MANAGEMENT OF CHRONIC VENOUS INSUFFICIENCY

Introduction

Chronic venous insufficiency (CVI) is an advanced chronic venous disease, which peculiarly affects the venous system of the lower extremities with venous hypertension. This condition encompasses a spectrum of pathologies including pain, edema, skin changes and ulcerations.^1-3Eberhardt RT, Raffetto JD. Chronic Venous Insufficiency. Circulation. 2005;111:2398-2409.
Alguire PC, Mathes BM. Chronic venous insufficiency and venous ulceration. J Gen Intern Med. 1997;12(6):374-83.
Taute BM. Chronic venous insufficiency. Internist (Berl). 2010;51(3):351-7.   It exerts a negative impact on the quality of life (QoL) of the affected individuals and is associated with significant morbidity and high economic burden.¹Eberhardt RT, Raffetto JD. Chronic Venous Insufficiency. Circulation. 2005;111:2398-2409.  ^,2Alguire PC, Mathes BM. Chronic venous insufficiency and venous ulceration. J Gen Intern Med. 1997;12(6):374-83.   A glance through the epidemiological data has revealed that the prevalence of CVI that usually affects lower limbs varies between 25% and 40% in women, and 10% to 20% in men.⁴Al Shammeri O, AlHamdan N, Al-Hothaly B, Midhet F, Hussain M, Al-Mohaimeed A. Chronic Venous Insufficiency: prevalence and effect of compression stockings. Int J Health Sci (Qassim). 2014;8(3):231-6.   However, a recent cross-sectional study⁴Al Shammeri O, AlHamdan N, Al-Hothaly B, Midhet F, Hussain M, Al-Mohaimeed A. Chronic Venous Insufficiency: prevalence and effect of compression stockings. Int J Health Sci (Qassim). 2014;8(3):231-6.   has ascertained the prevalence of CVI to be 61.1%; 69% in females and 45% in males in certain parts of the world (figure 1), which is a cause of considerable concern. The immense burden of CVI underscores the need for prompt diagnosis and appropriate therapeutic strategy. In context to this, diosmin, a venoactive drug has emerged as a promising agent for the management of CVI.⁵European and American guidelines on primary chronic venous disease: what’s new? Available at: http://www.medicographia. com/2011/12/european-and-american-guidelines-onprimary-chronic-venous-disease-what%E2%80%99s-new/ Accessed on: 10.2.2015.  ^,6Maksimovic ZV, Maksimovic M, Jadranin D, Kuzmanovic I, Andonovic O. Medicamentous treatment of chronic venous insufficiency using semisynthetic diosmin–a prospective study. Acta Chir Iugosl. 2008;55(4):53-9.  

An overview of the mechanisms underlying normal venous function

A comprehensive knowledge about the normal venous anatomy and function is imperative in order to appreciate the pathophysiology of CVI. The peripheral venous system acts as a reservoir to store blood and also functions as a channel to return blood to the heart, as depicted in figure 2.¹Eberhardt RT, Raffetto JD. Chronic Venous Insufficiency. Circulation. 2005;111:2398-2409.  ^,2Alguire PC, Mathes BM. Chronic venous insufficiency and venous ulceration. J Gen Intern Med. 1997;12(6):374-83.  ^,7Black CM. Anatomy and physiology of the lower-extremity deep and superficial veins. Tech Vasc Interv Radiol. 2014;17(2):68-73.   Proper functioning of the peripheral venous system depends on a series of valves and muscle pumps. Venous valves direct flow from the superficial to the deep system and from the distal to the proximal deep veins. The valves on the distal side are greater in number, where the hydrostatic pressure is the highest. The pumping action of the leg muscles is mainly involved in causing movement of the blood from the legs toward the heart. As blood is expelled from the deep system by muscular contraction, it is drawn from the superficial to the deep system, thereby reducing the superficial venous pressure. The valves prevent regurgitation

during muscle relaxation, and protect the superficial veins and capillaries from sudden elevation in venous pressure. The normal venous pressure in the superficial system during ambulation is 15-30 torr. It has been suggested that pressures higher than this may constitute venous hypertension, that is considered the chief predisposing factor in CVI.¹Eberhardt RT, Raffetto JD. Chronic Venous Insufficiency. Circulation. 2005;111:2398-2409.  ^,2Alguire PC, Mathes BM. Chronic venous insufficiency and venous ulceration. J Gen Intern Med. 1997;12(6):374-83.  ^,7Black CM. Anatomy and physiology of the lower-extremity deep and superficial veins. Tech Vasc Interv Radiol. 2014;17(2):68-73.  

Pathophysiology of chronic venous insufficiency

The pathophysiology of CVI is intriguingly complex. The fact that many putative mechanisms have been proposed to explain its underlying pathophysiology reflects complexity of its mechanism of development. Overall, it appears plausible that CVI develops as a result of various concurrently occurring and intertwined pathological processes, which ultimately culminate in the development of this disorder. Previous studies emphasize on the role of mechanical valve failure, however, rapid research has resulted in the surfacing of many startling facts which reveal the significant role of other mechanisms such as systemic dysregulation of connective tissue synthesis, mechanical forces of venous hypertension, and cellular inflammatory reaction (figure 3).⁸Schmid-Schonbein GW, Takase S, Bergan JJ. New advances in the understanding of the pathophysiology of chronic venous insufficiency. Angiology. 2001;52 Suppl 1:S27-34.  ^,9Chieh-Min Fan. Venous Pathophysiology. Semin Intervent Radiol. 2005; 22(3): 157-161.  

Accumulating evidences suggest that pressures higher than normal venous pressure may lead to venous hypertension which results in the development of CVI, particularly in the presence of valvular incompetence or venous obstruction. Moreover, loss of the normal reflexive constriction of the precapillary arterioles during standing, which usually protects the capillary bed from surges in hydrostatic pressure, may further augment the deleterious effects of venous hypertension. The raised pressure gets transferred directly to the capillary network of the skin, thereby resulting in several morphologic changes due to sustained hypertension at the capillary level, such as elongation and dilation of the capillary bed, enhanced surface area of the endothelium, increased type IV collagen in the basement membrane, and the formation of a pericapillary fibrin cuff. This may increase the permeability of the capillaries which may in turn enable the entry of large molecules such as fibrinogen. It is presumed that leaked fibrinogen may convert to fibrin in the pericapillary space. Besides these changes in microcirculation, fragmentation and obliteration of the cutaneous lymphatic network may occur resulting in reduced lymphatic flow.

Investigators have suggested that these changes play a role in determining the severity of the venous hypertension, and may contribute to the local edema and inflammation, commonly associated with CVI. Furthermore, an association between rheologic disorders and venous hypertension has been established. Low shear stresses which are commonly observed with high venous pressure are associated with erythrocyte aggregation. Erythrocyte aggregation in turn decreases oxygen transport capacity, decelerates arteriolar circulation, and expands the capillary spaces. Additionally, leukocytes may also aggregate in capillary beds with low shear stresses and may activate and release proteolytic enzymes, leading to increased capillary permeability and local inflammatory changes. It has been suggested that indicators of an inflammatory reaction that serve as active players in the development of primary venous valve dysfunction can be determined during early stages of CVI.²Alguire PC, Mathes BM. Chronic venous insufficiency and venous ulceration. J Gen Intern Med. 1997;12(6):374-83.  ^,8Schmid-Schonbein GW, Takase S, Bergan JJ. New advances in the understanding of the pathophysiology of chronic venous insufficiency. Angiology. 2001;52 Suppl 1:S27-34.  ^–11Rathbun SW, Kirkpatrick AC. Treatment of chronic venous insufficiency. Curr Treat Options Cardiovasc Med. 2007;9(2):115-26.   An array of risk factors have been identified which contribute to the development of CVI.

Risk factors for chronic venous insufficiency

Evidence emerging from accrued clinical reports suggests a number of risk factors to be associated with CVI including old age, female gender, family history of varicose veins, obesity, pregnancy, phlebitis, and previous leg injury. In addition, environmental or behavioral factors may be associated with CVI such as standing for a longer duration and perhaps a sitting posture at work.¹Eberhardt RT, Raffetto JD. Chronic Venous Insufficiency. Circulation. 2005;111:2398-2409.  ^,12Jawien A. The Influence of Environmental Factors in Chronic Venous Insufficiency. Angiology. 2003;54Suppl1:S19-S31.  ^,13Fowkes FGR, Evans CJ, Lee AJ. Prevalence and Risk Factors of Chronic Venous Insufficiency. Angiology. 2001;52Suppl1:S5-S15.   Herman and colleagues conducted a study¹⁴Musil D, Herman J. Chronic venous insufficiency–outpatient study of risk factors. Vnitr Lek. 2004;50(1):14-20.   involving 100 patients with CVI to evaluate various factors that predispose to CVI. The results unveiled that CVI cases were more prevalent in overweight and obese (BMI > 25 kg/ m2) men and women. It was observed that CVI cases were less common in nulliparous/uniparous women as compared to multiparous women (31.7% vs. 68.3%; figure 4). Moreover, a positive family history accounted for a majority of patients with CVI (71%); 88.7% cases were reported in first grade relatives. Posture at work also contributed significantly; 59% patients used to stand while working and 32% had a sedentary lifestyle. Moreover, only 27% patients with CVI were smokers. CVI was also common among those women who had a significant history of hormonal treatment (37.8%), especially those who were younger than 40 years (48%). Apart from these, other risk factors such as accidents and surgeries of lower extremities, recurrent thrombophlebitis were documented in a small proportion of patients (table 1).¹⁴Musil D, Herman J. Chronic venous insufficiency–outpatient study of risk factors. Vnitr Lek. 2004;50(1):14-20.   Furthermore, some of the factors such as

diet, physical activity and exogenous hormone use are not well established. However, they may play a pivotal role in the development of chronic venous disease and its clinical manifestations.¹⁵Beebe-Dimmer JL, Pfeifer JR, Engle JS, Schottenfeld D. The epidemiology of chronic venous insufficiency and varicose veins. Ann Epidemiol. 2005;15(3):175-84.  

Clinical presentation

Chronic venous insufficiency is a major problem and is associated with widely varied clinical manifestations comprising vascular, dermal, and subcutaneous tissue damage and restructuring.^8  ,16Karch A, Kasperczyk J. Somatic risk factors for chronic venous insufficiency in women–preliminary report. Wiad Lek. 2002;55 Suppl 1:212-6.   The most prevailing form of CVI is the varicose vein. Progression of CVI is usually accompanied by a tan or reddish brown hue to the skin, typically at the medial ankle. As the disease advances, small erosions with weeping and excoriations may develop on the skin due to scratching. Furthermore, lipodermatosclerosis, a fibrosing panniculitis of the leg, may develop with rise in severity and can be felt as a firm induration at the medial ankle, and in the most advanced cases, can extend circumferentially up to the mid-leg. The skin over the panniculitis is often heavily pigmented and bound down to the subcutaneous tissues. Occurrence of substantial and constrictive fibrosis may girdle the lower third of the leg resulting in a brawny edema above the fibrosis and on the foot below. Investigators have suggested that an advanced case of lipodermatosclerosis may look like an inverted champagne bottle (figure 5). It is noteworthy that within the areas of heavy pigmentation, 2- to 5-mm

macules of depigmentation and atrophie blanche may be present, which represents avascular, fibrotic skin and are likely to cause ulcer formation. Venous ulcers may develop on the medial ankle, in the area of lipodermatosclerosis. These ulcers may be single or multiple, and are typically tender, shallow, and have a red base that may be exudative. The borders are generally irregular and not undermined, but if left unattended or untreated, the ulcer may extend to cover the entire circumference of the leg. The aforementioned features may in turn significantly impair the QoL.²Alguire PC, Mathes BM. Chronic venous insufficiency and venous ulceration. J Gen Intern Med. 1997;12(6):374-83.  

Impact of chronic venous insufficiency on the quality of life

Chronic venous insufficiency compromises the QoL of the affected individuals to a considerable extent. The Venous Insufficiency Epidemiological and Economical Study (VEINES)⁹Chieh-Min Fan. Venous Pathophysiology. Semin Intervent Radiol. 2005; 22(3): 157-161.   assessed the effect of CVI on the QoL of the study population. The results demonstrated that 65.2% of individuals with varicose veins had additional venous disease processes such as edema, skin changes and ulceration. Moreover, a decline in both, physical and mental QoL scores was witnessed with increase in severity of concomitant venous disease.⁹Chieh-Min Fan. Venous Pathophysiology. Semin Intervent Radiol. 2005; 22(3): 157-161.   Another study by Andreozzi¹⁷Andreozzi GM, Cordova RM, Scomparin A, Martini R, D’Eri A, Andreozzi F; Quality of Life Working Group on Vascular Medicine of SIAPAV. Quality of life in chronic venous insufficiency. An Italian pilot study of the Triveneto Region. Int Angiol. 2005;24(3):272-7.   also reported progressive impairment in the QoL of patients with CVI, especially involving the physical items and the emotional role. Worsening of mental items occurred only in advanced stages. Thus, the negative impact of CVI on the QoL underscores the need for early diagnosis and optimal management.1¹⁷Andreozzi GM, Cordova RM, Scomparin A, Martini R, D’Eri A, Andreozzi F; Quality of Life Working Group on Vascular Medicine of SIAPAV. Quality of life in chronic venous insufficiency. An Italian pilot study of the Triveneto Region. Int Angiol. 2005;24(3):272-7.  

Diagnosis

Chronic venous insufficiency may result in devastating sequelae in terms of patients’ lifestyles, thereby warranting a timely and optimal diagnostic workup.¹⁸Krishnan S, Nicholls SC. Chronic Venous Insufficiency: Clinical Assessment and Patient Selection. Semin Intervent Radiol. 2005; 22(3): 169-177.  ^,19Mussa FF, Peden EK, Zhou W, Lin PH, Lumsden AB, Bush RL. Iliac vein stenting for chronic venous insufficiency. Tex Heart Inst J. 2007;34(1):60-6.   This comprises recording of a meticulous history, careful physical examination, and bedside diagnostic tests. The CEAP scale that includes clinical, etiologic, anatomic and pathophysiologic aspects can be employed to assess this disorder. Clinical and etiological grading is as mentioned in table 2. The diagnosis can be further confirmed by a plethora of tests available such as duplex ultrasonography, venography, plethysmography, and ambulatory venous pressure measurement. Since decades, ultrasound doppler remains the benchmark for the diagnosis of venous system, however, among the various methods, ascending phlebography is considered the most precise and useful method to obtain detailed anatomy of the venous system, venous patency and identify perforans veins followed by descending phlebography that can aid in determining the venous reflux and morphology of venous valves. Another radiological method which can evaluate the mapping of venous network is varicography that involves injection of the contrast medium directly into the veins. Furthermore, an invasive study but not exposing to the emission of ionizing radiation, is a measurement of the ambulatory venous pressure.¹⁸Krishnan S, Nicholls SC. Chronic Venous Insufficiency: Clinical Assessment and Patient Selection. Semin Intervent Radiol. 2005; 22(3): 169-177.  ^,20Kasperczak J, Ropacka-Lesiak M, Breborowicz HG. Definition, classification and diagnosis of chronic venous insufficiency – part II. Ginekol Pol. 2013;84(1):51-5.  ^,21Thorisson HM, Pollak JS, Scoutt L. The role of ultrasound in the diagnosis and treatment of chronic venous insufficiency. Ultrasound Q. 2007;23(2):137-50.  Based upon the findings of these examinations, an accurate diagnosis

can be made which may in turn help in instituting a pertinent management approach.¹⁸Krishnan S, Nicholls SC. Chronic Venous Insufficiency: Clinical Assessment and Patient Selection. Semin Intervent Radiol. 2005; 22(3): 169-177.  

Management

An overview of treatment strategies

Treatment goals for patients with CVI include reduction of venous valvular reflux, thereby blocking the pathologic inflammatory process that usually occurs as a consequence; elimination of lipodermatosclerosis; and healing of ulcers.²Alguire PC, Mathes BM. Chronic venous insufficiency and venous ulceration. J Gen Intern Med. 1997;12(6):374-83.  ^,11Rathbun SW, Kirkpatrick AC. Treatment of chronic venous insufficiency. Curr Treat Options Cardiovasc Med. 2007;9(2):115-26.   The treatment modalities can be categorized into mechanical, drug and surgical. Mechanical approach comprising compression therapy that makes use of pumps, bandages, and/ or graded compression stockings remains the cornerstone of treatment.²²Raffetto JD, Marston WA. Venous ulcer: what is new? Plast Reconstr Surg. 2011;127 Suppl 1:279S-288S.   A wealth of data suggests its efficacy in reducing venous hypertension, impeding development of inflammation and pathologic skin changes. Pharmacologic agents such as diuretics and topical steroid creams may reduce swelling and pain for a short duration, however, they do not provide long-term advantage.¹¹Rathbun SW, Kirkpatrick AC. Treatment of chronic venous insufficiency. Curr Treat Options Cardiovasc Med. 2007;9(2):115-26.   Among the several pharmacological agents available, diosmin, a venoactive drug has emerged as an effective drug for the management of CVI.⁵European and American guidelines on primary chronic venous disease: what’s new? Available at: http://www.medicographia. com/2011/12/european-and-american-guidelines-onprimary-chronic-venous-disease-what%E2%80%99s-new/ Accessed on: 10.2.2015.  ^,6Maksimovic ZV, Maksimovic M, Jadranin D, Kuzmanovic I, Andonovic O. Medicamentous treatment of chronic venous insufficiency using semisynthetic diosmin–a prospective study. Acta Chir Iugosl. 2008;55(4):53-9.   Apart from these therapies, endovascular and surgical techniques may hold great promise in treatment of primary and secondary venous valvular reflux by improving venous hemodynamics and promoting healing of venous ulcers. Other endovascular treatments of varicose veins using laser, radiofrequency ablation, and chemical foam sclerotherapy may also be employed, tailored to individual patients’ needs.1¹¹Rathbun SW, Kirkpatrick AC. Treatment of chronic venous insufficiency. Curr Treat Options Cardiovasc Med. 2007;9(2):115-26.  ^,23Shenoy MM. Prevention of venous leg ulcer recurrence. Indian Dermatol Online J. 2014;5(3):386-9.  

Pharmacotherapy: Diosmin as a potential candidate in chronic venous insufficiency

Robust research in basic and clinical neurosciences highlights the immense potential of several agents for the treatment of CVI. Among numerous pharmacological agents that have been proposed, diosmin, a drug belonging to the class of venoactive drugs offers great potential in management of patients with CVI.⁵European and American guidelines on primary chronic venous disease: what’s new? Available at: http://www.medicographia. com/2011/12/european-and-american-guidelines-onprimary-chronic-venous-disease-what%E2%80%99s-new/ Accessed on: 10.2.2015.  ^,24Gohel MS, Davies AH. Pharmacological agents in the treatment of venous disease: an update of the available evidence. Curr Vasc Pharmacol. 2009;7(3):303-8.   The precise mechanism of action of venoactive drugs remains obscure. However, they are associated with significant clinical benefits due to their various modes of action. Diosmin, a member of the citrus flavonoid family, prolongs the vasoconstrictor effect of norepinephrine on the vein wall, raises the venous tone, and thus decreases venous capacitance, distensibility, and stasis. In addition, it ameliorates lymphatic drainage by increasing the frequency and intensity of lymphatic contractions and decreases the diameter of the lymphatic capillaries simultaneously. It also exhibits anti-inflammatory, free-radical scavenging, and antimutagenic properties. Some of the metabolic effects of diosmine are mentioned in table 3. Furthermore, it has been suggested that capillary hyperpermeability is primarily involved in the occurrence of inflammation. Diosmin effectively reduces capillary hyperpermeability and augments capillary resistance by protecting microcirculation from the damaging processes. Voluminous data also indicates its role in reducing the expression of endothelial adhesion molecules and inhibiting the adhesion, migration, and activation of leukocytes at the capillary level, thereby decreasing inflammation and permeability and thus reducing edema. The various modes of action of diosmin and its benefits are illustrated in figure 6.²⁵Noorafshan A, Karbalay-Doust S, Karimi F. Diosmin reduces calcium oxalate deposition and tissue degeneration in nephrolithiasis in rats: a stereological study. Korean J Urol. 2013;54(4):252-7.  ^–31Perrina M, Rameletb AA. Pharmacological Treatment of Primary Chronic Venous Disease: Rationale, Results and Unanswered Questions. European Journal of Vascular and Endovascular Surgery. 2011;41(1):117-125.  

The literature is replete with the benefits of diosmin in CVI. Andonovic and colleagues⁶Maksimovic ZV, Maksimovic M, Jadranin D, Kuzmanovic I, Andonovic O. Medicamentous treatment of chronic venous insufficiency using semisynthetic diosmin–a prospective study. Acta Chir Iugosl. 2008;55(4):53-9.   evaluated the efficacy of diosmin in 80 patients with CVI, who were not subjected to any other mode of treatment previously. The results demonstrated significant improvement in terms of lowered numerical values of some of the clinical signs, after treatment with diosmin; edema (1.50 vs. 0.94), pain (1.84 vs. 1.10), feeling of heaviness (1.96 vs. 1.20), and tightness (1.78 vs. 1.14; figure 7). Moreover, considerable

improvement was observed in the parameters of physical, social, and psychological quality-of life, accompanied with significantly improved CEAP stage of CVI (3.40 vs. 3.00). Another study³²Kirienko AI, Bogachev VIu, Zolotukhin IA, Golovanova OV. Semisynthetic Diosmin (Phlebodia 600) for therapy of lower limb chronic venous insufficiency. Angiol Sosud Khir. 2006;12(2):73-5.   also revealed favorable outcomes on treatment with diosmin in patients with II-III CEAP classes of CVI. The drug was highly effective and exhibited a good safety profile. Owing to its advantages, diosmin based formulations are also widely used.

Advantages of Micronization

Mounting evidence suggests that micronization remarkably intensifies the protective effects of the purified flavonoid fraction. This improvement is likely to be attributed to the fact that micronized formulations are associated with better absorption, which in turn raises the efficacy of the molecule.³³Cyrino FZ, Bottino DA, Lerond L, Bouskela E. Micronization enhances the protective effect of purified flavonoid fraction against postischaemic microvascular injury in the hamster cheek pouch. Clin Exp Pharmacol Physiol. 2004;31(3):159-62.   In clinical trials, micronized diosmin based formulation has demonstrated its efficacy in CVI by improving venous tone and vein elasticity assessed by plethysmography.³⁴Struckmann JR. Clinical efficacy of micronized purified flavonoid fraction: an overview. J Vasc Res. 1999;36 Suppl 1:37-41.   A double blinded study³⁵Garner RC, Garner JV, Gregory S, Whattam M, Calam A, Leong D. Comparison of the absorption of micronized (Daflon 500 mg) and nonmicronized 14C-diosmin tablets after oral administration to healthy volunteers by accelerator mass spectrometry and liquid scintillation counting. J Pharm Sci. 2002;91(1):32-40.   was conducted to assess the influence of particle size on the overall absorption of diosmin after oral administration of micronized (mean particle size = 1.79 microm, with 80% of particles having a size lower than 3.45 microm) and nonmicronized diosmin (mean particle size = 36.5 microm, with 80%

of particles comprised between 19.9 and 159 microm). The findings unraveled higher clinical efficacy of micronized formulation due to better absorption of the drug. Similar findings were corroborated in another randomized, double-blind, multicenter trial36 which compared the pharmacodynamic and clinical activities of micronized and nonmicronized diosmin in 90 patients with CVI of the lower limbs. Although statistically significant changes occurred in both treatment groups on comparison with baseline values, remarkable improvements were noticed in all clinical symptoms and plethysmographic parameters (maximum increase of venous volume at 60 mmHg and total time for emptying) in the micronized group than the nonmicronized diosmin group. The clinical and laboratory acceptability was similar in both groups. However, the percentage of satisfied patients was 95% and 80% in the micronized

and nonmicronized diosmin groups, respectively (figure 8). The investigators thus suggested better outcomes with micronized than nonmicronized formulation of diosmin, thereby rendering it advantageous for the treatment of CVI. Furthermore, findings of two randomized, double-blind placebo controlled trials showed that administration of micronized diosmin based formulation significantly reduced ankle or calf circumference, and improved various symptoms of CVI and plethysmographic parameters.³⁷Lyseng-Williamson KA, Perry CM. Micronised purified flavonoid fraction: a review of its use in chronic venous insufficiency, venous ulcers and haemorrhoids. Drugs. 2003;63(1):71-100.  

As mentioned before, CVI exerts negative impact on the patients’ QoL. Information available from the

RELIEF (Reflux assEssment and QoL improvEment with micronized Flavonoids) Studya href=”#” class=”tooltip”>³⁸ unveiled significant and progressive improvement in the signs of CVI owing to significant changes in the clinical class of the CEAP classification. Continuous clinical improvement was recorded throughout the study and was also associated with a remarkable and continuous progression in the QoL scores of all patients.³⁷Lyseng-Williamson KA, Perry CM. Micronised purified flavonoid fraction: a review of its use in chronic venous insufficiency, venous ulcers and haemorrhoids. Drugs. 2003;63(1):71-100.  ^,38Jantet G. Chronic venous insufficiency: worldwide results of the RELIEF study. Reflux assEssment and quaLity of lIfe improvement with micronized Flavonoids. Angiology. 2002;53(3):245-56.   It was thus suggested that the micronized drug is an effective and well tolerated treatment option in patients with CVI. Due to the comprehensive mode of action of micronized diosmin based formulation on the veins, lymphatics, and microcirculation, it is considered as an excellent option in the management of CVI, not only in the early stages but also in the severe stages, often in combination with compression treatment, sclerotherapy, and surgery if appropriate.³⁷Lyseng-Williamson KA, Perry CM. Micronised purified flavonoid fraction: a review of its use in chronic venous insufficiency, venous ulcers and haemorrhoids. Drugs. 2003;63(1):71-100.  ^,39Ramelet AA. Clinical benefits of Daflon 500 mg in the most severe stages of chronic venous insufficiency. Angiology. 2001;52 Suppl 1:S49-56.  

Conclusion

It has been suggested that pressures higher than normal venous pressure (15-30 torr) may constitute venous hypertension, considered the chief predisposing factor in CVI. Treatment goals for patients with CVI include reduction of venous valvular reflux, thereby blocking the pathologic inflammatory process that usually occurs as a consequence, elimination of lipodermatosclerosis, and healing of ulcers. Among the several pharmacological agents available, diosmin, a venoactive drug has emerged as an effective agent for the management of CVI. Furthermore, a wealth of data suggests that micronized form of diosmin is associated with comparatively favorable outcomes in terms of better absorption. Pharmacological and clinical studies have demonstrated the comprehensive mode of action of micronized diosmin based formulations; it increases venous tone, improves lymph drainage, and protects the microcirculation, thus considered a potent drug in the treatment of CVI.

References

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