Chronic venous disease is a condition in which blood does not flow efficiently through the veins in the legs toward the heart. Spider veins and varicose veins are common signs of early-stage chronic venous disease.

Untreated varicose veins are associated with increased risk of deep vein thrombosis (DVT)—potentially deadly blood clots in the legs. Therefore, varicose veins and chronic venous disease should be taken seriously even in the early stages.

Phlebotonics are compounds that improve circulatory function, such as horse chestnut seed extract, diosmin, pycnogenol, and Centella asiatica.

Risk Factors

• Increasing age
• Female gender
• Tall stature
• Family history
• Previous history of DVT in the legs
• Pregnancy
• Prolonged sitting or standing
• Obesity

Signs, Symptoms and Complications

• The early stages of venous disease may have no symptoms. As the disease progresses, several symptoms affecting the legs may arise, including heaviness, tiredness, itching, cramps, tingling, swelling, and pain.
• Clinical Classification of Chronic Venous Disease
• C0: No visible or palpable sign of venous disease
• C1: Spider veins or reticular veins (veins that “feed” spider veins)
• C2: Varicose veins
• C3: Edema (swelling)
• C4: Changes in skin and tissues
• A: Pigmentation or eczema
• B: Thickening, hardening, swelling, redness, inflammation, scarring
• C5: Healed venous ulcer
• C6: Active venous ulcer

Note: Some potential complications of venous disease, such as DVT, can occur even in people who have no overt signs. One potentially deadly consequence of DVT is pulmonary embolism when the blood clot dislodges from the deep vein and travels to the lungs. Anyone who suspects they may have a DVT should consult a qualified healthcare provider right away.

Conventional Treatment Includes:

• Compression therapy. Compression can be accomplished with stockings (the most common form), bandages, boots, and pneumatic devices.
• Sclerotherapy. This common procedure involves injecting a compound into the vein to damage the vessel lining, causing the vein to degrade and eventually be reabsorbed by the body.

Novel and Emerging Therapies Include:

• CHIVA, a French acronym for “conservative hemodynamic cure for venous insufficiency,” is unique among venous disease treatments in that it preserves rather than destroys superficial veins.
• Oxerutin, a mixture of semisynthetic flavonoids derived from rutin, is commonly used in Europe in the treatment of venous disorders. Multiple clinical trials have demonstrated that oxerutin reduces edema and pain associated with venous disease.

Dietary and Lifestyle Considerations Include:

• Physical activity encourages return of venous blood from the legs back to the heart by activating the pumping action of the muscles.
• Weight loss reduces pressure on leg veins and improves blood circulation.
• A high-fiber diet can help prevent varicose veins by producing soft, well-formed stools to ease bowel movements and eliminate chronic straining.

Integrative Interventions Include:

• Diosmin. A naturally occurring flavonoid found in many plants. A 2016 review and analysis of randomized controlled trials found that diosmin significantly reduced leg and ankle swelling and lower leg pain.
• Horse chestnut seed extract (Aesculus hippocastanum). A review and analysis of randomized controlled trials concluded that horse chestnut seed extract is a safe and effective short-term treatment for chronic venous insufficiency.
• Pycnogenol. Pycnogenol, a standardized extract of French maritime pine bark, has been shown to promote healing of venous ulcers and reduce leg edema and the risk of blood clots during long flights.
• Nattokinase. Nattokinase, a protein-digesting enzyme extracted from natto, has been shown in several laboratory studies to reduce the risk of blood clot formation and break up existing blood clots.
• Centella asiatica (Gotu kola). A rigorous review of randomized controlled clinical trials found evidence that Centella asiatica likely exerts beneficial effects on the signs and symptoms of chronic venous insufficiency.

Chronic venous disease is a condition in which blood does not flow efficiently through the veins in the legs toward the heart. It can be caused by problems with the vein walls or valves, which cause blood to pool in the leg veins—a condition called venous stasis. Spider veins and varicose veins are common signs of early-stage chronic venous disease. In advanced stages, chronic venous disease can cause leg swelling, changes in skin appearance and texture, and ulcers; the more advanced condition is called chronic venous insufficiency (Eberhardt 2014; Fort 2017a; Fort 2017b; Douketis 2016b; Eklof 2009).

Up to 35% of adults in the United States have some form of venous disease, and more than 25 million American adults have varicose veins (Eberhardt 2014; Fort 2017b).

Some people may dismiss varicose veins as a mere cosmetic nuisance that accompanies normal aging (Eberhardt 2014; Gloviczki 2011). However, untreated varicose veins are associated with increased risk of deep vein thrombosis—potentially deadly blood clots in the legs (Shaydakov 2016). Therefore, varicose veins and chronic venous disease should be taken seriously even in the early stages.

Conventional treatment options for varicose veins range from conservative management with compression stockings to more invasive methods such as endovenous ablation or surgical removal of affected veins (Stucker 2016; Eberhardt 2014; Wittens 2015; Scherger 2012). These treatments provide cosmetic improvement, relieve symptoms, and may prevent complications (Douketis 2016a; Scherger 2012).

However, conventional treatments do not prevent the formation of new varicose veins: recurrence rates are as high as 33% at five years. Also, invasive therapies are associated with adverse effects including bleeding, infection, nerve damage, and blood clots (Douketis 2016a; Wittens 2015; Zhan 2014; Scherger 2012).

Fortunately, newer minimally invasive strategies for treating varicose veins have been developed, including the FDA-approved VenaSeal system. This novel procedure uses a medical grade glue, rather than heat or cutting, to seal varicose veins, allowing for rapid recovery (FDA 2015; Gibson 2017). In addition, some bioengineered skin substitutes such as Dermagraft and Apligraf have been developed to accelerate the healing of venous ulcers (Nicholas 2016; Serena 2014).

Also, several natural compounds that function as phlebotonics can be helpful in the management of chronic venous disease and varicose veins. Phlebotonics are compounds that improve circulatory function, such as horse chestnut seed extract, diosmin, pycnogenol, and Centella asiatica (Fort 2017b; Martinez-Zapata 2016).

This protocol provides an overview of chronic venous disease and its various manifestations, particularly varicose veins. This protocol also covers conventional as well as emerging treatment options for chronic venous disease, and reviews natural agents and dietary habits that support vein health.

There are three types of veins in the legs (Eberhardt 2014; Wittens 2015):

• Superficial veins are located just beneath the skin, above layers of connective tissue and muscle. The major superficial veins in the legs are the great saphenous vein and the small saphenous vein.
• Deep veins that run along the main arteries of the legs, underneath the deep layer of muscle and connective tissue.
• Perforator veins cross through the deep muscle layer in the legs to connect the superficial veins to the deep venous system.

The contraction of calf muscles during walking pushes blood upward against gravity through the deep veins in the legs toward the heart. One-way valves in leg veins channel blood toward the heart and close to prevent backward blood flow down the legs (Fort 2017a; NIH 2014a).

In chronic venous disease, the valves in leg veins malfunction and blood flows in the reverse direction (ie, venous reflux), pooling in the veins and creating increased venous pressure. The buildup of blood pressure causes the characteristic changes in varicose veins—stretching, twisting, and bulging of the superficial veins (Fort 2017a; Eberhardt 2014; Wittens 2015; Jones 2008).

Although dysfunction of the valves in leg veins is the typical cause of increased venous blood pressure, other factors can also contribute, including obstruction of the veins (eg, by blood clots) and decreased contraction of calf muscles (eg, due to leg immobility). When increased venous blood pressure in the legs occurs as a result of a deep vein thrombosis, it is termed post-thrombotic syndrome (Wittens 2015; Eberhardt 2014; Fort 2017b).

Inflammation may play a role in the progression of venous disease and contribute to complications such as blood clots and leg ulcers. Inflammation results in part from damage to vein walls caused by turbulent blood flow as well as elevated pressure within the veins (Poredos 2015; Ligi 2016; Bergan 2006). Studies have reported significantly increased levels of inflammatory markers such as C-reactive protein (CRP) and interleukin-6 (IL-6) in varicose vein blood compared with systemic blood (Lattimer 2016; Poredos 2015; Kalodiki 2015).

Risk factors for chronic venous disease and varicose veins include (Fort 2017a; Eberhardt 2014; NIH 2016; Scherger 2012):

• Increasing age
• Female gender
• Tall stature
• Family history of chronic venous disease
• Previous history of deep vein thrombosis in the legs
• Pregnancy; history of one or more previous pregnancies
• Prolonged sitting or standing
• Obesity

Symptoms

The early stages of venous disease may not cause any symptoms. As the disease progresses, several symptoms affecting the legs may arise, including heaviness, aching, tiredness, itching, cramps, tingling, swelling, and pain. Symptoms become worse later in the day, and are worsened by menses, heat, and standing for long periods (Fort 2017a; Wittens 2015; Scherger 2012).

Signs

Clinical signs of chronic venous disease are classified along a continuum according to the Clinical-Etiology-Anatomy-Pathophysiology (CEAP) criteria. In general, an increasing clinical score corresponds to increasing disease severity (Fort 2017a; Eberhardt 2014).

Clinical Classification of Chronic Venous Disease

• C0: No visible or palpable sign of venous disease
• C1: Telangiectasias (spider veins) or reticular veins (veins that “feed” spider veins)
• C2: Varicose veins
• C3: Edema (swelling)
• C4: Changes in skin and tissues underneath the skin
• A: Pigmentation or eczema
• B: Thickening, hardening, swelling, redness, inflammation, scarring
• C5: Healed venous ulcer
• C5: Healed venous ulcer
• C6: Active venous ulcer

It is important to note that some potential complications of venous disease, such as deep vein thrombosis, can occur even in people who have no overt signs corresponding with any of the aforementioned stages.

Complications

Complications of untreated chronic venous disease include (Fort 2017a; Eberhardt 2014; NIH 2014b; Nicholls 2005):

• Superficial venous thrombophlebitis – a blood clot in a vein close to the skin surface; may cause severe pain and other problems.
• Bleeding – often results from local trauma but can be spontaneous; elderly patients have increased risk; can be life threatening if extensive.
• Lymphedema – buildup of lymphatic fluid in tissues under the skin.

Venous ulcers are one complication of venous disease that requires careful attention. The ulcers typically affect the lower part of the leg and ankle, are typically painful, exude fluids, and can become quite large; venous ulcers are also often recurrent (Bongiovanni 2015). It is important that a trained physician diagnose venous ulcers to differentiate them from other types of ulcers that can affect the legs, such as arterial ulcers and pressure ulcers. Venous ulcers are the most common type of chronic ulcer affecting the lower leg, accounting for 70‒80% of leg ulcers. Although the development of venous ulcers is complex, the primary mechanism involves high pressure in the leg veins, which causes fluids and molecules to leak into the surrounding tissue causing inflammation and tissue damage. Venous ulcers can cause substantial pain, and considerably reduce quality of life. Evidence suggests that the best outcomes can be achieved when ulcers are managed by a multidisciplinary wound-care team (Marola 2016).

Physical Examination

The diagnosis of chronic venous disease is typically based on a detailed history and physical examination (Fort 2017a; Fort 2017b). The primary goal of the initial evaluation is to rule out serious conditions that can manifest similarly to venous disease (Fort 2017b; Fort 2017a; Wittens 2015).

Imaging Studies

Duplex ultrasonography. Duplex ultrasonography is the gold standard for evaluating the veins. Combining traditional ultrasound with Doppler ultrasound, duplex ultrasound is a non-invasive diagnostic tool that uses sound waves to capture images of both the superficial and deep venous systems, and of the movement of blood through the veins. It can detect reflux at malfunctioning valves, as well venous obstruction (Wittens 2015; Scherger 2012).

For the routine evaluation of venous disease, duplex ultrasonography has largely replaced other diagnostic techniques such as handheld Doppler and venography. Duplex ultrasound is also used to assess treatment results (Wittens 2015; Fort 2017a).

Air plethysmography. Air plethysmography is a noninvasive test that measures changes in leg volume. It gives information about venous reflux, obstruction, and calf muscle pump function. Although used less frequently since the advent of duplex ultrasound, its use is indicated when the results from duplex ultrasound are inconclusive (Wittens 2015; Fort 2017a; Dezotti 2017; Gloviczki 2011).

Venography. Venography is a more invasive and complex imaging modality that also has been largely supplanted by duplex ultrasound. However, it retains an important role in more advanced disease including post-thrombotic syndrome and is critical for venous evaluation prior to surgical procedures (Fort 2017a; Gloviczki 2011).

Conservative Management

The initial management of chronic venous disease and varicose veins relies on conservative strategies to reduce symptoms, avoid complications, and prevent disease progression (Eberhardt 2014; St. George 2012).

Compression therapy. Compression therapy is a first-line, non-invasive, conservative management option for chronic venous disease (NICE 2013; Wittens 2015). Compression can be accomplished with stockings, bandages, boots, and pneumatic devices. Of these, stockings are the most common form, though initial therapy with elastic bandages has been recommended for advanced disease and leg ulcers (Wittens 2015; Stucker 2016; Douketis 2016b).

Compression stockings provide external pressure on the superficial veins, which may shunt more blood to the deep veins. This decreases venous reflux and venous pressure; improves the efficiency of the muscle pump system; and reduces leg edema (Stucker 2016; Wittens 2015; Eberhardt 2014; Scherger 2012; NICE 2013). Compression stockings may be more effective when applied at the beginning of the day, before edema worsens (Douketis 2016b).

Shortcomings of compression therapy include low compliance due to discomfort and inconvenience, as well as an inability to address the underlying disease process (Zhan 2014).

Conventional graduated compression stockings apply high pressure at the ankles and decreasing pressure towards the knees. These are known as degressive compression stockings (Couzan 2012; Lim 2014). When used as directed, degressive stockings improve edema, discomfort, ability to remain active, and overall well-being. However, degressive stockings are often considered difficult to put on, particularly in the elderly, and estimates of non-compliance with this method of compression range from 30‒65% (Couzan 2012; St. George 2012; Wittens 2015).

Progressive compression stockings are a newer method of compression therapy directed at improving comfort, efficacy, and compliance. These stockings provide a higher pressure at the calf than at the ankle, and have been demonstrated to be superior for symptom relief, reduction of occupational edema, and improving venous pumping. In addition, progressive stockings have been found to be more comfortable and easier to put on than degressive stockings (Couzan 2012; Mosti 2012; Mosti 2013).

More studies are needed to determine the most beneficial regimen with progressive and degressive compression stockings (Wittens 2015; Douketis 2016b; Eberhardt 2014).

Periodic elevation of legs. Periodic elevation of the legs above heart level is recommended to reduce leg swelling and promote relief of symptoms. In patients with advanced venous disease, leg elevation reduces leg volume and venous blood pressure, as well as improves circulation in inflamed skin. Leg elevation improves healing of leg ulcers and reduces their recurrence rate (Fort 2017a; Wittens 2015; Scherger 2012).

Unna boot inelastic bandages. The Unna boot is a treatment for venous ulcers. Zinc oxide-infused gauze is applied to the legs, covered with inelastic compression bandages, and worn continuously for up to seven days (UWHealth 2015; Douketis 2016b; de Abreu 2015; Wittens 2015). In a 13-week randomized clinical trial, the Unna boot was found to achieve better healing of large venous ulcers than standard elastic bandages (de Abreu 2015).

Intermittent pneumatic compression devices. Pneumatic compression devices are becoming more popular as adjuvants to conventional compression stockings. A pneumatic compression device is a sleeve or cuff that fits around the leg(s), filling with air to compress the legs and enhance venous circulation. The cuffs go through cycles of compression and relaxation that push venous blood back toward the heart and allow oxygen-rich arterial blood to continue flowing into the legs. These devices also support the activity of the muscles that promote venous blood flow in the foot and calf (Hettrick 2009). Intermittent pneumatic compression devices may be recommended to people at risk of deep vein thrombosis or those who have undergone recent surgery. The devices are typically used in the hospital but may be used at home in some cases (Johns Hopkins Medicine 2017). Intermittent pneumatic compression is contraindicated in individuals with an acute wound infection, deep vein thrombosis, or decompensated congestive heart failure (Kolluri 2011).

Pharmacological Therapy

Pentoxifylline. Pentoxifylline (Trental) is a drug that enhances blood flow and is indicated for certain types of vascular disease. Pentoxifylline also inhibits the secretion of the inflammatory cytokine tumor necrosis factor-alpha (TNF-α) (McCarty 2016; Pollice 2001). Multiple randomized trials have shown that pentoxifylline, alone or in conjunction with compression bandaging, accelerates healing of chronic venous ulcers (Jull 2012; Parsa 2012). Side effects of pentoxifylline are uncommon and mild, primarily gastrointestinal distress (Hallett 2014; Jull 2012).

Interventional Management

Sclerotherapy. Venous sclerotherapy is commonly used to treat varicose veins. This procedure involves injecting a compound into the vein to damage the vessel lining, causing the vein to degrade and eventually be reabsorbed by the body. The injection can consist of material in liquid or foam form. Sclerotherapy is inexpensive, generally provides rapid results, and is suitable for use in older or frail patients (Wittens 2015; Brittenden 2014).

Compounds used in sclerotherapy procedures include detergents, osmotic agents (hypertonic saline), or chemical irritants (chromated glycerin) (Wittens 2015). Sclerotherapy may be used alone or to complement surgical procedures in the treatment of chronic venous insufficiency (Scherger 2012).

After a sclerotherapy procedure, compression may be necessary to preserve vein closure (NIH 2014c; Alaiti 2017). Possible complications of sclerotherapy include superficial thrombophlebitis (inflammation of the vein wall), skin darkening, and blood clots (deep vein thrombosis or pulmonary embolism) (Wittens 2015; Scherger 2012).

Endovenous ablation. Endovenous ablation is a minimally invasive procedure for treating malfunctioning veins (ACP 2016; Fort 2017a). Laser ablation and radiofrequency ablation, the two most common techniques, generate heat energy to ablate (close off) diseased veins. Chemical ablation using ultrasound-guided foam sclerotherapy is also an option (Fort 2017a; Wittens 2015).

Laser and radiofrequency ablation are as effective as surgical vein stripping, but with faster recovery and less pain, and have become popular alternatives to stripping. Potential complications of endovenous ablation, though relatively rare, include burns, bruising, thrombophlebitis, deep vein thrombosis, and pulmonary embolism (Fort 2017a; Eberhardt 2014; Wittens 2015; Scherger 2012).

External laser therapy. External or transcutaneous laser therapy using long-pulsed lasers is partially effective for small spider veins and reticular (“feeder”) veins with a diameter of < 0.5 mm. In this procedure, pulses of laser light are transmitted through the skin to the targeted vein. The light energy is absorbed by hemoglobin in the vein and converted to heat energy, which closes the vein (Wittens 2015; Scherger 2012).

External laser therapy is less effective and more expensive than sclerotherapy for treating spider veins. However, external laser therapy is relatively risk-free, and can be a valuable alternative when sclerotherapy is contraindicated. These situations include allergy to sclerosing agents, fear of needles, and blood vessels too small for a fine needle (Wittens 2015; Meesters 2014; Scherger 2012). In addition, newer lasers, and combinations of laser treatment and sclerotherapy appear promising (Wittens 2015).

Conventional Surgery

Surgery is reserved for more advanced cases of venous disease that do not fully respond to less invasive procedures (Eberhardt 2014). However, not all randomized trials have found that surgery leads to better results than less invasive methods (Rasmussen 2011; Shadid 2012; Brittenden 2014; Wittens 2015; Scherger 2012). Varicose veins recur in 20‒60% of patients within five years of surgery (Gad 2012). Complications of surgical intervention for venous disease include bruising, infection, scarring, nerve injury, and injury to arteries (Zhan 2014; Scherger 2012; Weiss 2016; Gad 2012).

Vein ligation and stripping. Vein ligation and stripping is reserved for chronic venous insufficiency, to treat symptomatic disease involving reflux in the saphenous vein system (Weiss 2016).

Vein ligation and stripping is usually performed on an outpatient basis and under general anesthesia. Small incisions are made in the skin, and the damaged vein is tied off and removed. Recovery time is approximately one to four weeks. Good cosmetic results, symptom relief, and avoidance of long-term risks related to varicose veins are benefits of this procedure. Vein stripping does not, however, prevent the formation of new varicose veins (Wittens 2015; NIH 2014c; Scherger 2012).

Ambulatory phlebectomy. Similar to vein stripping, ambulatory phlebectomy involves the removal of varicose veins through small incisions in the skin. This procedure is generally performed for varicose veins close to the skin surface. Ambulatory phlebectomy is often used in conjunction with endovenous ablation (Fort 2017a; NIH 2014c; Wittens 2015).

Unlike vein stripping, ambulatory phlebectomy is a minor procedure performed under local anesthesia in a physician’s office. It is safe and provides immediate symptom relief along with excellent cosmetic results (Fort 2017a; Wittens 2015).

Subfascial endoscopic perforator vein surgery. Perforator vein surgery is a newer, minimally invasive procedure indicated for advanced venous insufficiency. With this procedure, the incision site can be further away from the affected area, which can be advantageous in cases where local tissue damage prevents surgical access. This approach is indicated in patients who have compromised perforator veins, and is associated with a high rate of ulcer healing and a low rate of ulcer recurrence (Eberhardt 2014; Scherger 2012).

VenaSeal Closure System

The VenaSeal closure system is an in-office procedure that uses a liquid adhesive (a specially formulated cyanoacrylate) injected through a catheter ins vein. The VenaSeal system was approved by the Food and Drug Administration (FDA) in 2015 for treating symptomatic superficial varicose veins of the legs, and allows patients to quickly resume normal activities (FDA 2015). Multiple clinical trials have shown VenaSeal to be safe and effective for treating refluxing and malfunctioning great saphenous veins and relieving symptoms (Gibson 2017; Almeida 2015; Morrison, Gibson, McEnroe 2015; Morrison, Gibson, Vasquez 2017; Proebstle 2015).

Patients who are hypersensitive to the VenaSeal adhesive; have venous blood clots with acute inflammation; or have systemic infections should not undergo the VenaSeal procedure. Potential side effects from VenaSeal are typical of treatments for chronic venous disease and include phlebitis (vein inflammation) and paresthesia (burning or tingling) in the treatment region (FDA 2015).

CHIVA (Conservative Hemodynamic Cure for Venous Insufficiency)

CHIVA, a French acronym for “conservative hemodynamic cure for venous insufficiency,” is an office-based, minimally invasive, well-studied procedure for treating varicose veins that result from chronic venous insufficiency. CHIVA is more readily available in Europe than in the United States or elsewhere. CHIVA is unique among venous disease treatments in that it preserves rather than destroys superficial veins, attempting to restore healthy blood flow by correcting venous hypertension (Bellmunt-Montoya 2015; Mowatt-Larssen 2010; Gohel 2014; Franceschi 2016).

CHIVA accomplishes this with detailed duplex ultrasound scanning and pre-operative mapping of blood flow in the venous system. Then, precisely placed vein ligations (tying off) redirect blood flow into deeper veins, bypassing the superficial veins, and minimizing reflux. Another unique aspect of CHIVA is that rather than attempting to completely eliminate all reflux, as in other surgical methods, CHIVA’s goal is interruption of venous hypertension at its source, higher up in the venous system (Mowatt-Larssen 2010; Franceschi 2016).

Multiple studies have found the CHIVA method results in a low rate of recurrence, including when compared with surgical vein stripping and endovenous laser ablation, with comparable or superior clinical and cosmetic improvement. Compared with vein stripping, CHIVA is associated with fewer adverse effects including bruising and nerve injuries, less damage, and rapid recovery (Bellmunt-Montoya 2015; Zmudzinski 2017; Wang 2016).

Skin Substitutes

Skin substitutes made of synthetic or naturally-derived materials can help the healing of chronic wounds including venous ulcers. Skin substitutes provide a structural framework and biological factors that promote healing. They can be used as a complement to traditional wound care (Nathoo 2014).

Dermagraft is a skin substitute created from human fibroblast cells that are grown on a bioactive mesh scaffold material. Dermagraft is FDA approved for the treatment of diabetic foot ulcers, and has been studied for the treatment of venous leg ulcers (Hart 2012).

Dermagraft improved healing of venous ulcers when combined with compression therapy (Harding 2013; Omar 2004). In a multicenter, randomized, controlled trial in patients with venous leg ulcers, among those with ulcers of less than 12 months duration, significantly more of those treated with Dermagraft plus compression therapy were healed by week 12 than control participants treated with compression therapy alone (Harding 2013).

Dermagraft is fairly safe, though complications such as skin and bone infections have been reported (Nathoo 2014).

Apligraf is a bilayer skin substitute that blends viable human fibroblasts and skin cells with bovine collagen. It is FDA approved for venous ulcers of greater than one month duration that have not adequately responded to standard therapy, as well as diabetic foot ulcers of greater than one-month duration (Nicholas 2016; Nathoo 2014).

Treatment with Apligraf plus compression therapy has been shown to be superior to compression alone, particularly in the healing of larger and deeper ulcers. Apligraf is also more effective for ulcers present for more than six months duration (Nicholas 2016; Zaulyanov 2007; Falanga 1998).

EpiFix is a skin substitute composed of dehydrated human membranes along with their epithelial cells, which exhibit stem cell-like features (Nicholas 2016; Serena 2014). In a randomized controlled clinical trial, leg ulcers treated with EpiFix in addition to multilayer compression therapy had an average reduction in size over four weeks of 48.1% compared with 19% for those treated with compression only (Serena 2014).

EpiFix’s ability to recruit stem cells to the ulcer site is one potential mechanism for its clinical effect. These adult stem cells play an important role in the maintenance and repair of wounded tissue (Massee 2016).

“Spray-On Skin” Cell Therapy

A spray-applied cell therapy consisting of a mixture of human skin cells and proteins may help heal chronic venous leg ulcers without the use of skin grafts (Kirsner 2012).

In a randomized controlled trial, researchers applied one of two different strength formulations of human keratinocytes and fibroblasts derived from human skin to patients’ venous ulcers every 7 or 14 days for 12 weeks. Patients in the treatment groups had a significantly greater average reduction in wound area compared with patients in the placebo group. Adverse effects were similar between the groups (Kirsner 2012). In a 24-week follow-up study, the authors concluded that the benefit of this treatment persisted for several weeks beyond the last application (Kirsner 2013).

Sulodexide

Sulodexide is a highly purified complex of glycosaminoglycans (naturally occurr ulcers. Sulodexide reduces the formation of blood clots and has anti-inflammatory properties (Wu 2016; Eberhardt 2014; Coccheri 2014).

Clinical studies have shown that sulodexide promotes healing of venous ulcers, improves symptoms, and is safe and well tolerated when used alongside local wound care (Wu 2016; Andreozzi 2012). Other evidence suggests sulodexide may reduce the risk of blood clot recurrence in people with a history of venous thromboembolism (Shaydakov 2016; Andreozzi 2015).

Although available in some countries in Europe, South America, and Asia, sulodexide is not approved for use in the United States (Pullen 2011).

Oxerutin. Oxerutin (hydroxyethylrutosides) is a standardized mixture of semisynthetic flavonoids derived from rutin, a naturally occurring flavonoid (Aziz 2015; Firuzi 2011).

Oxerutin is commonly used in Europe in the treatment of venous disorders. Multiple clinical trials have demonstrated that oxerutin reduces edema and pain associated with venous disease (Wadworth 1992; Petruzzellis 2002; Eberhardt 2014).

These benefits of oxerutin have been attributed to an ability to reduce excessive permeability (leakage of fluid) of veins, which can result in edema, and to an improvement in venous blood circulation (Rabe 2013; Yildiz 2016).

Avoid Prolonged Sedentary Periods and Exercise Regularly

Physical activity—even small amounts—encourages return of venous blood from the legs back to the heart by activating the pumping action of the musculature (Bergan 2006). In contrast, standing or sitting for long periods can cause elevated pressure in the veins, which may contribute to the development of varicose veins (NIH 2014c; Scherger 2012). In a randomized controlled trial, increased physical activity consisting of leg exercises and walking significantly improved wound healing in patients with venous leg ulcers (Heinen 2012). Suggestions for avoiding prolonged sedentary periods include:

• Breaking from standing or sitting as often as possible to move the legs. The Centers for Disease Control and Prevention recommends standing and walking at least every two to three hours to help prevent deep vein thrombosis (CDC 2017).
• Flexing ankles frequently at work and during long car or plane trips. Avoid crossing legs while sitting. Of note, extended air travel is often thought to increase risk of venous thrombosis. However, any extended travel, not just by plane, is associated with increased venous thrombosis risk. There are no factors unique to air travel that influence blood clotting to any greater degree than other forms of travel that entail extended sitting; indeed, the term “travelers’ thrombosis” has been proposed by the Aerospace Medical Association’s Air Transport Medicine Committee in attempt to eliminate the misconception that flying uniquely increases risk. Therefore, prolonged sitting during travel, or any other setting for that matter, should be avoided if possible. Travelers should stand frequently and walk or exercise their legs if their surroundings permit it (Johnston 2014).
• Elevating legs when lying down or sleeping.
• Raising legs above heart level whenever possible (Fort 2017a; NIH 2014c; Scherger 2012).

Avoid Tight Clothing and Restrictive Footwear

Tight clothes, especially around the waist and upper thighs, can exacerbate varicose veins. Wearing shoes with lower heels can strengthen calf muscles, which promotes better blood flow through the veins (NIH 2014c).

Maintain a Healthy Weight

Being obese or overweight increases the risk of chronic venous disease and varicose veins (Fort 2017b; Eberhardt 2014; NIH 2016; Danielsson 2002). Weight loss reduces pressure on leg veins and improves blood circulation. It also increases energy, mobility, and overall health and wellness (NIH 2014c; Fort 2017b; Scherger 2012).

Eat a High-Fiber Diet

A diet lacking in fiber may be associated with small, hard stools and the need to strain to have a bowel movement. Straining during bowel movements increases intra-abdominal pressure that contributes to increased pressure in the veins of the legs. Ultimately, chronic straining resulting from a low-fiber diet can weaken vein walls and lead to varicose veins (MacKay 2001).

A high-fiber diet can help prevent varicose veins by producing soft, well-formed stools to ease bowel movements and eliminate chronic straining (MacKay 2001). Greater intake of dietary fiber also reduces the risk of cardiovascular disease (Threapleton 2013).

Primary Support

Diosmin. Diosmin is a naturally occurring flavonoid found in many plants, primarily citrus fruits. Diosmin, a phlebotonic, improves vein integrity and reduces inflammation and risk of blood clotting; it also promotes lymphatic drainage (Gohel 2009; Gohel 2010; MacKay 2001). Diosmin comprises 90% of the European drug Daflon, which is one of the most studied preparations for the treatment of varicose veins and chronic venous disease (Szymanski 2016; Gohel 2009; MacKay 2001).

A 2016 review and analysis of randomized controlled trials found that a 90% diosmin preparation significantly reduced leg and ankle edema and lower leg pain (Martinez-Zapata 2016). In another analysis of five randomized controlled trials involving over 700 subjects with venous ulcers, treatment with the diosmin preparation combined with conventional therapy increased the chances of ulcer healing by 32% at six months compared with conventional therapy alone (Coleridge-Smith 2005).

Numerous animal and clinical studies have established that the diosmin-containing preparation micronized purified flavonoid fraction, which is the preparation used in most studies, is safe and well tolerated. Adverse effects are rare and usually mild, and there are no contraindications to its use (MacKay 2001).

Clinical practice guidelines issued by the Society for Vascular Surgery and the American Venous Forum endorse the use of diosmin. Diosmin is recommended in conjunction with compression therapy to treat pain, swelling, and ulcers due to chronic venous disease (Gloviczki 2011).

Horse chestnut seed extract (Aesculus hippocastanum). Horse chestnut seed extract (Aesculus hippocastanum) is a traditional herbal remedy for swelling and inflammation used extensively in Europe to treat venous disorders. A review and analysis of randomized controlled trials concluded that horse chestnut seed extract is an effective and safe short-term treatment for chronic venous insufficiency (Pittler 2012; Yu 2013; AMR 2009).

The benefits of horse chestnut seed extract in chronic venous insufficiency have been attributed to anti-inflammatory and anti-edema properties. Horse chestnut seed also improves the tone of vein walls, resulting in improved blood flow and decreased blood congestion in the venous system (Dudek-Makuch 2015).

While horse chestnut seed extract contains flavonoids such as quercetin and proanthocyanidins, most of its benefit in venous disorders is attributed to its main active component, escin (Dudek-Makuch 2015; AMR 2009).

In a review of 17 randomized controlled trials, supplementation with horse chestnut seed extract in people with chronic venous insufficiency resulted in marked improvement in leg pain, swelling, and itching. Horse chestnut seed extract compared favorably to compression stockings for treatment of leg pain. Adverse effects were mild and infrequent (Pittler 2012).

Pycnogenol. Pycnogenol is a standardized extract of French maritime pine bark. Clinical studies have shown that pycnogenol improves symptoms of chronic venous insufficiency, promoting healing of venous ulcers and reducing leg edema and the risk of blood clots during long flights (Gulati 2014; Toledo 2017). Pycnogenol has strong anti-inflammatory, vasodilating and anti-clotting properties, which are due largely to active constituents called procyanidins (Gulati 2014). Supplementation with pycnogenol in early stages of varicose veins may slow progression to chronic venous insufficiency (Belcaro 2014).

In one study, supplementation with pycnogenol at 100 mg/day for eight weeks reduced venous leg edema by 40% (Belcaro 2015). In another trial, 150 mg per day of pycnogenol for eight weeks reduced a composite score by nearly 24%; the score included edema, pain, restless limbs, and skin changes and redness associated with venous insufficiency (Cesarone 2006).

Nattokinase. Chronic venous disease increases the risk of a blood clot in a deep leg vein; this is known as deep vein thrombosis (Shaydakov 2016). Nattokinase, a protein-digesting enzyme extracted from natto, a traditional Japanese food made from fermented soybean, has been shown in several laboratory studies to reduce the risk of blood clot formation and break up existing blood clots (Kurosawa 2015; Xu 2014; Jang 2013; Chandrasekaran 2015; Fujita 1995; Sumi 1990).

Nattokinase works in part by directly degrading fibrin, the fibrous protein that forms the matrix of blood clots. It also breaks down fibrinogen, the protein precursor to fibrin, and other clotting factors, while increasing concentrations of anti-clotting factors (Kurosawa 2015; Jang 2013; Rottenberger 2013; Dabbagh 2014).

In a clinical trial, oral ingestion of nattokinase for two months significantly reduced plasma levels of the clotting factors fibrinogen, factor VII, and factor VIII—all risk factors for cardiovascular disease. Nattokinase treatment was safe and similarly effective in both healthy volunteers and patients with cardiovascular disease (Hsia 2009). In another study, a single dose of nattokinase (2000 fibrinolytic units) significantly increased the breakdown of fibrin and fibrinogen and enhanced anti-coagulation activity in the blood of healthy male subjects (Kurosawa 2015).

Centella asiatica. Centella asiatica (C. asiatica), also called Gotu kola, is a tropical plant with a long history of use as a traditional medicine in Southeast Asia. C. asiatica is rich in carotenoids and vitamins C and B complex (Chandrika 2015; MacKay 2001). A rigorous review of randomized controlled clinical trials found evidence that C. asiatica likely exerts beneficial effects on the signs and symptoms of chronic venous insufficiency (Chong 2013).

Natural plant compounds called triterpenes are important constituents of C. asiatica. Animal studies have shown that triterpenes derived from C. asiatica exhibit anti-inflammatory and antibacterial activity. These compounds also promote wound healing by stimulating synthesis of collagen and the formation of new blood vessels (angiogenesis) (Chandrika 2015; Chong 2013).

In a randomized controlled trial in patients with venous hypertension, C. asiatica extract significantly improved edema-related symptoms in patients with venous hypertension as well as ankle edema (De Sanctis 2001).

In another randomized controlled trial in 94 patients with venous insufficiency, treatment with an extract of C. asiatica significantly reduced edema and heaviness in the legs. In addition, C. asiatica treatment resulted in markedly better overall self-evaluation of symptoms by the patients. C. asiatica also improved the capacity of veins to stretch or dilate (Pointel 1987).

Additional Support

Vitamin E. Vitamin E is a fat-soluble vitamin and free radical scavenger (Higdon 2015). Studies have shown that vitamin E inhibits blood clots, which are a potential complication of chronic venous disease (Murohara 2004; Eberhardt 2014).

In the Women’s Health Study that followed nearly 40 000 women, 600 IU of supplemental vitamin E on alternate days, over approximately 10 years, reduced the risk of venous thromboembolism by 21% and pulmonary embolism by 28% compared with placebo. In women genetically predisposed to venous thromboembolism, vitamin E supplementation was even more protective, cutting the risk by about half (Glynn 2007).

Grape seed extract. Proanthocyanidins, active components of grape seeds, inhibit enzymes that degrade collagen and elastin, which provide structure and resilience to blood vessel walls (Wali 2002). This activity of proanthocyanidins may play a role in their efficacy in enhancing vascular function and circulation (MacKay 2001).

In a double-blind study in patients with peripheral venous insufficiency, symptoms were significantly reduced in 75% of participants who received 300 mg of grape seed proanthocyanidins daily. Another study reported increased venous tone in patients with extensive varicose veins following a single administration of 150 mg proanthocyanidins (MacKay 2001).

Vitamin C. Vitamin C is an important scavenger of free radicals that also contributes to venous dilation. Vitamin C is necessary for the synthesis of collagen, a crucial structural protein in blood vessels; and vitamin C has an important role in wound healing. Vitamin C deficiency leads to degradation of collagen-rich connective tissue in blood vessel walls (Calderon Mdel 2015; Kishimoto 2013; Grossmann 2001; Wali 2002; May 2013).

In one study, plasma levels of vitamin C were lower in patients with chronic leg ulcers than in patients without leg ulcers (Lazareth 2007). In another study in patients with venous ulcers, supplementation with 500 mg of vitamin C and topical application of a type of antimicrobial honey resulted in complete healing of all ulcers (Sherlock 2010; Calderon Mdel 2015).

Butcher’s broom (Ruscus aculeatus). Extracts of the herb butcher’s broom (Ruscus aculeatus) have been used traditionally to treat varicose veins, and contemporary scientific research helps explain the mechanisms behind this efficacy (MacKay 2001; AMR 2001).

The primary active constituents of butcher’s broom are compounds called ruscogenins. Ruscogenins from extracts of butcher’s broom inhibit elastase enzymes, which degrade the elastin protein that imparts flexibility to veins. Butcher’s broom also reduces vascular permeability, which contributes to edema (AMR 2001; Scallan 2010).

Several controlled clinical trials have found that butcher’s broom improved venous function and reduced symptoms of chronic venous insufficiency including itching, cramping, and swelling (AMR 2001; MacKay 2001).

Standardized red vine leaf extract (AS 195). Red vine leaf extract is derived from the leaves of the wine grape plant (Vitis vinifera). It contains activated forms of quercetin, the powerful flavonoid present in many plants. Clinical trials in patients with chronic venous insufficiency have found that red vine leaf extract (AS 195) reduces leg edema, enhances blood flow, and improves symptoms such as pain and sensation of heaviness and swelling (Stucker 2016; Rabe 2013; Rabe 2011; Fernandes 2013).

The anti-inflammatory properties of red vine leaf flavonoids are believed to be responsible for much of the clinical benefit of red vine leaf extract, including the normalization of venous permeability (Stucker 2016; Rabe 2013). Red vine leaf extract (AS 195) appears to increase production of nitric oxide, a potent vasodilator, and decrease oxidative stress, contributing to improved circulation (Grau 2016; Shu 2015).