Low-Molecular-Weight Heparin Benefited Outpatients with High Risk of Venous Thromboembolism Early in COVID-19 Pandemics

Background. Risk factors for severe COVID-19 and venous thromboembolism (VTE) are similar, suggesting a shared thrombo-inflammatory pathophysiology. Low-molecular-weight heparin (LMWH) improves outcomes in hospitalized COVID-19 patients. In our HUS Helsinki University Hospital we have had risk-stratified VTE thromboprophylaxis guidance in place since 2004. Before vaccinations or any available treatments, the directorship of the largest university hospital in Finland initiated the administration of LMWH thromboprophylaxis to COVID-19 outpatients at high-risk COVID-19 progression and of VTE (LMWH+group).

Aims. The aims of this prospective observational study was to examine whether LMWH thromboprophylaxis for high-risk outpatients improved outcomes, such as duration of hospital stay, use of respiratory support, need of intensive care and 30-day mortality following hospitalization for COVID-19.

Methods. This prospective observational study included patients admitted to Finland’s largest university hospital during the two COVID-19 variant outbreaks, one from Apr to Aug 2020 and the other from Dec 2020 to May 2021. The study was approved by HUS leadership guidance by the CMO, by HUS 59/2021 and HUS325/2023 and THL, National Institute of Health and Welfare in Finland. LMWH was mostly administered at standard prophylactic dose across patient groups, but up to 50% of a treatment dose was allowed, and the treatment was organized via Health care centers targeting COVID-19 services. Use of other anticoagulants, dual antiplatelet agents, bleeding disorders and overt thrombosis were excluded. For comparative assessment, an individually matched control group, LMWH-group for the LMWH+group, was propensity score-matched, based on the comorbidities and risk factors, from the hospitalized population of COVID-19 patients (PCR-confirmed diagnosis) who had not received LMWH until admitted to hospital. The comorbidities included prior VTE, diabetes, cardiovascular, hematological, inflammatory diseases, and cancer. With logistic regression analysis we evaluated the relationships between the incidence of events (use of respiration support, need for intensive care) and contextual variables including the length of thromboprophylaxis, age, sex, and body-mass index.

Results. Among 1189 consecutive hospitalized patients identified from electronic health records, 241 were included in the outpatient LMWH+group and 482 were propensity-matched into the LMWH-group. The mean time (± SD) from COVID-19 diagnosis until outpatient LMWH administration in the LMWH+ group was only 1.9 (± 3.0) days; approx. 80% of patients in the LMWH+group received outpatient LMWH within 2 days of COVID-19 diagnosis. Longer duration of outpatient LMWH was associated with shorter hospital stays and less days with respiratory support (p <0.006-0.008). No major bleeds occurred in either group, and the incidence of VTE was similar: 4.6% in LMWH+group and 5.4% in LMWH-group. Finally, the 30-day overall mortality was 8.8%; 2.9-fold higher mortality (p=0.014) occurred in the propensity-matched LMWH-group (10.6%) than in the outpatient LMWH+group (3.7%).

Conclusions. The data represent two earliest SARS-CoV2 variant outbursts at the pre-vaccination era. Outpatient early LMWH thromboprophylaxis in high-risk COVID-19 patients was associated with improved survival, and other positive outcomes following hospitalization, including shorter hospital stays and respiratory support, and reduced need for intensive care. These findings also aligned with the length of the LMWH prophylaxis, suggesting an overall benefit of early initiation of LMWH in managing thrombo-inflammation in COVID-19.