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

Abstract

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, <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M1"><mml:mi>n</mml:mi><mml:mo>=</mml:mo><mml:mn>57</mml:mn></mml:math>; D/H-group, <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M2"><mml:mi>n</mml:mi><mml:mo>=</mml:mo><mml:mn>57</mml:mn></mml:math>). Symptoms significantly improved in both groups with adjusted mean VAS changes of -24.9 mm (<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M3"><mml:mi>p</mml:mi><mml:mo>&lt;</mml:mo><mml:mn>0.0001</mml:mn></mml:math>) in the D-group and -22.8 mm (<mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M4"><mml:mi>p</mml:mi><mml:mo>&lt;</mml:mo><mml:mn>0.0001</mml:mn></mml:math>) 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; <mml:math xmlns:mml="http://www.w3.org/1998/Math/MathML" id="M5"><mml:mi>p</mml:mi><mml:mo>&lt;</mml:mo><mml:mn>0.0001</mml:mn></mml:math>). 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.