Efficacy of Orally Administered Extract of Red Vine Leaf AS 195 (folia vitis viniferae) in Chronic Venous Insufficiency (Stages l-ll)

Summary Red vine leaf extract (RVLE) is a herbal medicine containing several flavonoids, with quercetin-3-O-ß-glucuronide and isoquercitrin (quercetin-3-O-ß-glycoside) as the main components. Objective – To assess the efficacy and safety of once-daily doses of 360 and 720 mg RVLE (pharmaceutical extract code AS 195; Antistax® Venenkapseln) compared to placebo in patients with stage I and incipient stage II chronic venous insufficiency (CVI). Design – A 12-week, randomized, double-blind, placebo-controlled, parallel-group, multi-center study. Patients – Male and female outpatients aged 25 to 75 years with stage I to stage II CVI (i.e. without extensive trophic changes), not having any other significant medical conditions and not treated with compression stockings, diuretics or other drugs affecting fluid balance. Intervention – Patients were randomly assigned to a double-blind treatment with placebo, 360 mg AS 195 or 720 mg AS 195 once daily for 12 weeks, preceded and followed by a single-blind 2-week placebo treatment for baseline run-in and end-of-trial washout, respectively. Study criteria were evaluated at baseline, after 6 and 12 weeks of treatment and 2 weeks after discontinuation of treatment. Results – Of the 260 patients enrolled and randomized, 219 completed the study in accordance with the protocol. In the intention-to-treat analysis (N = 257), the mean (± SD) lower leg volume (measured by water displacement plethysmography) of the patients treated with placebo (N = 87) increased by 15.2 ± 90.1 g (displaced water mass) and by 33.7 ± 96.1 g after 6 and 12 weeks compared to baseline. In contrast, for patients treated with AS 195, lower leg volume decreased, and after 12 weeks of treatment, the difference in mean lower leg volume between the active treatment groups and the placebo group was −75.9 g (95% CI: −106.1 to −45.8 g) and −99.9 g (95% CI: −130.3 to −69.6 g) for the group treated with 360-mg AS 195 (N = 86) and 720-mg AS 195 (N = 84), respectively. The changes in calf circumference showed a similar pattern: in patients treated with AS 195, both the higher dose (720 mg) and, albeit to a lesser extent, the lower dose (360 mg) resulted in a clear reduction in circumference over time, whereas, circumferences remained largely unchanged in patients treated with the placebo (95% CI of the estimated treatment effects vs. placebo after 12 weeks: -1.40 to -0.56 cm and -1.73 to -0.88 cm for 360 and 720 mg AS 195, respectively). These differences were statistically significant (p < 0.001). The reductions in ankle circumference were qualitatively similar but quantitatively less marked. Subjectively, there was an improvement in key CVI symptoms (VAS) at 6 weeks with all treatments, but a further improvement at week 12 was seen only in the active treatment groups; at 12 weeks, the changes compared to baseline were significantly greater (p < 0.001) in both active treatment groups than in the placebo group. The treatments were well tolerated; Adverse events were rare and usually mild. Two adverse events (AEs) during treatment with the placebo led to hospitalization and were hence labeled as ‘serious’. Three further patients were withdrawn because of AEs which occurred during treatment with the placebo. Conclusion – Once-daily doses of 360 and 720 mg AS 195 were confirmed to be safe and effective in the treatment of mild CVI, reducing significantly lower leg edema and circumference whilst improving key CVI-related symptoms to a clinically relevant extent. The edema reduction is at least equivalent to that reported for compression stockings and/or other edema-reducing agents. The higher dose was as well tolerated as the lower dose but resulted in a slightly greater and more sustained improvement.