Sulodexide in the Treatment of Patients with Early Stages of COVID-19: A Randomized Controlled Trial

  1. Alejandro J. Gonzalez-Ochoa
  2. Joseph D. Raffetto
  3. Ana G. Hernández
  4. Nestor Zavala
  5. Obed Gutiérrez
  6. Arturo Vargas
  7. Jorge Loustaunau

Reviewed by

Read the full article See related articles

Listed in

Log in to save this article

Abstract

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) may induce several vascular endothelial-dependent systemic complications, and sulodexide has pleiotropic actions on the vascular endothelium, which may prove beneficial. We aimed to assess the effect of sulodexide when used within 3 days of coronavirus disease 2019 (COVID-19) clinical onset. We conducted a randomized placebo-controlled outpatient trial. To be included, patients must have been at high risk for severe clinical progression. Participants received sulodexide (oral 1,000 LRU/d) or placebo for 21 days. The primary endpoint was the need for hospital care. Also assessed were patients' need for supplemental oxygen as well as D-dimer and C-reactive protein (CRP) levels, thromboembolic events, major bleeding, and mortality. A total of 243 patients were included in the per-protocol analysis from June 5 to August 30, 2020. Of these, 124 received sulodexide and 119 received a placebo. Only 17.7% of the patients in the sulodexide group required hospitalization, compared with 29.4% in the placebo group (p = 0.03). This benefit persisted in the intention-to-treat analysis (15% in sulodexide group vs. 24% with placebo [p = 0.04]). With sulodexide, fewer patients required supplemental oxygen (30 vs. 42% [p = 0.05]). After 2 weeks, fewer patients had D-dimer levels >500 ng/dL (22 vs. 47% [p < 0.01]), and patients also had lower mean CRP levels (12.5 vs. 17.8 mg/dL [p < 0.01]). There were no between-group differences in thromboembolic events, major bleeding, or mortality. Treatment of COVID-19 patients with sulodexide, when provided within 3 days of clinical onset, improved their clinical outcomes. Although the results should be confirmed, sulodexide could be valuable in an outpatient setting.

Article activity feed

  3. Version published to 10.1055/a-1414-5216
  4. ScreenIT

    SciScore for 10.1101/2020.12.04.20242073: (What is this?)

    Please note, not all rigor criteria are appropriate for all manuscripts.

    Table 1: Rigor

    Institutional Review Board StatementIRB: We conducted this trial according to the Declaration of Helsinki, and it was board reviewed by the Universidad Autonoma de Baja California Faculty of Medicine Mexicali Ethics and Investigation Committee, being designated with approval number FMM/CEI/0011/2020-2.
    Consent: If eligible, an informed consent form was signed, and the patient was scheduled at the earliest for blood exams and the COVID-19 polymerase chain reaction (PCR) test.
    RandomizationStudy design: This is a prospective, randomised placebo-controlled trial with a parallel-group design evaluating the clinical outcome of consecutive patients who suffer early clinical stages of COVID-19.
    BlindingAs a result of local logistic limitations imposed due to the regional pandemic lockdown, as well as to verify timely medication dispensation, the lead researcher was not blinded to group allocation.
    Power Analysisnot detected.
    Sex as a biological variableInclusion criteria were as follows: male or female, age over 40 years, with suspected COVID-19 clinical symptom within 3 days of onset or less and high risk (>50%) of a severe clinical disease progression according to the percentage of risk given by the COVID-19 Health Complication (C19HC) calculator (IMSS, Gobierno de Mexico),21 which considers different chronic comorbidities described in table 1.

    Table 2: Resources

    Software and Algorithms
    SentencesResources
    Estimates of risk ratios are presented with 95% Cis, and were calculated using the MedCalc software (MedCalc Software Ltd., Olsted,Belgium).
    MedCalc
    suggested: (MedCalc, RRID:SCR_015044)
    The SPSS software (IBM SPSS Statistics for Windows, version 26, IBM Corp., Armonk, NY, USA) was used for data analysis.
    SPSS
    suggested: (SPSS, RRID:SCR_002865)

    Results from OddPub: We did not detect open data. We also did not detect open code. Researchers are encouraged to share open data when possible (see Nature blog).

    Results from LimitationRecognizer: We detected the following sentences addressing limitations in the study:
    This trial does pose certain acknowledgeable limitations. Numerous asymptomatic carriers and lack of widespread diagnostic testing worldwide make it difficult to establish a real incidence of the disease, affecting accurate sample size calculations. With a significant part of the trial taking place in an outpatient setting, we did not foresee some of the logistic and infrastructure limitations due to the region’s pandemic lockdown. Key members of the staff were unavailable during part of the trail which forced the lead researcher to undertake data managing duties, breaking his blinding to group allocations. Other restrictions were also experienced in the hospital setting, for example, the impossibility to perform post-mortem examination. The different numbers and types of medications prescribed to the study population were very heterogenic. Moreover, there existed a noticeable difference between the prescription from primary physicians in the private sector vs. government care centres. Although evenly distributed among groups, the above factors should be taken into consideration during the interpretation of the study results. There is also reasoning for a later exploratory trial from an economic viewpoint. A significant benefit could be found when considering the total number of patient-hospital days (number of patients × mean number of hospital LOD) of 136 in the sulodexide group vs. 273 in the placebo group, with the consumed resources and cost 1-patient/day can represent. ...

    Results from TrialIdentifier: We found the following clinical trial numbers in your paper:

    IdentifierStatusTitle
    ISRCTN59048638NANA

    Results from Barzooka: We did not find any issues relating to the usage of bar graphs.

    Results from JetFighter: We did not find any issues relating to colormaps.

    Results from rtransparent:
    • Thank you for including a conflict of interest statement. Authors are encouraged to include this statement when submitting to a journal.
    • Thank you for including a funding statement. Authors are encouraged to include this statement when submitting to a journal.
    • No protocol registration statement was detected.

    About SciScore

    SciScore is an automated tool that is designed to assist expert reviewers by finding and presenting formulaic information scattered throughout a paper in a standard, easy to digest format. SciScore checks for the presence and correctness of RRIDs (research resource identifiers), and for rigor criteria such as sex and investigator blinding. For details on the theoretical underpinning of rigor criteria and the tools shown here, including references cited, please follow this link.

  5. Version published to 10.1101/2020.12.04.20242073v1 on medRxiv