Phlebotonic and Compression Stocking Therapy in Venous Edema Management: An Overview of Recent Advances with a Focus on Cyclo 3 Fort® and Progressive Compression Stockings

Abstract

Venous edema of the limb presents several challenges to clinicians, particularly with regard to its definition, pathophysiology and measurement, as well as those relating to its management. Compression therapy forms the cornerstone of standard care for thromboprophylaxis and management of lower limb venous and lymphatic disorders. Venoactive drugs, of plant or synthetic origin, have also been shown to be effective and safe in the management of venous edema and/or chronic venous disease-related symptoms. This article, based on a symposium held at the XXV World Congress of the International Union of Angiology on 2–5 July 2012 (Prague, Czech Republic), provides an overview of some of the recent developments in the use of phlebotonic and compression therapy in the management of patients with lower limb venous edema, with a focus on Cyclo 3 Fort® and progressive compression stockings.

Keywords

chronic venous disorder compliance compression therapy Cyclo 3 Fort®edema management phlebotonic therapy progressive compression stocking venous edema

Based on the recent VEIN-TERM consensus document, chronic venous disorders (CVD) encompass “the full spectrum of morphological and functional abnormalities of the venous system” [1]. The socioeconomic impact of CVD is significant, with 50–85% of Western populations affected by CVD and 2–3% or more of national health budgets consumed [1]. Although CVD affects both genders, the estimated prevalence in Western populations is higher in women (up to 40% in females and 17% in males) [2] and, as such, the identification and management of CVD represents an important aspect of women's health.

The revised Clinical–Etiology–Anatomy–Pathophysiology (CEAP) classification system covers all forms of CVD (C0–C6), with venous edema, considered to be an early sign of CVD of the legs, classified as CEAP C3 ( Box 1 ) [3]. Current available management options for CVD of the leg include medication (e.g., phlebotonic agents), compression (e.g., graduated compression stockings, bandages and intermittent pneumatic compression), local therapy (e.g., hydrotherapy and physiotherapy), sclerotherapy and surgery, with medication and compression being the accepted options for leg edema [4]. For the purposes of this article, the use of the term ‘compression therapy’ refers to compression stockings.

The challenges of venous edema

Venous edema presents a number of challenges, particularly with regard to its definition, pathophysiology and measurement, in addition to issues relating to edema management.

With regard to definitions, until recently there was a lack of universal consensus relating to the wide range of terms used for clinical venous disease, preventing the effective communication of information and clinical progress relating to CVD and venous edema [1]. However, based on the 2009 VEIN-TERM update of CVD terminology, edema (CEAP C3) through to active venous ulcer (CEAP C6) represent the range of venous abnormalities that are defined by the term chronic venous insufficiency (CVI) [1]. Furthermore, in order to augment and complement the descriptive CEAP classification system, an evaluative instrument, the Venous Clinical Severity Score (VCSS), was introduced in 2000 by Rutherford and colleagues [5]. The main purpose of the VCSS is to provide an instrument that is responsive to disease severity changes over time and in response to disease management [5]. A recent revision to the VCSS [6] allows the clinician to examine a patient's legs and, separately for each leg, choose a category that best describes the patient's pattern of venous leg edema, as shown in Box 2 [5,6].

Box 1.

Clinical–Etiology–Anatomy–Pathophysiology clinical classes

No visible or palpable signs of venous disease

Telangiectasias or reticular veins

Varicose veins (diameter ≥3 mm)

Edema

Changes in skin and subcutaneous tissue, secondary to chronic venous disorders

C4a: pigmentation or eczema

C4b: lipodermatosclerosis or atrophie blanche

Healed venous ulcer

Active venous ulcer

Data taken from [3].

From a pathophysiological perspective, there is a link between venous symptoms and venous edema. For example, in the Basel follow-up study, among 990 individuals with a C0–C1 status at study onset, those reporting symptoms had a significantly higher incidence of venous edema 11 years later, compared with individuals not displaying symptoms at the earlier time-point (p < 0.001) [7]. Indeed, data from the Basel follow-up study showed that risk factors for venous edema include venous symptoms, in addition to age, female gender, great saphenous vein varices and BMI.

As reviewed elsewhere, various pathophysiological mechanisms contribute to venous edema of the lower limbs [8 –11]. In brief, these mechanisms can include venous reflux (primary, secondary or congenital retrograde venous flow of abnormal duration in any venous segment), venous obstruction (partial or complete blockage of venous flow), calf pump dysfunction, venous hypertension, skin microvalve reflux, microvascular permeability, inflammatory vasodilation, lymphatic dysfunction and lymphatic microangiopathy [8 –10]. Furthermore, factors such as orthostatism, inactivity, lower limb orthopedic disorders, amyotrophy, obesity, diabetes, vasodilator drugs, undernutrition and hypoalbuniemia can all be associated with the pathophysiology of venous edema [9 –11].

How do we measure venous edema? Although no currently accepted ‘gold standard’ method exists, there are a number of proposed methods, including ankle perimeter measurement or perimeter measurements with modeling, optoelectronic volumetry, water displacement volumetry, impedancemetry, capillaroscopy/fluorescence capillaroscopy, ultrasound measurement of skin thickness and imaging techniques (CT scan and MRI reconstruction). Of these methods, water displacement volumetry using the methodology, introduced by Vayssairat and colleagues, is used widely [12,13].

Numerous clinical studies have evaluated a range of options for the potential management of venous edema of the leg; however, based on the findings of an International Task Force, the quality of studies and validity of their outcomes has historically been weak [4]. Nevertheless, the International Task Force concluded that medication (e.g., phlebotonic agents) and compression are the currently accepted management options for venous edema [4]. The purpose of the current short review, based on a symposium held at the XXV World Congress of the International Union of Angiology on 2–5 July 2012 (Prague, Czech Republic), is to provide an overview of some of the recent developments in the use of phlebotonic and compression therapy in the management of patients with venous edema, with a focus on Cyclo 3 Fort® and progressive compression stockings.

Phlebotonic therapy: recent advances

Venoactive drugs represent a heterogeneous group of drugs, of plant or synthetic origin, that have been shown to be effective and safe in the management of edema (C3) and/or symptoms related to CVD [14,15]. There are four major categories of venoactive agents: benzopyrones (e.g., coumarin, diosmin and micronized purified flavonoid fraction), saponins (e.g., Ruscus aculeatus extracts), other plant extracts (e.g., anthocyans) and synthetic products (e.g., benzarone and calcium dobesilate) [14]. The mechanisms of action of these venoactive agents include increased venous tone, anti-edema effects and inhibition of various trigger factors during the late stages of CVD [14]. The current article focuses on recent evidence reported with combined Ruscus aculeatus, hesperidin methylchalcone and ascorbic acid (Cyclo 3 Fort).

The efficacy and safety of the venoactive combination of Ruscus aculeatus, hesperidin methylchalcone and ascorbic acid (Cyclo 3 Fort) on venous symptoms have been well established in clinical trials; indeed, a meta-analysis of 20 randomized, double-blind clinical trials by Boyle and colleagues further confirmed the role of this phlebotonic combination in the management of CVI [16]. Compared with placebo, the authors demonstrated significant reductions in the severity of pain, cramps, heaviness, paresthesia and venous capacity with Cyclo 3 Fort; in addition, reductions in edema severity and decreases in calf and ankle circumference were shown in patients treated with Cyclo 3 Fort compared with placebo [16]. Moreover, Aguilar Peralta and colleagues demonstrated objective vascular changes, in particular at the capillary level, which occurred in tandem with improved clinical symptoms in 124 patients with CVI treated with combined Ruscus aculeatus, hesperidin methylchalcone and ascorbic acid (Cyclo 3 Fort) [17]. The capillary-level effect observed in these patients was proportional to the reduction in symptoms, with improvements seen from the second week of treatment.

More recently, Allaert and colleagues identified the need for an evaluation of the correlation between objective measures (assessment of venous muscle pump function by ambulatory strain-gauge plethysmography [18] and Doppler ultrasound testing of venous insufficiency) and the subjective evaluation of functional signs in patients receiving venoactive drugs [19]. In this open-label study, 62 active women (mean age: 38.1 ± 7.4 years) with C2 and C3 venous disease (mean duration: 22.8 ± 3.7 years) received combined Ruscus aculeatus, hesperidin methylchalcone and ascorbic acid (Cyclo 3 Fort) for 28 days and were evaluable for assessment. Functional signs and impact on work/daily activities were evaluated using a 0–100 mm visual analog scale; the severity of venous disease was assessed using the VCSS; and venous refilling time was measured using mercury strain-gauge plethysmography. Doppler ultrasound evaluation had to be abandoned due to the low incidence of deep venous reflux (17.2%), although this low incidence is comparable with that reported by Labropoulos and colleagues [20].

The study by Allaert et al. demonstrated that treatment with combined Ruscus aculeatus, hesperidin methylchalcone and ascorbic acid (Cyclo 3 Fort) for 28 days resulted in a significant improvement in subjective functional symptoms, a significant improvement in work and daily activities, and improved objective plethysmographic parameters [19]. Furthermore, the study demonstrated a correlation between improvements in subjective functional symptoms and improvements in objective plethysmographic parameters (Figure 1). Combined Ruscus aculeatus, hesperidin methylchalcone and ascorbic acid (Cyclo 3 Fort) was well tolerated, with only two patients (3.2%) discontinuing treatment due to adverse events (diarrhea and gastralgia) [19].

Figure 1.

Correlation between clinical and plethysmographic parameters in women with venous insufficiency (Clinical–Etiology–Anatomy–Pathophysiology C2–C3) after treatment with a combination of Ruscus aculeatus, hesperidin methylchalcone and ascorbic acid (Cyclo 3 Fort®). Concordance between ≥30% improvement in functional signs and ≥10% improvement in venous filling time was demonstrated.

Although, as discussed later in this review, compression therapy remains the cornerstone of conservative management for patients with CVD [21], compliance issues with compression therapy preclude its use in some patients. Indeed, epidemiological studies have shown that <30% of patients with CVD accept compression therapy; for example, Ziaja and colleagues recently reported that, in Poland, 27.9% of women and 20.3% of men treated for CVD use this form of therapy [22]. These observations correlate with data reported from the large Bonn Vein Study, in which 20.3% of the overall population were prescribed compression therapy for CVD [23].

Box 2.

Revised Venous Clinical Severity Score and instructions for using the revised Venous Clinical Severity Score to evaluate venous edema

Attribute

Venous edema (presumes venous origin)

None: 0

None

Mild: 1

Limited to foot and ankle area

Moderate: 2

Extends above the ankle but below the knee

Severe: 3

Extends to the knee and above

Instructions

The clinician examines the patient's legs and, separately for each leg, chooses the above category that best describes the patient's pattern of leg edema

The clinician's examination may be supplemented by asking the patient about the extent of leg edema that is experienced

Data taken from [6].

There are a number of well-documented reasons for compression therapy nonuse [22,24,25]; based on US data from more than 3000 new CVD patients, the main reasons for nonuse included patient perception that the stockings did not help (14%), binding/'cutting off’ the circulation (13%), too hot to wear (8%), unable to apply without help (2%), limb soreness (2%), itching (2%), poor cosmetic appearance (2%) and cost (2%) [24]. In patients not accepting compression therapy, venoactive drug therapy becomes the only method of conservative treatment for CVD. However, not all CVD patients benefit from venoactive drugs as some patients are noncompliant with pharmacotherapy.

A recent nationwide study, conducted in Poland, assessed the use of pharmacotherapy in patients with CVD who were compliant (n = 5134) or noncompliant (n = 4663) with compression therapy, with the objective of determining the factors that limit the use of the venoactive drugs, Ruscus aculeatus extracts (Cyclo 3 Fort), micronized purified flavonoid fraction preparations and horse chestnut seed extracts in CVD patients [26]. Venoactive drugs were used significantly less frequently in patients who were noncompliant with compression therapy compared with compression therapy-compliant patients (95.2 vs 97.27%; p < 0.001). Table 1 highlights the factors that influence the use of venoactive drugs; in addition to noncompliance with compression therapy, male gender, older age and comorbidity (including obesity) are all factors that decrease the use of venoactive drugs [26]. The authors of this study acknowledge that the effect of various psychosocial factors that potentially limit the use of venoactive drugs was not evaluated; therefore, future studies that assess psychosocial aspects are warranted.

Table 1.

Factors that influence the use of venoactive drugs based on a study of patients with chronic venous disorders who were compliant (n = 5134) or noncompliant (n = 4663) with compression therapy.

Association	Compression therapy (neg)	Age	Smoking	Primary healthcare	Chronic illness	Obesity	Male gender
Any venoactive drug
OR	–	0.991	–	0.836	0.673	0.836	0.926
(95% CI)		(0.989–0.993)		(0.794–0.880)	(0.626–0.723)	(0.791–0.884)	(0.876–0.980)
p-value	ns	<0.001	ns	<0.001	<0.001	<0.001	<0.01
Ruscus aculeatus extracts
OR	0.870	0.982	1.258	0.611	0.785	0.765	0.759
(95% CI)	(0.819–0.924)	(0.980–0.985)	(1.178–1.344)	(0.572–0.652)	(0.723–0.853)	(0.715–0.820)	(0.705–0.816)
p-value	<0.001	<0.001	<0.001	<0.001	<0.001	<0.001	<0.001
Micronized purified flavonoid fraction preparations
OR	0.886	–	0.831	1.124	0.645	0.918	1.118
(95% CI)	(0.831–0.946)		(0.775–0.891)	(1.051–1.201)	(0.594–0.701)	(0.854–0.987)	(1.036–1.206)
p-value	<0.001	ns	<0.001	<0.001	<0.001	<0.05	0.01
Horse chestnut seed extracts
OR	–	1.011	–	2.506	0.614	1.427	–
(95% CI)		(1.006–1.015)		(2.247–2.795)	(0.525–0.717)	(1.275–1.596)
p-value	ns	<0.001	ns	<0.001	<0.001	<0.001	ns

Analyses include Clinical–Etiology–Anatomy–Pathophysiology stage as a confounding variable.

neg: Negative; ns: Nonsignificant; OR: Odds ratio.

Adapted with permission from Edizioni Minerva Medica [26].

Compression therapy: recent advances

For many decades, graduated (degressive) elastic compression stockings (GECS) have successfully been used for the management of CVI. Based on current management guidelines and best available clinical evidence, GECS represent the cornerstone of standard care for thromboprophylaxis and the management of venous and lymphatic disorders of the lower limbs [27,28]. Indeed, a recent systematic review of GECS for the prevention of deep vein thrombosis reviewed evidence from 18 randomized controlled clinical trials and concluded that the risk of deep vein thrombosis in hospitalized patients is diminished with the use of GECS [29]. The rationale for GECS with a degressive gradient is that higher compression pressure at the ankle level is necessary to counteract the higher hydrostatic pressure; under physiological conditions, graduated compression improves venous return from a distal point with higher pressure to a proximal point with lower pressure [101].

More recently, a new concept in compression therapy, namely ‘progressive’ elastic compression stockings (PECS), has been developed, whereby there is a higher compression pressure over the calf area than over the ankle (inversely graduated compression stockings). The rationale for this approach is based on the observations of Stranden and colleagues that, during walking, muscle contractions produce physiologically very high intravenous pressure peaks and greater ambulatory venous pressure reductions in the foot than in the calf veins [30]. As a consequence, proximal intravenous pressure greater than distal pressure is produced with every step (in normal subjects and patients with superficial venous incompetence); thus, a continuous intravenous pressure gradient is not a general physiological principle [30]. In addition, based on research with regard to blood pooling and leg and foot pumps [31,32], it can be postulated that the highest blood volume is pooled in the mid-calf area (with poor content in the distal parts of the leg) and higher compression over the strongest leg pump squeezes this blood out more vigorously compared with the ankle area (weaker leg pump and a smaller volume of blood) covered by the lower compression; as a result, the highest pressure occurs where it is required.

Inversely graduated ('progressive') elasticated compression stockings have been shown to have beneficial effects in sports medicine [33], and in patients with mild [34] or moderate-to-severe CVI [35], or severe superficial CVI [36].

The randomized, double-blind, multicenter study by Couzan and colleagues was conducted in 401 evaluable patients with moderate-to-severe CVI (66% of patients were classified as CEAP C3) [35]. At 3 months, progressive compression stockings were more effective than conventional degressive stockings in improving pain and lower leg symptoms, resulting in a significantly higher overall success rate (primary outcome) with the progressive stockings (p = 0.03). Furthermore, up to 6 months, the progressive stockings were considered easy to apply by more patients than the degressive stockings (86.2 vs 57.1%; p < 0.0001).

In a recent study by Mosti and Partsch, 30 patients with severe superficial CVI were randomized to either a standard stocking (designed to exert a higher pressure at the ankle and a degressive pressure profile; GECS) or a progressive stocking (designed to exert a pressure at the calf approximately 50% higher than that at the ankle; PECS); both stockings had an ankle pressure between 15 and 25 mmHg [36]. The venous calf pumping function, assessed by measuring the ejection fraction from the lower leg by a plethysmographic method during a standardized exercise, was significantly (p < 0.001) higher with the PECS than with the GECS. A significant correlation was also observed between the ejection fraction and the stocking pressure measured at calf level during standing and walking [36].

What effect do antigradient compression stockings have on venous edema formation? To address this question, a study was recently conducted to determine whether, compared with GECS, PECS favor occupational edema or are able to prevent edema formation in 30 healthy volunteers (operating theater nurses [mainly standing] and office employees [mainly sitting]) during their working shift [102]. The main outcome measure in this study was leg volume (assessed by water displacement), determined at baseline, without any stocking, with a standard GECS on one leg and a PECS on the other leg (randomized). The study showed that, in contrast to promoting edema formation, PECS reduce occupational edema in a healthy working population more effectively than GECS (Figure 2). Stocking comfort and ease of application, secondary outcomes, were also greater for the PECS than the GECS (not significant) [102]. The findings from this study may possibly be explained by the fact that higher pressure over the calf may reduce venous pooling capacity (reduced venous volume leads to less reflux, less stasis and less edema), and the redistribution of leg fluid potentially leads to a global fluid reduction [102]. Future studies to evaluate the effect of progressive stockings on other clinical conditions, such as thromboprophylaxis or edema treatment, are warranted.

Figure 2.

Effect of standard ('degressive') and antigradient ('progressive') compression stockings on leg volumetry (water displacement) in 30 normal healthy working volunteers. (A) Baseline, without stocking and with degressive/progressive stockings, and (B) percentage increase/decrease in leg volumetry for each stocking type compared with baseline/no stocking.

One such Phase III study has been initiated in order to evaluate the effect of PECS on the reduction of venous edema in patients with CVD [103]. The primary objective of this randomized, multicenter, double-blind, parallel-group, placebo-controlled study is to assess the clinical effect of a progressive stocking (ankle pressure: 10 mmHg and calf pressure: 23 mmHg; V0322BC, Pierre Fabre Médicament) on leg volume reduction (at 7 days) and subsequent volume control (3 months), measured by Vayssairat boot [12,13], in patients with venous edema. Other study objectives include an evaluation of symptoms (pain and heaviness) and quality of life/burden improvements at day 7 and at 1 month (Assessment of Burden in Chronic-Venous Disease) and 3 months (Specific Quality of Life and Outcomes Response-Venous), and to document clinical, cutaneous and systemic adverse events throughout the study. The study planned to recruit approximately 100 patients, randomized to receive either the progressive stocking (V0322BC) or a matched placebo medical compression stocking [103].

Inclusion criteria include male or female patients, aged ≥18 years, with permanent edema of venous origin (CEAP C3) and venous hemodynamic abnormality (CEAP Pr [reflux] or Po [obstruction]) at Doppler or Duplex ultrasound examination; signed written informed consent; and registered with, or benefiting from, health insurance. Exclusion criteria include the use of compression therapy in the 5 days before study inclusion; patients with contraindications for compression stocking use; lipedema, lymphedema or edema of systemic origin; pregnancy, breastfeeding or potential pregnancy; and NSAIDs, steroids, calcium blockers, ACE and A2 inhibitors, estrogen, diuretics or venoactive drugs initiated or modified <1 month prior to study inclusion [103].

The results from this study are currently undergoing full analysis and their future publication is awaited with interest.

Conclusion & future perspective

A number of different venoactive agents exist for the pharmacological management of venous edema (CEAP C3) and/or symptoms related to CVD. While there is not enough evidence to fully support the efficacy of all phlebotonic agents for CVI, there is evidence that phlebotonics are efficacious with regard to venous edema management. Recent developments in the area of phlebotonic therapy indicate that combined Ruscus aculeatus, hesperidin methylchalcone and ascorbic acid (Cyclo 3 Fort) in women with CEAP C2 and C3 venous disease significantly improves subjective functional symptoms and also results in a significant improvement in the work and daily lives of these patients. Importantly, there was a correlation between improvements in subjective functional symptoms and improvements in objective plethysmographic parameters in patients receiving a combination of Ruscus aculeatus, hesperidin methylchalcone and ascorbic acid (Cyclo 3 Fort).

Patients who are noncompliant with compression therapy are more frequently noncompliant with pharmacological therapy; in particular, coexisting obesity and other chronic illnesses decrease adherence to pharmacotherapy.

Based on the use of GECS for many decades, it is well established that they represent the cornerstone of standard care in patients with CVD. The rationale for GECS with a conventional degressive pressure gradient, is that higher compression pressure at the ankle level is necessary to counteract the higher hydrostatic pressure; under physiological conditions, graduated compression improves venous return from a distal point with higher pressure to a proximal point with lower pressure. In recent studies, PECS have shown greater efficacy than GECS in increasing the venous ejection fraction from the leg in patients with advanced venous insufficiency. Moreover, PECS have been shown to prevent occupational edema formation in a healthy working population more effectively than GECS. With regard to future developments in the area of venous edema management, data from studies evaluating the clinical effect of PECS in reducing edema in patients with venous edema are awaited with anticipation.

Acknowledgements

All authors participated in a symposium, sponsored by Pierre Fabre Médicament, which was held at the XXV World Congress of the International Union of Angiology on 2–5 July 2012, in Prague, Czech Republic.

Financial & competing interests disclosure

All authors received a travel grant and honorarium for their participation in the symposium at the XXV World Congress of the International Union of Angiology. J Chudek was the principal investigator in the nationwide survey concerning chronic venous disorders therapy in Poland, which was funded by Pierre Fabre Médicament Poland. P Carpentier discloses having scientific collaborations with Pierre Fabre Médicament, Servier, Sigvaris and Innothéra. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.

The authors are grateful to DP Figgitt, Content Ed Net, for providing valuable editorial assistance in the preparation of this manuscript. Funding for editorial assistance was provided by Pierre Fabre Médicament, France.

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