Abstract
Venoactive agents and their utilization
The Venous Taskforce within the Society for Vascular Medicine (SVM) focuses on issues of clinical, education, quality, research, and advocacy of matters related to venous disease to enhance patient care. The Venous Taskforce has been focusing on bringing attention to and providing guidance on areas that are important in clinic practice.
Venoactive agents (VAs) are frequently used and mentioned in various guidelines as an option for management of chronic venous disease (CVD). The targetable modes of action for VAs are decreasing capillary permeability, reducing release of inflammatory mediators, improving venous tone, reducing reactive oxygen species, and preserving the glycocalyx. 1 As such, they can help alleviate symptoms associated with CVD, including pain and swelling. By understanding their indications, mechanism of action, dosages, and potential side effects, providers can make informed decisions and improve the utilization of VAs in clinical practice.
Recently, Drs Syed Ahsan and Omar Esponda, co-chairs of the SVM Venous Taskforce, discussed the types of VAs with Venous Taskforce members to promote their use in managing CVD.
Dr Syed Ahsan is the Head of Vascular Medicine at the Heart and Vascular Institute at Henry Ford Health in Detroit, Michigan. He has been involved with the vein clinic and wound care clinic and currently serves as the Medical Director of the Henry Ford Lymphedema Program. Dr Omar Espondais a dedicated vascular medicine specialist and phlebologist at Vein Specialists clinic, located in Fort Myers, Florida. Dr Wenzhu Li is a general cardiologist in China, appointed at Shanghai Vascular Aging and Cardio-Cerebrovascular Disease Council. She has expertise on antithrombotic therapy in vascular disease, especially for venous thromboembolism and its sequela. Dr Reza Amini is a cardiologist and vascular medicine specialist at Loma Linda University Medical Center, Loma Linda, California. He is director of the vascular medicine program within the cardiology division. Dr Maxim Shaydakov is a vascular surgery fellow at the University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania. Dr Jason Wheeler is a vascular medicine specialist at Cleveland Clinic, Weston, Florida. He is Co-Director of the Cleveland Clinic Vein Center. Dr Eri Fukaya is an associate professor at Stanford in Stanford, California. She practices vascular medicine at the Stanford Vascular Clinics and Advanced Wound Care Center.
How do you think VAs can complement the treatment of venous disease?
VAs may complement the treatment of venous disease by enhancing venous function through multiple mechanisms and can be an effective adjunct in managing CVD for patients who cannot use compression garments, have intolerance to them or have continued symptoms despite attempts at other treatments or when there are no other treatment options available. 2
What are the current recommendations on VAs?
VAs are used worldwide to treat the signs and symptoms of CVD. In the updated European Society for Vascular Surgery guidelines, they have a unified class IIa recommendation for use of VAs for medical management of symptomatic CVD. 3 This is similar to the recommendation made by the Society for Vascular Surgery and the American Venous Forum who also give a grade 2 recommendation for the use of VA in CVD. 4
What are some of the VAs commonly used or encountered in your practice?
The most common VAs encountered are different types of over-the-counter flavonoids, horse chestnut seed extract, grape seed extract, rutin, and butcher’s broom extract.
During training years in Europe, micronized purified flavonoid fraction (MPFF) was frequently used to treat advanced CVD defined as C3-6 on the CEAP classification index.
The use of VAs is not prevalent in practice but has been used for expedited wound healing. I have used Vasculera (Primus Pharmaceuticals, Inc., AZ) for my patients, but the issue has been insurance coverage. Other VA supplements are available internationally that are being used for the same purpose.
In my practice in Florida, many international patients use VAs for swelling or discomfort, but the underlying disease remains unaffected, such as venous reflux – which in most cases remains unresolved.
VAs are frequently used in China, mostly by traditional medicine practitioners. The precise ingredients are unclear.
Why do you think VAs are underutilized by both patients and health care providers?
The underutilization of VAs is attributed to factors such as lack of knowledge, limited research, lack of guideline support, inadequate regulation, unclear dosing, and cost-related challenges.
The other challenge is that efficacy is unclear compared to standard forms of treatment for CVD.
MPFF is a well-known flavonoid; could you further elaborate on its clinical benefit and use?
MPFF is a flavonoid preparation derived from various plant sources containing diosmin and hesperidin. 5 The recommended daily dose of diosmin is 600 mg, and approximately 10% of individuals may experience moderate gastrointestinal discomfort or dermatitis.
It can potentially be used in all venous insufficiency patients, but the challenge is that efficacy or improvement is not always clear and there is a lack of strong clinical studies that show meaningful outcomes.
In my practice, we trialed diosmiplex (Vasculera) (which is categorized as medical food) for 1 month, without strong evidence the response was very subjective and was expensive. We would need to be able to trial this longer and have measurable outcomes to be able to determine if this is effective or not.
In my experience, Detralex (Les Laboratoires Servier, France) seems to be used commonly in Europe for C3-6 disease but is not utilized in the USA.
Horse chestnut seed extract is a popular choice. What is the active ingredient?
Horse chestnut seed extract contains a compound called escin. Horse chestnut seed extract is thought to have antiinflammatory properties that contribute to its therapeutic benefits in CVD. The typical dosage of horse chestnut seed extract for CVI ranges from 300 mg to 600 mg per day. A 2015 review suggests that horse chestnut seed extract is effective for CVD; however, additional large-scale trials are advised to provide further evidence of its efficacy. Horse chestnut seed extract should be used cautiously as it can increase the risk of bleeding. 6
What properties does grape seed extract have?
Grape seed extract possesses venoactive properties that reduce symptoms such as leg discomfort, edema, and varicose veins. 7
How does grape seed extract compare to compression garments in terms of efficacy, and are there any issues with using it alongside other vitamins?
A randomized, placebo-controlled, double-blind study demonstrated that grape seed extract at doses of 150 mg twice a day or 360 mg and 720 mg once daily can be equivalent in efficacy to compression garments for the treatment of CVD. Grape seed extract should be avoided while taking vitamin C as it may cause an increase in blood pressure. 8
What are rutosides or rutin, and how is it commonly used?
Rutin is also a plant-based flavonoid found in various fruits and vegetables. It is commonly found in combination with other VAs such as diosmin or hesperidin. Dosages typically range from 500 mg to 1000 mg per day. Rutin has no known severe adverse effects, except for mild gastrointestinal symptoms and medication interactions. 9
How does butcher’s broom extract alleviate symptoms, and are there any significant side effects associated with its use?
Butcher’s broom extract is thought to have antiinflammatory properties that improve endothelial function and promote healing, thereby reducing leg heaviness, pain, and discomfort associated with venous pooling in CVD There are no known significant side effects associated with the use of butcher’s broom extract. 10
What precautions should be taken when using VAs alongside other treatment modalities?
Providers should familiarize themselves with VAs, including their mechanism of action, indications, dosages, potential side effects, and drug–drug interactions. Though some studies have found VAs to be as effective as, or, in rare cases, better than compression therapy, it is essential to evaluate each patient’s condition and tailor the treatment approach accordingly.
How can the optimal utilization of VAs be achieved?
This is a complex process. Conducting further research to assess efficacy and safety will increase awareness and allow incorporation of VAs into treatment guidelines. This will also address regulatory and cost-related challenges, determining appropriate dosing and administration routes, promoting utilization among health care providers.
I would recommend using VAs in complex management of advanced CVD, including patients with venous ulcers, especially when standard treatment is not sufficient to control symptoms.
Currently, the use of VAs is very limited due to lack of data on VAs. We need more research to demonstrate a positive benefit-to-harm ratio.
I would recommend using it in patients who are not candidates for standard treatments and adding VAs would be acceptable in advanced venous disease C3-6.
I would recommend using them in very specific situations where data support its use and standard treatment has failed.
What further research is needed to assess the efficacy and safety of VAs?
Research is needed to determine the efficacy and safety of VAs. Large-scale trials should be conducted to assess their efficacy, particularly in comparison to alternative treatment modalities such as compression therapy. Furthermore, research should investigate potential drug interactions, long-term effects, optimal dosing, and administration methods. VAs are already incorporated in the European and US guidelines and have the potential to be an effective adjunct therapy for CVD.
Conclusion
VAs may have a role in the care of advanced CVD but may not be necessary for everybody. This may be an alternate treatment for patients who have either failed or are not a candidate for standard treatments. It should be used with caution as an adjunct therapy. VAs may help with symptomatic improvement, but it is still unclear how it may address the underlying pathology.
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