elevated D dimers), and used an endpoint that was specific to the mechanism of intervention (a composite of major thromboembolism and mortality). Although it can be argued that the urgency of the pandemic required broader outcomes to speed up discovery, perhaps the time has come for us to rethink how we study the coagulopathy of COVID-19, returning to principles that led to traditional antithrombotic clinical trial designs.…”

Heparin and Derivatives for Advanced Cell Therapies

“…The benefits of prophylactic or therapeutic UFH or LMWH for patients with thromboembolic events and sepsis-induced disseminated intravascular coagulation, concomitant with high D-dimer and fibrinogen and low anti-thrombin levels, are currently discussed and investigated in clinical trials [ 19 , 38 , 40 ]. In a recent multicenter randomized clinical trial (HEP-COVID) a clear benefit of therapeutic-dose LMWH (with enoxaparin, major thromboembolism or death in 28.7%) compared to prophylactic or intermediate-dose heparin regimens (with UFH, enoxaparin or dalteparin, major thromboembolism or death in 41.9%) in inpatients with high D-dimer levels has been reported [ 41 ]. Preliminary data from a large multiplatform of randomized controlled trials (ATTACC, REMAP-CAP and ACTIV-4a trial platforms), including more than 2000 patients comparing therapeutic LMWH or UFH to local venous thromboembolic prophylaxis in severely and moderately ill COVID-19 patients, showed divergent results [ 39 ].…”