Venoactive drugs (VADs) can be used as a first-line treatment in all stages of chronic venous disease (CVD). In more advanced CVD, VADs can be used together with surgery or endovascular procedures (
In a previous studies designed to identify the subpopula-tions of patients with CVD, an interest finding is that there is no strong correlation between pain and CVD severity (
It is difficult to determine a causal relationship between symptoms such as heaviness, cramping, and itchiness and varicose veins, so it is often difficult for a clinician to predict whether the symptoms will improve after surgery for varicose veins. CVD is considered a progressive disease, so it is a necessary part of the opinion that surgery is necessary. According to the Edinburgh study, CVD worsened or developed newly in 57.8% of 334 patients with CVD after 13 years of follow-up. The risk of varicose veins increased in those with a family history, and the risk of disease increased in those with a higher body mass index. Conversely, 42.2% of the patients appear to have at least worsened or not progressed (
There is a lack of correlation between these clinical symptoms and varicose veins, so surgical treatment is recommended for patients with C2 or higher who are accompanied by symptoms and reflux. In other patients, with non-varicose pain in mind, first, conservative treatment should be provided to control symptoms (
Currently used VADs are as follows: flavonoids including diosmin, micronized purified flavonoid fraction (MPFF), rutin and troxerutin and saponins including horse chestnut seed extract (HCSE) and Ruscus extract, such as butcher’s broom. These are recommended for grade 1 disease. Additionally, there are anthocyans and synthetic drugs, which are recommended for grade 2 disease by the 2018 L’Union Internationale de Phlébologie (UIP) guidelines (
There is a difference in the mechanism of action of each drug. Previous studies (
The 2018 UIP guideline subdivided VADs according to symptoms, signs, and quality of life, with magnitude of effect (
The 2020 Cochrane Review investigated treatment using several VADs according to symptoms, and found that it was effective in improving symptoms such as edema, skin changes, pain, cramping, restless legs, and abnormal sensa-tions overall (
As for the reviews on VADs, an umbrella review was published in 2022 and a total of 11 systematic reviews (SRs) were reviewed (
In summary, there were differences between guidelines and reviews, but roughly, it seems that the following drugs can be selectively used according to the symptoms men-tioned by patients (Table 1).
recommended VADs according to previous guideline and reviews
|Symptoms||UIP 2018 (1)||Cochrane 2020 (8)||Umbrella review 2022 (9)||Commercial durgs in Korea|
|Edema||Cyclo3, HCSE||Diosmin, Rutosides||베니톨, 플라벤, 디오스민, 치센, 엘라스에이|
|Ankle circumference||Cyclo3, HCSE||Diosmin||MPFF, Ruscus, Oxerutins||베니톨, 플라벤, 디오스민, 치센, 뉴베인|
|Leg volume||Cyclo3, HCSE, ca+ dobesilate||ca+dobesilate||MPFF, Ruscus, HCSE||베니톨, 플라벤, 디오스민, 치센, 독시움|
|Pain||MPFF, Cyclo3, Oxerutins, HCSE||Diosmin, Rutosides, ca+dobesilate||MPFF, Ruscus, HCSE||베니톨, 플라벤, 디오스민, 치센, 뉴베인,|
|Cramps||MPFF, Oxerutins||Diosmin, Rutosides, ca+dobesilate||MPFF, Ruscus||베니톨, 플라벤, 디오스민, 치센, 독시움|
|Heaviness||MPFF, Cyclo3, Oxerutins, ca+dobesilate||Diosmin, Rutosides||MPFF, Ruscus||베니톨, 플라벤, 디오스민, 치센, 뉴베인, 독시움|
|Feeling of swelling||MPFF, Cyclo3||ca+dobesilate||MPFF||베니톨, 플라벤|
|Ulcer||MPFF, Oxerutins||베니톨, 플라벤, 뉴베인|
|Functional discomfort||MPFF||MPFF||베니톨, 플라벤|
|Skin change||MPFF||Diosmin||MPFF||베니톨, 플라벤, 디오스민|
|Burning sensation||MPFF||베니톨, 플라벤|
Cyclo 3 fort®, Ruscus extract+hesperidin methyl chalcone (HMC)+vitamin C UIP, L’Union Internationale de Phlébologie. MPFF: micronized purified flavonoid fraction, HCSE: horse chestnut seed extract.
In general, it is not recommended to use multiple VADs in the same prescription. The 2018 UIP guideline has also mentioned that it is not appropriate to take a combination of several VADs on one prescription (
There seems to be no complex agent produced in South Korea. However, these multi-ingredient formulations are already being used in several countries (VS formula, Mylabs Formula Inc, USA [contained diosmin, hesperidin, Gotu Kola extract, vitis vinifera extract, pinus extract, vitamin C, vitamin E, and Haematococcus pluvialis extract]). A sys-tematic review and meta-analysis by Kakkos SK et al. reported the effectiveness of VADs containing Ruscus+ HMC+vitamin C, constituents of Cyclo 3 fort® (Laboratoires Pierre Fabre, Paris, France) (
There is only one German guideline that mentions a treatment duration and recommends taking VADs contin-uously for 2 to 4 weeks for a full effect (Grade 1C) (
Most of the abnormal symptoms of VADs are gastro-intestinal disorders, which are not considered serious. There appear to be no studies directly reporting the safety of long-term use of VAD. There was a paper that studied the changes in the intestinal microbiome after long-term admini-stration of polyphenols. Polyphenols are abundant in plant-derived foods such as vegetables, fruits, tea, wine, and coffee. Flavonoid is a kind of polyphenol extracted from plants. Changes in the intestinal microbiome have been noted when VADs are taken for a long time (
Micronized diosmin combined with hesperidin (diosmin 90%+hesperidin 10%) as a MPFF has been used exten-sively. However, diosmin is not recommended for use in children, pregnant women, or women who are breastfeeding. However, clinical data is limited. With regard to its interac-tions, serum concentrations may be increased by the concomitant administration of drugs metabolized by cyto-chrome P450 (CYP-450) 2E1 or 2C9 or P-glycoprotein. For example, serum concentration of chlorzoxazone, diclofenac sodium, and fexofenadine may increase when taken with diosmin (
Entelon Tab [vitis vinifera seed dried ext.], the represen-tative drug in grape seed extract, is reported that allergy reaction could be occurred by FD&C Yellow No. 4 (Tartrazine) and FD&C Yellow No. 5 (Sunset Yellow FCF). Interestingly, it has been reported that grape seed extract may increase bleeding tendency by enhancing the effects of antithrombotic or platelet agents (
CVD is a comprehensive concept that includes all abnormal findings in the venous system; among these, if the observed symptoms or signs that require examination or treatment are found as morphological and functional abnormalities, it is termed CVD. CVD is classified clini-cally from C0 to C6, but the symptoms may or may not be present throughout all stages. Treatment is required if the symptoms or signs are combined. Drug therapy with/ without compression stocking is the first-line therapy and can be used in all stages from C0 to C6.
In CVD, lower extremity pain is mainly caused by venous hypertension and hypoxia in various clinical conditions. There is no correlation between CVD severity and clinical symptoms, and patients without truncal reflux may also report pain. All chronic venous diseases cannot be treated with surgery alone. According to the recent guidelines (
This content was presented at the 42nd Conference of the Korean Society for Phlebology on April 17th, 2022.
The authors declare no potential conflict of interest.