Is Nonmicronized Diosmin 600？mg as Effective as Micronized Diosmin 900？mg plus Hesperidin 100？mg on Chronic Venous Disease Symptoms? Results of a Noninferiority Study

Background. Phlebotonics have beneficial effects on some symptoms related to chronic venous disease (CVD) of the lower limbs. The most commonly used one is diosmin, available in a pure semisynthetic form or as a micronized purified flavonoid fraction. Patients and Methods. The primary objective of this single-blind, randomized, parallel-group, prospective study was to assess the clinical noninferiority of nonmicronized diosmin 600？mg once daily (D-group) compared to micronized diosmin 900？mg plus hesperidin 100？mg once daily (D/H-group) over a 6-month treatment period. Adult patients with a symptomatic CVD of the lower limbs (C0-C3 grade; 20-60？mm on a 100？mm visual analog scale (VAS)) were included. The primary endpoint was the change (from baseline to last postbaseline value) of the intensity of the lower-limb symptoms on VAS. Results. 114 patients (mean age, 44.4 years; women, 90.4%) were randomized in the per-protocol analysis (D-group, ; D/H-group, ). Symptoms significantly improved in both groups with adjusted mean VAS changes of -24.9？mm ( ) in the D-group and -22.8？mm ( ) in the D/H-group, corresponding to approximately 50% reduction in basal symptom intensity. The difference between groups was -2.1？mm with an upper limit of one-sided 90% confidence interval equal to 1.0？mm for a noninferiority margin set at 20？mm (noninferiority demonstrated). Intent-to-treat analysis confirmed per-protocol analysis. Difficulty in swallowing the tablets (VAS) was significantly lower in the D-group compared to the D/H-group (9.4？mm and 54.7？mm at 6 months, respectively; ). The overall safety of both study drugs was good. Conclusion. Nonmicronized diosmin 600？mg was proven to have a noninferior efficacy compared to micronized diosmin 900？mg plus hesperidin 100？mg, associated with greater ease in swallowing the tablet