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Ann Phlebology 2022; 20(1): 1-5

Published online June 30, 2022

https://doi.org/10.37923/phle.2022.20.1.1

© Annals of phlebology

Practical Use of Venoactive Drugs for Chronic Venous Disease in Korea

Sangchul Yun, M.D., Ph.D., R.P.V.I., R.V.T.

Department of Surgery, Soonchunhyang University Seoul Hospital, Seoul, Korea

Correspondence to : Sangchul Yun, 59 Daesakwan-ro, Yongsangu, Seoul 04401, Korea, Department of Surgery, Soonchunhyang University Seoul Hospital
Tel: 02-710-3240, Fax: 02-749-0449
E-mail: ys6325@schmc.ac.kr

Venoactive drugs can be used as a first-line treatment in all stages of chronic venous disease. In a more advanced stage, drugs can be used together with surgery or endovascular procedures. However, 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 drugs are flavonoids including diosmin, micronized purified flavonoid fraction, rutin and troxerutin, and saponins including horse chestnut seed extract and Ruscus extract such as butcher’s broom, anthocyans, and synthetic drugs. There is a difference in the mechanism of action of each drug, and these drugs seem to be selectively used according to the symptoms mentioned by patients. The drug indications according to the guidelines and research and precautions are summarized in this review.

Keywords Medical therapy, Chronic venous disease, Clinical practice guideline, Varicose vein, Drugs

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 (1,2). The main purpose of the use of VADs is to control swelling and pain caused by venous hypertension and hypoxia (3). However, clinical symptoms such as pain and swelling do not show a close correlation with CVD severity. In a study involving 132 patients, Howlader and Smith reported no statistical relationship between the pain score or heaviness score, assessed on a 10-point visual analog scale, and the clinical severity of venous disease. The median pain score was 2.8 in the class C2 venous disease group, 4.5 in C3, 0.5 in C4, and 0 in C5 (4).

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 (5). In Edinburgh Vein Study of more than 1500 subjects aged between 18 and 64 years, Bradbury et al. reported that varicose veins and three lower extremity symptoms in women (pain, heaviness or tension, and itching) are statistically significant, but the correlation between each of these symptoms and varicose veins is too weak to determine a relationship of the discomfort or pain with CVD. Although there was a strong relationship between heaviness or tension, pain, and itchiness in women and the presence of trunk varices, this may have limited clinical value. For example, although a linear trend between pain and trunk varices in women was significant (p<0.001), pain was present in 45% of women without varicose veins and 63% of women with grade 2 and 3 varicose veins. The difference was only 18%. Thus, many asymptomatic patients not only have trunk varicose veins on clinical examination, but others experienced some symptoms of lower extremity, despite little or no clinical evidence of venous disease. It should be assumed that these patients have deep vein or non-venous disease to explain their symptoms.

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 (6). Non-surgical treatment seems sufficient for at least 40% of the patients with mild disease without risk factors.

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 (7).

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 (1).

There is a difference in the mechanism of action of each drug. Previous studies (1) have indicated that drugs that are effective for venous tone or venous wall and valve can be used for varicose veins in the lower extremities, and drugs that are effective for capillary leakage or lymph circulation are effective for lower extremity edema. They seem effective, and the effect on partial pressure of oxygen, such as blood supply or removal of active oxygen, seems helpful in symptom control.

The 2018 UIP guideline subdivided VADs according to symptoms, signs, and quality of life, with magnitude of effect (1). MPFF is strongly recommended strong for pain, heaviness, feeling of swelling, functional discomfort, cramps, leg redness, skin changes, edema, and quality of life, and but not so strongly for paresthesiae and burning. Ruscus extract+hesperidin methyl chalcone (HMC)+Vitamin C (Ruscus+HMC+ascorbic acid, [Cyclo 3 fort®])is strongly recommended for pain, heaviness, feeling of swelling, leg fatigue, paresthesia, and edema, but not so strongly for cramps and pruritus. Oxerutins are strongly recommended for pain, heaviness, and cramps, and but not so strongly for edema. Moreover, the recommendation of HCSE is strong for the treatment of pain, pruritus, and edema, while that of calcium dobesilate is weak due to the possibility of agranulocytosis.

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 (8).

As for the reviews on VADs, an umbrella review was published in 2022 and a total of 11 systematic reviews (SRs) were reviewed (9). VADs are classified according to effective symptoms. Six SRs with edema as an outcome compared active treatment with placebo, MPFF, Ruscus extracts, and HCSE and revealed that these drugs were significantly superior in reducing the ankle circumference. In one of the SRs, MPFF (-0.8±0.53 cm), hydroxyethy-lrutosides (-0.58±0.31 cm), and Ruscus extract (-0.58±0.47 cm) resulted in a reduction in the ankle circumference, but diosmin (-0.20±0.5 cm) did not. With respect to com-parisons amongst the VADs, MPFF was superior to hydroxyethylrutosides and Ruscus extracts. In an SR evaluating MPFF, volume reductions >100 mL were more evident in the MPFF group (64.3%) than in placebo (36.6%; p=0.04). In another SR, HCSE (standard mean deviation [SMD] 0.34; 95% confidence interval [CI] 0.15 to 0.52) and Ruscus extract (SMD -0.61; 95% CI -0.91 to -0.31) were efficacious in reducing leg volume.

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).

Table 1 . recommended VADs according to previous guideline and reviews

SymptomsUIP 2018 (1)Cochrane 2020 (8)Umbrella review 2022 (9)Commercial durgs in Korea
EdemaCyclo3, HCSEDiosmin, Rutosides베니톨, 플라벤, 디오스민, 치센, 엘라스에이
Ankle circumferenceCyclo3, HCSEDiosminMPFF, Ruscus, Oxerutins베니톨, 플라벤, 디오스민, 치센, 뉴베인
Leg volumeCyclo3, HCSE, ca+ dobesilateca+dobesilateMPFF, Ruscus, HCSE베니톨, 플라벤, 디오스민, 치센, 독시움
PainMPFF, Cyclo3, Oxerutins, HCSEDiosmin, Rutosides, ca+dobesilateMPFF, Ruscus, HCSE베니톨, 플라벤, 디오스민, 치센, 뉴베인,
CrampsMPFF, OxerutinsDiosmin, Rutosides, ca+dobesilateMPFF, Ruscus베니톨, 플라벤, 디오스민, 치센, 독시움
HeavinessMPFF, Cyclo3, Oxerutins, ca+dobesilateDiosmin, RutosidesMPFF, Ruscus베니톨, 플라벤, 디오스민, 치센, 뉴베인, 독시움
Feeling of swellingMPFF, Cyclo3ca+dobesilateMPFF베니톨, 플라벤
UlcerMPFF, Oxerutins베니톨, 플라벤, 뉴베인
Functional discomfortMPFFMPFF베니톨, 플라벤
Skin changeMPFFDiosminMPFF베니톨, 플라벤, 디오스민
Restless legca+dobesilate독시움
Pruritis/ItchingOxerutins, HCSERutosidesHCSE뉴베인
ParaesthesiaCyclo3RutosidesMPFF베니톨, 플라벤
Leg fatiqueCyclo3
QoLMPFFMPFF베니톨, 플라벤
Burning sensationMPFF베니톨, 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 (1). Most VADs have common effects on swelling, pain, spasms, and weight. However, according to clinical guidelines and Cochrane reviews, the effects vary from drug to drug. As we found earlier, there is a difference in the efficacy of each drug, so it seems that complementary effects to cover a wide range of symptoms can be expected with a combination of VADs.

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) (10). They identified 10 trials involving 719 patients, and the study duration varied from 15 days to 14 weeks. The Ruscus mixture was observed to be highly effective in reducing symptoms and edema of patients with CVD. Belcaro et al. compared nine venoactive products, for at least 12 months and reported venoruton+ pyconogenol to be more effective than single-ingredient agents (11).

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) (12). A period of use is not mentioned in other guidelines. The period of use of VADs seems to differ depending on the clinical situation and as per the clinician’s discretion. According to previous reports (13), VADs have been used 2 weeks before surgery and 4 weeks after surgery in some studies. In the early stage of CVD with C0∼C2, it was used for 2∼3 months; in advanced disease with C3∼6, it was used for 3∼6 months; and in the case of post-thrombotic syndrome, it was used over a 2-year period, and meaningful outcomes were reported. It may be necessary to use the drug for 1∼2 months to evaluate the effect of VADs. Subsequently, in patients who show an effect, it may assist in the decision to stop the drug after more than 6 months of use.

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 (14).

Centella asiatica has been commercialized as treatment for CVD (CENSIA, centella extract 30 mg, Dongkook Co., Republic of Korea) to improve the symptoms related to venous and lymphatic insufficiency (bluntness of lower extremities, pain, restless leg symptoms) (15). An interesting precaution for the use of CENSIA is the recommendation for short-term use. This is probably because three cases of hepatotoxicity have been reported (16). The duration of the administration of Centella asiatica in three patients with hepatotoxicity was 20, 30, and 60 days, respectively. The pathologic diagnosis was granulomatous hepatitis with marked necrosis and apoptosis, chronic hepatitis with cirrhotic transformation, and intense neuroinflammatory activity. The active constituent pentacyclic triterpenoid saponoside was suspected to be the cause of the apoptosis and alteration in the cell membrane. Another interesting caution is that Gotu kola may have emmenagogue effects. Therefore, Centella asiatica is to be avoided during pre-gnancy and lactation.

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 (17-19). The most common adverse reactions include mild gastrointestinal and autonomic disorders (itching, erythema, dermatitis, epigastric pain, nausea, diarrhea, and dizziness). Cardiac arrhythmias and hemolytic anemia have also been reported (20).

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 (21-23).

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 (1,8,9), drugs can be selected according to the symptoms reported by the patients. It takes at least 2 to 4 weeks of treatment for an effect to be observed. It is, therefore, important to be aware of the precautions of these drugs when prescribing them to patients.

This content was presented at the 42nd Conference of the Korean Society for Phlebology on April 17th, 2022.

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  2. Mansilha A, Sousa J. Benefits of venoactive drug therapy in surgical or endovenous treatment for varicose veins: a systematic review. Int Angiol. 2019;38:291-8.
  3. Wittens C, Davies AH, Bækgaard N, Broholm R, Cavezzi A, Chastanet S, et al. Editor's Choice - Management of Chronic Venous Disease: Clinical Practice Guidelines of the European Society for Vascular Surgery (ESVS). Eur J Vasc Endovasc Surg. 2015;49:678-737.
  4. Howlader MH, Smith PD. Symptoms of chronic venous disease and association with systemic inflammatory markers. J Vasc Surg. 2003;38:950-4.
  5. Bradbury A, Evans C, Allan P, Lee A, Ruckley CV, Fowkes FG. What are the symptoms of varicose veins? Edinburgh vein study cross sectional population survey. Bmj. 1999;318:353-6.
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  7. Masuda E, Ozsvath K, Vossler J, Woo K, Kistner R, Lurie F, et al. The 2020 appropriate use criteria for chronic lower extremity venous disease of the American Venous Forum, the Society for Vascular Surgery, the American Vein and Lymphatic Society, and the Society of Inter-ventional Radiology. J Vasc Surg Venous Lymphat Disord. 2020;8:505-25.e504.
  8. Martinez-Zapata MJ, Vernooij RW, Simancas-Racines D, Uriona Tuma SM, Stein AT, Moreno Carriles RMM, et al. Phlebotonics for venous insufficiency. Cochrane Database Syst Rev. 2020;11:Cd003229.
  9. Mansilha A, Gianesini S, Ulloa JH, Lobastov K, Wang J, Freitag A, et al. Pharmacological treatment for chronic venous disease: an umbrella review of systematic reviews. Int Angiol.
  10. Kakkos SK, Allaert FA. Efficacy of Ruscus extract, HMC and vitamin C, constituents of Cyclo 3 fort, on improving individual venous symptoms and edema: a systematic review and meta-analysis of randomized double-blind placebo-controlled trials. Int Angiol. 2017;36:93-106.
  11. Belcaro G, Dugall M, Luzzi R, Corsi M, Ledda A, Ricci A, et al. Management of Varicose Veins and Chronic Venous Insufficiency in a Comparative Registry with Nine Venoactive Products in Comparison with Stockings. Int J Angiol. 2017;26:170-8.
  12. Stücker M, Debus ES, Hoffmann J, Jünger M, Kröger K, Mumme A, et al. Consensus statement on the symptom- based treatment of chronic venous diseases. J Dtsch Dermatol Ges. 2016;14:575-83.
  13. Kalinin R, Suchkov I, Kamaev A, Mzhavanadze N. Course duration for venoactivedrug treatment in chronic venous disease Phlebolymphology. 2021;28:26-33. Course duration for venoactivedrug treatment in chronic venous disease Phlebolymphology. 2021;28:26-33.
  14. Ma G, Chen Y. Polyphenol supplementation benefits human health via gut microbiota: A systematic review via meta-analysis. Journal of Functional Foods. 2020;66:103829.
  15. Chong NJ, Aziz Z. A Systematic Review of the Efficacy of Centella asiatica for Improvement of the Signs and Symptoms of Chronic Venous Insufficiency. Evid Based Complement Alternat Med. 2013;2013:627182.
  16. Jorge OA, Jorge AD. Hepatotoxicity associated with the ingestion of Centella asiatica. Rev Esp Enferm Dig. 2005;97:115-24.
  17. Rajnarayana K, Venkatesham A, Nagulu M, inivas M Sr, Krishna DR. Influence of diosmin pretreatment on the pharmacokinetics of chlorzoxazone in healthy male volunteers. Drug Metabol Drug Interact. 2008;23:311-21.
  18. Rajnarayana K, Venkatesham A, Krishna DR. Bioavail-ability of diclofenac sodium after pretreatment with diosmin in healthy volunteers. Drug Metabol Drug Interact. 2007;22:165-74.
  19. Bedada SK, Boga PK, Kotakonda HK. The effect of diosmin on the pharmacokinetics of fexofenadine in healthy human volunteers. Xenobiotica. 2017;47:230-5.
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  21. Mousa SA. Antithrombotic effects of naturally derived products on coagulation and platelet function. Methods Mol Biol. 2010;663:229-40.
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Review Article

Ann Phlebology 2022; 20(1): 1-5

Published online June 30, 2022 https://doi.org/10.37923/phle.2022.20.1.1

Copyright © Annals of phlebology.

Practical Use of Venoactive Drugs for Chronic Venous Disease in Korea

Sangchul Yun, M.D., Ph.D., R.P.V.I., R.V.T.

Department of Surgery, Soonchunhyang University Seoul Hospital, Seoul, Korea

Correspondence to:Sangchul Yun, 59 Daesakwan-ro, Yongsangu, Seoul 04401, Korea, Department of Surgery, Soonchunhyang University Seoul Hospital
Tel: 02-710-3240, Fax: 02-749-0449
E-mail: ys6325@schmc.ac.kr

Abstract

Venoactive drugs can be used as a first-line treatment in all stages of chronic venous disease. In a more advanced stage, drugs can be used together with surgery or endovascular procedures. However, 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 drugs are flavonoids including diosmin, micronized purified flavonoid fraction, rutin and troxerutin, and saponins including horse chestnut seed extract and Ruscus extract such as butcher’s broom, anthocyans, and synthetic drugs. There is a difference in the mechanism of action of each drug, and these drugs seem to be selectively used according to the symptoms mentioned by patients. The drug indications according to the guidelines and research and precautions are summarized in this review.

Keywords: Medical therapy, Chronic venous disease, Clinical practice guideline, Varicose vein, Drugs

INTRODUCTION

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 (1,2). The main purpose of the use of VADs is to control swelling and pain caused by venous hypertension and hypoxia (3). However, clinical symptoms such as pain and swelling do not show a close correlation with CVD severity. In a study involving 132 patients, Howlader and Smith reported no statistical relationship between the pain score or heaviness score, assessed on a 10-point visual analog scale, and the clinical severity of venous disease. The median pain score was 2.8 in the class C2 venous disease group, 4.5 in C3, 0.5 in C4, and 0 in C5 (4).

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 (5). In Edinburgh Vein Study of more than 1500 subjects aged between 18 and 64 years, Bradbury et al. reported that varicose veins and three lower extremity symptoms in women (pain, heaviness or tension, and itching) are statistically significant, but the correlation between each of these symptoms and varicose veins is too weak to determine a relationship of the discomfort or pain with CVD. Although there was a strong relationship between heaviness or tension, pain, and itchiness in women and the presence of trunk varices, this may have limited clinical value. For example, although a linear trend between pain and trunk varices in women was significant (p<0.001), pain was present in 45% of women without varicose veins and 63% of women with grade 2 and 3 varicose veins. The difference was only 18%. Thus, many asymptomatic patients not only have trunk varicose veins on clinical examination, but others experienced some symptoms of lower extremity, despite little or no clinical evidence of venous disease. It should be assumed that these patients have deep vein or non-venous disease to explain their symptoms.

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 (6). Non-surgical treatment seems sufficient for at least 40% of the patients with mild disease without risk factors.

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 (7).

CHOICES OF VADs

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 (1).

There is a difference in the mechanism of action of each drug. Previous studies (1) have indicated that drugs that are effective for venous tone or venous wall and valve can be used for varicose veins in the lower extremities, and drugs that are effective for capillary leakage or lymph circulation are effective for lower extremity edema. They seem effective, and the effect on partial pressure of oxygen, such as blood supply or removal of active oxygen, seems helpful in symptom control.

The 2018 UIP guideline subdivided VADs according to symptoms, signs, and quality of life, with magnitude of effect (1). MPFF is strongly recommended strong for pain, heaviness, feeling of swelling, functional discomfort, cramps, leg redness, skin changes, edema, and quality of life, and but not so strongly for paresthesiae and burning. Ruscus extract+hesperidin methyl chalcone (HMC)+Vitamin C (Ruscus+HMC+ascorbic acid, [Cyclo 3 fort®])is strongly recommended for pain, heaviness, feeling of swelling, leg fatigue, paresthesia, and edema, but not so strongly for cramps and pruritus. Oxerutins are strongly recommended for pain, heaviness, and cramps, and but not so strongly for edema. Moreover, the recommendation of HCSE is strong for the treatment of pain, pruritus, and edema, while that of calcium dobesilate is weak due to the possibility of agranulocytosis.

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 (8).

As for the reviews on VADs, an umbrella review was published in 2022 and a total of 11 systematic reviews (SRs) were reviewed (9). VADs are classified according to effective symptoms. Six SRs with edema as an outcome compared active treatment with placebo, MPFF, Ruscus extracts, and HCSE and revealed that these drugs were significantly superior in reducing the ankle circumference. In one of the SRs, MPFF (-0.8±0.53 cm), hydroxyethy-lrutosides (-0.58±0.31 cm), and Ruscus extract (-0.58±0.47 cm) resulted in a reduction in the ankle circumference, but diosmin (-0.20±0.5 cm) did not. With respect to com-parisons amongst the VADs, MPFF was superior to hydroxyethylrutosides and Ruscus extracts. In an SR evaluating MPFF, volume reductions >100 mL were more evident in the MPFF group (64.3%) than in placebo (36.6%; p=0.04). In another SR, HCSE (standard mean deviation [SMD] 0.34; 95% confidence interval [CI] 0.15 to 0.52) and Ruscus extract (SMD -0.61; 95% CI -0.91 to -0.31) were efficacious in reducing leg volume.

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).

Table 1 . recommended VADs according to previous guideline and reviews.

SymptomsUIP 2018 (1)Cochrane 2020 (8)Umbrella review 2022 (9)Commercial durgs in Korea
EdemaCyclo3, HCSEDiosmin, Rutosides베니톨, 플라벤, 디오스민, 치센, 엘라스에이
Ankle circumferenceCyclo3, HCSEDiosminMPFF, Ruscus, Oxerutins베니톨, 플라벤, 디오스민, 치센, 뉴베인
Leg volumeCyclo3, HCSE, ca+ dobesilateca+dobesilateMPFF, Ruscus, HCSE베니톨, 플라벤, 디오스민, 치센, 독시움
PainMPFF, Cyclo3, Oxerutins, HCSEDiosmin, Rutosides, ca+dobesilateMPFF, Ruscus, HCSE베니톨, 플라벤, 디오스민, 치센, 뉴베인,
CrampsMPFF, OxerutinsDiosmin, Rutosides, ca+dobesilateMPFF, Ruscus베니톨, 플라벤, 디오스민, 치센, 독시움
HeavinessMPFF, Cyclo3, Oxerutins, ca+dobesilateDiosmin, RutosidesMPFF, Ruscus베니톨, 플라벤, 디오스민, 치센, 뉴베인, 독시움
Feeling of swellingMPFF, Cyclo3ca+dobesilateMPFF베니톨, 플라벤
UlcerMPFF, Oxerutins베니톨, 플라벤, 뉴베인
Functional discomfortMPFFMPFF베니톨, 플라벤
Skin changeMPFFDiosminMPFF베니톨, 플라벤, 디오스민
Restless legca+dobesilate독시움
Pruritis/ItchingOxerutins, HCSERutosidesHCSE뉴베인
ParaesthesiaCyclo3RutosidesMPFF베니톨, 플라벤
Leg fatiqueCyclo3
QoLMPFFMPFF베니톨, 플라벤
Burning sensationMPFF베니톨, 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..


COMBINATION OF SEVERAL VADs

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 (1). Most VADs have common effects on swelling, pain, spasms, and weight. However, according to clinical guidelines and Cochrane reviews, the effects vary from drug to drug. As we found earlier, there is a difference in the efficacy of each drug, so it seems that complementary effects to cover a wide range of symptoms can be expected with a combination of VADs.

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) (10). They identified 10 trials involving 719 patients, and the study duration varied from 15 days to 14 weeks. The Ruscus mixture was observed to be highly effective in reducing symptoms and edema of patients with CVD. Belcaro et al. compared nine venoactive products, for at least 12 months and reported venoruton+ pyconogenol to be more effective than single-ingredient agents (11).

DURATION OF VADs

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) (12). A period of use is not mentioned in other guidelines. The period of use of VADs seems to differ depending on the clinical situation and as per the clinician’s discretion. According to previous reports (13), VADs have been used 2 weeks before surgery and 4 weeks after surgery in some studies. In the early stage of CVD with C0∼C2, it was used for 2∼3 months; in advanced disease with C3∼6, it was used for 3∼6 months; and in the case of post-thrombotic syndrome, it was used over a 2-year period, and meaningful outcomes were reported. It may be necessary to use the drug for 1∼2 months to evaluate the effect of VADs. Subsequently, in patients who show an effect, it may assist in the decision to stop the drug after more than 6 months of use.

PRECAUTIONS

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 (14).

Centella asiatica has been commercialized as treatment for CVD (CENSIA, centella extract 30 mg, Dongkook Co., Republic of Korea) to improve the symptoms related to venous and lymphatic insufficiency (bluntness of lower extremities, pain, restless leg symptoms) (15). An interesting precaution for the use of CENSIA is the recommendation for short-term use. This is probably because three cases of hepatotoxicity have been reported (16). The duration of the administration of Centella asiatica in three patients with hepatotoxicity was 20, 30, and 60 days, respectively. The pathologic diagnosis was granulomatous hepatitis with marked necrosis and apoptosis, chronic hepatitis with cirrhotic transformation, and intense neuroinflammatory activity. The active constituent pentacyclic triterpenoid saponoside was suspected to be the cause of the apoptosis and alteration in the cell membrane. Another interesting caution is that Gotu kola may have emmenagogue effects. Therefore, Centella asiatica is to be avoided during pre-gnancy and lactation.

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 (17-19). The most common adverse reactions include mild gastrointestinal and autonomic disorders (itching, erythema, dermatitis, epigastric pain, nausea, diarrhea, and dizziness). Cardiac arrhythmias and hemolytic anemia have also been reported (20).

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 (21-23).

CONCLUSION

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 (1,8,9), drugs can be selected according to the symptoms reported by the patients. It takes at least 2 to 4 weeks of treatment for an effect to be observed. It is, therefore, important to be aware of the precautions of these drugs when prescribing them to patients.

ACKNOWLEDGEMENTS

This content was presented at the 42nd Conference of the Korean Society for Phlebology on April 17th, 2022.

CONFLICT OF INTEREST

The authors declare no potential conflict of interest.

Table 1 . recommended VADs according to previous guideline and reviews.

SymptomsUIP 2018 (1)Cochrane 2020 (8)Umbrella review 2022 (9)Commercial durgs in Korea
EdemaCyclo3, HCSEDiosmin, Rutosides베니톨, 플라벤, 디오스민, 치센, 엘라스에이
Ankle circumferenceCyclo3, HCSEDiosminMPFF, Ruscus, Oxerutins베니톨, 플라벤, 디오스민, 치센, 뉴베인
Leg volumeCyclo3, HCSE, ca+ dobesilateca+dobesilateMPFF, Ruscus, HCSE베니톨, 플라벤, 디오스민, 치센, 독시움
PainMPFF, Cyclo3, Oxerutins, HCSEDiosmin, Rutosides, ca+dobesilateMPFF, Ruscus, HCSE베니톨, 플라벤, 디오스민, 치센, 뉴베인,
CrampsMPFF, OxerutinsDiosmin, Rutosides, ca+dobesilateMPFF, Ruscus베니톨, 플라벤, 디오스민, 치센, 독시움
HeavinessMPFF, Cyclo3, Oxerutins, ca+dobesilateDiosmin, RutosidesMPFF, Ruscus베니톨, 플라벤, 디오스민, 치센, 뉴베인, 독시움
Feeling of swellingMPFF, Cyclo3ca+dobesilateMPFF베니톨, 플라벤
UlcerMPFF, Oxerutins베니톨, 플라벤, 뉴베인
Functional discomfortMPFFMPFF베니톨, 플라벤
Skin changeMPFFDiosminMPFF베니톨, 플라벤, 디오스민
Restless legca+dobesilate독시움
Pruritis/ItchingOxerutins, HCSERutosidesHCSE뉴베인
ParaesthesiaCyclo3RutosidesMPFF베니톨, 플라벤
Leg fatiqueCyclo3
QoLMPFFMPFF베니톨, 플라벤
Burning sensationMPFF베니톨, 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..


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AP
Vol.21 No.2 Dec 31, 2023, pp. 53~98

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