Therapeutic options to delay the progress of chronic venous disease: the example of micronized purified flavonoid fraction

Hurrem Pelin YALTIRIK, MD

Global Medical Manager, Global Medical Affairs Department, Internal Medicine and Neuropsychiatry Division, Servier International, FRANCE

Address for correspondence: Hurrem Pelin YALTIRIK, MD, Servier International, 50 rue Carnot, 92284 Suresnes Cedex, FRANCE (email: hurrem-pelin.yaltirik@servier.com)

 

Abstract

Chronic venous disease is a global phenomenon that can affect both developed and developing countries, with high prevalence and risk of progression. Recent studies highlight the importance of the early detection of chronic venous disease by proper use of the clinical, etiological, anatomical, and pathophysiological (CEAP) classification system and the necessity for the earlier management of the disease. The causal and temporal sequences of events that occur during the development and progression of chronic venous disease have not been ascertained. Currently available drugs directed toward preventing or limiting the inflammatory response at all stages of the condition may play a significant role in preventing or slowing the development and recurrence of troublesome outward manifestations. More studies are needed to further elucidate the pathophysiology at the early stages of chronic venous disease, investigating the presence of evening reflux in the distal venules due to damage to microvalves, and to determine the role of venoactive drugs in the prevention of the progression of chronic venous disorders: eg, are all venoactive drugs able to prevent future morbidity? The aim of this article is to provide an overview about the pathophysiology and the possible hypothesis in the progression of chronic venous disease and to illustrate the potential benefits of early management of chronic venous disease in delaying the progression of the disease with micronized purified flavonoid fraction (MPFF).
 
Chronic venous disorders have a high prevalence,1,5which increases further with aging of the population.6 Some population-based surveys from the United States, Brazil, and Northern and Western Europe, based on clinical, etiological, anatomical, and pathophysiological (CEAP) classification, report prevalence rates ranging from 49% to 90%.7,12
 
The CEAP classification published in 199613 and updated in 200414 describes chronic venous disorder presentations in all its aspects. The classification is based on clinical, etiological, anatomical, and pathophysiological criteria, including the presence or absence of symptoms. Chronic venous disease so defined ranges from disease with no visible or palpable signs of venous disease symptoms (C0) to leg ulcers (C6). Patients complaining of “venous symptoms” but who do not have any clinical signs, anatomical anomalies, or physiological disorders that can be identified using the current complementary investigations involved in the CEAP classification are assigned to class C0s, En, An, Pn (Table I).14 The CEAP classification, now commonly used worldwide, has allowed collection of epidemiological data on a more homogeneous basis.
 

Table I. CEAP classification.
Abbreviation: CEAP, clinical, etiological, anatomical, and pathophysiological
classification system.
After reference 14: Eklöf et al. J Vasc Surg. 2004;40(6):1248-1252. © 2004, The
Society for Vascular Surgery. Published by Elsevier Inc.


The Vein Consult Program (VCP)—a large-scale international, observational, prospective survey—collected global epidemiological data on chronic venous disorders on the basis of CEAP classification in 20 countries from different geographical zones worldwide. The results allowed reliable comparisons due to the use of the same single protocol, the same internationally accepted classification system, and the centralized data management and processing.15
 
The VCP is one of the rare studies having quantified the proportion of patients classified as C0s among those consulting for potential chronic venous disorders, and it provided an immediate snapshot of a consultation in general practice in real life. According to the results, overall, the prevalence of chronic venous disorders was 83.6%: with 63.9% of the subjects with disease classification C1 to C6 and 19.7% with disease classification C0s. Furthermore, C0s to C3 stages were predominant regardless of the country (Figure 1).15 These results are similar to those of some other epidemiological studies revealing that patients classified as having early stages of the disease (C0s, C1, C2) are frequently encountered during consultations in the general population.16-19
 

Besides its high prevalence, chronic venous disease is a progressive disease. If untreated, the disease will probably become more extensive, resulting in more symptoms and a higher C-classification. Clinical progression of chronic venous disease is accompanied by progression of reflux in the superficial veins, and both clinical progression and progression of superficial venous reflux are significantly correlated with age.20 Notably, 4% of patients with established chronic venous disease progress to a higher CEAP clinical class each year.21 Lee et al22 published the progression results of the Edinburgh Vein study. After a follow-up period of 13.4 years, chronic venous disease was shown to have progressed in more than 58% of the patients.22 Additionally, up to 30% of the participants of the Bonn Vein study with varicose veins were shown to have progressed to higher clinical classes during the 6.6year follow-up.21 Furthermore, in a study by Kostas et al investigating the contralateral limbs of 73 patients undergoing varicose vein surgery, about half of the patients with unilateral varicosities developed chronic venous disease in the contralateral, initially asymptomatic limb within 5 years.23
 

Figure 1. Distribution of the CEAP clinical classes according to geographical areas in Vein Consult Program.
Abbreviation: CEAP, clinical, etiological, anatomical, and pathophysiological classification system.
After reference 15: Rabe et al. Int Angiol. 2012;31(2):105-115. © 2012, Edizioni Minerva Medica.


These studies show that chronic venous disease is a global phenomenon that can affect both developed and developing countries. They also highlight the importance of the early detection of chronic venous disease by proper use of the CEAP classification system and the necessity for the earlier management of chronic venous disease.
 
This article provides an overview of the pathophysiology and possible hypothesis for the progression of chronic venous disease and illustrates the potential benefits of early management of the disease with micronized purified flavonoid fraction (MPFF; registered under trade names Ardium, Alvenor, Arvenum 500, Capiven, Daflon, Detralex, Elatec, Flebotropin, Variton, and Venitol) to delay disease progression.
 

Pathophysiology

Although the causal and temporal sequences of events that occur during the development and progression of chronic venous disease have not been ascertained, the emerging twin themes of disturbed venous-flow patterns and chronic inflammation may underlie all the clinical manifestations of the disease (Figure 2).24
 

Figure 2. Clinical manifestations of chronic venous disease.
After reference 24: Bergan et al. N Engl J Med. 2006;355(5):488-498. © 2006, Massachusetts Medical Society


Evidence has accumulated in the past years that inflammation could be key in wall remodeling, valve failure, and subsequent venous hypertension.25,26 Research interest has recently focused on possible chronic inflammatory processes that can affect large and small venous vessels and valves.24,27,28
 
In such processes, various types of inflammatory mediators and growth factors are released, including vascular cell adhesion molecule-1 (VCAM-1), intercellular adhesion molecule-1 (ICAM-1), transforming growth factor β (TGF- β 1), fibroblast growth factor β (FGF- β 1) and vascular endothelial growth factor (VEGF). The inflammatory cascades in the vein wall and venous valves can cause progressive valvular incompetence and eventual valvular destruction.27
 
Degenerative changes and incompetence in microvenous valves can create reflux into the microvenous networks in the skin, which may be involved in the development of the severe skin changes that are observed with chronic venous disease. It is unknown whether microvalve alterations could also be responsible for symptoms that appear early in the progression of the disease, particularly in the C0s patients. Research is currently ongoing to determine the origin of the symptoms in C0s patients.28
 
Once initiated, venous valve damage will be self-reinforcing, exacerbating venous hypertension and disturbance of venous flow and causing further inflammation.29 Therefore, early diagnosis and earlier treatment aiming to prevent venous hypertension, reflux, and inflammation can alleviate symptoms of chronic venous disease and reduce the risk of ulcers, both of which reduce the quality of life and are expensive to treat.24
 

Role of venoactive drugs

Pharmacological treatment with venoactive drugs and compression therapy are currently used to treat C0s patients.24 Nevertheless, the role of venoactive drugs in the prevention of the natural history of chronic venous disease remains to be determined: are all venoactive drugs able to prevent future morbidity? Research advances have led to an appreciation of the importance of chronic inflammatory processes throughout the course of the condition. Such processes in the valves and walls of veins of all sizes and also in the skin lead toward the development of varicose veins and leg ulcers. Currently available drugs directed toward preventing or limiting the inflammatory response at all stages of the condition may play a significant role in preventing or slowing the development and recurrence of troublesome outward manifestations. These pharmacological agents deserve detailed study.29,30
 
Chronic-venous-disease–related symptoms constitute the most important indication for venoactive drugs in patients at any stage of the disease. There are insufficient data to specify those CEAP clinical classes for which the benefits will be greatest, but it is reasonable to assume that patients at all stages of the disease and particularly at the early C0s stage may benefit.29,31
 
Indeed, as regards venoactive drugs, the studies demonstrating the efficacy of MPFF in reducing the initial components of the inflammatory cascade, as well as the recent studies conducted in C0s and C1 patients showing that MPFF alleviated the transitory venous reflux and reduced the venous symptoms, suggest the possibility that MPFF could also be of benefit in the early stage of chronic venous disease and might inhibit inflammation-induced damage and disease progression.27,32,33
 

Pharmacological and therapeutic effects of micronized purified flavonoid fraction

MPFF is a flavonoid-based venoactive drug composed of 90% micronized diosmin and 10% other active combined flavonoids (expressed as hesperidin, diosmetin, linarin, and isorhoifolin—which all contribute to the pharmacological effect). This unique composition makes MPFF more potent than diosmin alone.34,35 In many guidelines, MPFF is indicated as a first-line treatment for chronic-venous-disease–related symptoms and edema in a broad spectrum of patients at all stages, and it is the only venoactive drug indicated as an adjunct treatment to conventional therapy for the treatment of venous leg ulcers, owing to its wide range of evidence-based pharmacological and therapeutic effects.30,36
 
Effects on venous tone
MPFF acts on venous tone by modulating noradrenergic signaling and reducing norepinephrine metabolism.36 The effect of MPFF (two 500-mg tablets daily) on venous tone was shown in an open-label study in women with unilateral varicose veins and, in the other leg, an abnormal elasticity modulus value, as measured using air plethysmography, but no visible varicose veins. The elasticity modulus increased significantly in the treated group, confirming that MPFF improves venous tone in patients with a high risk of developing varicose veins.37 In another trial, treating patients with MPFF (two 500-mg tablets daily) reduced venous distension and venous capacitance and improved venous tone in women with various grades of venous insufficiency, ie, healthy women, women with venous insufficiency related to postthrombotic syndrome, and pregnant women.38
Antioxidant action and effects on inflammatory mediators
MPFF inhibits oxygenated free radical production in vitro in zymosan-stimulated human neutrophils, rat leukocytes, and mouse macrophages. Additional trials demonstrated that MPFF normalizes the release of prostaglandin E2 (PGE2) and prostaglandin F2a (PGF2a) and synthesis of thromboxane B2 in inflammatory granulomas in rats; reduces the bradykininor ischemia-induced microvascular permeability in rat cremaster muscle; reduces the histamine-, bradykinin-, leukotriene-B4–induced ischemia and reperfusion or oxidant challenge in the hamster cheek pouch; and protects the endothelial cells from lipid peroxidation in bovine aortic endothelial cells and human skin fibroblasts.39-41
Effects on leukocyte activation and adhesion
Former pharmacological studies in animals have demonstrated that MPFF inhibits venous inflammation by reducing leukocyte rolling, adhesion, and migration; by decreasing the number of parenchymal dead cells after venular mesenteric occlusion; and by reducing leukocyte adhesion and/or migration after ischemia-reperfusion injury. In clinical studies, MPFF reduced the expression of monocyte or neutrophil CD62L and the endothelial activation markers ICAM-1 and VCAM-1 on human leukocytes from patients with venous ulcers.39-41
Effects on capillary permeability and resistance
MPFF decreases the volume of induced edema in the rat paw and improves microvascular reactivity and functional capillary density after ischemia and reperfusion in the hamster cheek pouch. In humans, MPFF significantly improved capillary hyperpermeability compared with placebo in patients with idiopathic cyclic edema, decreased the abnormal capillary filtration rate in patients with chronic venous insufficiency as evaluated using strain gauge plethysmography, and significantly improved capillary resistance compared with placebo in patients with abnormal capillary fragility.42,43
Effects on lymphatics
MPFF increases lymphatic drainage owing to its noradrenergic action on the lymphatic system. MPFF increases the frequency and strength of contractions of lymphatic vessels, significantly lowers intralymphatic pressure, limits the diameter of lymphatic capillaries, and increases the number of functional lymphatic capillaries, which results in an improvement in lymphatic drainage in patients suffering from skin changes.44,45
Protective effects of MPFF against inflammationrelated valve damage in chronic venous disorders
MPFF blocks the effects of chronic inflammation in the microcirculation and macrocirculation as shown in the pharmacological studies.41 In a model of venous occlusion and reperfusion, elevation of venous blood pressure increased inflammation and tissue injury.46 In MPFF-treated animals, markers of inflammation decreased in a dose-dependent manner. MPFF also significantly reduced parenchymal cell death, leukocyte rolling, adhesion to postcapillary venules, and migration.47 In rats with venous hypertension induced by creating an arteriovenous fistula, Takase et al showed that MPFF treatment resulted in a significant, dose-dependent reduction in the reflux rate in rats with higher than normal venous hypertension, demonstrating the protective effects of MPFF on the macrocirculation.48 These data suggest that by delaying or blocking the inflammatory reaction in venous valves and walls, MPFF may delay the development of venous reflux and suppress damage to valve structures in a rat model of venous hypertension. These outcomes were confirmed in another study using the same animal model. MPFF reduced edema and fistula blood flow produced by an acute arteriovenous fistula and reduced granulocyte and macrophage infiltration into the valves, in line with the previous study.49
 
In clinical trials, treatment with 1000 mg/day of MPFF for 2 months in patients consulting with complaints related to chronic venous disorders of the lower extremities but without visible signs (therefore, who are categorized as C0s according to the CEAP classification system [Table I]) and who presented with transient evening reflux in the great saphenous vein (GSV) resulted in the elimination of the GSV reflux in most of the treated patients and a decrease in vein diameter; it also had beneficial effects on symptom relief and quality of life (Figure 3).33
 

Figure 3. Symptom intensity on the 10-cm visual analog scale (VAS) before (baseline) and after MPFF treatment (at 2 months).
Abbreviation: MPFF, micronized purified flavonoid fraction.
After reference 33: Tsukanov et al. Phlebolymphology. 2015;22(1):18-24. © 2015,
Les Laboratoires Servier.


In another trial conducted recently with C1s patients presenting with telangiectasia and/or reticular veins and end-of-day leg complaints, a duplex scan examination was performed after a “day orthostatic loading test (DOL-test)” whereby measurements were taken after the patient spent a full day in the standing position. Transient reflux was found in half (55.2%) of the patients. The use of MPFF 1000 mg/day for 3 months significantly decreased the intensity of their chronic-venousdisease–related symptoms and improved their quality of life. In parallel, MPFF eliminated the transient reflux and decreased vein dilation. This provides additional proof of the capacity of MPFF to restore the viscoelastic properties of the venous wall, to protect valve structure at the very early stages of disease, and presumably to protect patients against further complications. 32
 
In addition, a subgroup of patients who were in CEAP class C2 and had GSV reflux even after surgery underwent a 3-month treatment with MPFF 1000 mg/day. After MPFF treatment, the reflux was significantly reduced in 60% of the patients, and the reflux was resolved in 40% of the patients.50
 
Investigators reported a correlation between the clinical and the ultrasound results of MPFF treatment and stated that of the patients with a situational GSV reflux, patients complained of evening heaviness in their legs (n=77), moderate pain at the end of the day (n=31), and nighttime cramps (n=47). By treatment with MPFF alone for C0s and C1S patients or the combination of MPFF and an elimination of the varicose tributaries and preservation of the GSV for C2 patients, it was possible to recover an impaired GSV function in 78.2% of patients with a situational GSV reflux and to significantly improve the GSV function (ie, reflux extent and duration) in 21.8% of cases. MPFF led to the complete disappearance of leg heaviness in 87.2% of patients, and 12.8% of patients felt a significant decrease in the intensity of the heaviness. Moderate pain at the end of the day and nighttime cramps disappeared in all patients. These clinical changes occurred synchronously with the elimination of GSV reflux (Figure 4).50
 

Figure 4. Correlation of clinical and ultrasound results of MPFF treatment.
Abbreviations: GSV, great saphenous vein; MPFF, micronized purified flavonoid fraction.
After reference 50: Tsukanov et al. Phlebolymphology.2017;24(3):144-151. © 2017, Les Laboratoires Servier.

Conclusion

Overall, a determined and proactive approach to the treatment of the early stages of chronic venous disease could reduce the number of patients progressing to higher CEAP classes each year.
 
MPFF, owing to its unique composition and features, demonstrates significant anti-inflammatory and venoprotective actions, and it is clearly distinguished from other venoactive drugs in that it provides rapid and substantial relief of chronicvenous-disease–related symptoms at all CEAP stages and also preserves the venous walls and valves both in experimental and clinical studies. Recently, treatment with MPFF has also been shown to reduce the transient orthodependent regional hypervolemia that results from a weakening of the muscular-tonic function of the venous wall and to eliminate the transient reflux in the GSV in most of the treated patients at the very early stages of chronic venous disease, besides its beneficial effects on symptom relief and quality of life. These data support an approach that aims to prevent chronic venous disease progression from early to severe stages, suggesting MPFF as a basic multipurpose treatment option.
 
Additional studies with longer follow-up periods are needed in C0s and C1s chronic venous disease patients in order to further elucidate the physiopathology in the early stages of the disease, to investigate the presence of evening reflux in the distal venules due to damage to microvalves, and to determine the role of venoactive drugs in the prevention of the progression of chronic venous disorders.

 

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