Treatment of Chronic Venous Disorders

Chronic venous disease (CVD) of the lower extremity is one of the most common chronic diseases in western Europe and the United States. The manifestations of CVD vary and include telangiectasias, enlarged reticular veins, varicose veins, lipodermatosclerosis, lower extremity pain and swelling, and venous ulcers. Its prevalence reported in studies from different countries ranges from 2% to 56% in men and 1% to 60% in women. ^, In the Edinburgh Vein Study from the UK, varicose veins were present in 40% of men and 16% of women, ankle edema was found in 7% of men and 16% of women, and ulcers were seen in 1% of men and women. In the same study, the incidence of superficial vein reflux was noted to be 9.4% in men and 6.6% in women, and to increase with age. A follow-up examination of patients from Edinburgh Vein Study 13 years later (13 ± 0.4 years [mean ± SD]), which included CVD reclassification to ascertain progression of development of venous pathophysiology and/or increase in severity of symptoms, found progression in 57.8% of cases (annual equivalent increase of 4.3%) and increase in symptoms in 31.9% of cases. The study also demonstrated that superficial venous reflux was a predictor for increased likelihood of progression, especially with co-existing deep venous reflux (Odds Ratio [OR], 2.57; 95% Confidence Interval [CI], 1.55–4.25) and when located in the small saphenous vein (OR, 4.73; 95% CI, 1.37–16.39), emphasizing the value of early treatment.

In the United States it is estimated that approximately 25% and 15% of women and men, respectively, have CVD symptom(s) and approximately 1% to 4% of the adult population is affected by more advanced stages of the disease including chronic, nonhealing venous ulcers (Class C6; Clinical Severity, Etiology or Cause, Anatomy, Pathophysiology [CEAP] classification). When disease progresses to the advanced stages and venous ulceration develops, it not only significantly reduces patients’ quality of life (QoL) but also imposes a significant economic burden on society related to increased direct healthcare costs and decreased productivity. ^, The estimated annual healthcare cost in the USA alone for the management of venous ulcers is between $1.9 and $3 billion with the greatest burden on the Medicare system. ^, These costs do not include decreases in mobility and work capacity, patients’ out-of-pocket expenses, and treatment of adverse psychologic effects related to venous ulcers. It should also be emphasized that CVD is increasing in prevalence as a result of increasing life expectancy in general and aging of the “baby boomer” generation; subsequently its impact on healthcare will likely become even more significant. A recent review from 2019 showed that CVD represents a growing economic burden and that estimated global market for varicose veins treatment alone in 2021 will increase approximately 35% when compared to 2016, with respective values of US $396 million and $290.59 million. Market analysis performed by The Millennium Research Group projected that total cost for treatment of varicose veins will reach approximately $8 trillion by the year 2021.

Whereas the invasive treatment of CVD includes surgical (high ligation of the saphenofemoral junction, saphenous vein stripping, stab phlebectomies), endovascular procedures (saphenous vein thermal and non-thermal techniques) and/or percutaneous stenting for iliac outflow venous obstruction, the initial treatment of CVD has traditionally been nonoperative, with the main goals of symptom control and QoL improvement. In addition, conservative measures are currently mandated by most third-party payers in the United States before approval of therapeutic surgical interventions. In this setting, the success of conservative management has long been considered to be a contraindication to more definitive surgical treatments. However, a QoL analysis from Lurie and Kistner questions the validity of this approach. In this study, the authors compared the outcomes of surgical therapy in patients with favorable and unfavorable responses to initial conservative management using the Specific QoL and Outcomes Response–Venous questionnaire. Patients who improved with conservative therapy and who elected to proceed with surgical correction were 15 times more likely to improve with surgery at 1 month and 21 times at 12 months of follow-up, compared with those who did not improve with conservative therapy. The authors concluded that conservative therapy should be used as a benchmark to predict success after surgical therapy, rather than as a contraindication to definitive intervention.

Nonoperative Treatment of CVD

The nonoperative approach to patients with CVD includes lifestyle modification, compression, and pharmacologic therapies.

Lifestyle Modification

The most common initial recommendations for lifestyle modification in patients with CVD are moderate exercise, leg elevation, and weight loss.

Exercise

In a review of literature, Brown concluded that although vigorous exercise may increase the likelihood of venous ulcerations, increased mobility and moderate physical activity may be beneficial for ulcer healing and may be an adjunct to compression therapies. In 2019 Lurie’s group analyzed the immediate effect of physical activity (30 lifts to tiptoes at a frequency of one time per second) on venous hemodynamics using ultrasonography in 61 patients with primary GSV incompetence. Data from this study showed statistically significant changes in reflux duration and reflux volume with respective rates of 4.85 seconds (interquartile range [IQR], 3.71–6.00 seconds) and 17.05 mL (IQR, 10.32–25.34 mL) before exercise and 2.86 seconds (IQR, 2.14–3.33 seconds) and 10.07 mL (IQR, 6.08–16.48 mL) after exercise. They also demonstrated that a decrease in the volume of reflux rate was inversely related to both the diameter of GSV and the Venous Clinical Severity Score (VCSS) of a patient ( r = −0.56, and r = −0.41, respectively, P < 0.0001). Findings from this study suggest that reduction of the volume of retrograde flow is due to the shortening of reflux time (and not the flow rate), implying that the GSV reflux is affected by exercise-induced changes in the volume of the lower extremity venous reservoir.

Overall, patients with CVD should be encouraged to engage in regular moderate physical activity. In a study by Roaldsen et al., it was observed that walking speed, endurance, and self-perceived exertion were significantly lower in 34 women aged 60 to 85 years with current or previous ulcers compared with age-matched controls. It was also noted that ankle plantar flexion and dorsiflexion were significantly reduced in patients with active ulcers, mostly because of pain. Patients with low levels of physical activity displayed stronger fear avoidance beliefs and more pain than those with higher levels of physical activity. These findings and observations from other studies emphasize the need for physical therapists to be highly involved in the care of patients with advanced C4–C6 disease, highlighting the importance of adequate pain control and a supervised exercise program tailored to improve ankle mobility and overall functional ability. ^,

Leg Elevation

Leg elevation has been shown to aid venous drainage, to increase venous return to the heart, and to reduce ankle edema. Patients with significant CVD are advised to elevate their legs 30 cm above the heart several times during the day. In addition, Abu-Own et al. have shown enhancement of cutaneous microcirculation after leg elevation using Doppler fluxometry in patients with lipodermatosclerosis, with a median 45% Doppler flux increase.

Transcutaneous tissue oxygen saturation levels have been used as an indicator of skin perfusion. These have been found to be reduced in patients with venous ulcers. Several authors have reported higher transcutaneous tissue oxygen saturation levels with compression strategies, standing position, and ambulation compared with leg elevation with or without compression. However, it is unclear how the transcutaneous tissue oxygen saturation levels correlate with ulcer healing. A retrospective Australian study of 122 patients with previous venous ulcers observed for 12 to 40 months found that significantly lower rates of recurrence were associated with compression therapy and longer leg elevation times (33 min/day). Recurrence was observed with a 14-min/day period of leg elevation. The authors of the study recognized limitations due to the retrospective design of their analysis and possible response bias, as all the measures of physical activity, psychosocial scales, and self-care activities were obtained from self-report questionnaires.

Leg elevation seems to be beneficial in symptom control in all patients with CVD. There is a trend supporting some advantage in ulcer healing, despite the evidence of levels of evidence 1 and 2 studies. In addition, the utility of leg elevation is limited by the practical difficulty of prolonged leg elevation for many patients.

Weight Loss

Numerous epidemiologic and clinical studies have identified obesity as an important factor for the development of CVD, disease progression, and correlation of symptoms. Three landmark epidemiologic studies (the Edinburgh Vein Study, the Bonn Vein Study, and the San Diego Study) showed that, in addition to age, obesity was an independent risk factors for the development and progression of CVD. ^, ^, ^, ^, Data from the Bonn Vein Study showed that patients with a BMI (kg/m ² ) of 25–29.9, 30–40, and >40 had odds ratio for the risk of disease progression of 2.26, 2.86, and 3.47, respectively, when compared to patients with a normal BMI. More recently, in 2020 Deol et al. showed an inverse relationship between progressive increase in BMI and CVD-related treatment outcomes efficacy as measured using the revised VCSS and Chronic Venous Insufficiency Quality of Life Questionnaire 20-item (CIVIQ-20). This study showed progressively worse outcomes in patients with a BMI >35 kg/m ² and poor outcomes in patients with a BMI ≥46 kg/m ² . Based on this data authors of the study consider BMI ≥46 kg/m ² to be a relative contraindication for treatment and recommend weight loss counseling for these patients.

Although pathophysiologic mechanism(s) pertinent to the role of obesity in the progression and severity of CVDs remains to be elucidated, sufficient evidence is available of its effects on disease severity and treatment outcomes to warrant recognition of obesity as significant comorbidity and to incorporate weight loss in the treatment of CVD.

Compression Therapy

Both Hippocrates (460–370 BCE) and Aurelius Celsus (25 BCE–AD14) utilized compression in their treatment of venous disease. ^, Although compression therapy is one of the oldest treatment modalities for patients with CVD it was only recently that quantitative parameters of compression were established. The “dose” of compression is the pressure amount applied by a compression device to the skin (referred as “interface pressure”). It is worth emphasizing that at the time of writing this chapter only graduated compression stockings are standardized using the interface pressure parameter. In addition, standardization of compression stockings usage required consensus among practitioners pertinent to determination of a specific anatomic point for the measurement of interface pressure in the lower extremity.

By consensus, the so called “B1 point” was defined to be the most feasible to determine clinically, as it is located approximately 80 mm above the ankle and is anatomically delineated as the most distal part of the medial gastrocnemius muscle (point on the skin overlying the anatomic location where a tendon inserts into the gastrocnemius muscle). “The B1 point” is used as the reference point for the label on all graduated compression stockings and it represents the pressure measured ex vivo at this point only. It is important to note that the aforementioned method utilized for labeling of compression stockings also implies the fact that the pressure applied outside of the point B1 is unknown and may significantly differ from the label on the stocking. ^,

Compression therapy is an essential component of the care of patients with CVD (C2–C6). The rationale for gradient external compression is to oppose the main pathologic factor underlying CVD, venous hypertension, and compression therapy has been found to have a number of additional benefits. Given a normal standing resting venous pressure of 60 to 80 mm Hg, major hemodynamic effects can be expected, with an interface compression of 35 to 40 mm Hg. External compression of more than 60 mm Hg has been found to occlude lower extremity veins in standing individuals. Therefore 60 mm Hg has been considered the safe upper limit for externally applied sustained compression, as shown by dermal blood flow investigations, even in patients with an ankle–brachial index above 0.5 and absolute ankle pressure higher than 60 mm Hg. ^, ^,

Compression therapy has also been shown to improve venous pump function. Enhanced venous flow velocities have been noted with low-grade interface pressure of 15 to 25 mm Hg with prevention of thromboembolic events in supine patients. The biomolecular mechanisms by which compression therapy functions are unclear. Animal and clinical studies have documented that compression therapy improves cutaneous microcirculation. Video capillary microscopy showed an increase in capillary density with decreased capillary diameter and pericapillary halo in 20 patients with varicose veins and lipodermatosclerosis treated with compression therapy. Several authors have also noted enhancement of lymphatic drainage and cutaneous oxygenation, as demonstrated by increased transcutaneous tissue oxygen saturation levels. ^, Decreased serum levels of tumor necrosis factor-α and vascular endothelial growth factor have been observed in patients with healing ulcers treated with four-layer graduated compression. The improved cutaneous microcirculatory environment has been thought to promote venous ulcer healing as has been suggested by several studies.

A number of compression garments are available. These include gradient elastic stockings and the CircAid garment, paste gauze boots (Unna boot), layered elastic and nonelastic compression bandages, and intermittent pneumatic compression (IPC).

Gradient Elastic Stockings

Gradient elastic stockings were first developed in the 1950s; they are currently manufactured by numerous companies and are available in various strengths and lengths. The compression applied by the stocking is calculated on the basis of the mechanical properties of the fabric used by each manufacturer. The pressure applied to the ankle by the stocking is expressed as a range and is a function of in vitro measurements based on leg circumferences.

Gradient compression stockings are currently available in 4 strengths: 10 to 15 mm Hg (class 1; over-the-counter); 20 to 30 mm Hg (class 2; prescription); 30 to 40 mm Hg (class 3; prescription); and 40 to 50 mm Hg (class 3 – high compression; prescription). They are also available in different lengths, including knee-high, thigh-high, and panty hose. They are fitted on the basis of measurements of circumference, usually at thigh, midcalf, and ankle levels, and may be individually customized in patients with atypical leg morphology, such as may be seen in the obese or patients with advanced CVD. Compression garments should be replaced every 6 to 9 months, as the elasticity is lost after this time.

Gradient compression stockings in C1–C2 disease

A number of studies have reported the efficacy of gradient elastic stockings in early and advanced stages of CVD. In a prospective randomized multicenter trial conducted in France of 125 women with CEAP classification of C1-3SEpAs1-5, it was noted that regular wearing of compression stockings (10–15 mm Hg) during a 15-day period was associated with significant symptom control when a high level of compliance in wearing the hose was achieved. In a review of 11 prospective randomized trials, 12 nonrandomized studies, and two guidelines, no agreement was found regarding the appropriate class of compression for the management of early CVD stages. Compression improved symptoms in patients with uncomplicated symptomatic varicose veins when high compliance was reached. However, the use of compression stockings was not shown to prevent disease progression or recurrence of varicose veins after treatment. The same review highlighted that the majority of the published literature was often contradictory and had methodologic flaws, and that the results of several studies were confounded by a high number of noncompliant patients.

It can be concluded that wearing of light compression stockings with a pressure below 20 mm Hg may be beneficial in the following indications: symptom control in C1s (grade 1B level of evidence); varicose veins in pregnancy (grade 1B level of evidence); prevention of leg edema related to prolonged sitting and standing (grade 1B level of evidence); and prevention of venous thromboembolism in non-ambulatory patients or after surgery (grade 1A level of evidence). The recommendation for use of class 2 compression stockings in uncomplicated symptomatic varicose veins is also weak (grade 2B level of evidence) and only for symptom relief. Class 2 stockings have also been found to be poorly associated with the prevention of varicose veins after surgery and the treatment of venous ulcers (grade 2B level of evidence).

Surgery versus compression in C2–C3 disease

In the “Randomised clinical trial, observational study, and assessment of cost-effectiveness of treatment of varicose veins” (REACTIV trial), out of 1009 patients, 357 patients were placed in 3 groups based on clinical severity and then randomized to treatment groups as follows: 34 patients with minor varicose veins and no superficial venous reflux (group 1) were randomized to conservative management versus sclerotherapy; 77 patients with moderate varicose veins and superficial venous reflux (group 2), were randomized to sclerotherapy versus surgery; and 246 patients with severe varicose veins and superficial venous reflux (group 3) were randomized to conservative treatment versus surgery. The remaining 652 patients were used to form the observational part of the trial. Conservative treatment included lifestyle modification, leg elevation, and compression stockings; the surgery arm included high ligation of the saphenofemoral junction, saphenous vein stripping, and phlebectomies. The study demonstrated a significant benefit in QoL, symptom relief, and patient satisfaction in the surgical treatment at two-year follow-up in groups 2 and 3. In group 1, sclerotherapy produced an incremental benefit over conservative therapy. Surgery was found to be more cost-effective than conservative management in patients with C2 disease. Injection sclerotherapy also appeared to be cost-effective for patients with superficial venous reflux but was found to produce less benefit compared with surgery.

Sell et al. analyzed 153 patients with class C2–C3 venous disease randomized to receive either conservative treatment with compression stockings (n = 77) or surgical stripping of the GSV (n = 76). At 2-year follow-up data from this study demonstrated that VCSS without compression stockings (VCSS-S) decreased from 4.6 to 3.5 in the compression group ( P <0.01) and from 4.8 to 0.6 in the surgery group ( P <0.001). Data also showed that Venous Segmental Disease Score (VSDS) decreased from 7.7 to 7.0 in the compression group and from 8.2 to 0.9 in the surgery group ( P <0.0001). Health-related quality of life (HR-QoL) measured with a disease-specific Aberdeen Varicose Vein Questionnaire (AVVQ) did not change in the compression group, but improved significantly in the surgery group at both 1 and 2-year follow-up.

The current guidelines from the Society for Vascular Surgery and the American Venous Forum recommend against conservative therapy alone for patients with C2 and C3 disease when there is a compelling indication for saphenous stripping or ablation. These guidelines also highlight the lack of scientific evidence to support the initial period of conservative therapy mandated by many health insurers in patients who are suitable candidates for surgical therapy.

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