Calcium Dobesilate Versus Micronised Purified Flavonoid Fraction of Diosmin in the Treatment of Chronic Venous Disease: a Randomized Prospective Study

Acta Medica Mediterranea, 2018, 34: 657

CALCIUM DOBESILATE VERSUS MICRONISED PURIFIED FLAVONOID FRACTION OF DIOSMIN IN THE TREATMENT OF CHRONIC VENOUS DISEASE: A RANDOMIZED PROSPECTIVE STUDY

EMINE SEYMA DENLI YALVAC1, MURAT DEMIROĞLU2, SIDIKA GURSEL1, EBUZER AYDIN1 ¹Medeniyet University Faculty of Medicine, Department of Cardiovascular Surgery, Istanbul, Turkey - 2Medeniyet University Faculty of Medicine, Department of Department of Orthopedics and Traumatology, Istanbul, Turkey

ABSTRACT

Introduction: Chronic venous disease (CVD) of the lower extremities has a substantial effect on quality of life. The clinical, etiology, anatomy, pathophysiology classification (CEAP) is a frequently used classification for CVD. Patients with varicose veins are classified as CEAP class C2. Veno-active drugs (VAD) such as Calcium Dobesilate or Micronised Purified Flavonoid Fraction of Diosmin (MPFF) reduce the symptoms of pain associated with CVD. However, although the effectiveness of VAD is well established, it is controversial. The aims of the this study were to compare the efficacy of two VAD (Calcium dobesilate and MPFF in the treatment of CVD in view of the intended visual analogue scale (VAS) and duplex scanning (DS) changes such as measuring great saphenous vein (GSV) diameter. Materials and methods: A total of 24 patients who had no prior VAD treatment with CEAP class C2, with no family history of CVD were treated; 12 received calcium dobesilate and 12 received MPFF for 60 days. Comorbidities such as hypertension (HT) and diabetes mellitus (DM) were examined. Before and after treatment period, the patients were investigated with DS for diameter of GSV and pain complaint according to VAS were recorded. Results: There were no difference in treatment groups in terms of age, gender, or the comorbidities. For the whole groups, no significant differences were recorded before and after treatment regarding DS parameters. On the other hand, pain was significantly reduced for the group 1 and 2 according to VAS (respectively p=0,04, p=0,03). Conclusion: In this study, pain was reduced in both groups, but no improvement was observed in DS findings. The role of VAD in treatment of patients with CVD needs to be improved in the existing recommendations.

Keywords: Chronic venous disease, Veno active drugs, Calcium dobesilate, Micronised purified flavonoid fraction, visual analogue scale.

DOI: 10.19193/0393-6384_2018_3_101 Received November 30, 2017; Accepted January 20, 2018

Introduction been associated with the development of CVD(2). The strongest known risk factor for CVD is old age Chronic venous disease (CVD) of the lower in both male and female patients(2). extremities caused by venous hypertension is com- Clinical findings show a wide spectrum rang- monly seen in the general population(1).Venous ing from spider veins which is very small vessels hypertension as a result of venous insufficiency can up to leg ulcers. CVD decreases quality of life due damage the vein valves and function.Loss ofthe to the symptoms such as pain, weight, swelling and veinvalve effectiveness is commonly resulted as cramps(1). Pain is usually reduced by walking or by varicose veins(1). 25% to 33% of female and 10% to elevating the legs. Clinical, etiologic, anatomical 20% of male adults suffer from varicose veins(1). and pathophysiological presentations of CVD are Many risk factors such as old age, female gender, described as the CEAP classification in order to family history, obesity and standing profession have provide a common communication and diagnos- 658 Emine Seyma Denli Yalvac, Murat Demiroğlu et Al tics(3). The CEAP classification is divided into 6 The exclusion criteria were as follows: 1. classes according to their clinical findings. These Patient under eighteen years, pregnant or malignan- are CEAP class1 (reticular and spider veins), CEAP cy(2). Patients with CEAP class1, 3, 4, 5, 6; 3. Prior class 2 (simple varicose veins), CEAP class 3 (vari- VAD treatment (4. History of venous thrombosis, cose veins with oedema), CEAP class 4 (skin vein surgery or sclerotherapy.They were random- changes without ulceration), CEAP class C5 ized by closed envelope method into two groups to (healed ulceration), and CEAP class C6 (active receive calcium dobesilate (500 mg peroral twice in ulcers). A duplex scanning (DS) is a noninvasive a day) as group 1 or MPFF (500 mg peroral twice procedure to determine CVD. DS combining B- in a day) as group 2. In patients with bilateral dis- mode and color flow imaging ensure assessment of ease, the leg with worse disease was evaluated in diameter of great saphenous vein (GSV) and under- the study. Patients were questioned for hypertension estimates the degree of venous reflux. Increased (HT) and diabetes mellitus (DM) disease. All the diameter of the GSV is an expected finding in vari- patients were prescribed low pressure(pressure 10- cose veins and larger GSV diameter is thought to 15 mm Hg) compression stockings. indicate more symptomatic patients(4). Veno-active Before and 60 days after VAD treatment, the drugs (VAD) alleviate the symptoms of CVD(5). patients answered the visual analogue scale (VAS) Calcium dobesilate (2,5 dihydroxybenzenesul- from 0 (none/absent) to 5 (severe) for the symp- fonate) is a synthetical drug that has an effect on toms of pain, cramps, heaviness, paresthesia, and CVD by contributing to an oedema-protective feeling of swelling. Twenty-six patients who did not effect(6). Micronized purified flavonoid fraction receive their VAD properly in their follow-up were (MPFF), an oral VAD, consists of 90% micronized excluded from the study. The study continued with diosmin and 10% flavonoids(7). twenty-four patients. The patients underwent DS of It improves venous tone and lymphatic the lower extremities in the upright position (after 4 drainage, and reduces capillary hyperpermeability pm) by the same physician and the diameter of because it protects microcirculation from inflamma- GSV in the symptomatic groin was measured 5 cm tory processes(8). The effectiveness of VAD has been distal to the saphenofemoral junction (SFJ) before reported in many studies.But there are very few and 60 days afterVAD treatment. Data analysis was studies about VAD to prove the effectiveness based performed with the ultrasound general electric logiq on a GSV diameter and a few studies evaluating p5.During the treatment, the patients wore com- these effects by looking at the visual analogue scale pression stockings all day long and removing (VAS) for the symptoms of pain, cramps, heaviness before bed. and paresthesia. The purposes of this randomized, prospective study are to evaluate and to compare Statistical analysis the effectiveness of these two VAD (Calcium dobe- NCSS (Number Cruncher Statistical System) silate and MPFF) on decreasing diameter of the 2007 (Kaysville, Utah, USA) program was used for GSV and VAS due to CVD. statistical analysis. In the comparison of quantita- tive data; Mann Whitney U test was used for two Materials and methods group comparisons of the variables with no normal distribution. Wilcoxon Signed Ranks test was used The hospital ethics committeehas approved for intragroup comparisons. Fisher’s Exact test was this study. All patients were informed about the used for comparison of qualitative data and p<0.05 study and written approval was obtained.This study was regarded significant. included fifty patients referred to our outpatient clinic between October 2016 and March 2017. Results Suffering from CEAP class2 was the main criteria for inclusion of the study. The diagnosis of CEAP Twenty-four patients comprising 15 women class 2 was described visible or palpable varicose (62.5%) and 9 men (37.5%) were enrolled in the veins without oedema with the patient standing. study. The ages ranged from 33 to 68 years with a The others criteria for inclusionwerethe duration of mean age 51,00 ± 11,68 years. There was no statis- the complaints with a minimum of one year and a tically significant difference between groups maximum of two years,no family history of CVD according to age, gender, HT and DM distribu- disease and nosmoking. tions(p>0,05) (Table 1). Calcium dobesilate versus micronised purified flavonoid fraction of diosmin in the treatment of chronic venous disease... 659

Drug groups The pretreatment VAS measure was 3,58±1,08 in group 1 (Table 3). The pretreatment VAS mea- Group 1 (n=12) Group 2 (n=12) (Calcium dobesilate) (MPFF) sure was 3,67±0,98 in group 2 (Table 3).

Min-Max (Median) 33-68 (54) 35-68 (44,5) The post-treatment VAS measure was Age (years) 2,17±1,19 in group 1 (Table 3). The post-treatment Mean+Sd 54,33±11,44 47,67±11,41 VAS measure was 58±1,00 in group 2 (Table 3). Female 8 (66,7) 7 (58,3) There was no statistically significant difference Gender n (%) Male 4 (33,3) 5 (41,7) between the pre-treatment and post-treatment VAS measures according to the groups (p> 0,05). The DM n (%) 3 (25,0) 3 (25,0) mean decrease of 1,42 units in post-treatment VAS HT n (%) 8 (66,7) 6 (50,0) measure was statistically significant in group 1 Table1: Evaluation of demographic variables according (p=0,004; p<0,01) (Table 3). The mean decrease of to groups. 2,08 units in post-treatment VAS measure was sta- aMann Whitney U Test bFisher’s Exact Test tistically significant in group 2 (p=0,003; p<0,01) Sd: Standard deviation (Table 3). Both products were well tolerated, with no dif- Drug Groups ference in the adverse event. The pre-treatment VAS Group 1 (n=12) Group 2 (n=12) mean diameter of GSV was 6,31±1,76 cm on the (Calcium dobesilate) (MPFF) symptomatic groin, in group 1 (Table 2). The pre- Min-Max (Median) 2-5 (3,5) 2-5 (3,5) treatment mean diameter of GSV was 6,43±2,07 cm Pre-treatment on the symptomatic groin, in group 2 (Table 2). Mean±Sd 3,58±1,08 3,67±0,98

The post-treatment mean diameter of GSV Min-Max (Median) 0-4 (2) 1-4 (1) was 5,95±1,70 cm on the symptomatic groin, in Post-treatment Mean±Sd 2,17±1,19 1,58±1,00 group 1 (Table 2). The post-treatment mean diameter of GSV was 6,13±1,99 cm on the symptomatic cp 0,004* 0,003* groin, in group 2 (Table 2). No statistically signifi- Difference Min-Max (Median) -3-0 (-1,5) -4-0 (-2) cant difference was detected between the groups by (Pre-treatment- Mean±Sd -1,42±0,90 -2,08±1,16 means of pre-treatment and post-treatment GSV Post-treatment) diameter (p>0.05) (Table 2). The mean decrease of Table 3: Evaluation of VAS according to groups. 0.36 units in post-treatment GSV diameters was not aMann Whitney U Test cWilcoxon Signed Rank Test *p<0,01 statistically significant in group 1 (p=0,063; VAS: Visual analogue scale p>0,05). The mean decrease of 0.31 units in post- treatment GSV diameters was not statistically sig- There was no statistically significant differ- nificant in group 2 (p=0,125; p>0,05) (Table 2). ence in VAS measures after drug treatment compared to the groups (p> 0.05). It is remarkable that Drug Groups VAS changes during treatment are high in group 2. GSV diameter (cm) Group 1 (n=12) Group 2 (n=12) The GSV diameter and VAS measures between pre- (Calcium dobesilate) (MPFF) treatment and post-treatment measurements were Min-Max (Median) 3,7-9,5 (6) 3,8-10,4 (5,8) compared and a noticeable improvement was Pre-treatment (cm) Mean±Sd 6,31±1,76 6,43±2,07 observed in the groups in terms of VAS measures.

Min-Max (Median) 3-9 (6,1) 4,2-10,8 (5,5) Discussion Post-treatment (cm) Mean±Sd 5,95±1,70 6,13±1,99

cp 0,063 0,125 The effectiveness of VAD has been reported in many studies. But there are very few studies about Difference Min-Max (Median) -1,6-0,3 (-0,5) -1,8-0,9 (-0,3) VAD to prove the effectiveness based on a GSV (Pre-treatment-Post- Mean±Sd -0,36±0,53 -0,31±0,72 treatment) diameter. Therefore we decided to build the study Table 2: Evaluation of pretreatment and posttreatment based on measurement of GSV diameter and VAS GSV diameter according to groups. due to evaluate the effectiveness of VAD. We mea- aMann Whitney U Test cWilcoxon Signed Rank Test sured the GSV diameter by DS whichis cheap, easy GSV:Great saphenous vein to perform and does not use radiation but DS is Sd: Standard deviation considered operator-dependent. 660 Emine Seyma Denli Yalvac, Murat Demiroğlu et Al

Operator dependent means variation of the Positive effects of Calcium dobesilate and results depending on the knowledge and experience MPFF on vasculoprotective parameters are estab- of the physician. That’s why it is crucial that the lished(20). Calcium dobesilate, MPFF and physician is accurately trained(9). Long-term stand- Hydroxyethyl-rutosides are the three most highly ing could change the GSV diameter by causing recommended VAD to treat symptoms, oedema and reversible reflux(10) and the probability of a false skin changes(21). Although it is remarkable that VAS positive diagnosis was high(11) so we tried to do the changes during treatment are high in group 2, both first measurements and the second measurements of treatments were well tolerated and effective. The the patients in the upright position (after 4 pm) by aims of this study have been achieved but the study the same physician. However, it has not always has several limitations. been possible to obtain objective values by the First, the number of patients in the groups method. Graduated compression stockings are fre- could be higher. At the beginning, fifty patients quently prescribed for CVD(3) and especially in were enrolledin the study. Slightly more than half patient with oedema(12). ofpatients were withdrawn from the study They apply the highest degree of compression becausethey did nottakeVAD on time. In the litera- in the ankle and they assistblood to flow upward ture, this rate is about the same as the proportion of toward the heart instead of foot(13). Low pressure patients who do not take the medication on time(22). compression stockings are as effective as high-com- Second, female sex hormones, obesity and a pression stockings so we prescribed low pressure standing occupation are effective on the GSV diam- compression stockings during the study(14). eter(23). Their absence in our study were other limita- The study was carried out between October tions. Third, we would like to have a potential and March because the higher temperature could objection to such work that is being measured by influence conformity with graduated compression DS due to difficulties in an equal conditions. stockings. The compression stockings have signifi- Fourth, long-term treatment with VAD may be cantly improved the quality of life parameters in more useful for sustained symptoms of patients but patients with painful legs(15). As a result of the study theRELIEF study hasreported that symptoms of the we had a decrease in the pain of our patients after patients who were treated with MPFF were noted two months of treatment. The reduction in pain the greatest improvements about within the first complaints may be due to medical treatment, com- two months (60 days) of the treatment so the 60- pressionstockings or both treatment modalities. day outpatient treatmentwas thought to be According to our experience, we think that both enough(24). treatment modalities reduce pain complaints. The patients with CVD are informed about However, which one is more effective remains their illness when they refer to our outpatient clinic. unclear. There may be many reasons about pain in They are advised to wear compression stockings, venous disease so symptoms caused by varicose not to stand for long periods and not to sit for long veins indicate difficulty in verifying and all patients periods. It is important to keep in mind that the with varicose veins can not be called sympto- quality of life of most patients is improved by com- matic(16,17). For this reason, patients with varicose pression and lifestyle changes. Adherence to these veins and pain lasting at least one year and up to recommendations may have reduced their VAS two years were included in the study. According to measures. Finally, it seems that calcium dobesilate Lane(18), the vein diameter assessment does not pro- and MPFF are effective in the treatment of pain, vide accurate prediction of patient symptoms and it cramps, heaviness, paresthesia, and feeling of is not correct to use vein diameter to describe a swelling. Such a study would require a larger num- worsening clinical status. Therefore, treatment of ber of patients. symptomatic patients would be more beneficial, regardless of vein diameter(19). Our study confirms these finding. The pain of our patients has decreased after medical treatment but GSV diameters have not decreased significantly. If the symptom was related to the GSV diameter, the symptom did not decrease as the diameter did not change. Calcium dobesilate versus micronised purified flavonoid fraction of diosmin in the treatment of chronic venous disease... 661

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