Chapter 11 Chronic venous insufficiency
AETIOLOGY AND EPIDEMIOLOGY
Chronic venous insufficiency (CVI) is a pathological disorder of the venous system, characterised by impaired venous blood flow in the lower limbs. The condition is manifested by pathological changes to the skin, subcutaneous tissue and vascular tissue.1 These manifestations, which can range from mild to severe, can be grouped into symptomatic complaints, such as leg heaviness, discomfort and pruritus, or advanced physical signs, including leg oedema, ochre pigmentation and lipodermatosclerosis. The condition, which is a precursor to varicose veins and venous leg ulceration, is not uncommon, affecting between 0.1% and 17% of men, and from 0.2% to 20% of women.1
This chronic and sometimes disabling disorder is believed to originate from an episode of macrovascular injury, which may be attributed to lower limb surgery, trauma, deep vein thrombosis (DVT) or pregnancy. This insult to the venous system can lead to valvular incompetence, venous reflux (or retrograde blood flow), ambulatory venous hypertension, venous wall dilatation and a subsequent rise in capillary filtration. As well as contributing to the formation of interstitial oedema, increased capillary filtration may also lead to localised hypoxia, malnutrition and eventual tissue destruction (see Figure 11.1). The extravasation of fibrinogen and the consequent formation of pericapillary cuffs, and the intraluminal trapping of leucocytes and subsequent release of toxic metabolites, proteolytic enzymes and tissue necrosis factor alpha (TNF-α)2 are some of the mechanisms linking elevated capillary filtration pressure to changes in tissue perfusion and local architecture. The extravasation of fibrinogen and leucocyte products into pericapillary tissue may also mediate inflammation, suggesting that CVI may be a disease of chronic inflammation.2
RISK FACTORS
Many risk factors, both modifiable and non-modifiable, are claimed to be responsible for the pathogenesis of venous insufficiency. Occupations requiring periods of prolonged standing (such as nurses, flight attendants and factory workers) have been observed across a number of studies to have a higher prevalence and severity of CVI and varicose veins.1 This could be attributed in part to excessive lower limb venous congestion secondary to reduced calf-muscle pump activity. Evidence linking other modifiable risk factors to chronic venous insufficiency, such as obesity, smoking, constipation, hormone therapy and hypertension, has been inconsistent however.1
In terms of non-modifiable risk factors, both family history and increasing age appear to be associated with an increased risk of CVI.1 Advancing age is also correlated with an increased prevalence of varicose veins1 and venous leg ulceration.3 While female gender has been associated with an increased risk of varicose veins1 and venous leg ulceration,4 there is conflicting evidence regarding the link between sex and CVI risk.
CONVENTIONAL TREATMENT
There are a number of different approaches to the management of CVI. Two approaches often recommended in conventional practice are compression therapy and surgery. Compression therapy is advocated in conventional practice as it helps to reduce leg oedema, venous reflux, venous hypertension and lipodermatosclerosis, while improving deep vein blood flow velocity, capillary clearance, calf-muscle pump function, venous refilling time and venous ejection volume.5 Compression therapy targets a number of processes associated with the pathogenesis of venous insufficiency, with a meta-analysis of 11 randomised controlled trials (n = 1453) finding compression therapy (10–15 mmHg) to be significantly more effective than low grade compression, placebo stockings and no treatment at reducing the symptoms of CVI, including lower limb oedema and discomfort.6 These results need to be interpreted with caution, however, given the heterogeneous populations and diverse assessment techniques used in these studies. It is also possible that the reported effectiveness of compression therapy may not reflect that observed in clinical practice due to the poor level of compliance observed with this treatment. Some of the reasons for the poor adherence to compression therapy may relate to the long duration of therapy, the visible appearance of the stockings, associated discomfort, skin reactions, and the cost and maintenance of the therapy.7
The surgical restoration or removal of diseased vessels also may be advised in the overall management of chronic venous insufficiency. The array of surgical techniques that may be recommended include sclerotherapy, venous ligation and stripping, endovenous laser treatment, phlebectomy and valvuloplasty. Evidence from a meta-analysis of three randomised controlled trials (RCTs) suggests that venous ligation and valvuloplasty may be more effective than ligation alone in improving ambulatory venous pressure and quality of life.8 Another meta-analysis of three RCTs found subfascial endoscopic perforator vein surgery (SEPS) to be significantly more effective than conventional surgery at reducing venous ulcer recurrence, wound infection and length of hospital stay in patients with CVI.9 It is not clear from either of these reviews, however, whether the benefits of these techniques outweigh the risks and costs of surgery, and whether these approaches are relatively more effective (both economically and clinically) than the conservative management of CVI.
KEY TREATMENT PROTOCOLS
Venous integrity
Enzymatic degradation
The abnormal venous tone observed in chronic venous insufficiency may be linked to an increase in lysosomal enzyme activity, as evidenced by the elevated levels of these enzymes in patients with CVI,10 and in the exudate of venous ulcers.11 The lysosomal enzymes hyaluronidase and elastase are believed to be responsible for this extravascular and extracellular matrix degradation,12 and the subsequent increase in capillary permeability and oedema formation. It is therefore hypothesised that a reduction in lysosomal enzyme activity could decrease the symptoms of CVI by restoring venous elasticity and contractility through improvements in collagen biosynthesis10 and proteoglycan recovery.12
The saponins and sapogenins of Hedera helix and Aesculus hippocastanum have been shown to inhibit hyaluronidase activity in vitro,12 whereas Ruscus aculeatus saponins,12 rutin13 and grape seed procyanidins14 have been found to inhibit elastase activity in vitro. By attenuating overactive lysosomal enzyme activity, these compounds may shift the equilibrium between proteoglycan synthesis and degradation, towards net synthesis. This reduction in enzyme activity against capillary wall mucopolysaccharides may improve vessel wall integrity and subsequently reduce oedema formation.15–17 Although the saponins appear to be responsible for the anti-exudative and vascular-tightening effect of several of these plant extracts, the effect of other constituents (such as the flavonoids) cannot be dismissed.
Oxidative damage
Another process implicated in the pathogenesis of CVI is oxidative injury. This process involves the peroxidation of venous lipids, production of oxygen free radicals18–19 and consequent destruction of lipids, proteins, collagen, proteoglycan and hyaluronic acid.20 Agents that exhibit significant antioxidant activity may interrupt this cascade of events and, as a result, preserve venous tissue and improve venous integrity.
Many phlebotonic agents exhibit good antioxidant activity in experimental models, particularly free radical scavenging activity, including Aesalus hippocastanum horse chestnut seed extract, (HCSE),18 Centella asiatica flavonoids,21 Vaccinium myrtillus extract,22 grape seed extract, pine bark extract,23 quercetin and rutin.24 When the active-oxygen scavenging activity of 65 plant extracts were compared in vitro, HCSE and Hamamelis virginiana demonstrated the greatest antioxidant activity. Both extracts were found to be more potent than ascorbic acid and α-tocopherol in scavenging superoxide anions, but less effective than ascorbic acid in scavenging hydroxyl radicals and inhibiting singlet-oxygen generation.19 As an indicator of cell protection, Masaki et al.19 explored the effect that the plant extracts had on fibroblast survival. HCSE, witch hazel and English oak (Quercus robur) were the most protective, increasing fibroblast survival at least threefold. As fibroblasts are a key source of collagen, elastin, proteoglycans and matrix metalloproteinases,11 increasing fibroblast survival is likely to improve venous integrity.
There is a large body of evidence to support the use of HCSE in the management of mild to moderate CVI. A Cochrane review of 17 RCTs found orally administered HCSE (standardised to 50–150 mg aescin daily, and administered for 20 days to 16 weeks (mean = 6 weeks)) to be more effective than placebo, and as effective as other phlebotonic agents, at reducing leg pain, oedema, pruritus, leg volume and ankle and calf circumference in patients with mild to moderate CVI.25 As for severe or advanced cases of CVI, it appears that HCSE may not be as effective.26
Inflammation
Chronic inflammation is another contributing factor in the development of CVI. It is hypothesised that the manifestation of venous hypertension leads to widened capillary pore diameter, causing intravascular components such as fibrinogen, erythrocytes and α2-macroglobulin to be leached into the interstitium.2 These potent chemoattractants up-regulate the expression of intracellular adhesion molecule 1 (ICAM-1) and, together with increased platelet reactivity,27 increase the expression of platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF). These growth factors trigger leucocyte migration. Once recruited, the white blood cells secrete or activate transforming growth factor-β1 (TGF-β1). Since TGF-β1 has been located in pericapillary cuffs, it is believed that this growth factor may be responsible for tissue remodelling and fibrosis, as well as capillary angiogenesis, increased capillary tortuosity and density.2 This factor may therefore contribute to some of the defining features of CVI, including varicose veins and lipodermatosclerosis. The increased expression of ICAM-1,28–30 TGF-β1,31 PDGF and VEGF32 in the dermis of patients with CVI lends some support to this sequelae of events.
Venotonic agents exhibiting antiinflammatory activity may attenuate the progression of CVI through a number of different pathways. Aescin (from HCSE)33 and Ruscus aculeatus extract,34 for instance, both inhibit histamine-induced vascular permeability in vivo, an important step in the pathogenesis of CVI. Aescin,33 grape seed extract35 and Vaccinium myrtillus anthocyanosides36 have also been shown to inhibit carrageen an-induced paw oedema, another measure of acute anti-inflammatory activity. French maritime pine bark extract (Pycnogenol™), on the other hand, exhibits anti-inflammatory activity by inhibiting nuclear factor kappa B (NFκB) and the proinflammatory cytokine interleukin-1 (IL-1);37 whereas rutin and quercetin reduce inflammation by inhibiting the secretion of TNF-α, IL-1, IL-6, IL-8 and immunoglobulin E-induced histamine release.38 Apart from grape seed extract,39 however, few of these agents have yet been found to inhibit the key chemical mediators of CVI pathogenesis, including PDGF, VEGF, ICAM-1 and TGF-β1.
The body of mechanistic data that supports many of these aforementioned treatments is supported by a growing body of clinical evidence. Many of these studies have, however, used complex formulations. This is problematic as it is almost impossible to extrapolate the effect of an individual agent from the effect of a complex formulation. Thus, when reviewing the best available evidence for these treatments, only those studies using monopreparations were included (see Table 11.1). In brief, evidence from RCTs indicate Ruscus aculeatus extract is statistically significantly superior to placebo in reducing leg volume, ankle and leg girth, and leg heaviness, fatigue and tension;40 titrated extracts of Centella asiatica are significantly more effective than placebo at reducing ankle circumference and oedema,41 lower leg volume42 and leg heaviness and oedema;43 Pycnogenol™ is significantly more effective than placebo at reducing leg heaviness and subcutaneous oedema;44–45 and red vine leaf extract is statistically significantly superior to placebo at reducing calf circumference.46–47
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