INTRODUCTION — Venous hypertension is associated with histologic and ultrastructural changes in the capillary and lymphatic microcirculation that produce important physiologic changes, which include capillary leak, fibrin deposition, erythrocyte and leukocyte sequestration, thrombocytosis, and inflammation. These processes impair oxygenation of the skin and subcutaneous tissues. The clinical manifestations of severe venous hypertension and tissue hypoxia are edema, hyperpigmentation, subcutaneous fibrosis, and ulcer formation.
The medical management of chronic venous disease with and without ulceration is discussed here. The etiology, presentation, and pathophysiology of chronic venous disorders are discussed elsewhere:
●(See "Classification of lower extremity chronic venous disorders".)
●(See "Clinical manifestations of lower extremity chronic venous disease".)
●(See "Pathophysiology of chronic venous disease".)
●(See "Diagnostic evaluation of lower extremity chronic venous insufficiency".)
OVERVIEW — Treatment goals for patients with chronic venous disease include improvement of symptoms, reduction of edema, prevention and treatment of lipodermatosclerosis (picture 1), and healing of ulcers [1,2]. An algorithm for the medical management of venous insufficiency is based upon available data and published recommendations (algorithm 1) [3-5].
Therapies enhancing venous flow (eg, limb elevation, exercise, and compression therapy) improve oxygen transport to the skin and subcutaneous tissues, decrease edema, reduce inflammation, and can be utilized for any patient with symptoms and signs of chronic venous disease. (See "Clinical manifestations of lower extremity chronic venous disease" and 'General measures' below and 'Compression therapy' below and "Compression therapy for the treatment of chronic venous insufficiency", section on 'Static compression therapy'.)
Patients with symptoms that are refractory to compression therapy or who are unable to tolerate compression therapy may benefit from systemic therapy. (See 'Pharmacologic therapy' below.)
Dry skin, itching, and eczematous changes are treated with various topical dermatologic agents. Contact dermatitis occurs not infrequently, so avoidance of topical products with common sensitizers is advised. (See 'Skin care' below.)
Venous ulceration is treated with a combination of ulcer wound management and compression therapy in the form of compression hosiery or compression bandaging systems. The treatment of chronic venous insufficiency with ulceration requires lifestyle changes to achieve treatment goals. An algorithm for medical management is based upon available data and published recommendations (algorithm 1). (See 'Compression therapy' below and 'Ulcer care' below and "Compression therapy for the treatment of chronic venous insufficiency", section on 'Static compression therapy'.)
Superficial vein ablation has been evaluated both for the treatment of venous ulcers and for prevention of recurrence. Surgery is thought to produce beneficial effects via reduction of venous reflux from the deep to the superficial veins by ablating or removing incompetent perforating and superficial veins, thereby modifying the effect of venous hypertension upon the cutaneous tissues [6]. The role of venous ablation therapy in the treatment of lower extremity chronic venous disease with or without ulceration is discussed separately. (See "Clinical manifestations of lower extremity chronic venous disease".)
GENERAL MEASURES — General measures to manage symptoms of chronic venous insufficiency include avoidance of prolonged standing, leg elevation, exercise, and appropriate skin care. These measures may be sufficient to relieve mild symptoms of chronic venous disease but alone are not likely to be adequate for more severe cases.
Leg elevation — Simple elevation of the feet to at least heart level for 30 minutes three or four times per day improves cutaneous microcirculation and reduces edema in patients with chronic venous disease. In one study of 15 patients with lipodermatosclerosis, leg elevation resulted in a 41 percent increase in blood flow velocity as measured by Doppler fluximetry [7]. Limb elevation also promotes healing of venous ulcers [7-9].
It may also not be practical for some people to elevate their legs several times per day because of the nature of their work. Elevation of the feet below the level of the heart, such as in a lounge chair, is ineffective for reducing venous hypertension.
Exercise — The efficiency of the calf muscle pump in pushing venous blood up the legs is usually impaired in patients with chronic venous insufficiency, contributing to the development and delayed healing of venous ulcers [10-12]. Moreover, physical activity in patients with chronic venous insufficiency and ulceration tends to be very limited. In one study, 35 percent of the patients did not have a 10-minute walk even once a week [13].
Daily walking and simple ankle flexion exercises while seated are inexpensive and safe strategies in the management of chronic venous disease. Several small studies have shown improvement in hemodynamic parameters with simple calf muscle (plantar flexion) exercises [14-17]. In a meta-analysis of six trials, the addition of exercise to usual care (mostly compression) was associated with increased venous leg ulcer healing at 12 weeks [18-24]. The type of compression used was not specified for some studies. A combination of progressive resistance exercise (heel lifts) and prescribed physical activity (walking, treadmill, and/or cycling 30 minutes per day three times per week) appeared to be the most effective.
Skin care — Proper skin care includes skin cleansing and the use of emollients and/or barrier preparations to help maintain an intact skin barrier. Prevention of dryness and fissuring, and reducing itching and scratching, are important to prevent the development of skin ulceration.
●Stasis dermatitis — Stasis dermatitis manifests as a combination of pruritus, skin color changes due to hemosiderin deposition, erythema, and scaling and is often seen with advanced venous disease (Clinical-Etiology-Anatomy-Pathophysiology [CEAP] category 4 or higher). Itching may be intense, and sometimes blistering and oozing occurs. For areas of chronic dryness, a petroleum-based emollient can be used. Symptoms of oozing or vesiculation may require treatment of the involved areas with mid-potency topical corticosteroids. (See "Clinical manifestations of lower extremity chronic venous disease" and "Stasis dermatitis", section on 'Skin care' and "Topical corticosteroids: Use and adverse effects".)
●Contact dermatitis — Allergic contact dermatitis can develop from sensitization to a variety of products used in the treatment of stasis dermatitis and venous ulceration; thus, avoidance is the main preventive measure. (See "Irritant contact dermatitis in adults", section on 'Management' and "Management of allergic contact dermatitis".)
Contact sensitization occurs more readily in areas of stasis dermatitis. Contact dermatitis in patients with chronic venous insufficiency is common and may be difficult to diagnose without a high index of suspicion since it often mimics stasis dermatitis or cellulitis. Symptoms include redness, pruritus, and vesicle or bullae formation. The patient with contact dermatitis does not typically experience a dramatic clinical worsening but rather a failure to improve with treatment. Some patients develop an eczematous rash in other areas of the body, a form of "id" or autoeczematous reaction. Contact dermatitis may also be a direct trigger to development of an ulcer in patients with venous insufficiency [25]. The routine use of systemic or topical antimicrobials may also increase the incidence of contact dermatitis [26-28]. (See "Stasis dermatitis", section on 'Contact sensitization' and "Stasis dermatitis", section on 'Autosensitization'.)
COMPRESSION THERAPY — Static compression therapy is an essential component in the treatment of chronic venous disease [29-31]. Because venous disease and peripheral artery disease (PAD) commonly coexist, it is important to evaluate the pedal pulses prior to prescribing compression therapy. For patients with evidence of moderate to severe PAD (ankle-brachial index ≤0.6), referral for vascular evaluation is appropriate. (See 'Indications for Referral' below and "Noninvasive diagnosis of upper and lower extremity arterial disease", section on 'Ankle-brachial index'.)
The options, characteristics, and choice of compression hosiery or compression bandages, and in particular their use in the treatment of chronic venous insufficiency, are reviewed elsewhere. (See "Compression therapy for the treatment of chronic venous insufficiency".)
Efficacy and choice of compression
Superficial venous insufficiency and varicose veins — Many patients with varicose veins report rapid symptomatic improvement with use of compression hosiery [32-34]. However, due to methodological shortcomings, there are few high-quality data that demonstrate the effectiveness of compression hosiery for managing superficial venous insufficiency or symptomatic varicose veins [35]. In clinical trials assessing the effectiveness of compression therapy, symptoms subjectively improved. In the absence of clinical data, if the patient tolerates wearing compression hosiery, most patients can determine within a short period of time if their symptoms are sufficiently controlled enough to continue therapy, or whether to seek additional treatment. Treatment algorithms in studies comparing various endovenous therapies typically use a threshold of three months of conservative management prior to offering treatment [36]. (See "Compression therapy for the treatment of chronic venous insufficiency", section on 'Compression hosiery' and "Approach to treating symptomatic superficial venous insufficiency".)
Deep venous insufficiency — Randomized trials have repeatedly demonstrated the benefits of long-term compression therapy (hosiery, multilayer compression bandage system) in patients with severe chronic venous disease associated with edema or venous stasis ulcers often due to deep venous insufficiency [31]. While active infections including cellulitis are contraindications to compression therapy, the incidence of recurrent cellulitis may be reduced for those who are compliant with compression therapy [37].
Issues related to the initial choice and application of compression therapy for the treatment of chronic venous insufficiency are discussed separately. (See "Acute cellulitis and erysipelas in adults: Treatment" and "Compression therapy for the treatment of chronic venous insufficiency", section on 'Choice of initial therapy'.)
ULCER CARE — Chronic venous ulcers are challenging to manage. In addition to providing appropriate compression therapy, local treatment of chronic venous ulcers includes using basic wound care techniques (debridement, dressings) that minimize infection and facilitate healing but also address problems that affect the patient's well-being, such as odor, bleeding, itching, excess exudate, and pain [38]. (See "Overview of treatment of chronic wounds", section on 'Local care of chronic wounds'.)
Role of systemic antibiotics — Systemic antibiotics should be used only in patients who have signs and symptoms of acute cellulitis or a clinically infected ulcer. There is no evidence to support the routine use of systemic antibiotics to promote healing in venous leg ulcers [39,40]. (See "Acute cellulitis and erysipelas in adults: Treatment".)
Routine swabbing of leg ulcers is unnecessary in the absence of signs of infection. Most venous ulcers are heavily contaminated with both gram-positive and gram-negative bacteria (Staphylococcus, Streptococcus, Escherichia coli, Proteus, Pseudomonas).
The routine use of antibiotics in uncomplicated ulcers does not reduce bacterial colonization or improve healing rates but can cause the emergence of resistant organisms [26-28]. In one study, routinely administered systemic antibiotics were associated with the development of resistant organisms in 94 percent of patients treated with ciprofloxacin, 12 percent treated with trimethoprim, and 4 percent receiving placebo [26].
Systemic antibiotics are reserved for patients who have one or more of the following signs and symptoms suggesting significant infection:
●Local heat and tenderness
●Increasing erythema of the surrounding skin
●Lymphangitis (red streaks traversing up the limb)
●Rapid increase in the size of the ulcer
●Fever
The presence of infection may impede wound healing. If infection is suspected clinically, a tissue specimen should be sent for gram stain, culture, and sensitivity to confirm infection (greater than 100,000 bacteria per gram of tissue) and to guide selection of antimicrobial therapy. The ulcer is irrigated to remove surface debris, and then a tissue specimen is obtained by biopsy from the base of the ulcer and sent for culture. Some practitioners inject sterile saline (1 to 2 mL) into the dermis surrounding the ulcer and then quickly withdraw the fluid, which is sent for culture.
Empiric treatment pending culture results should target gram-positive and negative organisms, including Pseudomonas. Methicillin-resistant Staphylococcus aureus (MRSA) is an important cause of soft tissue infections. (See "Methicillin-resistant Staphylococcus aureus (MRSA) in adults: Treatment of skin and soft tissue infections".)
Patients with rapidly progressing infections, particularly if associated with fever and other signs of systemic toxicity, should be hospitalized and receive intravenous antibiotics with broad coverage. Diabetics are more prone to develop rapidly progressive infections. (See "Necrotizing soft tissue infections" and "Acute cellulitis and erysipelas in adults: Treatment".)
Ulcer debridement — Wound debridement is an essential component of the management of venous ulcers. The presence of devitalized tissue increases the potential for local bacterial infection and sepsis, reduces wound healing rates, and reduces the effectiveness of topical therapies and systemic antibiotics. Removal of necrotic tissue and fibrinous debris in venous ulcers, using surgical, enzymatic, or biologic methods, aids in formation of healthy granulation tissue and enhances re-epithelialization. (See "Basic principles of wound management", section on 'Wound debridement' and 'Topical agents' below.)
In a systematic review that compared debridement of venous ulcers using various autolytic agents (three trials), hydrogel, Edinburgh University Solution of Lime (EUSOL), and biocellulose significantly increased the number of wounds completely debrided [41]. Reduction in wound size was assessed in one three-armed trial comparing cadexomer iodine to paraffin gauze (mean difference 24.9 cm², 95% CI 7.27-42.53) and hydrocolloid compared with paraffin gauze (mean difference 23.8 cm², 95% CI 5.48-42.12). No serious adverse events were reported in any trial. The small number of patients in each of these trials reduces the certainty of any benefit for these agents.
Use of a topical eutectic mixture of local anesthetics (EMLA) reduces the pain of venous ulcer debridement. A systematic review of six trials (343 participants) evaluated treatment with EMLA to manage pain associated with ulcer debridement. The between-group difference in pain measured on a 100 mm scale significantly favored the EMLA group (mean difference -20.65, 95% CI -29.11 to -12.19) [42].
Topical agents — A moist environment is essential for wound healing; however, ulcer healing rates are not improved with the use of most topical agents such as topical antiseptics, topical antibiotics, and growth factors [39,40]. Many topically applied products are irritating and can cause contact sensitization, or are cytotoxic, resulting in delayed healing. Current evidence does not support the routine use of honey [39,41,43]. (See 'Skin care' above.)
Traditional agents
●Cadexomer iodine – A systematic review found some evidence from four trials that topical application of cadexomer iodine enhances ulcer healing rates compared with standard care (with and without compression) (relative risk 2.17, 95% CI 1.3-3.6) [39]. The treatment regimen was complex, and it is unclear if the results are generalizable to most clinical settings. Iodine-induced hyperthyroidism has been documented with the use of cadexomer iodine for leg ulcers [44].
●Silver sulfadiazine – Silver sulfadiazine (eg, Silvadene) is a topical antiseptic cream with a long tradition in the treatment of cutaneous wounds including burns, partial-thickness wounds, and skin graft donor sites. It releases silver ions in concentrations that are toxic to bacteria and inhibits the growth in vitro of nearly all pathogenic bacteria and fungi, including some species resistant to sulfonamides. Silver sulfadiazine has been used in contaminated or infected wounds; however, it is messy to use and forms a pseudoeschar requiring removal prior to redressing the wound and may stain the skin. To address some of these issues, silver-containing dressings have become more popular than silver cream preparations due to their absorbent qualities and ease of use (see 'Ulcer dressings' below). Adverse effects associated with the use of silver sulfadiazine include induction of bacterial resistance and hypersensitivity, either as contact dermatitis or major allergic reaction (sulfa allergy). While little silver is absorbed through the wound, systemic toxicity is a theoretical concern in very large open wounds (eg, major burns) [45]. One systematic review concluded that there was insufficient evidence to support or refute the routine use of silver sulfadiazine for preventing infection or augmenting venous ulcer healing [46]. Another found no benefit [39].
●Other antiseptic agents – Studies of other topically applied antiseptics, including peroxide-based compounds, povidone-iodine, acetic acid, and sodium hypochlorite, are of poor quality, and definitive conclusions about their effectiveness cannot be made [39]. These topical antiseptics in vitro and in animal studies have cellular toxicities that exceed their bactericidal activities. For this reason, they should not be used [47-49].
Growth factors and cell-based therapy — Several growth factors play a role in wound healing, including platelet-derived growth factor, epidermal growth factor, fibroblast growth factors, transforming growth factors, and insulin-like growth factors. A few well-controlled randomized trials have assessed the use of growth factors in the healing of a variety of chronic diabetic and pressure ulcers and reported conflicting results [50-53]. In a study of chronic venous ulcers, topical application of human recombinant epidermal growth factor caused a greater reduction in ulcer size compared with placebo (7 versus 3 percent reduction) and resulted in a larger number of healed ulcers (35 versus 11 percent); this trial was small and the results were not statistically significant [54]. Epithelialization was not significantly affected.
Intradermal injections of granulocyte-macrophage colony stimulating factor (GM-CSF) appear to promote healing of chronic leg ulcers, including venous ulcers [55,56]. A randomized trial in 60 patients with venous ulcers found that four weekly injections with GM-CSF 200 mcg or 400 mcg led to significantly higher rates of healing compared with placebo at 13 weeks (57, 61, and 19 percent, respectively) [56]. The use of intradermal GM-CSF is limited by the pain from the injections.
A novel cell-based topical therapy consisting of growth-arrested keratinocytes and fibroblasts in a ratio of 1:9 (investigational drug HP802-247) and delivered to the wound surface via a fibrin spray vehicle has been used to treat wounds, including chronic venous ulcers [57-60]. The living cells are stored frozen and are rapidly thawed just prior to administration. A phase II trial randomly assigned 205 patients with chronic venous ulcers to one of four HP802-247 groups (two doses, two treatment intervals) or to the vehicle alone over a study period of 12 weeks [57]. All patients also received compression therapy. A significantly greater mean reduction in wound area was associated with active treatment in the 46 patients who received a dose of 0.5 ×106 cells/mL every 14 days (mean reduction 16 percent, 95% CI 5.56-26.41). Among 183/205 subjects available at 24 weeks follow-up, more patients previously treated with cells and entering follow-up with an open wound achieved closure compared with vehicle alone (43 percent [21/49] versus 35 percent [7/20]), while more patients treated with vehicle experienced reopening of a previously closed wound compared with those treated with cells (17 percent [3/18] versus 10 percent [11/106]), although these differences were not statistically significant [60]. A multivariate analysis found that wound duration and specific quantities of certain bacterial species affected wound healing in the vehicle group, while wound duration, wound area, wound location, and specific quantities of certain bacterial species influenced healing in the cell-treated groups. Age, sex, race, diabetes, HbA1C levels, peripheral neuropathy, and serum prealbumin did not significantly affect healing. Body mass index was positively associated with healing in cell-treated patients [61]. Additional studies are needed to define the role of this therapy to the treatment of chronic venous ulcers.
Ulcer dressings — Dressings are an important component of ulcer care. Dressings control exudate, maintain moisture balance, control odor, and help control pain [29]. Dressings also maintain an environment that facilitates epithelialization and speeds ulcer healing [62]. Options for dressing venous ulcerations include semipermeable adhesive films, simple nonadherent dressings, paraffin gauze, hydrogels, hydrocolloids, alginates, and silver-impregnated dressings or foams.
The relative advantages or disadvantages of the different dressing types depend upon ulcer characteristics, frequency of dressing changes, and cost [63,64]. The type of dressing used can be tailored to the characteristics of the ulcer. Dressings are characterized by their composition and properties (eg, adherence, absorbency, conformability) (table 1 and table 2) [64-67]. In practice, several different dressings are used during the course of caring for a venous ulcer. (See "Basic principles of wound management" and "Overview of treatment of chronic wounds".)
Although the utility of dressings to treat ulcers in general is clear, the specific dressing used does not significantly affect ulcer healing when compression therapy is also used [68].
●A systematic review of 42 trials evaluating the efficacy of various venous ulcer dressings including hydrocolloids, foams, alginates, and hydrogels, but not silver, found no evidence to support one dressing type over another [69].
●A network meta-analysis that included 78 trials reporting 40 direct comparisons assessed the probability of complete ulcer healing associated with alternative dressings and topical agents [63]. There was some evidence that silver dressings may increase the probability of venous leg ulcer healing, compared with nonadherent dressings (relative risk [RR] 2.43, 95% CI 1.58-3.74). These results must be interpreted in the context of overall low-quality evidence for the entire network.
●A review of five trials comparing various alginate dressings to each other, alginate dressings to hydrocolloid dressings, and alginate dressings to plain nonadherent dressings found no significant differences in the healing of venous leg ulcers between the various options [70].
●A systematic review of 12 trials (1023 patients) involving 14 comparisons of foam with other dressings found no differences in ulcer healing outcomes [71]. In a separate systematic review evaluating topical therapies, pain scores were significantly lower in patients treated with foam dressings releasing ibuprofen compared with local best practice (RR 1.63, 95% CI 1.24-2.15) [42].
●A systematic review of trials evaluated various silver-containing dressings in the treatment of venous ulcers; none of the trials identified were of high quality, and a variety of dressings were used as controls [72]. A pooled analysis found evidence for improved wound healing based on wound size reduction but no significant differences in rates of wound healing or completion of healing. In other trials of wound healing, in general, the use of silver dressings was associated with significantly decreased odor and leakage [73].
Wound coverage — Uncontrolled surgical trials and expert opinion support the role of skin grafting for very large venous ulcers or for ulcers present for more than 12 months [62]. (See "Overview of treatment of chronic wounds", section on 'Wound coverage/closure'.)
A systematic review of clinical trials determined that bilayer artificial skin in conjunction with compression bandages increases ulcer healing compared with compression and a simple dressing [74]. Human skin equivalents should not be thought of as an alternative to initial compression therapy for venous ulcers but may be considered in patients who do not respond to compression therapy.
Several human skin equivalents created from human epidermal keratinocytes, human dermal fibroblasts, and connective tissue proteins are available for the treatment of venous leg ulcers (eg, Apligraf, Dermagraft, Integra) [75-77]. The graft is fairly easily applied in an outpatient setting. (See "Skin substitutes".)
In a study of 293 patients with venous ulcers, compression therapy alone was compared with compression therapy plus treatment with a human skin equivalent [78]. The latter group demonstrated significantly improved wound healing as measured by the percentage of patients healed at six months (63 versus 49 percent) and the median time to wound closure (61 versus 181 days). In addition, the human skin equivalent was superior to compression therapy alone for healing larger (>1 cm2) ulcers, deeper ulcers, and ulcers of more than six months' duration. Adverse events were similar in both groups, the most common being wound infection, cellulitis, and pain.
Ineffective adjuncts to ulcer care
Hyperbaric oxygen — A systematic review of hyperbaric oxygen therapy in patients with chronic wounds found only one trial of 16 participants with venous ulcers [79]. A decreased wound size was found at six weeks, but no difference in wound size or number of ulcers healed was apparent at 18 weeks.
A subsequent trial analyzed complete ulcer healing of chronic nonhealing venous ulcers characterized by transcutaneous oxygen measurements indicative of a hypoxic wound [80]. Thirty-one patients were randomly assigned to hyperbaric oxygen therapy or sham treatment. At 12 weeks there was no significant difference between groups in complete ulcer healing.
Electromagnetic therapy — A systematic review identified three trials (94 patients) that compared the use of electromagnetic therapy with sham therapy; only two trials reported healing rates [81,82]. One trial (44 participants) found that more ulcers healed in the electromagnetic therapy group compared with the sham group, but the large number of patients lost to follow-up may have biased the results in favor of treatment. A second trial found no significant difference in the rate of ulcer healing, while a third trial (31 participants) reported reductions in ulcer size associated with electromagnetic therapy compared with the control, but differences in the prognostic characteristics may have accounted for the observed outcome.
Therapeutic ultrasound — A systematic review evaluated 11 trials to determine whether venous leg ulcers treated with ultrasound heal more quickly [83]. Whether therapeutic ultrasound (either high or low frequency) improved ulcer healing is uncertain due to inconsistency of the findings. One trial reported a greater percentage of patients experiencing a reduction in ulcer size at four weeks with high-frequency ultrasound whereas a second study reported no change at seven weeks. High-frequency ultrasound may be associated with more non-serious adverse effects and little difference to quality of life. Adverse effects, quality of life, and cost were not reported for low-frequency ultrasound treatment.
Ulcer healing and recurrence — The continued use of graduated compression hosiery after ulcer healing reduces recurrence, and patients should be offered the strongest compression (up to 40 mmHg) (table 3) with which they can comply [84,85]. In one study with 36 months follow-up, ulcers recurred in 100 percent of patients who were noncompliant versus 16 percent in those who were [86].
A systematic review identified four trials comparing ulcer recurrence rates for patients treated with compression hosiery versus no compression. One trial suggested that compression reduces venous ulcer recurrence compared with no compression [74]. Two trials compared high compression with moderate compression; one found no difference in ulcer recurrence after five years, while the other found lower recurrence rates at three years using high-compression hosiery.
Patients with ulcers that persist (present for more than six months) or who have recurrent ulcers should undergo venous duplex ultrasound to identify segments of venous incompetence amenable to vein ablation therapies. Patients have improved ulcer healing and lower rates of recurrence following venous ablation therapies with primary venous etiologies achieving more benefit compared with secondary etiologies (ie, post-thrombotic) [87]. (See "Overview of lower extremity chronic venous disease", section on 'With deep venous reflux' and "Approach to treating symptomatic superficial venous insufficiency", section on 'Persistent ulceration'.)
PHARMACOLOGIC THERAPY
Venoactive agents for treating resistant edema — For patients with resistant edema despite compression therapy or for patients with contraindications or intolerance of compression therapy, a variety of systemic agents that effect venous tone have been used [88-92]. Venoactive drugs are a heterogeneous group of agents of natural or synthetic origin including flavonoids, rutosides, and other less studied agents such as aminaphthone, calcium dobesilate, Centella asiatica (gotu kola), naftazone, and chromocarbe [88,93]. Most venoactive drugs have been shown to increase venous tone by a mechanism related to the norepinephrine pathway [91]. Other actions include reduction of capillary hyperpermeability, improved lymphatic drainage, anti-inflammatory effects, and decreased blood viscosity [92,94]. These agents may be useful for managing any class of venous disease. The use of these agents is variable around the world depending upon their availability and experience using them.
Available trials studying venoactive drugs are generally small but support their effectiveness for relieving venous edema and related symptoms such as extremity heaviness and pain [88,95]. In a Cochrane review, although these agents overall showed significantly beneficial effects for reducing edema and ankle circumference (mean difference -4.27 mm, 95% CI -5.61 to -2.93 mm; 15 studies), there were no differences in the proportion of ulcers healed compared with placebo [88]. Most studies evaluating these agents provide only low-quality evidence of benefit. As an example, only 28 percent of the studies included in the Cochrane review [88] provided standard diagnostic criteria for chronic venous insufficiency, and misclassification of disease is possible. The studies used different methods to identify signs and symptoms. The outcomes were not categorized by severity of disease. Importantly, most of these agents have been studied over relatively short durations, typically three months; thus, long-term efficacy and safety cannot be assured.
In the United States, some venoactive drugs are available without a prescription as dietary supplements. Concerns over accuracy of labeling, lack of standardization, and potential presence of undisclosed ingredients in dietary supplements sold in the US are reviewed elsewhere. (See "Overview of herbal medicine and dietary supplements", section on 'Quality'.)
Flavonoids include rutin, rutoside, diosmin and hidrosmin, disodium flavodate, pycnogenol, French maritime pine bark extract, grape seed extract, and various combinations of these. These agents appear to be safe when administered during pregnancy [96]. The most studied of these are reviewed briefly below.
Hydroxyethylrutoside — Hydroxyethylrutoside (HR; oxerutin) is well tolerated and effective at reducing leg volume, edema, and symptoms of chronic venous insufficiency [88]. It has been used in Europe for more than 30 years where standardized preparations are available (eg, Paroven) but is not available in the United States. HR is well tolerated for at least six months, even in older adults, but longer follow-up is not available [97,98].
HR is a standard mixture of semisynthetic flavonoids that act mainly upon the endothelium of the microvasculature to reduce permeability [98]. The efficacy of HR for the management of symptoms associated with chronic venous insufficiency was analyzed in a meta-analysis of 15 randomized placebo controlled trials involving over 1900 patients [99]. The HR group had a significantly higher response (disappearance of symptoms) in all categories examined, including pain (38 versus 27 percent with placebo), cramps (38 versus 26 percent), tired legs (34 versus 22 percent), swelling (49 versus 35 percent), and restless legs (50 versus 26 percent).
In one study, 75 percent of patients achieved a positive response with HR, which was superior to horse chestnut seed extract (HCE) [100]. In a second study, the combined treatment of compression hosiery and HR was superior to compression hosiery plus placebo in the reduction of leg volume; similar to HCE, the treatment effect was noted for six weeks after withdrawal of the active drug [101]. However, the effectiveness of HR for the treatment of venous ulcers has been equivocal [98]. A systematic review of randomized trials concluded that while use of flavonoids was associated with an increased number of healed ulcers, this result needed to be interpreted cautiously, as most of these trials were subject to a risk of bias in favor of treatment [102].
Escin (horse chestnut seed extract) — HCE at a dose of 300 mg (standardized to 50 mg of escin [aescin], the active compound) twice daily may be used in patients unable or unwilling to use compression, or for those in whom compression is contraindicated (eg, occlusive arterial disease). HCE reduces leg volume and edema in patients with chronic venous insufficiency [100,103]. In the United States it can be purchased without a prescription as a dietary supplement, but its purity and standardization cannot be guaranteed. An herbal monograph for HCE is available from the European Medicines Agency (EMA) [104].
HCE stimulates the release of F series prostaglandins (eg, PGF2-alpha), which induce venoconstriction, decreasing the permeability of vessel walls to low molecular proteins, water, and electrolytes [105].
Several placebo controlled trials and at least two meta-analyses have concluded that HCE improves symptoms related to chronic venous insufficiency when compared with placebo [100,103,106-108]. In one study, HCE at a dose of 50 mg of escin twice daily not only was superior to placebo, it was equivalent to compression hosiery for reducing leg volume and edema [103]. Adverse effects are usually mild and infrequent.
Micronized purified flavonoid fraction (MPFF) — Micronized purified flavonoid fraction (MPFF; Daflon, Detralex) is a mixture of diosmin and hesperidin, two flavonoids that are micronized to increase absorption [94]. In the United States, a formulation of MPFF is available (diosmiplex) that is categorized as a medical food and not as a drug [94]. Given the beneficial effects and few side effects associated with these agents, a therapeutic trial can be considered where these agents are available.
MPFF may be useful as an adjunct to compression therapy to improve healing of ulcers, with the greatest impact on ulcers ≤10 mm, edema, trophic changes, and many subjective symptoms of chronic venous insufficiency [94,95,109-111]. In a meta-analysis of five trials, compared with placebo, MPFF significantly reduced leg symptoms (eg, pain, heaviness, cramps, paresthesias). MPFF also reduced ankle circumference and leg redness and improved skin changes and quality of life [110]. In an earlier review, seven trials evaluated the efficacy of MPFF for healing venous ulcers [109]. Patients were allocated to usual care (compression and local ulcer care) or usual care plus MPFF, two 500 mg tablets daily. The overall rate of ulcer healing at six months was significantly higher in the MPFF group compared with usual care (61.3 versus 47.6 percent), and time to healing was less (16 versus 21 weeks). Compared with other venoactive drugs, MPFF may reduce lower extremity edema to a greater extent. In a meta-analysis of 10 trials, mean ankle circumference was reduced by -0.80 cm for MPFF but -0.58 cm and -0.20 cm for hydroxyethylrutoside and diosmin alone, respectively [95].
The safety of these drugs during pregnancy and lactation has not been established. According to the MPFF product information in Europe, animal data are reassuring and adverse effects in human pregnancy have not been reported [112-114].
Antithrombotic agents for treating resistant ulcers
●Aspirin — Aspirin has been recommended as an inexpensive, universally available therapy for healing of venous ulcers, reduction in healing time, or reduction in ulcer size. Randomized trials and systematic review have not been supportive of earlier studies [115-118]. As such, there is no support for the use of aspirin with the aim of improving healing of venous ulceration, or at best there is insufficient evidence to detect either a beneficial effect or even harm associated with aspirin therapy.
●Stanozolol — Stanozolol (stanazol), an oral anabolic steroid, stimulates blood fibrinolysis and has been evaluated for the treatment of the more advanced skin changes associated with lipodermatosclerosis. Several randomized trials noted improvement in the area of lipodermatosclerosis, reduced skin thickness, and possibly faster ulcer healing rates with stanozolol [119,120].
●Pentoxifylline — A number of trials have studied the effect of pentoxifylline (varying doses), with or without adjunctive compression therapy, in patients with venous ulcers [121,122]. A meta-analysis evaluated 11 trials of variable quality; pentoxifylline was significantly more effective for complete or partial ulcer healing than placebo or no treatment (relative risk 1.7, 95% CI 1.3-2.2) [121]. Pentoxifylline used as an adjunct to compression was more effective than medication without compression. When used without compression, it was more effective than placebo or no treatment at a dose of 800 mg three times a day [123]. Gastrointestinal side effects (nausea, indigestion, diarrhea) were relatively common in patients treated with pentoxifylline.
●Prostacyclin analogues — The synthetic analogue of prostacyclin, iloprost (carboprostacyclin, given parenterally at 0.5 to 2 ng/kg per min), is a potent vasodilator that inhibits platelet aggregation and adhesion, increases red blood cell deformability, alters neutrophil function (including free radical production) and capillary permeability, and may help repair damaged endothelium [124]. In a single randomized trial, intravenous infusion of iloprost compared with saline in a three-week protocol increased the rate of ulcer healing and the percentage of patients with resolution of their lower extremity ulcers (100 versus 84 percent at 150 days) [125]. Intravenous iloprost is not available in the United States.
●Sulodexide — Sulodexide is a highly purified glycosaminoglycan that is available in Europe and other parts of the world but not the United States. It has antithrombotic and profibrinolytic activity related to its affinity for antithrombin III and heparin cofactor II, among other pharmacologic effects [126]. A meta-analysis of three trials suggested that an increase in the proportion of ulcers completely healed with sulodexide as an adjuvant to local treatment (including wound care and compression therapy) compared with local treatment alone (49.4 versus 29.8 percent) [89]. In the largest of the trials, which included 230 patients, ulcers most likely to heal with sulodexide were smaller than 10 cm2 and of relatively recent onset (up to 12 months) [127]. These findings suggest that, where available, sulodexide may be an effective adjunct to local wound therapy. The mechanism by which it affects ulcer healing in patients with venous insufficiency is not clear but may be related to its effects on leukocyte-platelet activation and its antithrombotic, profibrinolytic, and fibrinogen-lowering properties.
●Defibrotide — Defibrotide is a deoxyribonucleic acid derivative with antithrombotic and profibrinolytic properties that has been studied more in the context of superficial and deep vein thrombosis [128,129]. In a trial involving 288 patients with ultrasound-confirmed deep venous insufficiency, all patients were treated with adequate elastic compression and randomly assigned to receive oral defibrotide (800 mg/day) or placebo. Patients with active or prior leg ulcer were excluded. Ankle circumference was significantly reduced with defibrotide from day 120 through the end of the study (day 360). The number of episodes of superficial and deep vein thrombosis was significantly lower for defibrotide compared with placebo (2 versus 10). The majority of these events occurred in the subset of patients with documented prior deep vein thrombosis.
INDICATIONS FOR REFERRAL — Patients with chronic venous insufficiency who are not responding to medical management strategies (one to three months) should be referred to a venous specialist for further evaluation and possible intervention. Many patients with deep venous insufficiency and/or superficial venous insufficiency can be treated using venous ablation therapies, which reduce ulcer recurrence and may improve ulcer healing. The United Kingdom Early Venous Reflux Ablation (EVRA) trial provided support for early (within two weeks versus once the ulcer has healed) endovenous ablation of superficial venous reflux in addition to compression therapy and appropriate wound care [130,131]. Early intervention reduced time to ulcer healing and more patients healed their ulcers. Thus, sooner rather than later referral to a venous specialist for patients with a venous ulcer is appropriate and from EVRA is likely to be cost effective. (See "Approach to treating symptomatic superficial venous insufficiency".)
Chronic or recalcitrant edema or ulceration presumed to be venous that are unresponsive to appropriate management should also be evaluated for other etiologies and contributing factors.
Specialty referral (eg, vascular, dermatology, other) is recommended for the following problems [29]:
●Arterial insufficiency
●Nonhealing ulcers
●Ulcer recurrence
●Persistent stasis dermatitis
●Suspected contact dermatitis
●Resistant or recurrent cellulitis
●Diagnostic uncertainty
SOCIETY GUIDELINE LINKS — Links to society and government-sponsored guidelines from selected countries and regions around the world are provided separately. (See "Society guideline links: Chronic venous disorders".)
INFORMATION FOR PATIENTS — UpToDate offers two types of patient education materials, "The Basics" and "Beyond the Basics." The Basics patient education pieces are written in plain language, at the 5th to 6th grade reading level, and they answer the four or five key questions a patient might have about a given condition. These articles are best for patients who want a general overview and who prefer short, easy-to-read materials. Beyond the Basics patient education pieces are longer, more sophisticated, and more detailed. These articles are written at the 10th to 12th grade reading level and are best for patients who want in-depth information and are comfortable with some medical jargon.
Here are the patient education articles that are relevant to this topic. We encourage you to print or e-mail these topics to your patients. (You can also locate patient education articles on a variety of subjects by searching on "patient info" and the keyword(s) of interest.)
●Basics topics (see "Patient education: Varicose veins and other vein disease in the legs (The Basics)")
●Beyond the Basics topics (see "Patient education: Lower extremity chronic venous disease (Beyond the Basics)")
SUMMARY AND RECOMMENDATIONS
●Manifestations of chronic venous disease – Chronic venous disorders are common. Symptoms include pain and/or lower extremity heaviness that typically worsen as the day progresses. Clinical signs include mild venous dilation, varicose veins, swelling, skin changes, or ulceration. (See 'Overview' above.)
●General measures – General measures are appropriate for patients with any disease severity and include (see 'General measures' above):
•For all patients with chronic venous symptoms, we suggest leg elevation (when possible), leg exercises (ankle flexion, walking) to increase calf muscle strength, and compression hosiery (Grade 2C). (See 'Compression therapy' above.)
•For patients who are unable to tolerate, are not compliant with, or in whom compression therapy is contraindicated (eg, occlusive arterial disease), we suggest horse chestnut seed extract (Grade 2B). A typical dose is 300 mg (standardized to 50 mg of escin) twice daily. (See 'Escin (horse chestnut seed extract)' above.)
•Dry skin, itching, and eczematous changes are treated with moisturizers and, if needed, a mid-potency topical corticosteroid. We avoid using topical products with common sensitizers (eg, lanolin, neomycin, nickel). (See 'Skin care' above.)
●Severe chronic venous insufficiency – Severe chronic venous insufficiency includes manifestations that may include severe edema, weeping, eczema, ulceration, or recurrent episodes of cellulitis. Venous ulceration is managed with wound debridement, as needed, barrier creams to protect adjacent skin, and wound dressings tailored to the environment of the wound (eg, absorbent dressings for weeping wounds). (See 'Ulcer care' above.)
•For most patients with severe chronic venous insufficiency, we recommend compression therapy (Grade 1B). Compression hosiery or compression bandaging systems (elastic or nonelastic) can be used. When choosing compression bandages, we suggest multilayered compression bandages rather than single-layer bandages (Grade 2B). However, multilayered compression bandages are more costly. (See 'Efficacy and choice of compression' above.)
•Patients with slowly healing ulcers, persistent dermatitis, or resistant or recurrent cellulitis should be referred to the appropriate subspecialist (algorithm 1). (See 'Indications for Referral' above.)
ACKNOWLEDGMENT — The editorial staff at UpToDate acknowledges Patrick C Alguire, MD, FACP, who contributed to an earlier version of this topic review.
