Summary
Background
Superficial vein thrombosis (SVT) of the legs is a common disease linked with venous thromboembolism (VTE), with an uncertain recurrence risk. Data on secondary prevention of recurrent or extending SVT and on its natural history are lacking. Mesoglycan (MGY) shows a mild antithrombotic effect and the capacity to repair the endothelial layer, by restoring the integrity of the glycocalyx. This study aimed to evaluate the efficacy and safety of MGY for secondary prevention of VTE after an episode of lower-limb SVT.
Methods
This was a multicentre, randomised, double-blind, placebo-controlled, superiority, phase II study conducted at 16 sites in Italy. Patients (aged > 18 years) with lower-limb SVT, who completed a 45-day treatment course of fondaparinux were randomised (1:1) to receive either oral MGY 50 mg or matching placebo twice-daily for 12 months, and were subsequently followed-up for another 12 months. The efficacy outcome was a composite of symptomatic recurrence or extension of SVT; new symptomatic or asymptomatic proximal deep-vein thrombosis, or new symptomatic distal deep-vein thrombosis, or new symptomatic non-fatal pulmonary embolism, or fatal pulmonary embolism at 12 months (primary outcome) and 24 months (secondary outcome) post-enrolment. The primary safety outcome was the incidence of major bleeding and clinically relevant non-major bleeding at 12 months. This trial was registered with EudraCT (2016-005184-13) and ClinicalTrials.gov (NCT03428711).
Findings
Between March 26, 2018, and Dec 31, 2024, 553 patients were randomly allocated to treatment (272 to MGY and 281 to placebo), below the planned sample size due to slow recruitment because of SARS-CoV2 pandemic. At 12 months, the cumulative rate of efficacy events was 21.8% (54 patients) in the MGY group and 24.5% (63 patients) in the placebo group, respectively, showing no difference between these two groups (HR 0.89, 95% C.I. 0.62–1.29; p = 0.56). At 24 months, the cumulative rate of efficacy events was 30.6% (74 patients) in the MGY group and 42.5% (105 patients) in the placebo group, respectively (p = 0.043). This difference was entirely accounted for by a lower rate of recurrent SVT in the MGY group. The 24-month recurrence rate of SVT was 39% in the placebo group. No bleeding events were observed in either group.
Interpretation
No significant differences were observed between MGY and placebo in terms of recurrent or extending SVT, at the end of the 12-month treatment course. However, we recorded a significant difference in favour of MGY at 24 months. These findings should be interpreted cautiously, given that the incidence of recurrent or extending SVT in the placebo group was higher than previously reported and the planned sample size was not reached due to slow recruitment. Our findings need to be confirmed in future, larger studies.
Funding
Neopharmed Gentili S.p.A.
Keywords: Superficial vein thrombosis, Mesoglycan, Recurrence, Secondary prevention, Glycocalyx
Research in context.
Evidence before this study
We searched PubMed from January 1, 2000, to December 31, 2017, without language restrictions for studies investigating the prevention of recurrence in patients with one or more previous episodes of superficial vein thrombosis. We found no randomised clinical trials or prospective observational studies providing data on pharmacological secondary prevention of superficial vein thrombosis recurrence, nor on the prospective long-term recurrence rate in patients with a prior episode of superficial vein thrombosis who were not receiving any medication after the acute phase treatment had concluded. A few retrospective studies or registries reported that up to 15% of patients experienced recurrent superficial vein thrombosis or venous thromboembolism within three months to five years following the initial episode. There is a lack of prospective data on pharmacological secondary prevention of recurrent or extending superficial vein thrombosis and on SVT natural history.
Added value of this study
We found no significant differences between the two study groups at the 12-month mark. To our knowledge, no other similar studies in the literature address the long-term secondary prevention of superficial vein thrombosis recurrence. Published research, whether cohort or randomised, typically explores the efficacy of various treatment strategies over a period of only 90 days. In contrast, we observed a significant cumulative efficacy event reduction at 24 months in patients treated with mesoglycan, compared to those receiving a placebo, which was primarily driven by a decrease in recurrent or extending superficial vein thrombosis. The 24-month recurrence or extension rate of superficial vein thrombosis in the placebo group was 39%, providing, for the first time, prospective data on the natural course of superficial vein thrombosis following appropriate initial treatment.
Implications of all the available evidence
Our findings suggest that patients with symptomatic superficial vein thrombosis of the legs face a higher-than-expected long-term risk of recurrence. Long-term administration of mesoglycan resulted in a reduced rate of recurrence, suggesting a potential restorative effect on the endothelial layer. Cautious interpretation is needed; this trial did not reach its planned sample size due to slow recruitment. These findings need to be confirmed in future, larger studies.
Introduction
Superficial vein thrombosis (SVT) is a common condition characterised by pain, inflammation, and the formation of a blood clot in a superficial vein.1 Its exact incidence is uncertain; however, according to a French community-based study, its annual rate is around 0.64%, varying by age and sex.2 SVT, once considered almost harmless, is nonetheless associated with deep vein thrombosis (DVT) in up to 25% of cases, as well as with symptomatic (13%) and asymptomatic (33%) pulmonary embolism (PE), especially when involving the great saphenous vein at the thigh.2, 3, 4, 5, 6
Subcutaneous fondaparinux (2.5 mg once daily for 45 days), as compared with placebo, is a safe and effective treatment for acute SVT, reducing symptomatic venous thromboembolism (VTE) by approximately 85%, without increased bleeding risk.7 On these premises, fondaparinux is currently recommended as first-line treatment for SVT by international guidelines (grade 2B), while the evidence for other anticoagulants is less established.8,9
According to retrospective studies and registries, up to 15% of patients experience recurrent SVT or VTE within three months to five years following the initial episode.5,10, 11, 12, 13, 14, 15, 16 Nonetheless, prospective data on long-term pharmacological prophylaxis of recurrent SVT are lacking.
Mesoglycan (MGY) is a blend of natural glycosaminoglycans (47.5% heparan sulphate, 35.5% dermatan sulphate, 8.5% chondroitin sulphate, and 8.5% slow-mobility heparin).17, 18, 19 Available literature suggests that MGY exerts a mild antithrombotic effect by binding to antithrombin and heparin cofactor II, enhances fibrinolysis by stimulating tissue plasminogen activator, and reduces inflammation by lowering cytokine levels. Finally, ex vivo studies indicate that MGY reintegrates endothelial function by repairing the glycocalyx surface, thus restoring the electronegativity of the damaged endothelium and the integrity of the capillary membrane.20, 21, 22, 23, 24 None of the actions of MGY on blood coagulation significantly impact coagulation parameters.19, 20, 21, 22, 23, 24
In this study, we chose to use mesoglycan instead of a low-dose direct oral anticoagulants (DOACs), which have shown a significant reduction in the risk of VTE, for several reasons: because of mesoglycan’s very low bleeding risk compared to DOACs; due to mesoglycan’s anti-inflammatory properties and effect on the venous wall, which DOACs lack (given inflammation is a dominant feature of SVT); and, finally, owing to the fact that in Italy DOACs are neither indicated nor reimbursed for either the acute phase of SVT or long-term secondary prevention, making them an expensive therapy entirely out of pocket. As such, this study aimed to assess the efficacy and safety of MGY for long-term secondary prevention of recurrent SVT of the lower limbs, after an initial 45-day course of fondaparinux.
Methods
Study design and ethics
The MEsoglycan for the secondary prevention of superficial vein ThROmbosis (METRO) was a prospective, multicentre, randomised, double-blind, placebo-controlled, phase II study conducted at 16 certified Italian vascular centres. Given the lack of evidence of any pharmacological treatment in this setting, we felt that the use of a placebo was ethically acceptable. The trial was designed and overseen by a Steering Committee (Supplementary Appendix), and funded by Neopharmed Gentili, Milan, Italy. The study was prospectively registered with EUdraCT (n.2016-005184-13) and ClinicalTrials.gov (NCT03428711), and the study protocol has been published.24
The Coordinating Centre was the First Chair of Internal Medicine and Thrombotic-Haemorrhagic Diseases at Padua University Hospital. The trial received ethical approval from the North-East Regional Ethics Committee of Veneto (4068/AO/17; sessions held on Feb 16, 2017 for main protocol; Nov 9, 2017, and Jan 25, 2018 for amendments) and the Ethics Committees of the other participating centres. The study was conducted according to the principles of the Declaration of Helsinki, and all participants gave written informed consent before their enrollment in the study. The authors guarantee the accuracy and completeness of the data, as well as the fidelity of the trial and this report to the protocol.
Participants
Non-hospitalized patients (aged 18 years or older) with either varicose veins SVT (associated with trauma, prolonged immobilisation, prolonged standing, oral contraceptive use, or family or personal history of VTE); or non-varicose veins SVT of the lower limb confirmed by ultrasonography were eligible for the study, provided they had a thrombus at least 5 cm long, located more than 3 cm from the saphenous junctions, and had received fondaparinux, 2.5 mg once daily, for at least 45 days. For inclusion, patients were to be screened within 15 days of completing the initial 45-day treatment course. Before randomisation, patients underwent a screening visit, including an ultrasonographic assessment of the lower limbs to rule out DVT or SVT extension, and laboratory tests. Patients with poor adherence to, or early discontinuation of, the 45-day fondaparinux course, or those receiving other anticoagulants, were excluded. Main exclusion criteria were: an interval of more than 15 days between the end of therapy with fondaparinux and randomisation in the study; mandatory anticoagulant treatment for other medical reasons; life expectancy of less than 24 months; planned phlebological surgery during the whole study period (24 months); chronic voluntary (patients unwilling to withdraw from) use of venoactive drugs, steroids, non-steroidal anti-inflammatory drugs (except for <7 days courses), dual antiplatelet therapy, or high-dose aspirin (more than 160 mg/day), or centrally acting pain medications.
Graduated compression stockings (GCS) were allowed, according to the discretion of the investigators. The full list of exclusion criteria, the details of the standardised ultrasound procedure, and the list of laboratory tests are available in the Supplementary Appendix.
Randomisation and masking
Eligible patients, with no exclusion criteria, who signed the informed consent, were randomised (1:1ratio) to receive either 50 mg oral MGY or a matching placebo, twice daily for 12 months. Treatment allocation was performed using a computer-generated randomisation list (nQuery Advisor, v9, Statsol, Cork, Ireland) with variable-size blocks (4–6 units), and was stratified by age (under 60 years, and 60 years or older), sex (male and female), and centre.
The day of randomisation was designated as Day 1. Data were recorded on an ‘Electronic Data Capture’ (EDC) system, based on the ‘Research Electronic Data Capture’ online platform (REDCap, produced and distributed by Vanderbilt University and the ‘REDCap Consortium’), in compliance with the GDPR (EU 2016/769).
Treatment packages were labelled with numerical codes known only to the packaging manager. Patients, researchers, the Steering Committee, the Adjudication Committee, and the Data Safety Monitoring Board were all blinded to treatment allocation. The blinding seal was to be opened only after the database had been locked for outcome analysis, except in cases of medical emergencies where treatment details needed to be disclosed. Each centre maintained a drug accountability form for every patient to monitor doses.
Procedures
Study visits were scheduled at 90 ± 7, 180 ± 7, 270 ± 7, and 365 ± 7 days after randomisation. On each appointment, we recorded the patient’s clinical status, drug compliance, concomitant treatments, and adverse events. Study participants were requested to report immediately to the relevant study centre for evaluation in case of a suspected thromboembolic or haemorrhagic event, or of any other adverse event.
On each visit, the investigators completed a revised Venous Clinical Severity Score (rVCSS) form, and the patients completed a VEnous INsufficiency Epidemiological and Economic Study Quality of Life/symptoms (VEINES QOL/Sym) questionnaire, to evaluate disease severity and quality of life.25, 26, 27, 28 At the 365 ± 7-day visit, patients also underwent ultrasonography and blood testing.
During the first study year, patients were contacted by telephone monthly, except when a scheduled visit was due, to assess for adverse events, outcomes, drug compliance, and the use of new concomitant medications. After the 12-month treatment period, event-free patients were followed up for an additional 12 months, resulting in a total study duration of 24 months. During the follow-up period, patients were contacted by telephone every three months to assess for adverse events and outcomes. A final visit was scheduled for all who completed the entire 24-month study period.
Compliance with oral treatment, defined as the total number of tablets actually taken divided by the total number of tablets expected and multiplied by 100, was categorised into “<65%” and “ ≥ 65%.”
Outcomes
The primary composite efficacy outcome was a composite of symptomatic recurrence or extension of SVT, new DVT (asymptomatic or symptomatic proximal, symptomatic isolated distal), or symptomatic non-fatal PE, or fatal PE, whichever occurred first, during the 12-month treatment phase. For the definition of extension and recurrence, we adopted the criteria used in the CALISTO study.7 A full description of these criteria, as well as of the standardised diagnostic approach used to confirm the primary composite outcome, is reported in the Supplementary Appendix.29
The primary safety outcome was the occurrence of major bleeding and clinically relevant non-major bleeding, as defined by the International Society on Thrombosis and Haemostasis.30,31
The secondary efficacy outcome was the same as above, assessed at the end of the 12-month follow-up period (overall 24 months from enrolment). The latter was specifically designed to evaluate the natural history of SVT in the placebo group and to assess the potential long-lasting protective effect of MGY after treatment withdrawal.
We also assessed other secondary outcomes, as follows: change in the rVCSS score (as a clinical indicator of treatment efficacy) and modification of the VEINES/Sym-QoL scores (as indicators of the subject’s satisfaction and quality of life), during the study period; evaluation of the recanalization rate of the index SVT (by means of CCDU); and of development of new deep and/or superficial venous reflux (by means of CCDU), at the end of the study period. Finally, we assessed whether the use of GCS had an impact on both the primary and secondary efficacy end-points, and if C-reactive protein (CRP) levels predicted the onset of the primary end-point.
An independent Adjudication Committee assessed all symptomatic outcomes, and data quality was evaluated by an independent Data and Safety Monitoring Board, both consisting of three VTE experts blinded to treatment allocation.
Statistical analysis
Based on the literature, we hypothesised that the primary efficacy outcome would occur in 15% of patients in the placebo group and in 7.5% of patients in the MGY group (hazard ratio = 0.5).3,13, 14, 15, 16 The planned recruitment period was 24 months, with 50% enrolment within the first 12 months, accounting for a 10% lost-to-follow-up rate in both groups. We estimated that, using a two-sided log-rank test, a sample size of 650 participants (325 per group) would provide 90% power at a significance level (alpha) of 0.025.
Categorical data were summarised by frequency tables, and continuous variables were described by means and standard deviations. Primary and secondary composite efficacy and safety analyses were conducted on the modified intention-to-treat population (subjects who received at least one dose of the study drug). For the time-to-event analysis of the primary and secondary efficacy outcomes, we estimated the cumulative rate and its 95% confidence limits at 12 and 24 months using the Kaplan–Meier survival table. The treatment hazard rate was estimated using a multivariate Cox proportional hazards regression model, adjusting for potential risk factors, including age, sex, obesity, varicose veins, cancer, and other covariates that were significantly associated with the composite outcome in univariate analysis. Significant covariates were identified through forward stepwise methods and Wald statistics. The proportional hazards assumption was evaluated using a log-minus-log plot and by analysing the log-hazard ratio over time with Schoenfeld residuals. In the event of non-proportional hazards, the Tharone-Ware post-hoc analysis was used.
A post-hoc subgroup analysis using the Kaplan–Meier method was added to provide evidence of the effect of the presence of basal varicose veins. No sensitivity analysis was performed.
Changes in rVCSS, VEINES-Sym, and VEINES-QoL scores during follow-up were analysed using a repeated-measures ANOVA. The primary safety analysis used the continuity-adjusted chi-square test. Additionally, a summary of adverse events was included.
All statistical tests were performed by IBM SPSS Statistics, Version 29 (IBM Corp., Armonk, US). Sample size determination was done by nQuery Advisor, version 9.0 (Statistical Solution Ltd., Cork, Ireland).
Role of the funding source
The funder of the study had no role in study design, data collection, data analysis, data interpretation, or writing of the report.
Results
Between March 26, 2018, and Dec 31, 2022, 553 patients (272 in the MGY group and 281 in the placebo group; Fig. 1) were enrolled. From the outset, recruitment was unexpectedly slow. The outbreak of the SARS-CoV-2 pandemic further slowed or even halted recruitment altogether. Consequently, on Dec 31, 2022, the decision was taken to stop recruitment before the planned sample size of 650 patients had been reached.
Fig. 1.
Patient flow of the patients through the study as shown in the CONSORT diagram.
The baseline demographic and clinical characteristics were well balanced across groups, as shown in Table 1. All participants were outpatients, predominantly female. Both varicose and non-varicose vein SVT events were evenly distributed across the study groups, with the great saphenous vein affected in most cases (69.3%). Of note, recognized risk factors for SVT recurrence, such as varicose veins, a history of cancer, and personal or familiar history of VTE, were equally represented in both groups (Table 1).
Table 1.
Baseline demographics of the study population.
| Mesoglycan | Placebo | |
|---|---|---|
| Baseline patient characteristics | n. 272 | n. 281 |
| Age (years); mean ± SD | 63.9 ± 13.6 | 64.2 ± 13.7 |
| Weight (kg); mean ± SD | 79.8 ± 16.3 | 78.9 ± 14.9 |
| Body Mass Index; mean ± SD | 27.8 ± 4.9 | 27.5 ± 4.4 |
| Male; No. (%) | 112 (41.2) | 112 (39.8) |
| Female; No. (%) | 160 (58.8) | 169 (60.2) |
| Medical conditions (present or previous); No. (%) | ||
| Hypertension (>140 mmHg) | 122 (45.4) | 130 (46.8) |
| Diabetes | 16 (5.9) | 29 (10.5) |
| Chronic obstructive pulmonary disease | 6 (2.2) | 9 (3.2) |
| Ischemic heart disease | 6 (2.2) | 9 (3.2) |
| Peripheral arterial disease | 2 (0.7) | 1 (0.4) |
| Stroke | 4 (1.5) | 8 (2.9) |
| Renal dysfunction | 7 (2.6) | 5 (1.8) |
| Dyslipidemia | 64 (23.8) | 64 (23.1) |
| History of Cancer | 26 (9.7) | 23 (8.3) |
| Autoimmune disease | 7 (2.6) | 7 (2.5) |
| Musculoskeletal disorders | 30 (11.2) | 34 (12.3) |
| Laboratory values; mean ± SD | ||
| Haemoglobin (g/L) | 134.3 ± 29.3 | 130.9 ± 34.5 |
| Platelets 100 × 10.9/L | 273.7 ± 70.0 | 245.6 ± 65.6 |
| Creatinine clearance (ml/min) | 91.1 ± 36.3 | 88.9 ± 33.2 |
| C-reactive protein (mg/L) | 1.1 ± 1.5 | 1.2 ± 1.3 |
| Index superficial vein thrombosis event; No. (%) | ||
| Recurring event | 102 (37.6) | 108 (38.6) |
| Ipsilateral and same site | 53 (54.6) | 67 (63.8) |
| Ipsilateral and new site | 17 (17.5) | 17 (16.2) |
| Contralateral and same site | 12 (12.4) | 11 (10.5) |
| Contralateral and new site | 15 (15.5) | 10 (9.5) |
| Varicose veins | 148 (54.4) | 145 (51.6) |
| rVCSS score; mean ± SD | 4.7 ± 2.5 | 4.8 ± 2.7 |
| VEINES QoL score; mean ± SD | 43.3 ± 6.4 | 44.1 ± 5.7 |
| VEINES Sym score; mean ± SD | 39.2 ± 6.9 | 39.4 ± 6.6 |
| CEAP–No. (%) | ||
| C0–Not detectable signs of venous disease | 17 (6.3) | 18 (6.5) |
| C1–Teleangiectasia or venous reticular network | 33 (12.3) | 36 (13.0) |
| C2s–Varicose veins | 174 (64.7) | 173 (62.5) |
| C3–Edema | 34 (12.6) | 32 (11.6) |
| C4–Pigmentation and/or eczema or lipodermatosclerosis and/or white atrophy | 11 (4.1) | 14 (5.1) |
| C5–Healed venous ulcer | 0 | 2 (0.7) |
| C6–Active venous ulcer | 0 | 2 (0.7) |
| Use of graduated compression stockings | 190 (69.8) | 182 (64.7) |
SD, standard deviation.
Most patients (61.7%) presented with a first episode of SVT, and the remaining (38.3%) had a recurrence. Graduated compression stockings were prescribed to 74.7% of the patients. Details regarding the baseline CEAP classification of the study group and concomitant medications are provided in the Supplementary Appendix (Table 1 and Supplementary Table S1, respectively).
The mean follow-up period was 508.3 days (±290.2) for the MGY group and 493.2 days (±285.8) for the placebo group (Table 2). No patient died during the study period. Compliance with the study drug (either MGY or placebo) was reported by most patients (95.3% in the MGY and 90.1% in the placebo group).
Table 2.
Primary and secondary efficacy and safety outcomes.
| Mesoglycan n. 272 | Placebo n. 281 | p | |
|---|---|---|---|
| Follow-up length, days; mean ± SD (Q1, Q2, Q3)a | 508.3 ± 290.2 (190, 714, 720) | 493.2 ± 285.7 (187, 616, 720) | 0.54 |
| Premature withdrawal, No. patients (%) | 50 (18.4) | 54 (19.2) | 0.83 |
| Loss of consent for COVID-19 | 25 (9.2) | 27 (9.6) | 0.10 |
| Adverse event | 12 (4.4) | 5 (1.8) | |
| Lost to follow-up | 11 (4.0) | 16 (5.7) | |
| Other | 2 (0.7) | 6 (2.1) | |
| Composite primary efficacy outcome (12-month period), No. (%)c | 54 (21.8)b | 63 (24.5)b | 0.56 |
| Symptomatic SVT, No. patients (%)c | 50 (20.3)b | 59 (23.1)b | 0.51 |
| Recurrence | 45 (90.0)b,d | 56 (94.9)b,d | NA |
| Extension | 5 (10.0)b,d | 3 (5.1)b,d | NA |
| DVTc | 9 (4.1)b | 9 (3.5)b | 0.90 |
| Non-Fatal PE | 0 | 1 (0.4)b | 1 |
| Fatal PE | 0 | 0 | NA |
| Without varicose veins | 7 (14.9) | 9 (10.1) | 0.55 |
| With varicose veins | 45 (22.7) | 54 (26.2) | |
| Composite secondary efficacy outcome (24-month period), No. (%)c | 74 (30.6)b | 105 (42.5)b | 0.04 |
| Symptomatic SVTc | 65 (27.2)b | 94 (39.0)b | 0.05 |
| Recurrence | 59 (90.8)b,d | 90 (95.7)b,d | NA |
| Extension | 6 (9.2)b,d | 4 (4.3)b,d | NA |
| DVTc | 14 (7.1)b | 19 (10.2)b | 0.43 |
| Non-Fatal PE | 1 (0.4)b | 1 (0.4)b | 1 |
| Fatal PE | 0 | 0 | NA |
| Without varicose veins | 12 (26.4) | 13 (27.5) | 0.03 |
| With varicose veins | 60 (31.2) | 91 (46.4) |
SD, standard deviation; SVT, superficial vein thrombosis; DVT, deep vein thrombosis; PE, pulmonary embolism; NA, not available.
25%, 50%, 75% quartiles of distribution.
Multiple events could occur in the same patient, including superficial vein thrombosis, deep vein thrombosis, and pulmonary embolism.
Cumulative rate by the Kaplan–Meier method.
Percentage of subjects who developed symptomatic SVT.
Overall, the primary composite efficacy outcome (12 months) occurred in 117 of 553 randomised patients (21.2%). Namely, 54 patients (cumulative rate 21.8%; 95%CI, 16.7% to 26.9%) in the MGY group and 63 patients (cumulative rate 24.5%; 95%CI, 19.2% to 29.8) in the placebo group reached the outcome (Table 2). No major or clinically relevant non-major bleeding events were observed in either study group. No differences were observed among subjects with or without varicose veins (Table 2; post-hoc subgroup analysis).
The secondary composite efficacy outcome (24 months) was observed in 179 of 553 (32.4%) randomised patients. Specifically, 74 patients (cumulative rate 30.6%; 95%CI, 25.0% to 36.2) in the MGY group and 105 patients (cumulative rate 42.5%; 95%CI, 36.3% to 48.7) in the placebo group reached the outcome (Table 2). Of interest, the observed results were entirely driven by the reduction in SVT recurrence or extension in the MGY group (Table 2). Notably, the cumulative rate of 24-month recurrence or extension of SVT in the placebo group was 39%. The presence of varicose veins was associated with a higher risk of observing a composite secondary efficacy event, linked to a clear benefit of treatment with mesoglycan (Table 2; post-hoc subgroup analysis).
At the univariate analysis, age more than 60 years, recurrent SVT as index event, occluding SVT, or SVT on varicose veins, a longer thrombus length, a larger thigh size, a higher rVCSS or VEINES-Sym scores, and the use of graduated compression stockings, were significantly associated with the secondary composite efficacy outcome. No significant association was found with sex, personal history of VTE, cancer, body mass index, CEAP class, or VEINES-QoL score (Supplementary Appendix, Supplementary Tables S2 and S3).
The prespecified multivariate proportional hazard Cox regression for the primary composite efficacy outcome (12 months) showed no difference in the MGY and placebo group (HR 0.89, 95% C.I. 0.62–1.29; p = 0.56). Conversely, at the end of follow-up (24 months), a significantly lower incidence of recurrent or extending SVT was recorded in the MGY group versus placebo (p = 0.043). Notably, for the secondary efficacy outcome (24 months), we used a post-hoc Tarone–Ware test rather than the prespecified Cox model or the log-rank test, because the proportional hazards assumption was violated for the comparison of trial arms over the 24-month period. Fig. 2 presents the Kaplan–Meier time-to-event analysis covering both the treatment phase and the subsequent 12-month follow-up period.
Fig. 2.
Time-to-event analysis by Kaplan–Meier product limit method with Tarone–Ware test.
Overall, 38 (6.9%) adverse events were observed (21 serious, 17 not serious), leading to 17 (3.1%) study drug discontinuations (5 in the placebo and 12 in the MGY group; Table 3 and Supplementary Table S4 in Supplementary Appendix). Nine (1.6%) events were considered drug-related (one asthenia, two headaches, two skin rashes, one nausea, two diarrhoea, one myalgia) by the blinded investigators.
Table 3.
Adverse events for anatomical systems.
| Arm |
Placebo |
Mesoglycan |
Total | Resolved | ||
|---|---|---|---|---|---|---|
| Adverse event | Not Serious | Serious | Not Serious | Serious | ||
| Cardiac–Non-compact myocardium | 1 | 1 | No | |||
| Cardiac–Atrial fibrillation | 2 | 1 | 3 | Yes | ||
| Blood and Lymphatic System–Non-Hodgkin lymphoma | 1 | 1 | No | |||
| Hepato-biliary System–Gallbladder distention/stone | 2 | 2 | Yes | |||
| Immune System–Allergic skin reactions | 1 | 1a | 2 | Yes | ||
| Nervous System–TIA | 2 | 2 | Yes | |||
| Nervous System–Headache | 2a | 2 | Yes | |||
| Reproductive System–Hysterectomy | 1 | 1 | Yes | |||
| Urinary Tract–Kidney stones | 1 | 1 | Yes | |||
| Urinary Tract–Chronic kidney disease | 1 | 1 | Yes | |||
| Skin–Erysipelas | 1a | 1 | Yes | |||
| Skin–Erythema multiforme | 1 | 1 | Yes | |||
| Gastrointestinal–Diarrhea | 2a | 2 | Yes | |||
| Gastrointestinal–Abdominal distention/pain | 1 | 1 | 1 | 3 | Yes | |
| Gastrointestinal–Nausea | 1 | 1a | 2 | Yes | ||
| Gastrointestinal–Constipation | 1 | 1 | Yes | |||
| Musculoskeletal–Knee injury | 1 | 1 | Yes | |||
| Musculoskeletal–Pain in the extremities | 1 | 1 | Yes | |||
| Musculoskeletal–Myalgia | 1a | 1 | Yes | |||
| Musculoskeletal–Knee replacement | 1 | 1 | Yes | |||
| Eyepieces–Maculopathy | 1 | 1 | No | |||
| Thoracic–Pleural effusion | 1 | 1 | Yes | |||
| Injuries–Fall | 1 | 1 | Yes | |||
| Injuries–Elbow fracture | 1 | 1 | Yes | |||
| Injuries–Hip fracture | 2 | 1 | 3 | Yes | ||
| Systemic–Asthenia | 1a | 1 | Yes | |||
| Total | 9 | 8 | 12 | 9 | 38 | 35 |
| 17 | 21 | |||||
TIA, Transient Ischemic Attack.
Blinded Investigator judged adverse event as drug-related: 9.
Of the three vascular scores evaluated, only the rVCSS showed a significant decrease during follow-up in subjects treated with MGY (Table 4); neither compression therapy nor baseline C-reactive protein levels were correlated with the efficacy outcomes. Some of the 179 patients reaching the secondary composite efficacy outcome experienced more than one thrombotic event. Specifically, 159 had symptomatic SVT (recurrence or extension), 33 were diagnosed with DVT, and two experienced non-fatal PE.
Table 4.
Behaviours of different venous scores during follow-up.
| Time points | Mesoglycan mean (SD) | Placebo mean (SD) | pa | |
|---|---|---|---|---|
| Patients, No. | 272 | 281 | ||
| rVCSS score | basal | 4.8 (2.7) | 4.7 (2.5) | 0.05 |
| 12-month | 3.9 (2.8) | 4.2 (2.5) | ||
| 24-month | 3.3 (2.5) | 3.9 (2.4) | ||
| VEINES-Sym score | basal | 39.2 (6.9) | 39.4 (6.6) | 0.56 |
| 12-month | 41.2 (5.6) | 40.2 (7.5) | ||
| 24-month | 40.5 (6.1) | 40.1 (3.5) | ||
| VEINES-QoL score | basal | 43.3 (6.4) | 44.1 (5.8) | 0.36 |
| 12-month | 43.2 (5.9) | 43.2 (5.8) | ||
| 24-month | 43.9 (5.5) | 42.4 (6.2) |
SD, standard deviation.
Repeated measures ANOVA between-subjects effect.
Discussion
We investigated the efficacy of a 12-month course of MGY for secondary prevention of SVT, symptomatic VTE, or fatal PE in patients with symptomatic (first-ever or recurrent) SVT of the legs, initially treated with a standard 45-day course of fondaparinux.
We found no significant difference in terms of efficacy between the study groups at 12 months (primary efficacy outcome); while we observed a significant (p = 0.043) effect of MGY compared with placebo at 24 months (secondary efficacy outcome). No bleeding events were observed in either patient group. Patients administered MGY showed significant improvements in the rVCSS score at 12 and 24 months compared with placebo (p = 0.05; Table 4).
Finally, the cumulative rate of recurrence or extension rate of SVT in the placebo group was 23.1% at 12-month, and 39.0% at 24 months, providing, for the first time, prospective data on the natural course of SVT in patients given an appropriate initial treatment.
Following our initial assumption that MGY administration would result in a 50% relative reduction of the primary composite efficacy outcome compared with placebo, we found no significant differences between the two study groups at 12 months. To our knowledge, no other similar studies address this issue in the literature, and published work on acute treatment of SVT, either cohort or randomised, explores the efficacy of several treatment strategies over 90 days only.7,32,33 Instead, we recorded a significant reduction of the cumulative rate of the secondary composite efficacy outcome at 24 months in patients given MGY as compared with placebo, entirely driven by a decrease in recurrent or extending SVT (Supplementary Appendix, Supplementary Table S2).
A possible explanation for these findings may reside in the anti-inflammatory properties of MGY, demonstrated both in the general circulation and in the varicose veins.34 It is well known that SVT is associated with inflammation of the venous wall and surrounding tissues, and that such inflammation is negatively associated with venous recanalisation.34, 35, 36 In turn, incomplete vein recanalisation is associated with a higher risk of recurrence.34, 35, 36 Therefore, by reducing venous wall inflammation, MGY could prevent recurrent SVT. In this regard, MGY retained a similar 24-month efficacy even in patients with a history of more than one episode of SVT (Supplementary Appendix, Supplementary Table S3). The observed delayed long-term efficacy of MGY, persisting at one year after its withdrawal, may be related to its ability to restore the endothelial glycocalyx, damaged by inflammation and thrombosis.23,34 It has been already reported that patients treated with MGY display significantly reduced levels of circulating biochemical markers of endothelial dysfunction (e.g., metalloproteinases, interleukins, syndecans, etc.) after three months of treatment.34 Thus, it is plausible that a one-year course of MGY may fully restore the integrity of the endothelial layer, possibly translating into a long-term reduction in thrombotic events.
Notably, this hypothesis corroborates the clear benefit from MGY in significantly reducing SVT recurrence in the higher-risk group of patients presenting with, compared to without, varicose veins (Table 2).
In this context, it is noteworthy that the 24-month recurrence or extension rate of SVT in the placebo group, representing its natural history, was around 40%, that is almost two to three times higher than that reported in the literature.7,13,14,32,37
The use of graduated compression stockings, left to the discretion of the investigators, did not differ between the two study groups, and was somewhat unexpectedly associated with a higher incidence of recurrent SVT at 24 months. A possible explanation for this counterintuitive finding may lie in a prescription bias by the investigators; in the sense that patients felt to be at higher risk of recurrence could have been more frequently prescribed stockings than lower-risk patients.
The strengths of our study are that we used a rigorous methodology, employing a double-blind randomised design, with variable block size, appropriate allocation concealment, and precise endpoint definition to minimise selection, performance, and detection bias. Fewer than 5% of the study patients were lost to follow-up, with similar rates in either group, a figure considered appropriate to reduce attrition bias.38 Clearly, since our results are essentially neutral, we believe reporting bias should not be a concern.
It is important to highlight some key limitations of the study. Firstly, since most of the research was conducted during the SARS-CoV-2 pandemic, we were unable to enroll the planned number of patients; this forced us to extend the enrolment period to approach the initial sample size and prevented us from conducting the formal interim analysis as originally planned. Furthermore, as a proof-of-concept study based on very limited evidence, we overestimated both the extent of recurrent or extending SVT reduction by MGY and the time needed to achieve such results when designing the study. Secondly, we acknowledge that the use of VCSS and VEINES scores in patients with non-varicose SVT could represent a limitation. However, we used those scores to classify all patients included in the study, encompassing those with SVT on non-varicose veins or without symptoms altogether. Thirdly, the study protocol did not require to specify race, ethnicity, or gender (only sex); thus it is likely that the generalisability of our results could be limited in this sense. Finally, since a venous ultrasound was performed only at the one-year visit or in case of new leg symptoms, we could potentially have missed some asymptomatic events.
In summary, MGY administration was associated with a non-significant reduction of recurrent or extending SVT at the end of a 12-month treatment course, as compared with placebo. However, we observed a significant reduction of recurrent or extending SVT in the MGY group after another 12 months of follow-up, suggesting a long-term restorative effect on the endothelial layer. Notably, patients with symptomatic SVT of the legs face a higher-than-expected long-term risk of recurrence. These findings should be interpreted cautiously, given that the planned sample size was not reached due to slow recruitment and that the incidence of recurrent or extending SVT in the placebo group was higher than previously reported. A larger, randomised trial is warranted to confirm our findings.
Contributors
GC, EB, FN, and CB designed and planned the study. All contributors were responsible for enrolling participants in each centre, and for treatment of patients, data and trial management and analysis, and review of the report. FN performed the statistical analysis. GC, EB, FN and CB wrote the manuscript. All Authors contributed to revision of the manuscript, and read and approved the final draft before submission. GC, EB and FN accessed and verified the underlying data and are the guarantors of the study. GC was responsible for the decision to submit the manuscript. The corresponding author (GC) attests that all listed Authors meet ICMJE authorship criteria and that no others meeting the criteria have been omitted.
Data sharing statement
The dataset is available through direct contact with the corresponding author or with the statistician (FN—franco.noventa@gmail.com). The original protocol and SAP are available online at: https://www.quovadis-ass.it/Protocols_pub/METRO_STUDY_PROTOCOL_1.7_24102017_EudraCT_n.2016-005184-13%20-%20English%20version.pdf.
Declaration of interests
We declare no competing interests. There are no other relationships or activities that could appear to have influenced the submitted work.
Acknowledgements
Neopharmed Gentili, Milan, Italy sponsored the trial with an unrestricted grant and provided the study drug (mesoglycan). We thank all the patients at centres throughout Italy whose willingness to participate made this study possible. We are grateful to all principal investigators, sub-investigators, and local centre staff including nursing research teams and data staff, for their dedication and commitment to recruiting patients to the study. We thank all members of the Independent Adjudication Committee [P.P. (Chair), E.C, R.P.] and of the Independent Data Safety Monitoring Board [L.S. (Chair), C.S., M.T.S].
Footnotes
Translation: For the Italian translation of the abstract see the Supplementary Materials section.
Supplementary data related to this article can be found at https://doi.org/10.1016/j.eclinm.2026.104010.
Contributor Information
Giuseppe Camporese, Email: giuseppe.camporese@aopd.veneto.it.
METRO Investigator Study Group:
Paolo Prandoni, Elena Campello, Raffaele Pesavento, Luca Spiezia, Chiara Simion, Paolo Scarinzi, Ngoc Vo Hong, Michela Nardin, Sara Maggiolo, Adriana Visonà, Paola Bigolin, Tatiana Scanduzzi Piovesan, Ida Maria Muratori, Francesco Contorno, Francesco Sartore, Laura Franco, Mara Graziani, Luca Santoro, Sergio Zacà, Lucia Di Stefano, Alessia Abenante, Benedetta Volpe, Silvia Frasca, Mauro Pinelli, Laura Giantomassi, Vincenza Pedone, Federica Dimitri, Raffaele Pulli, Laura Paperetti, Alessandro Saturni, Sara Mangiacapra, Francesca Cannavacciuolo, and Giovanni Di Minno
Appendix A. Supplementary data
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