Efficacy and safety of therapeutic or intermediate-dose heparins for thromboprophylaxis in high-risk hospitalized patients with COVID-19

1. In a group of hospitalized COVID-19 patients, a therapeutic dose of low-molecular-weight heparin reduced major thromboembolic events and death.

Evidence Rating Level: 1 (Excellent)

Thrombotic events such as a deep vein thrombosis and pulmonary embolisms are common in patients hospitalized with COVID-19. Severely ill patients with COVID-19 often experience thrombosis despite receiving the recommended thromboprophylaxis of a standard dose of low-molecular-weight heparin (LMWH). There is limited and conflicting data about the efficacy of utilizing a therapeutic dose of anticoagulation in such patients. Therefore, this randomized-controlled trial aimed to test the hypothesis that a therapeutic dose would be beneficial for inpatients with COVID-19 demonstrating high-risk features or with critical illness. Eligible participants were hospitalized nonpregnant adults diagnosed with COVID-19 requiring supplemental oxygen and a plasma D-dimer level of greater than 4 times the upper limit of normal or a sepsis-induced coagulopathy score of 4 or greater. A total of 253 participants (mean [SD] age, 66.7 [14.0] years; 53.8% males [136]) were included in the analysis. 124 participants were assigned to receive a prophylactic dose of LMWH (control group) while 129 were assigned to receive a greater, therapeutic dose of LMWH (enoxaparin 1 mg/kg subcutaneously twice daily; intervention group). The primary outcome measured was incidence of thrombotic events (venous [VTE] or arterial thromboembolism [ATE]) or death from any cause within 30+2 days after randomization. It was found that a therapeutic dose of LMWH significantly reduced the incidence of thromboembolism compared to a prophylactic dose (29.0% vs 10.9%; RR, 0.37; 95% CI, 0.21-0.66; p<0.001). There was no significant difference in death between the two groups. Secondary outcomes included the composite primary outcome within 14 days after admission, progression to acute respiratory distress syndrome, new-onset atrial fibrillation, acute kidney injury, nonfatal cardiac arrest, endotracheal intubation, extracorporeal membrane oxygenation, and rehospitalization within 30 ± 2 days. Therapeutic-dose LMWH was found to reduce the incidence thromboembolism 14 from hospitalization (36.3% vs 23.3%; RR, 0.64; 95% CI, 0.43-0.95; p =0.02). There were no statistically significant differences in the remaining secondary outcomes. Finally, the principal safety outcome was major bleeding based on International Society on Thrombosis and Haemostasis criteria within 30 ± 2 days after randomization. There were 8 (3.2%) major bleed events, 2 (1.6%) in the prophylactic-dose vs 6 (4.7%) in the therapeutic-dose groups (RR, 2.88; 95% CI, 0.59-14.02; P = .17), none of which were fatal. Overall, this was a well-designed trial that concluded therapeutic-dose LMWH would benefit hospitalized COVID-19 with elevated D-dimer levels by reducing thromboembolic events without increasing major bleeding. Thus, it provides support for changing current standard of care for such patients.

Click to read the study in JAMA Internal Medicine

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