Prevention of Recurrent Superficial Venous Thrombosis: First Randomized Trial with Mesoglycan

Superficial venous thrombosis (SVT) is a very common condition. Although generally considered a “benign” disease, when particularly extensive or close to the deep venous system it may progress to deep vein thrombosis or pulmonary embolism (2). Current guidelines provide recommendations—albeit weak ones—on the acute treatment of SVT (mainly based on the CALISTO trial), but no indications exist regarding preventive strategies for recurrence due to the near-total lack of randomized controlled clinical trials (3,4).

The METRO Study

The Italian METRO study randomized 553 patients who had just completed guideline-recommended treatment consisting of 45 days of fondaparinux 2.5 mg once daily for symptomatic SVT (≥5 cm in length and ≥3 cm from the deep venous system) to receive mesoglycan 50 mg twice daily or placebo for 12 months. The great saphenous vein was involved in 69% of cases. The study population was on average overweight (BMI 27), and approximately half of the patients had varicose veins. Thirty‑eight percent had experienced a previous SVT episode. Patients were followed for an additional 12 months after treatment discontinuation (1).

Graduated compression stockings were prescribed to 74.7% of participants; however, as commonly occurs with elastic compression, actual patient compliance is difficult to assess, and the authors did not provide data on this aspect.

A total of 272 individuals were assigned to mesoglycan and 281 to placebo in a double‑blind fashion. After one year of treatment, no significant reduction was observed in the composite primary outcome (SVT recurrence or extension, symptomatic or asymptomatic proximal deep vein thrombosis, symptomatic distal DVT, or symptomatic pulmonary embolism) among those receiving mesoglycan (21.8% vs 24.5%; HR 0.89, 95% CI 0.62–1.29).

However, the subsequent double‑blind follow‑up yielded unexpected findings. At 24 months, patients previously treated with mesoglycan showed a significant reduction—approximately 30%—in secondary outcome events compared with the placebo group (30.6% vs 41.5%; p=0.043). This difference was almost entirely driven by a reduction in SVT recurrences. The effect was particularly evident when the initial SVT occurred in the presence of varicose veins. No fatal pulmonary embolism, major bleeding, or clinically relevant non‑major bleeding occurred.

How Can the METRO Results Be Explained?

“The interpretation we can provide is clinical,” explained Prof. Giuseppe Camporese of the University of Padua, “since the drug has the ability to ‘restore’ the venous wall (the glycocalyx damaged by the thrombotic event)… evidently the mechanism through which this occurs is slow, and the effect required time to accumulate in this patient population (one year of therapy) to achieve efficacy in reducing events beyond twelve and up to twenty‑four months.”

Indeed, several studies have documented the effect of mesoglycan in reducing vascular wall inflammation (a key driver of chronic venous disease) and in restoring the damaged endothelial glycocalyx (1). In particular, a recent study showed that patients with lower‑limb varicose veins treated with mesoglycan exhibited reduced circulating levels of biochemical markers of endothelial damage (metalloproteases, interleukins, syndecans) after three months of treatment (5).

The intriguing hypothesis proposed by the researchers—potentially forming the basis for future studies—is that a full year of treatment may completely restore endothelial layer integrity, translating into a long‑term reduction in thrombotic events.

The Natural History of Superficial Venous Thrombosis

Both clinicians and patients commonly observe that SVT tends to recur after resolution, but until now information on the true long‑term incidence of new episodes has been lacking. The few retrospective data available in the literature report up to a 15% recurrence rate between 3 months and 5 years after the thrombotic event (2,3).

“This is the first time that long‑term prospective data on recurrence incidence in patients who, after completing treatment, receive no further therapy—as the natural history of the disease—have been reported in the international literature,” noted Camporese.

Specifically, 39% of patients assigned to placebo in the METRO study experienced a recurrence at two years—an incidence more than double what had been expected, highlighting the impact of the disease on patients’ quality of life and long‑term risks.

Caution in interpreting the promising METRO results is warranted due to early study termination caused by slow enrollment and the high incidence of SVT recurrences in the placebo group, which was much greater than previously reported.

Therefore, pending further clinical trials confirming the long‑term clinical efficacy (even after treatment discontinuation) of therapies aimed at restoring the endothelial glycocalyx, the results underscore the urgent need to address risk factors and implement strategies for preventing recurrent superficial venous thrombosis.

Camporese G. et al. eClinicalMedicine (2026)

Bibliography

1. Camporese G, Bernardi E, Bortoluzzi C et al.Mesoglycan for long-term secondary prevention in patients with superficial vein thrombosis (METRO): a multicentre randomised clinical trial in Italy eClinicalMedicine, 2026; 97 DOI: 1016/j.eclinm.2026.104010
2. Decousus H, Quéré I, Presles E, et al. Superficial venous thrombosis and venous thromboembolism: a large, prospective epidemiologic study. Ann Intern Med. 2010;152(4):218-224. doi:10.7326/0003-4819-152-4-201002160-00006
3. .Jørgensen CT, Brækkan SK, Førsund E, et al. Incidence of venous thromboembolism, recurrence, and bleeding after isolated superficial vein thrombosis: findings from the Venous Thrombosis Registry in Østfold Hospital. J Thromb Haemost. 2024;22(2):526-533. doi:1016/j.jtha.2023.10.017
4. Decousus H, Prandoni P, Mismetti P, et al. Fondaparinux for the treatment of superficial-vein thrombosis in the legs. N Engl J Med. 2010;363(13):1222-1232. doi:1056/NEJMoa0912072
5. Stevens SM, Woller SC, Kreuziger LB, et al. Antithrombotic Therapy for VTE Disease: Second Update of the CHEST Guideline and Expert Panel Report. Chest. 2021;160(6):e545-e608. doi:1016/j.chest.2021.07.055
6. Santoliquido A, Carnuccio C, Santoro L, et al. Local and Systemic Endothelial Damage in Patients with CEAP C2 Chronic Venous Insufficiency: Role of Mesoglycan. Int J Mol Sci. 2025;26(9):4046. Published 2025 Apr 24. doi:3390/ijms26094046

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