As COVID-19 is associated with an increased risk of thromboembolic complications, the question arises as to whether intervention with prophylactic-dose low-molecular-weight heparin (LMWH) during the early stages of COVID-19 might prevent later complications in at-risk outpatients. The ETHIC trial compared prophylactic enoxaparin vs. standard of care (SOC) in this setting, showing no clinical benefit of LMWH over SOC. These results suggest that LMWH prophylaxis should not be used routinely in this setting.
COVID-19 is associated with an increased risk of thromboembolic complications. Low-molecular-weight heparin (LMWH) has been validated for its efficacy and safety in preventing venous thromboembolic disease in patients at high risk in both the acute hospitalised and post-discharge settings. The question arises as to whether intervention with LMWH during the early stages of COVID-19 might prevent later complications. Certainly, its use has been advocated as part of routine care for patients with COVID-19 in the community, despite the absence of prospective clinical evidence in this setting. Therefore, the Early Thromboprophylaxis In COVID-19 (ETHIC) trial evaluated the efficacy and safety of prophylactic enoxaparin vs. standard of care (SOC) in at-risk outpatients with COVID-19.
The ETHIC trial was an open-label, multicentre, randomised, controlled, phase IIIb trial done at fifteen centres in six countries (Belgium, Brazil, India, South Africa, Spain, and the UK). This study enrolled participants aged at least 30 years who had not received a COVID-19 vaccine and had symptomatic (up to nine days in duration) confirmed COVID-19 in the outpatient setting, plus at least one risk factor for severe disease (among others, previous venous thromboembolism, anaemia, or immunocompromised state). Eligible patients were randomly assigned 1:1 to receive either enoxaparin for 21 days (40 mg once daily if they weighed <100 kg and 40 mg twice daily if they weighed ≥100 kg) or the current standard of care (without enoxaparin). Patient data were collected at 21 days, 50 days, and 90 days following randomisation by the treating physician using an electronic case report form designed by the Thrombosis Research Institute. The primary efficacy endpoint was the composite of all-cause hospitalisation and all-cause mortality 21 days after randomisation. Secondary endpoints were the diagnosis of venous thromboembolism on days 21, 50, and 90, and bleeding events on days 21 and 50. Bleeding events on day 90 were added as a post-hoc outcome.
Following the advice of the Data and Safety Monitoring Board, this study was terminated early due to slow enrolment and a lower-than-expected event rate. Between October 2020 and November 2021, 219 patients with COVID-19 were enrolled and randomly assigned to receive SOC (N= 114) or enoxaparin (N= 105). The median age of patients in both groups was 59.0 years, and more patients were male (56%) than female (44%). Due to the very low number of events and the study’s early termination, only the primary efficacy outcome was tested for statistical significance. Median follow-up in both groups was 21 days. There was no difference in the composite of all-cause mortality and hospitalisation at 21 days between the enoxaparin group and the SOC group (11% vs. 11% of patients, respectively; unadjusted HR[95%CI]: 1.09[0.49-2.43]; p= 0.83). At 21 days, two (2%) of 105 patients in the enoxaparin group (one minor bleed and one bleed of unknown severity) and one (1%) of 114 patients in the standard-of-care group (major abnormal uterine bleeding) had a bleeding event. One death was recorded in the enoxaparin group, and the cause of death was unknown. Twelve patients were hospitalised in each treatment group. Among the twelve patients in the enoxaparin group who were hospitalised, four were admitted to intensive care units or required acute medical care, and three received mechanical ventilation or extracorporeal membrane oxygenation. No patients in the SOC group were similarly admitted or treated. Furthermore, 21% of patients in the enoxaparin group and 11% of patients in the SOC group had adverse events (AEs). The most common AE in both groups was COVID-19-related pneumonia (6% vs. 4% of patients in the enoxaparin and SOC groups, respectively). AEs were less likely to be serious in the enoxaparin group (13 [59%] of 22 patients) than in the standard-of-care group (12 [92%] of 13 patients). Most AEs were related to the clinical course of COVID-19 and seemed unrelated to the administration of the study drug according to post-hoc clinical judgement. At 50 and 90 days, 2% and 3% of the patients had bleeding events in the enoxaparin group, and 2% and 3% in the SOC group. In terms of AEs, 22% and 23% of patients had AEs in the enoxaparin group at 50 and 90 days, and this was 15% and 17% in the SOC group.
The ETHIC trial showed no difference in the composite endpoint of all-cause mortality and hospitalisation at 21 days between at-risk COVID-19 patients receiving prophylactic enoxaparin and SOC treatment. These results suggest that early anticoagulation for preventing thromboembolic complications in these patients might have no clinical benefit and should not be used routinely in this clinical setting. Although this trial was terminated early, these results are in line with previous studies (ACTIV-4B trial), and provide further insights to inform international guidelines and influence clinical practice.
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