Targeting the Endothelium in the Treatment of COVID-19 Early Clinical Stages: Results of a Randomized Placebo-Controlled Trial

Background: SARS-CoV-2 can induce several vascular endothelial-dependent systemic complications and treatment targeting endothelial cells has been suggested. Sulodexide is a heparin and glycosaminoglycan compound that has pleiotropic properties within the vascular endothelium that can prove beneficial in COVID-19 patients.

Aims: We aimed to evaluate the effect of sulodexide when used in the early clinical stages of COVID-19.

Methods: In an outpatient setting, we conducted a randomized placebo-controlled trial. Key inclusion criteria were patients within three days of COVID-19 clinical onset and being deemed at high risk (> 50%) of severe clinical disease progression. The risk was assessed using the COVID-19 Health Complication (C19HC) calculator, which clusters the importance of various chronic comorbidities into a percentage value. After inclusion, patients were randomly assigned to receive an oral dose of sulodexide (500 LRU twice a day) or a placebo for 21 days. We performed follow-ups to assess the study endpoints via remote communication with participants or household members every seven days or as deemed necessary. Participants continued the standard of care under the supervision of their healthcare provider's primary physician. The need for hospital care was the primary outcome. Also evaluated, were the need for supplemental oxygen support, D-dimer and C reactive protein (CRP) serum levels, thromboembolic events, and mortality. Physicians responsible to determine the need for hospital care or supplemental oxygen at home were blinded to group allocation. This trial was conducted throughout the regional lockdown caused by the first wave of COVID-19 which caused some unforeseen limitations during the trial. Differences in means were calculated using the Student's t-test, while differences in percentages were assessed using the χ ² test. Before and after serum levels in the same patients were analyzed using two paired t-tests. If the data were not normally distributed, a Wilcoxon test was used. A Kaplan-Meier curve was used to graphically compare time-to-endpoint for hospital admission and mortality.

Results: 312 patients were included in the intent to treat analysis. At 21 days follow-up, 23 of 155 patients required hospitalization in the sulodexide group compared to 38 of 157 in the placebo group [relative risk (RR), 0.6; 95% confidence interval (CI), 0.38-0.97; p=0.037]. The benefit persisted with a per-protocol analysis (RR 0.6, p=0.031). Fewer patients required oxygen support in the sulodexide group [39 of 155 vs. 56 of 157; RR, 0.61; 95% CI, 0.38 to 0.9; p=0.04], and for fewer days (9 ± 7.2 in the sulodexide group vs. 11.5 ± 9.6 in the placebo group; p=0.02). Mean D-dimer levels at week 2 were significantly higher in the placebo group than in the sulodexide group (p < 0.01). 28 of the 155 patients (18%) in the sulodexide group showed a D-dimer value > 500 ng/dl, compared to 59 out of 157 (37.5%) in the placebo group (RR of 0.48; 95% CI of 0.31 to 0.67; p > 0.01). Mean C-reactive protein levels at week 2 were lower in the sulodexide group than in the placebo group (p < 0.01). There was no between-group difference concerning, hospital length of stay, thromboembolic events, major bleeding, or mortality.

Conclusions: Early intervention on COVID-19 patients with sulodexide resulted in a reduced need for supplemental oxygen and hospital care. The synergistic activity of sulodexide's antithrombotic and non-antithrombotic effects on different biological targets may play an essential role in limiting disease progression. Added a low risk of bleeding or significant side effects, sulodexide might be an alternative to other oral anticoagulants which makes it a valuable medication in the outpatient treatment of COVID-19.