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Review 1: "Sulodexide in the treatment of patients with early stages of COVID-19: a randomised controlled trial"

Reviewer: Győző Szolnoky (University of Szeged) | 📗📗📗📗◻️

Published onMay 05, 2022
Review 1: "Sulodexide in the treatment of patients with early stages of COVID-19: a randomised controlled trial"
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key-enterThis Pub is a Review of
Sulodexide in the treatment of patients with early stages of COVID-19: a randomised controlled trial

AbstractBackgroundTargeting endothelial cells has been suggested for the treatment of patients with COVID-19 and sulodexide has pleiotropic properties within the vascular endothelium that can prove beneficial to the same. We aimed to evaluate the effect of sulodexide when used in the early clinical stages of COVID-19.MethodsWe conducted a single-centre, outpatient setting, randomised controlled trial with a parallel-group design in Mexico. Including patients within three days of clinical symptom onset, who were at a high risk of severe clinical progression due to chronic comorbidities. Participants were randomly allocated to receive an oral dose of sulodexide (500 LRU twice a day) or the placebo for 21 days. Primary outcomes were need and length of hospitalisation, need and length of oxygen support.ResultsBetween June 5 and August 30, 2020, 243 patients were included in the “per-protocol” analysis. One hundred twenty-four of them received sulodexide, while 119 received placeboes. At 21 days follow-up, 22 of 124 patients required hospitalisation in the sulodexide group compared to 35 of 119 in the placebo group [relative risk (RR), 0·6; 95% confidence interval (CI), 0·37-0·96; p=0·03]. Fewer patients required oxygen support in the sulodexide group [37 of 124 vs. 50 of 119; RR, 0·71; 95% CI, 0·5 to 1; p=0·05], and for fewer days (9±7·2 in the sulodexide group vs. 11·5±9·6 in the placebo group; p=0·02). There was no between-group difference concerning the length of hospital stay.InterpretationEarly intervention in COVID-19 patients with sulodexide reduced hospital admissions and oxygen support requirements, although with no significant effect on mortality. This has beneficial implications in the patient well-being, making sulodexide a favourable medication until an effective vaccine or an antiviral becomes available.FundingResearcher independently initiated, partially funded by Alfasigma, Mexico.Listed in the ISRCTN registry under ID ISRCTN59048638.

RR:C19 Evidence Scale rating by reviewer:

  • Reliable. The main study claims are generally justified by its methods and data. The results and conclusions are likely to be similar to the hypothetical ideal study. There are some minor caveats or limitations, but they would/do not change the major claims of the study. The study provides sufficient strength of evidence on its own that its main claims should be considered actionable, with some room for future revision.



This article has a pleiotropic potential and besides anticoagulation sulodexide is able to reduce inflammation, improve hemorheology, exert anti-senescent activity and restore glycocalyx. This feature is of paramount importance since endothelial glycocalyx damage is not only considered but recognized as the key mechanism of COVID-19-associated vasculopathy also in the lung vasculature. However, these beneficial properties are all attributed to sulodexide but the medical community just wondered whether it could really work against in vivo SARS-Cov-2-associated vasculopathy. Ultimately this clinical trial gave numerous proofs to elucidate uncertainty. 

According to standard recommendations, the normal daily dosage of sulodexide is 250 LRU twice a day. The authors made a rationale decision as doubled the dosage which is coherent with the findings of SURVET study in which a favorable antithrombotic effect was safely achieved using 500 LRU b.i.d.

Collaborator medical staff has made intensive and probably fortified attempts to solicit a large cohort of patients at a high risk of severe progression in an out-patient setting, as a result, „only” 656 eligible patients were recruited. Nearly half of them were excluded and the remaining 312 patients were randomly allocated into study and control groups but further, ~ 20% were dropped out in both branches which is quite robust but group size calculation, fortunately, allowed it. Nevertheless, inclusion, exclusion, and elimination criteria were accurately set. The major advantage of this investigation is mirrored by patients’ mean ages, and comorbidities (high frequency of diabetes mellitus, hypertension, other cardiovascular diseases, COPD) so it was purely a real-life study that tried to filter out massive obesity. Another important benefit of this comparative study is the precise specification of baseline medications and those that were given due to SARS-Cov-2 infection subsequently.  One “confounded” feature is the seemingly moderate but significant difference in corticosteroid therapy. More people in the study cohort received this group of anti-inflammatory medications compared to control probands. The clinical study tried to shed light on patients’ adherence and medication consuming habits which is an excellent endeavor since it is quite difficult to follow the participants in an outpatient setting.  

I wondered how high incidences of adverse events were detected which is in contrast with general experience. To the best of my conviction, they could partly be attributed to the higher dosage of oral sulodexide.  I think the authors disputed this question in a fairly good way however it may claim further explanations but not essentially. 

It is obvious that sulodexide significantly reduced the need for hospital care and oxygen support and also the length of oxygen therapy but had no impact on mortality. Another interesting feature is late D-dimer and CRP values that are notably lower among patients receiving oral sulodexide therapy which may support antithrombotic and anti-inflammatory properties. The determination of primary and secondary endpoints was good however mortality did not appear to be consistent with the solid expectations.  

What I liked most is the discussion chapter: the authors do not draw irrevocable conclusions but duly compose their observations and try to clarify the background. The list of limitations is understandably quite huge and appropriately constructed. 


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