Phlebology Suppl.
1 (1994) 15-18
© 199~ !he Venous Forum of the Royal Society
of Medicine and Societas Phlebologica Scandinavica
Chronobiology and Clinical Activity of Dafton 500 mg in Chronic
Venous Insufficiency
G. Menyhei", G. Acsady", A. Hetenyi", D. Dubeaux" and G. RadoS
IDepartment of Surgery, University Medical School, Ifjusag u.13, Hungary; 2Department of Cardiovascular Surgery
Semmelweis Medical University, Budapest, Hungary; 3Department of Vascular Surgery, Magyar I. Hospital Aik '
Hung.ary; "Angiology Therapeutic Division, IRIS, Courbevoie, France; SOutpatient Clinic for Phlebology, S~ Ja~:~
Hospital, Budapest, Hungary
ABSTRACT
Objective: To assess the chronobiological effect on
therapeutic activity of Daflon 500 mg and to determine
the optimum method of administration.
Design: Multicentre, randomized, double-blind, con-
trolled trial.
Setting: Hospital outpatient clinics for vascular diseases
In Hungary.
Patients: Three hundred and twenty ambulatory
patients with symptoms of chronic venous insufficiency
randomized to three groups.
Interventions: Oral administration daily of 1000 mg of
Daflon 500 mg for 2 months in three different ..ways
(morning or evening or morning and evening).
Main outcome measures: Symptoms and clinical signs of
chronic venous insufficiency.
Results: In each group, a statistically significant improve
~e.nt was observed between the first (DO) and the last
VISIt (D60) concerning all symptoms. Oedema dis-
appeared in a mean percentage of patients ranging
~etween 26% and 43%, according to the group and the
s!de.affected (p <0.001). For the most affected leg, a
sIgmficant decrease (p <0.001) of ankle and calf cir-
c~m.ferences was observed in each group. The first
sIgmficant improvement, in comparison to DO,occurred
b~tween D15 and D30 for all symptoms and ankle
cIrcumference. The comparison between the groups did
not disclose any difference concerning the improvement
of symptoms and signs.
~onclusion: In this study, Daflon 500 mg demonstrated
!ts therapeutic activity in chronic venous insufficiency,
Irrespective of the daily drug administration schedule.
~eywords: Chronobiology; Flavonoids; Micronized
diosmm; Oedema; Venous insufficiency; Venous tone
• Also registered as Capiven, Detralex, Arvenum 500 mg.
Introduction
Daflon 500 mg* is a purified and micronized flavonoid
fraction comprising 90% diosmin and 10% hesperidin
wit!t 500 m~ ~f active principle per tablet. Its pharmaco-
logical activity has been documented in numerous
studies, w~ich !tave shown v~t;t0tonic activity [1-3] as
well as microcirculatory activity decreasing capillary
permeability and increasing resistance [4,5], and that it
has a favourable effect on blood rheology [6]. The
therapeutic effi.cacy and s~fety of. Daflon 500 mg was
demonstr~ted I.n veno'!s insufficiency in controlled,
double-bhnd tnals against placebo and in long-term
tre~t!Uent of 1 year's duration [7-9]. The bioavailability,
activity or safety of a drug can be influenced by different
physiological conditions during the chronobiological
rhythm and can depend on the time of administration.
The activity of Daflon 500 mg has been demonstrated
after a single administration of two tablets [7] and after
two adminis~rations of one tablet per day [10]. How-
ever, the optimum method of administration has still to
be demonstrated. Thus, a clinical trial was designed to
compare the therapeutic activity of Daflon 500 mg after
either a single dosage of two tablets in the morning or in
the evening, or after two dosages of one tablet in the
morning at;td one in the ~vening, administ~red daily for
2 months, m a double-blind, controlled tnal in patients
suffering from chronic venous insufficiency.
Patients and Methods
Ambulatory patients with known chronic venous insuf-
ficiency due to primary varicose veins, post-thrombotic
syndrome or functional venous insufficiency were
selected for the study. The exclusion criteria were:
recent deep or superficial venous thrombosis, recent
varicose vein surgery or sclerotherapy, symptoms and
signs of arterial, neurological or metabolic origin, use of
 16 G. Menyhei et al.
a venotropic drug in the preceding 3 months and use of repeated measures on time was performed to compare
compression bandage or stocking for less than 3 months. between groups the change over time of functional
Each patient received four tablets per day of rando- discomfort and circumference measurements of the
mized treatment: Daflon 500 mg (two tablets) and most affected leg (highest malleolar circumference). In
placebo (two tablets). The partition of the tablets case of significant group x time interaction, an analysis
according to each group was as follows: was carried out to study the group effect at each time.
Group 1: two tablets of Daflon 500 mg in the morning, Moreover, change over time in each group was studied
two tablets of placebo in the evening using a one-way analysis of variance (time) with
repeated measures on time, completed by a Newman-
Group 2: one tablet of Daflon 500 mg and one tablet of Keuls test. Change over time of intensity of symptoms
placebo in the morning and in the evening was studied using a Friedman test. Qualitative variables
Group 3: two tablets of placebo in the morning, two (oedema, trophic disorders, adverse events) were ana-
tablets of Daflon 500 mg in the evening. t
lysed by a test or a Fischer exact test according to the
The use of any treatment known to interfere with sample size. Moreover, a Cochran test was performed
functional venous symptoms (calcium inhibitors, diure- to study the within-group change over time for oedema.
tics, anti-inflammatory drugs) was prohibited through-
out the trial period. Patients using elastic support
therapy in the form of bandage or stocking at the time of Results
inclusion in the trial and for the previous 3 months had
to continue the same prescription throughout the trial This study involved 320 patients suffering from chronic
period. The duration of the treatment was 2 months. venous insufficiency due to primary varicose veins
The following evaluations were performed on entry into (45.5%), post-thrombotic syndrome (48.5%) or func-
the trial (DO) and during the treatment after 15 days tional venous insufficiency (15.8%). By misdelivery of
(DIS), 30 days (D30) and at the end of the treatment the test medication, 12 patients (3.8%) of the total
(D60): population were not included in the global analysis. The
mean age of the analysed population (n = 308) was 49.9
1. Functional discomfort evaluated by the patient on a years (range 20-84 years) and the sex ratio was 107
visual analogue scale. males to 201 females. Of the 308 patients included for
2. Symptoms of venous insufficiency assessed by the statistical analysis, six did not complete the trial (four
investigator using a four-point scale. because of adverse event occurrence and two for
3. Circumferences of limbs measured at the level of reasons not related to the therapy).
ankles and calves. The studied population was randomized to the three
4. Alteration of signs (oedema and trophic disorders), scheduled groups and no relevant significant difference
recording their evolution under treatment and by was observed between the three groups at inclusion
taking photographs. (before treatment) in terms of biometric and biological
5. Adverse events and, if present, description of these characteristics as well as parameters of evaluation of
chronic venous insufficiency. At inclusion, the studied
events.
population was considered as homogeneous and the
The following laboratory blood tests were carried out three groups as comparable.
at the start and at the end of the treatment: full blood In each group, a statistically significant (p <0.001)
·count, differential white cell count, haemoglobin, improvement was observed between DO and 060 con-
haematocrit, fibrinogen, cholesterol, triglycerides, cerning functional discomfort and intensity of
transaminases, creatinine and urea. symptoms, but without significant difference between
At the end of the study, the patients were asked for an the three groups. The improvement became significant,
overall assessment of the effect of the treatment on the in comparison to DO, between 015 and 030 and was
symptoms of their disease. Overall assessment of sustained until the end of the treatment (Fig. 1).
acceptability was also given by the patient and by the . Of the 263 fully documented patients who presented
clinician, who stated whether the treatment was well leg oedema at inclusion (93, 87 and 83 patients in groups
tolerated or not. 1,2 and 3, respectively), clinical examination disclosed
All patients admitted to the study gave their informed a disappearance of oedema during the 2-month treat-
consent in accordance with the Declaration of Helsinki. ment in a mean percentage of patients ranging between
28.0% and 43.4% according to the group and the side
Statistics affected (p <0.001). There was no significant difference
between groups at D60 for oedema on the right and left
For quantitative variables and laboratory tests, a one- limbs (Fig. 2). The clinical improvement was confirmed
way analysis of variance (group) was carried out to by calf and malleolar circumference measurements. If
assess the comparability of groups. For quantitative only initially oedematous legs were taken into account
variables, a i test or a Fisher exact test was used (with random choice of side in cases of bilateral
according to the sample size. oedema), a decrease of average circumference measure-
A two-way analysis of variance (group, time) with ments was noted, ranging between 6.9 mm and 9.3 mm
 Chronobiology and Clinical Activity in Chronic Venous Insufficiency 17
Functional discomfort Calf
on a visual scale Group 1 : circumference (mean ± sem)
(mean ± semI Group 2: (mm) Group I: _ _
10
Group 3: Group 2: _ . _
410
Group3: _ _
9

8 400

390
6

5
380

4
~
Supra-malleolar
circumference (mean ± sem)
3 (mm)

250

~-1
2

240
o
DO 015 030

Fig. 1. Functional discomfort from DO to D6O.

060
"lr'-'-'-'-'-'1
L...-_---J'--_---' --'-_ _.... Visits
230
~

DO 015 030 060

Fig. 3. Circumference measurements on the most affected leg.

Number of legs with oedema
80 Group I. _ _
Group 2: - - - -
Group 3. "- -..., circumference measurements in each group (p <0.001).
For calf circumference, changes over time differed
70
between the groups (p = 0.025), with a higher decrease
for group 1 (Table 1, Fig. 3). The number of patients
...... ...... with trophic disorders did not change with time in either
80 ....... , of the groups, but the number of ulcers decreased.
,, There was no significant difference at 060 between the
,, groups for hypodermitis, telangiectasis and ulcers.
,
50
"'... ...... ...... ......
......
......
} Left leg
There was a statistically significant difference in
change over time between the groups for haematocrit
(p = 0.040), but these changes were not biologically
40 relevant and the haematocrit remained within the
normal ranges. For all other laboratory variables, there
was no change over time from 00 to 060, and no
} Right leg
30
significant difference between the three groups.
Fifteen adverse events occurred during the study
performed in 308 analysed patients (4.9%). The most
frequent events were nausea and other mild gastro-
20
intestinal discomfort. There was a significant difference
DO 015 030 060 for the number of adverse events between the groups:
Fig. 2. Number of patients with oedema on the left and right leg. 1.0% in group 1, 3.9% in group 2 and 10.1% in group 3
(p = 0.009). No adverse event was classified by the
investigator as being probably related to the test medi-
for the ankle and between 3.5 mm and 8.5 mm for the cation.
calf, according to the group. The overall assessment of activity and acceptability
For the most affected leg, a statistically significant both by the patients and by the investigators was
decrease was observed between DO and D60 for the excellent in each group.
18 G. Menyhei et al.
Table 1. Change over time of the most affected leg between DO and D60

Variables Groups DO DIS D30 D60 Group x time Time

interaction effect

Calf circumference (mm) x2 Morning 400.4 398.9 394.5 392.2 p<O.OOI

Morning-evening 391.4 388.5 386.3 387.1 p=0.025* p<O.OOI
x2 Evening 390.6 388.8 386.8 386.4 p<O.OOI
Malleolar circumference (mm) xz Morning 248.4 245.7 241.6 239.6 p<O.OOI
Morning-evening 241.7 239.9 234.9 234.5 p=0.767 p<O.OOI
x2 Evening 247.3 244.7 240.4 239.4 p<O.OOI

Group effect: DO, p=0.201; DIS, p=0.151; D30, p=0.321; D60, p=0.580.

Discussion groups. Moreover, this frequency of adverse events

observed in group 3 was not reported in other studies
For treatment of chronic venous insufficiency, there are where Daflon 500 mg was administered in a dosage of
different therapeutic options. Patients with primary six tablets daily [12].
varicose veins, and a smaller proportion of patients with We conclude that different daily drug administration
deep venous problems, can be treated effectively with schedules do not interfere in the therapeutic activity of
surgery. In many patients with post-thrombotic syn- Daflon 500 mg and this drug appears to be a valuable
drome, surgery is either not indicated or not possible, so tool in treating patients with chronic venous insuffi-
elastic compression and venotonic drugs are the thera- ciency.
peutic choices in these cases. Moreover, phlebotonic
drugs are the best method of treating patients with
functional venous insufficiency (patients with symptoms References
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