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 Table of Contents  
ORIGINAL ARTICLE
Year : 2022  |  Volume : 28  |  Issue : 1  |  Page : 83-87

An observational study to evaluate the efficacy of micronised purified flavonoid fraction in improving venous clinical severity score


Department of General Surgery, Government Medical College, Kozhikode, Kerala, India

Date of Submission06-Apr-2022
Date of Decision15-Apr-2022
Date of Acceptance04-May-2022
Date of Web Publication14-Jul-2022

Correspondence Address:
Dr. G Adhip
Department of General Surgery, Government Medical College, Kozhikode, Kerala
India
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/ksj.ksj_9_22

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  Abstract 


Background: Medical care of chronic venous disease (CVD) entails different strategies that can be used either alone or in combination. Micronised purified flavonoid fractions (MPFFs) are venomodulator drugs used for CVD. Aim: In the present study, the efficacy of MPFF in lowering Venous Clinical Severity Scoring (VCSS) for CVD [Clinical, Etiological, Anatomical and Pathological (CEAP) C3 disease] is assessed and identified a subgroup who will benefit from the therapy. Materials and Methods: This was an observational study based on 35 cases of CVD CEAP Class C3 attending a tertiary hospital. Their initial VCSS was assessed and the same was reassessed after 6 months of MPFF therapy. The data were statistically analysed. Results: The mean age among the study participants was 45.9 ± 9.4 years. Almost half of the study participants, 16 (45.7%), belonged to 41–50 years. More than half of the study participants were female. The median pain score was statistically significantly lower after flavonoid administration compared to baseline (P < 0.001). Similarly, statistically significant lower median oedema and VCSS scores were obtained after flavonoid administration (P < 0.001). However, no significant decrease was observed in the VCSS after flavonoid administration. The median VCSS was statistically significantly lower in females aged 41–50 years after flavonoid administration compared to baseline (P < 0.001). Conclusion: MPFFs are efficient in lowering VCSS in CEAP Class C3 cases of CVD in all age groups. The best efficiency was noted in 41–50 years' age group females. Patients with venous pain and venous oedema had the best response. The least response was noted in clinically demonstrable varices.

Keywords: Chronic venous disease, micronised purified flavonoid fractions, varicose vein, Venous Clinical Severity Scoring


How to cite this article:
Adhip G, Gopi E V. An observational study to evaluate the efficacy of micronised purified flavonoid fraction in improving venous clinical severity score. Kerala Surg J 2022;28:83-7

How to cite this URL:
Adhip G, Gopi E V. An observational study to evaluate the efficacy of micronised purified flavonoid fraction in improving venous clinical severity score. Kerala Surg J [serial online] 2022 [cited 2022 Sep 24];28:83-7. Available from: http://www.keralasurgj.com/text.asp?2022/28/1/83/350909




  Introduction Top


Chronic venous disease (CVD) is a persistent, progressive and frequently underestimated condition widely represented in the general population, having a huge socioeconomic, physical and psychological impact associated.[1] It affects a large number of people in the world, with an the estimated prevalence of CVD ranging from 60% to 80%. According to the Clinical, Etiological, Anatomical and Pathological (CEAP) classification, most cases are defined as C0 and C1 disease, while approximately 25% of patients are diagnosed with varicose veins (C2). Chronic venous insufficiency (CVI) (C3–C6) concerns small percentage of patients with CVD, representing up to 5% of patients. The incidence of Varicose vein (VV) was about 2.6% for females and 1.9% for males, according to the Framingham study.[2] It also increases with age and may entail important consequences for the quality of life of the affected individuals. If untreated, they will progress to Chronic venous insufficiency (CVI). In India, 10 million CVD cases are reported per year. Hence, CVD represents one of the most frequent vascular diseases in the world.[3],[4] Patients frequently show a malleolar oedema with getting worse under situations in which venous pressure increases and the lymphatic drainage is impaired.

CVD can be treated pharmacologically through various venoactive agents. Pharmacological treatments range from saponins, flavonoids, pentoxifylline, micronised purified flavonoid fractions (MPFFs) and acetylsalicylic acid. The main applications of these pharmacological agents are guided to treat non-serious symptoms such as pain or oedema at initial stages.[5] MPFF is a major drug used for venous insufficiency. Diosmin and hesperidin are the main MPFFs available in the Indian market. MPPF acts mainly by inhibiting these microcirculatory effects and reduces the venous wall permeability. They also modulate WBC adhesion venous tone and protect cell from hypoxia.[6] The objective of this study was to assess the role of MPPF in improving Venous Clinical Severity Score (VCSS) in our clinical setup.


  Materials and Methods Top


An observational study was conducted at the outpatient unit of general surgery at a tertiary hospital in patients presenting with symptomatic CVD, CEAP Class C3 [Figure 1] from May 2020 to October 2020.
Figure 1: CEAP Classification. CEAP: Clinical, Etiological, Anatomical and Pathological

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Sample size was calculated as below:

n = (Zα + Zβ) 2 SD2/d2

As per Vadim Yu Bogachev study using VCSS, standard deviation was 2.1 d-effective size

Zα_ = 1.96 Zβ = 0.84

Sample size = 35

All patients with venous insufficiency attending the outpatient department with CEAP score of C3, who opted for best available medical therapy and who refused surgical intervention were included in the study. Patients with coexisting peripheral occlusive arterial disease and neuropathy, those planned for venous interventions and those already had undergone previous venous intervention were excluded from the study. Thirty-five CVI cases with CEAP Class C3 disease, prescribed with MPFF, were identified and their initial VCSS [Table 1] was assessed with proper history and clinical examination. They were followed up for a period of 6 months, VCSS reassessed and subgroup analysis was done.
Table 1: Venous Clinical Severity Score

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The MPFF components including diosmin, diosmetin, linarin and isorhoifolin are synthesised from hesperidin, extracted from Citrus aurantium var. amara, a type of immature orange [Figure 2]. Diosmin and its aglycone diosmetin (3', 5, 7-trihydroxy-4'-methoxyflavone) belong to the flavonol and flavone groups, while hesperidin, which differs from diosmin by the absence of a double bond between two carbon atoms, is part of the flavanone group. These compounds also occur naturally in citrus fruits. Both linarin (acacetin 7-rutinoside) and isorhoifolin are derived from flavones.
Figure 2: Harvest of small immature fruits (10 to 20 mm in diameter) to produce MPFF (Hesperidin). MPFF: Micronised purified flavonoid fractions

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The data were coded and entered into Microsoft Excel for Windows 7, and statistical analysis was done using the software Statistical Package for the Social Sciences. Appropriate statistical tests were used for analysis. The institutional ethics committee clearance was obtained. Informed consent was obtained from each study subject. Confidentiality of the subjects was maintained in all stages of the study. Appropriate referrals and advice were given whenever necessary.


  Results Top


The mean age among the 35 study participants was 45.9 ± 9.4 years (range, 29–65 years). When age was categorised into groups, almost half of the study participants, 16 (45.7%), belonged to 41–50 years' age group, followed by age group of 29–40 and 51–65 years. More than half of the study participants (18/35%–51%) were female.

The VCSS consists of 10 clinical descriptors. We considered the three initial clinical descriptors: pain, clinically evident varices (varicose vein) and venous oedema. It was measured before and after flavonoid administration. [Figure 3] shows the components of VCSS before flavonoid administration. The same number of participants had pain score of 2 and varicose vein score of 1. However, oedema score of 1 was present in almost two-third of participants.
Figure 3: VCSS before flavonoid administration

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[Figure 4] shows the components of VCSS after flavonoid administration. The same number of participants had pain score of 0 and clinically evident varices score of 1. However, oedema score of 0 was present in half of the participants.
Figure 4: VCSS after flavonoid administration

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[Table 2] shows the comparison of median among components of VCSS before and after flavonoid administration. The signed-rank test was used to assess the association between both the groups. The median pain score was lower after flavonoid administration compared to baseline, and it was statistically significant (P < 0.001). Similarly, lower median oedema and VCSS scores were obtained after flavonoid administration, and it was statistically significant (P < 0.001). However, no significant decrease was observed in the varicose vein score (patients with clinically evident varices) after flavonoid administration.
Table 2: Median score before and after flavonoid administration

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[Table 3] shows the association between sociodemographic characteristics and median scores before and after flavonoid administration. The Kruskal–Wallis test was used to assess the association between age and VCSS. The median score was lower in the 29–40 years' age group compared to the 41–50 and 51–60 years' age group before flavonoid administration, and it was statistically significant (P < 0.03). However, the median score dropped significantly in the 41–50 years' age group after flavonoid administration, and it was statistically significant. The rank-sum test was used to assess the association between gender and scores of both the groups. The median VCSS was lower in females before flavonoid administration compared to males, and it was statistically significant (P < 0.01). Similar results were obtained in VCSS after flavonoid administration, and it was statistically significant (P < 0.03).
Table 3: Association between sociodemographic characteristics and median scores of study participants

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[Table 4] shows the association between sociodemographic characteristics and median scores before and after flavonoid administration. The signed-rank test was used to assess the association between age and gender with scores. The median VCSS was lower in males aged 29–40 years after flavonoid administration compared to baseline, and it was statistically significant (P < 0.009). However, the median VCSS was lower in females aged 41–50 years after flavonoid administration compared to baseline, and it was statistically significant (P < 0.001). Similarly, the results were obtained in VCSS after flavonoid administration among the males aged 51–65 years, and it was statistically significant (P < 0.04).
Table 4: The association between sociodemographic characteristics and median scores before and after flavonoid administration

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  Discussion Top


CVD remains one among the most common vascular diseases worldwide. Despite the advanced treatment modalities, CVD still exists as a major health issue that affects the quality of life of individuals. MPFF is a commonly prescribed venomodulator drug for CVD. VCSS is an effective scoring system used to grade the severity of CVD and CVI. In the present study, the efficacy of MPFF in improving the VCSS in CEAP C3 disease is assessed.

Out of 35 participants, more than half of the participants were female. The incidence of VVs was about 2.6% for females and 1.9% for males, according to the Framingham study.[2] Thus, it is recognised that the risk for suffering from VV and CVI is higher in women than men. From the Bonn Vein Study by Rabe et al.,[4] the prevalence of varicose veins ranges from 1% to 73% in females, and 2%–56% in males, whereas CVI ranges from 1% to 40% in females, and from 1% to 17% in males. The results vary by geographic region as well as by the methods used for evaluation.

The mean age among the study participants was 45.9 ± 9.4 years. When age was categorised into groups, almost half of the study participants, 16 (45.7%), belonged to 41–50 years' age group. More than half of the study participants were female. Among those female participants, about 61.1% belonged to 41–50 years' age group, i.e., the perimenopausal age group.

This results show a partial concordance with the Budapest Vein Study by Bihari et al.[7] state that the prevalence of CVD advances with age and shows a prevalence of 68.4% in age group 41–50. A study conducted by Vuylsteke et al.[8] showed that age and female gender were major risk factors for developing CVD. The most common symptoms were feeling of heavy legs (70.4%), pain (54.0%) and sensation of swelling (52.7%). The number of symptoms increases with age (P < 0.001). Female patients have significantly more symptoms in comparison with male patients in all age groups. In both females and males, age is negatively correlated with VCSS (P < 0.001). The estimated probability of having CVD was significantly higher for woman compared to men and increases with age for both genders. This signifies that, as age advances, the chance of getting CVD also increases; hence, age is a risk factor for CVD. The results from the former study also partly signify the present study.

All the 35 study participants had clinically significant varicose vein. 52% of them had isolated branch varices or clusters, i.e., Grade 1 (mild) according to the VCSS. The rest 48% were suffering from extensive calf and thigh VV. Oedema and pain were the two other major issues faced by CEAP C3. Two-third of the patients showed features of Grade 1 oedema according to the VCSS. Half of the study population had a pain score of 1. Majority of the study participants were seeking medical advices for chief complaints such as pain and oedema rather than clinically apparent varicosities.

Vuylsteke et al.[8] showed that the most common symptoms were feeling of heavy legs (70.4%), pain (54.0%) and sensation of swelling (52.7%) in patients with early CVD. The findings in the present study showed a partial concordance with the present study.

Patients in the present study were advised with MPFF 1000 mg once daily dosage for a period of 6 months.

The median VCSS before MPFF administration was 5, (4–5) and after 6 months of MPFF it was found to be 3 (2–4). This finding was statistically significant (P < 0.001). This signifies that the median VCSS is decreasing after the administration of MPFF, i.e., MPFF efficient enough to reduce the VCSS in CEAP C3 disease. Hence, in early stages of CVD, MPFF was efficient enough to prevent the progression of disease and symptomatic relief.

Kakkos and Nicolaides[9] conducted a randomised double-blind placebo-controlled trail with MPFF on CVD patients and found that on qualitative analysis, MPFF significantly improved nine defined leg symptoms including pain, heaviness, feeling of swelling, cramps, paraesthesia, burning sensation and pruritus, but also functional discomfort compared with placebo, leg redness, skin changes and quality of life. On quantitative analysis, MPFF compared with placebo, assessed as a categorical variable, reduced leg pain (risk ratio [RR]: 0.53, P = 0.0001, number needed to treat [NNT] = 4.2), heaviness (RR: 0.35, P < 0.00001, NNT = 2.0), feeling of swelling (RR: 0.39, P < 0.00001, NNT = 3.1), cramps (RR: 0.51, P = 0.02, NNT = 4.8), paraesthesia (RR: 0.45, P = 0.03, NNT = 3.5) and functional discomfort (RR: 0.41, P = 0.0004, NNT = 3.0). Regarding objective assessments of leg oedema, the use of MPFF compared with placebo reduced ankle circumference (standardised mean difference [SMD]: 0.59, 95% confidence interval [CI]: −1.15 to − 0.02) and leg redness (SMD: 0.32, 95% CI: −0.56 to − 0.07, RR: 0.50, P = 0.03, NNT = 3.6), improved skin changes (RR: 0.18, P = 0.0003, NNT = 1.6) and quality of life (SMD: 0.21, 95% CI: −0.37 to − 0.04) and was associated with clinical improvement as assessed by the physician (RR: 0.28, P < 0.00001, NNT = 2.5).

In the present study, the median pain score was lower after flavonoid administration compared to baseline (P < 0.001). Similarly, lower median oedema and VCSS scores were obtained after flavonoid administration (P < 0.001). However, no significant decrease was observed in the varicose vein score (patients with clinically evident varices) after flavonoid administration. Hence, it can be concluded that MPPF got good efficacy in controlling pain and oedema in CEAP C3 disease and got minimal benefit in patients with clinically demonstrable varices. This existing evidence suggests the efficacy of MPFF on symptomatic improvement of CVD. This above-stated study also signifies the finding in the present study.

The median VCSS was lower in the 29–40 years' age group compared to the 41–50 and 51–60 years' age group before flavonoid administration, and it was statistically significant (P < 0.03). This signifies the first finding, i.e., as age advances, CVD clinical severity also increases. However, the median score dropped significantly in the 41–50 years' age group after flavonoid administration compared to the other two groups, and it was statistically significant. The initial median VCSS in 41–50 age categories was 4.5 (3–5). The second VCSS after MPFF therapy was 2 (1–3). This shows a statistical significance with P < 0.03. In case of gender, the female participants showed a better improvement in VCSS after MPFF therapy compared to male participants.

It was found that the median VCSS was lower in males aged 29–40 years after flavonoid administration compared to baseline, and it was statistically significant (P < 0.009). However, the median VCSS was lower in females aged 41–50 years after flavonoid administration compared to baseline (P < 0.001). Similar results were obtained in VCSS after flavonoid administration among the males aged 51–65 years (P < 0.04). Hence, a better reduction in VCSS was obtained in females aged 41–50 years.

There is evidence to recommend the use of flavonoids as an adjunct in CVD, in particular for pain, discomfort and oedema. Flavonoids can be used for patients in all phases of the disease with little risk. However, large, well-designed randomised, controlled, long-term studies are needed to confirm the clinical efficacy and cost-effectiveness of long-term use of flavonoids in preventing the development and progression of CVD. Because flavonoid preparations do not contain defined, individual active substances, the efficacy of each preparation must be established independently.

Since CVD is a very common disorder, and this study is only dealing with a small number of subjects, these results have to be followed up with a bigger study to use this as a clinical/therapeutic tool.


  Conclusion Top


MPFF fractions are efficient in lowering VCSS in CEAP Class C3 cases of CVD in all age groups. The best efficiency was noted in 41–50 age group females in reducing VCSS. Hence, 41–50 age group females are getting more benefited from MPFF therapy in this study population. Patients presenting with venous pain and venous oedema had the best response coming out of MPFF therapy. The least response was noted on improving the state of clinically demonstrable varices and probably not suited for medical therapy.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
  References Top

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Uhl JF, Gillot C. Anatomy of the veno-muscular pumps of the lower limb. Phlebology 2015;30:180-93.  Back to cited text no. 3
    
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Rabe E, Berboth G, Pannier F. Epidemiology of chronic venous diseases. Wien Med Wochenschr 2016;166:260-3.  Back to cited text no. 4
    
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Lyseng-Williamson KA, Perry CM. Micronised purified flavonoid fraction: A review of its use in chronic venous insufficiency, venous ulcers and haemorrhoids. Drugs 2003;63:71-100.  Back to cited text no. 5
    
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Wrona M, Jöckel KH, Pannier F, Bock E, Hoffmann B, Rabe E. Association of venous disorders with leg symptoms: Results from the Bonn vein study 1. Eur J Vasc Endovasc Surg 2015;50:360-7.  Back to cited text no. 6
    
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Bihari I, Tornoci L, Bihari P. Epidemiological study on varicose veins in Budapest. Phlebology 2012;27:77-81.  Back to cited text no. 7
    
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Vuylsteke ME, Thomis S, Guillaume G, Modliszewski ML, Weides N, Staelens I. Epidemiological study on chronic venous disease in Belgium and Luxembourg: Prevalence, risk factors, and symptomatology. Eur J Vasc Endovasc Surg 2015;49:432-9.  Back to cited text no. 8
    
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Kakkos SK, Nicolaides AN. Efficacy of severity purified flavonoid fraction (Daflon®) on improving individual symptoms, signs and quality of life in patients with chronic venous disease: A systematic review and meta-analysis of randomized double-blind placebo-controlled trials. Int Angiol 2018;37:143-54.  Back to cited text no. 9
    


    Figures

  [Figure 1], [Figure 2], [Figure 3], [Figure 4]
 
 
    Tables

  [Table 1], [Table 2], [Table 3], [Table 4]



 

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