Management of lower-limb venous symptoms: what the guidelines tell us




Zbigniew RYBAK, MD, PhD
Department for Experimental Surgery and Biomaterials
Research, Wrocław Medical University, Wrocław
POLAND

Management of lower-limb venous symptoms: what the guidelines tell us


by Z. Rybak, Poland



Venoactive drugs (VADs) are an integral part of the treatment of symptomatic chronic venous disease (CVD), especially in early stages. Recommendations for the use of VADs for the symptomatic treatment of CVD have evolved greatly in the past ten years. Landmark events in the development of today’s recommendations include the 2005 Cochrane review, 2005 International Consensus Statement, 2008 guidelines for the management of chronic venous disorders of the lower limbs, 2011 Perrin and Ramelet review, and most recently, the current 2014 guidelines. At each step, new evidence has been added and the status quo reassessed. Most VADs improve venous tone, scavenge free radicals, and reduce capillary leakage, while a few reduce capillary permeability, prevent skin degeneration, improve lymphatic drainage, and reduce blood viscosity and/or erythrocyte aggregation. VADs have also been shown to diminish pain in CVD. Pain, which is induced by inflammation and/or vein wall distension, is a major symptom in C0s patients, symptomatic patients with no visible or palpable sign of venous disease. A fifth of CVD patients could be clinical, etiological, anatomical, pathophysiological (CEAP) grade C0s. While patient reassurance and lifestyle modification could also be useful in these patients, the rationale for compression therapy suffers from a weak evidence base. The 2014 guidelines emphasize the “central and unique role” of VADs, particularly in early CVD. VADs with higher levels of guideline recommendation should be used preferentially.

Medicographia. 2015;37:50-55 (see French abstract on page 55)


Development of chronic venous disease

Chronic venous disease (CVD) is a common condition—associated with depression, social isolation, and reduced quality of life—whose prevalence increases with age.1 The main cause of CVD is venous hypertension, which over time leads to the extravasation of macromolecules into dermal interstitium and to chronic inflammation.2 Initially, venous hypertension dilates veins and causes valve leaflets to deform, resulting in valve loss and valve failure.

Valve failure in turn leads to turbulent flow, blood stasis, or reflux, all of which can provoke local inflammatory and thrombotic responses. These responses include the production of prothrombotic agents (monocyte chemoattractant protein 1 and vascular cell adhesion molecule 1) and growth-promoting agents (angiotensin II, endothelin 1, and platelet-derived growth factor), leukocyte and neutrophil migration, and promotion of apoptosis.2


Table I
Table I. Evidence-based modes of action of the main venoactive drugs.

Abbreviation: HR, hydroxyethylrutoside. *No data available.
Modified from reference 1: Int Angiol. 2014;33:87-208. © 2014, Edizioni Minerva Medica.



Chronic reflux, along with venous hypertension, raises blood pressure in capillaries of the microcirculation. Capillary hypertension leads to a vicious circle of leakage, edema, and inflammation, which ultimately result in pathological skin changes and venous ulceration.2 Chronic reflux, which is evident before large veins become visible, is a preclinical sign of CVD in at-risk individuals.3 As CVD progresses, common symptoms that manifest include aching legs, heaviness, tension, cramp, swelling, itching, and restless legs.2 The clinical, etiological, anatomical, pathophysiological (CEAP) classification is today used worldwide to classify CVD.1,4

Development of current chronic venous disease guidelines

As CVD symptoms can appear in the absence of clinical signs of venous disease and at every clinical stage of CVD,1 symptom control in CVD is critical. Venoactive drugs (VADs), of which there are different types with different effects (Table I), are one of the pillars of the symptomatic management of CVD in the latest guidelines.1 The way in which evidence quality and recommendations for VADs are determined has evolved greatly over the last decade.

In 2005, a Cochrane review of 59 randomized controlled trials showed that treatment with VADs reduced most symptomatic CVD outcomes without increasing the incidence of adverse events vs placebo.5 In the same year, a panel of CVD experts set out to determine the efficacy of VADs by assessing 83 randomized controlled trials and meta-analyses in the literature.6 Evidence quality was graded A (randomized clinical trials with large sample sizes, meta-analyses combining homogeneous results), B (randomized clinical trials with small sample sizes, single randomized trial only), or C (other controlled trials, nonrandomized controlled trials).

On this basis, micronized purified flavonoid fraction (MPFF), calcium dobesilate, and hydroxyethylrutosides were classified grade A, horse chestnut seed extract and Ruscus extract grade B, and other VADs grade C. These experts also concluded that VADs should be indicated to relieve symptoms in all clinical classifications of CVD, from class C0s to C6s.6





Guidelines in 2008 amalgamated the grade recommendations of the 2005 International Consensus Statement with the drug indications of the 2005 Cochrane review.7 The 2008 guidelines also provided more information on the use of VADs in C6 patients and safety of VADs. Importantly, they proposed that VADs could be used as a first-line treatment for symptoms and edema in CVD. In 2011, a new set of recommendations for the use of VADs, based on the Grading of Recommendations Assessment, Development and Evaluation (GRADE) system, was tentatively proposed.8 The GRADE system differed from the earlier 2005 International Consensus Statement and 2008 guidelines in that treatment recommendation and quality of evidence were assessed independently. Treatment recommendation was classified as strong (grade 1) or weak (grade 2), while quality of evidence was classified as high (grade A), moderate (grade B), or low (grade C).


Table II
Table II. Summary of the present guideline recommendations for the use of venoactive drugs for symptom relief, according to the
GRADE system.

Abbreviations: CEAP, clinical, etiological, anatomical, pathophysiological; CVD, chronic venous disease; GRADE, Grading of Recommendations Assessment, Development, and Evaluation; VAD, venoactive drug.
Modified from reference 1: Int Angiol. 2014;33:87-208. © 2014, Edizioni Minerva Medica.



The 2011 review of Perrin and Ramelet, which accepted the fact that evidence of moderate or high quality could originate from large observational studies,8 included evidence for the longer-term safety of MPFF, which was ascertained in a large population in the open-label observational study RELIEF (Reflux assEssment and quaLity of lIfe improvEment with micronized Flavonoids).9 It also highlighted negative concerns about the benefit-risk balance of calcium dobesilate, due to reports of agranulocytosis. MPFF and rutosides were given strong recommendations based on moderate evidence (grade 1B for both drugs) with GRADE.8

The latest 2014 guidelines entitled Management of Chronic Venous Disorders of the Lower Limbs: Guidelines According to Scientific Evidence, an update of the 2008 guidelines,7 have retained the GRADE system to evaluate the efficacy of VADs for the relief of CVD symptoms.1 In these new guidelines, MPFF has kept its 1B classification, while that of rutosides has been downgraded to 2B (Table II); other VADs were classified 2B or 2C.1 No VAD yet has a GRADE rating with a “high” quality of evidence. Evidence is still needed to confirm that treatment with VADs may prevent progression towards complications of CVD. Nevertheless, the 2014 guidelines not only restate the 2008 conclusions that VADs can be used to relieve CVD-associated symptoms and edema at any clinical stage of CVD, but also emphasize the “central and unique role” of VADs in treating symptoms in patients in the initial stages of CVD.1 Advice on the management of C0s patients, symptomatic patients with no visible or palpable sign of venous disease, was introduced in the 2014 guidelines.

♦ The C0s patient
The revised 2004 CEAP classification first drew attention to the existence of C0s patients, or more specifically C0sEnAnPn patients, with no detectable reflux or visible signs.1,10 This patient profile is very commonly encountered in clinical practice, as seen in the recent Vein Consult Program epidemiological survey.11,12 Nearly a fifth (15 290/77 716) of patients in this survey were CEAP grade C0s.12 Compared with 46 451 other symptomatic or asymptomatic patients with clinical CVD (C1 to C6), C0s patients were more likely to be younger (55.5± 15.3 vs 48.6±16.7 years) and male (22.6% vs 33.5%) (both P<0.0001). The overall prevalence of CVD symptoms in C0s patients was less common: 58.5% vs 80.0% for pain in the legs; 52.4% vs 73.9% for sensation of swelling; and 29.1% vs 62.7% for night cramps (all P<0.0001). C0s patients also present with fewer symptoms (2.1±1.1 vs 3.1±1.0; P<0.0001). The overall population in the Vein Consult Program was much more likely to receive VADs (39.7% vs 7.9%), compression therapy (24.4% vs 1.4%), or lifestyle advice (51.6% vs 13.1%) than C0s patients.12

Pain, which is induced by inflammation and/or vein wall distension, is one of the most oppressive symptoms in C0s patients.2,13 Numerous different factors can provoke venous inflammation: oxidative stress,14 shear stress,15 toxicity, bacterial infection, venous hypertension, hypoxia,16 and mechanical injury, among others. These factors are often silent and difficult to detect. Excessive distension of veins can be due to prolonged standing, pregnancy, heavy labor, or hereditary deficiency of elastic and/or muscular vein wall components. Distension and inflammation lead to the activation of nociceptors (sympathetic C fibers) found in venous intima and media.Management of pain and other CVD symptoms in C0s patients includes oral VADs, compression hosiery, and patient reassurance and lifestyle modification.1

♦ Oral venoactive drugs
VADs have been shown to be an effective way of alleviating pain in CVD and of treating nearly all CVD symptoms.1,5 Most VADs have been shown to reduce capillary leakage and improve venous tone (Table I).1 Agents that improve venous tone act by modulating noradrenergic signaling, either by reducing noradrenaline metabolism (MPFF and hydroxyethylrutosides) or by stimulating venous α1-adrenergic receptors (Ruscus extracts). Horse chestnut seed extract has a different mechanism of action for improving venous tone, inducing calcium-dependent contractions in vena cava in a rat model. Most VADs also have free-radical scavenging properties and have now been demonstrated to have anti-inflammatory effects in CVD; several acting at more than one step of inflammatory pathways.17,18

VADs can also reduce capillary permeability,19 prevent skin degeneration related to abnormal capillaries, improve lymphatic drainage, and reduce blood viscosity and/or erythrocyte aggregation.1 Fewer VADs (flavonoids, α-benzopyrones, and calcium dobesilate) have been shown to have an effect on lymphatic drainage or hemorheological disorders (Table I),1 while only MPFF has been shown to prevent the degradation of venous wall and venous valves. VADs also have a role in chronic venous insufficiency (CEAP C4 to C6). MPFF used alongside compression and local wound care has been shown to increase the rate of healing of larger ulcers (5 cm to 10 cm) and established ulcers (6 months to 12 months) vs standard wound treatment alone.20

There are five main categories of VAD: flavonoids (γ-benzopyrones), α-benzopyrones, saponins, other plant extracts, and synthetic products (Table I).1 The largest of these categories is the flavonoids (hesperidin, diosmin, oxerutins, β-hydroxyethlyrutosides, quercetin, kaempferol, and proanthocyanidins), which are known to have potent antioxidant properties. Flavonoids prevent the production of oxidizing agents, scavenge free radicals (thus avoiding cellular damage), block the propagation of oxidative reactions, and strengthen inherent cellular antioxidant capacity.21-24 All flavonoids reduce leg edema and many also improve symptoms (Table III). The flavonoids in red vine leaf extract have been shown to improve venous blood flow, while those in MPFF improve quality of life, ulcer healing, and clinical severity of CVD (reduction in CEAP class).


Table III
Table III. Flavonoid products prescribed for the treatment of chronic venous disorders and
chronic venous insufficiency and their origins, active ingredients, and clinical benefits.

Abbreviation: CEAP, clinical, etiological, anatomical, pathophysiological.
Modified from reference 1: Int Angiol. 2014;33:87-208. © 2014, Edizioni Minerva Medica.



VAD mixtures are common; examples include MPFF, Gingko extracts, and Ruscus extracts. MPFF is made of a 90%/10% micronized mixture of the flavonoid diosmin and other flavonoids (hesperidin, diosmetin, linarin, and isorhoifolin). Gingko extracts contain Gingko biloba, heptaminol, and troxerutin; and Ruscus extracts contain Ruscus aculeatus, hesperidin, methyl chalcone, and ascorbic acid.

VADs are an integral part of treatment in symptomatic venous disease, particularly during the early stages. VADs are particularly useful in patients with pruritic symptoms, in hot countries, and in patients reluctant to use compression therapy. VADs should also be considered when surgical treatment of CVD is unsuitable (eg, fear, previous negative experience). Although good evidence exists for recommending the use of VADs in CVD, in order to strengthen the scientific rationale for their use, larger study populations (>200 patients), comprehensive patient description using CEAP classification, choice of outcome measures, the use of validated tools, and longterm studies should be the focus of future research activity.25 Preference should be given to those treatments with established evidence of efficacy and those recommended by current guidelines.

♦ Compression therapy
Medical compression therapy is also considered an option in C0s patients,12 and the rationale for its use is explained in the 2014 guidelines.1 However, a recent review of the literature highlighted the lack of good quality evidence for determining the effectiveness of compression stockings or for making comparisons between the different types available.26 Furthermore, more data are needed to show that the real-life efficacy of compression therapy is comparable with that observed in trials, as treatment compliance may be an issue.27,28

♦ Topical treatment and lifestyle
The cooling sensation of topical preparations containing VADs or heparinoids can sometimes provide relief for symptoms of heaviness or swelling.1 Although there is no evidence to substantiate the benefit of modifying lifestyle, the everyday experience of phlebologists indicates that many simple measures could reduce symptoms in C0s patients. Measures such as weight loss, raising the legs at night or during breaks, swimming, substituting walking for driving, and calf exercises could all play a valuable role.

Conclusion

Over the last decade, a constant message has emerged in chronic venous disorder guidelines, reviews, and consensus statements: VADs are effective for controlling symptoms at all stages in CVD. This includes the earliest stage of chronic venous disorders, where patients show no visible or palpable signs of venous disease (C0s). The major symptom in C0s patients, pain, can be alleviated by VADs. The role of VADs in the management of CVD in the 2014 guidelines is described as “central and unique.” These guidelines also advocate lifestyle modification in C0s patients, but call for further assessment of compression therapy. Treatment regimens in CVD should be based on VADs, like MPFF, with higher levels of guideline recommendation.


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Keywords: chronic venous disease; chronic venous disorder; compression therapy; guideline; venoactive drug; venous symptom