Management of CVI

Introduction

Chronic venous insufficiency (CVI) is a common primary care problem associated with significant morbidity and health care costs, with presentation ranging from mild telangiectasias to skin ulceration and tissue loss.¹Alguire PC, Mathes BM. J Gen Intern Med. 1997;12(6):374-83.   The disorder may have poor prognosis, with serious impact on quality of life, seeing that in addition to poor cosmesis it can lead to chronic lifethreatening manifestations (infections/ulcers) of the lower extremities. Even so, it is often underdiagnosed in general practice owing to a wide range of initial symptoms.²Thorisson HM, Pollak JS, Scoutt L. Ultrasound Q. 2007 Jun;23(2):137-50.  

Essentially, CVI defines functional abnormalities of the venous system, and is caused by inadequate blood flow through the veins, usually in the lower limbs; and this can result in considerable discomfort with symptoms such as pain (pain, particularly after ambulating, is a hallmark of the disease), itchiness and tiredness in the legs, and edema. Besides, characteristic changes – lipodermatosclerosis – to the skin of the lower extremities lead to eventual skin ulceration.³Martinez MJ, Bonfill X, Moreno RM, et al. Cochrane Database Syst Rev. 2005;(3):CD003229.  ^,4Partsch H. Vasa. 2009;38(4):293-301.  

Epidemiology in the primary care setting

Prevalence estimates of CVI vary widely by geographic location and gender. Reports of prevalence vary from less than 1% to 40% in females and from less than 1% to 17% in males. In contrast, prevalence estimates for varicose veins, the consequence of CVI, are higher (<1% to 73% in females and 2% to 56% in males). The reported ranges presumably reflect differences in the population distribution of risk factors, accuracy in application of diagnostic criteria, and the quality and availability of medical diagnostic and treatment resources.⁵Beebe-Dimmer JL, Pfeifer JR, Engle JS, et al. Ann Epidemiol. 2005;15(3):175-84.   Peak incidence occurs in women aged 40-49 years and in men aged 70-79 years.⁶Brown KE. Available at: http://emedicine.medscape.com/ article/461449-overview [Accessed on 22/11/2012]  

Diagnosis

Generally, CVI is diagnosed by history and physical examination, often accompanied with functional venous testing. Classification systems have been developed to stratify according to the severity of the disorder and help guide therapeutic endeavours.⁷White JV, Ryjewski C. Perspect Vasc Surg Endovasc Ther. 2005;17(4):319-27.   For practical purposes, the disorder is characterized by advanced skin changes of hyperpigmentation, edema, ulceration, and scarring from healed ulcers or open ulcerations, summarized in the CEAP classification as Classes 4, 5 and 6 (Table 1).⁸Khilnani N. Available at: http://www.miit.com/2004/sat2004/ PathophysiologyKhilnani.pdf [Accesssed on 22/11/2012]  

Clinical presentation

The clinical presentation of CVI spans a spectrum from asymptomatic but cosmetically troublesome small blue ectatic veins and varicosities, to severe fibrosing panniculitis, dermatitis, edema, and ulceration.⁹Alguire PC, Mathes BM. Available at: http://cmbi.bjmu.edu.cn/uptodate/vascular%20medicine/Venous%20insufficiency-thromboembolism/Epidemiology%20and%20clinical%20manifestations%20of%20chronic%20venous%20insufficiency.htm [Accessed on 22/11/2012].   In general, edema, hyperpigmentation, and lipodermatosclerosis are the early manifestations; and late complications include cutaneous ulceration and

delayed healing. An epidemiological, cross-sectional, multicenter study aimed to describe the general characteristics, risk factors and clinical symptoms of patients seeking medical care at the primary care setting because of CVI found that heaviness in the legs and itching were the most common symptoms, whereas ankle edema was the most frequent sign followed by telangiectasia (figure 1).¹⁰Callejas JM, Manasanch J; ETIC Group. Int Angiol. 2004 Jun;23(2):154-63.  

Overall, the most common physical signs of venous insufficiency are those attributed to the progressive syndromes of chronic venous stasis and chronic venous hypertension – these signs include: swelling; edema; hyperpigmentation; venous dermatitis; chronic cellulitis; dilated vein above the ankle; cutaneous infarction; and ulceration.¹¹Weiss R. Available at: http://emedicine.medscape.com/article/1085412-overview [Accessed on 22/11/2012].  

As follows, patients may develop serious symptoms such varicose veins, venous claudication, and leg ulcers (Table 2).⁶Brown KE. Available at: http://emedicine.medscape.com/ article/461449-overview [Accessed on 22/11/2012]  ^,12Nicolaides AN. Circulation. 2000;102(20):E126-63.   Whilst varicose veins are more likely to develop in women, men more commonly have venous ulcers.7 More than 80% of varicose veins seen on the leg are caused by venous insufficiency or a leaky valve in the great saphenous vein, which terminates near the inguinal ligament as it joins the common femoral vein.¹¹Weiss R. Available at: http://emedicine.medscape.com/article/1085412-overview [Accessed on 22/11/2012].  

Investigations

While the clinical manifestations of venous insufficiency are quite obvious, including edema, skin changes, and venous ulceration, and are often sufficient to make a diagnosis of venous hypertension in primary care in absence of diagnostic testing; nevertheless, testing such as Doppler ultrasonography may be warranted in some circumstances to confirm the diagnosis, determine the etiology (e.g., reflux, obstruction, or venous pump dysfunction), localize the anatomic site and level of disease, or rule out concurrent peripheral arterial disease.¹³Alguire PC, Mathes BM. Available at: Ahttp://cmbi.bjmu.edu.cn/uptodate/vascular%20medicine/Venous%20insufficiencythromboembolism/Diagnosis%20of%20chronic%20venous%20insufficiency.htm [Accessed on 23/11/2012]   Duplex Doppler ultrasonography may be the single best test to rule out deep venous thrombosis and other entities that can mimic CVI.1 Color Doppler-duplex sonography seems to be the diagnostic method of choice.¹⁴Renner R, Simon J. Dtsch Med Wochenschr. 2009;134(43):2181-90.  

In-clinic method – Trendelenburg test

Trendelenburg test, a traditional part of the physical examination, may help in distinguishing distal venous congestion caused by superficial venous reflux from that caused by incompetence of the valves in the deep venous system.¹¹Weiss R. Available at: http://emedicine.medscape.com/article/1085412-overview [Accessed on 22/11/2012].   However, its reliability, accuracy, and sensitivity are indefinite. The patient lies supine with the leg elevated to empty the veins, and a tourniquet is applied just below the saphenofemoral junction, about 3 cm below the inguinal ligament. The patient then stands up, the tourniquet is released.¹³Alguire PC, Mathes BM. Available at: Ahttp://cmbi.bjmu.edu.cn/uptodate/vascular%20medicine/Venous%20insufficiencythromboembolism/Diagnosis%20of%20chronic%20venous%20insufficiency.htm [Accessed on 23/11/2012]  

Results are interpreted as below:

• The veins will fill quickly from above if the saphenofemoral valve is incompetent.
• The veins will fill slowly from below if the valve is competent.
• The veins will fill rapidly from above before the release of the tourniquet if an incompetent valve is present at the entry of the long saphenous into the femoral vein.

Treatment

CVI requires “chronic management” to reduce both clinical symptoms and the development of chronic venous disease.¹⁵Boyle P, Diehm C, Robertson C. Int Angiol. 2003;22(3):250-62.   Regular activity, such as walking or running, bicycling, and swimming, is an important ameliorating factor in patients with early or mild venous insufficiency syndrome given that prolonged standing or sitting can aggravate the symptoms of venous insufficiency. However, patients with advanced disease do not tolerate activity well.¹¹Weiss R. Available at: http://emedicine.medscape.com/article/1085412-overview [Accessed on 22/11/2012].  

Initial nonsurgical treatments for CVI include: Leg elevation; Compression stockings; Unna boots (rolled bandages containing a combination of calamine lotion, glycerin, zinc oxide, and gelatin; mainstay of treatment for people with venous ulcers); and injection sclerotherapy (usually reserved for telangiectatic lesions rather than CVI).⁶Brown KE. Available at: http://emedicine.medscape.com/ article/461449-overview [Accessed on 22/11/2012]  ^,16Marusiak J, Strincl J, Rambousek Z, et al. Rozhl Chir. 2003; 82(3):161-9.  

Pharmacotherapy: Need beyond mechanical compression

Whilst treatment of venous insufficiency and venous ulceration had for many years relied on established principles of compression and limb elevation, a better understanding of the pathological mechanisms underlying skin damage in venous disease has allowed more rational pharmacotherapeutic approaches to be made.¹⁷Cheatle TR, Scurr JH, Smith PD. JR Soc Med. 1991; 84(6):354-8.  

Essentially, in practice, conservative therapy of CVI, which consists largely of compression treatment, often causes discomfort and has been associated with poor compliance. Moreover, epidemiological data show that standard compression therapy for leg ulceration in CVI often fails to effectively improve patients’ condition.¹⁸Roztocil K, Stvrtinová V, Strejcek J. Int Angiol. 2003; 22(1):24-31.   These facts make oral drug treatment an attractive management option.¹⁹Pittler MH, Ernst E. Cochrane Database Syst Rev. 2006;(1):CD003230.   Besides, available data suggest that a combination of pharmacologic and compression therapy may have additive effects.²⁰Wollina U, Abdel-Naser MB, et al. Int J Low Extrem Wounds. 2006;5(3):169-80.   Thus, safe and effective oral therapies for CVI would provide an important alternative or adjunct to mechanical compression treatment.²¹Siebert U, Brach M, Sroczynski G, et al. Int Angiol. 2002; 21(4):305-15.  

In fact, drug therapy remains the main and integral part of CVI treatment, aimed to protect venous wall, normalize permeability and alleviate CVI symptoms at microcirculatory level.²²Stoîko IuM, Gudymovich VG. Angiol Sosud Khir. 2006; 12(3):77-82.  

Venoactive drugs

Effectively, in many countries, the use of venoactive drugs (VADs) is generally considered as an adjunct to sclerotherapy or surgery. It seems that presently the best hypothesis is that the mechanisms responding to drugs are that involving leukocyte activation and their interaction with endothelial cells, followed by inflammatory processes.²³Marinović Kulišić S, Lupi D. Acta Dermatovenerol Croat 2012;20(3):197-200.  

Venoactive drugs are a group of medicinal products of plants or synthetic origin, which have effects on the edema and/or symptoms related to chronic venous disease. The main mechanisms of action are anti-edematous effect, increase in venous tone, and inhibition of different trigger factors of the last stages of chronic venous disease, for instance adherence of WBCs to venous wall and valves,

release of mediators of inflammation and synthesis of prostaglandins, and improvement of fibrinolysis and blood rheology. In general, VADs have two pathophysiological mechanisms of action. They alter macrocirculatory changes in venous wall and valves, and they also act at the microcirculatory level where they increase venous tone by the mechanisms related to noradrenaline pathway; here, they also attenuate various elements of the inflammatory cascade responsible for valve failure.²³Marinović Kulišić S, Lupi D. Acta Dermatovenerol Croat 2012;20(3):197-200.   In effect, actions of VADs on microcirculation include effects on capillary resistance, lymphatic drainage, protection against inflammation, and effects on blood flow.²³Marinović Kulišić S, Lupi D. Acta Dermatovenerol Croat 2012;20(3):197-200.  

Choice of VADs

Venoactive drugs can be classified as naturally occurring, synthetic drugs, and animal derived extracts.²³Marinović Kulišić S, Lupi D. Acta Dermatovenerol Croat 2012;20(3):197-200.   The alpha-benzopyrone coumarin has been used either alone or in combination with other VADs for the treatment of lymphedema. However, the risk of hepatotoxicity has dramatically limited its use.²³Marinović Kulišić S, Lupi D. Acta Dermatovenerol Croat 2012;20(3):197-200.   Oxerutins and rutosides are commonly prescribed in many European countries, but the heterogeneity between studies and the lack of large, recent randomized trials limit their worldwide use.²³Marinović Kulišić S, Lupi D. Acta Dermatovenerol Croat 2012;20(3):197-200.   Horse chestnut seed extract (HCSE) has been assessed in patients with venous ulceration, but studies have generally failed to demonstrate any clinical benefit.²³Marinović Kulišić S, Lupi D. Acta Dermatovenerol Croat 2012;20(3):197-200.  

Other plant extracts like Ruscus extracts (reduce capillary permeability), ginkgo biloba and proanthocyanidines, such as the maritime pine tree bark extract have been investigated, but only limited clinical benefits were observed and sample sizes were generally small.²³Marinović Kulišić S, Lupi D. Acta Dermatovenerol Croat 2012;20(3):197-200.   Pentoxifylline was the drug to be extensively studied; however, its current use is limited by the frequent occurrence of side effects (chiefly gastrointestinal).²³Marinović Kulišić S, Lupi D. Acta Dermatovenerol Croat 2012;20(3):197-200.  

Diosmin – the choice amongst VADs

Diosmin, a naturally occurring flavonoid, is considered to be a vascular-protecting agent used to treat CVI, and is widely used to relieve symptoms of CVI.²⁴Araujo D, Viana F, Osswald W. Pharmacol Res. 1991 Oct; 24(3):253-6.   The mechanisms of action prevent endothelial damage and suggest use of the drug in the early and advanced stages of CVI. As a flavonoid, diosmin also exhibits anti-inflammatory, free-radical scavenging, and antimutagenic properties.²⁵Diosmin Monograph. Alternative Medicine Review 2004;9(3).   Figure 2 shows the multimodal mechanisms of action of diosmin – the drug could affect inflammatory reactions associated

with venous hypertension, inhibition of leukocyte activation, adhesion and migration. Specifically, it may modify leukocyte endothelial interactions, inhibiting the expression of intercellular adhesion molecules (ICAM-1) and vascular adhesion molecules (VCAM), as well as the expression of leukocyte adhesion molecules on monocytes and neutrophils. Unlike other venoactive drugs, diosmin has proven efficacy in ulcer healing.²³Marinović Kulišić S, Lupi D. Acta Dermatovenerol Croat 2012;20(3):197-200.  

Long-term efficacy of diosmin in CVI

Diosmin is an effective drug of choice in all stages of CVI, including aggravated forms of the disorder. Batchvarov et al evaluated the efficiency of diosmin 600 mg received for one year by 256 patients with CVI, and found it to be effective in the management of pain, heaviness and swelling by reducing them. Patients in all phases of CVI demonstrated good tolerance to the drug, which was found to have the best effect in reducing the edema in patients with initial symptoms. Also, it had a very good effect on pain intensity in patients feeling heaviness and continuous pains in the lower legs in walking. The drug when applied for a longer period (2.5-3 months) and combined with routine surgical treatment, diosmin 600 mg has a good effect on severe trophic changes.²⁶Batchvarov IV, Batselova MG, Damyanov II. J Biomed Clin Res 2010;3(1).  

Micronized diosmin – an instance of further modification

The absorption of diosmin is improved by its micronization.²⁷Lyseng-Williamson KA, Perry CM. Drugs. 2003;63(1):71-100.   This micronized diosmin was found to have a statistically significant clinical effect on middle-sized trophic ulcers (5 – 10 cm2) that persisted for 6 – 12 months²⁸Savel’ev VS, Pokrovskií AV, Sapelkin SV, et al. Angiol Sosud Khir. 2006;12(3):53-60.  , and in pre- and postoperative period after phlebectomy helped to attenuate pain syndrome, to decrease postoperative hematomas and accelerate their resorption, to increase exercise tolerance in early postoperative period.²⁹Pokrovsky AV, Saveljev VS, Kirienko AI, et al. Angiol Sosud Khir. 2007;13(2):47-55.   Essentially, micronization enhances its capillary protective effect.

Surgical therapy

Surgical interventions are generally reserved for patients with discomfort or ulcers refractory to medical management, and directed towards correction of the underlying abnormal venous physiology, which involves removal of varicose veins and ablation of incompetent axial veins and relevant perforating veins. Patients with varicose veins who undergo surgical removal of affected veins are benefitted by diosmin pre- and post-therapy (two weeks before and for 30 consecutive days after surgery) and achieve measurable reduction in postoperative hematomas, pain severity, and limb heaviness, as well as better exercise tolerance and improved quality of life.³⁰Haas R. Available at: http://www.lef.org/magazine/mag2009/sep2009_A-Prescription-for-Beautiful-Healthy-Legs_01.htm?source=search&key=A%20Prescription%20for%20Beautiful%20and%20Healthy%20Legs%20Life%20Extension   ^,31Savel’ev VS, Pokrovskiî AV, Sapelkin SV, et al. Angiol Sosud Khir. 2006;12(3):53-60.  

Summary

Chronic venous insufficiency, a recurrent medical problem, is an important and frequent disease for general practitioners that can be managed by primary care physicians with relatively inexpensive treatment modalities in association with lifestyle modification if diagnosed in initial stages. However, more advance cases may require definite surgical intervention. Therefore, it may be emphasized to follow a complex therapy in case of each patient together with using compressive and pharmacotherapy as the best strategy in this group of patients, and reserving surgery for more recalcitrant cases.

As advances in the understanding of the pathophysiology of venous disease have illustrated the importance of inflammation and hypoxia as the potential key processes in the skin manifestations of chronic venous hypertension, it also represent a potential drug target. Venoactive agents help prevent these processes and are considered as effective and safe in treating CVD. Diosmin represents a potent venoactive agent that facilitated by its multimodal mechanisms of action impact the CVI pathophysiology at both macro- and microvascular level; thus, ameliorating the consequent symptoms of CVI.

References

1. Alguire PC, Mathes BM. J Gen Intern Med. 1997;12(6):374-83.
2. Thorisson HM, Pollak JS, Scoutt L. Ultrasound Q. 2007 Jun;23(2):137-50.
3. Martinez MJ, Bonfill X, Moreno RM, et al. Cochrane Database Syst Rev. 2005;(3):CD003229.
4. Partsch H. Vasa. 2009;38(4):293-301.
5. Beebe-Dimmer JL, Pfeifer JR, Engle JS, et al. Ann Epidemiol. 2005;15(3):175-84.
6. Brown KE. Available at: http://emedicine.medscape.com/ article/461449-overview [Accessed on 22/11/2012]
7. White JV, Ryjewski C. Perspect Vasc Surg Endovasc Ther. 2005;17(4):319-27.
8. Khilnani N. Available at: http://www.miit.com/2004/sat2004/ PathophysiologyKhilnani.pdf [Accesssed on 22/11/2012]
9. Alguire PC, Mathes BM. Available at: http://cmbi.bjmu.edu.cn/uptodate/vascular%20medicine/Venous%20insufficiency-thromboembolism/Epidemiology%20and%20clinical%20manifestations%20of%20chronic%20venous%20insufficiency.htm [Accessed on 22/11/2012].
10. Callejas JM, Manasanch J; ETIC Group. Int Angiol. 2004 Jun;23(2):154-63.
11. Weiss R. Available at: http://emedicine.medscape.com/article/1085412-overview [Accessed on 22/11/2012].
12. Nicolaides AN. Circulation. 2000;102(20):E126-63.
13. Alguire PC, Mathes BM. Available at: Ahttp://cmbi.bjmu.edu.cn/uptodate/vascular%20medicine/Venous%20insufficiencythromboembolism/Diagnosis%20of%20chronic%20venous%20insufficiency.htm [Accessed on 23/11/2012]
14. Renner R, Simon J. Dtsch Med Wochenschr. 2009;134(43):2181-90.
15. Boyle P, Diehm C, Robertson C. Int Angiol. 2003;22(3):250-62.
16. Marusiak J, Strincl J, Rambousek Z, et al. Rozhl Chir. 2003; 82(3):161-9.
17. Cheatle TR, Scurr JH, Smith PD. JR Soc Med. 1991; 84(6):354-8.
18. Roztocil K, Stvrtinová V, Strejcek J. Int Angiol. 2003; 22(1):24-31.
19. Pittler MH, Ernst E. Cochrane Database Syst Rev. 2006;(1):CD003230.
20. Wollina U, Abdel-Naser MB, et al. Int J Low Extrem Wounds. 2006;5(3):169-80.
21. Siebert U, Brach M, Sroczynski G, et al. Int Angiol. 2002; 21(4):305-15.
22. Stoîko IuM, Gudymovich VG. Angiol Sosud Khir. 2006; 12(3):77-82.
23. Marinović Kulišić S, Lupi D. Acta Dermatovenerol Croat 2012;20(3):197-200.
24. Araujo D, Viana F, Osswald W. Pharmacol Res. 1991 Oct; 24(3):253-6.
25. Diosmin Monograph. Alternative Medicine Review 2004;9(3).
26. Batchvarov IV, Batselova MG, Damyanov II. J Biomed Clin Res 2010;3(1).
27. Lyseng-Williamson KA, Perry CM. Drugs. 2003;63(1):71-100.
28. Savel’ev VS, Pokrovskií AV, Sapelkin SV, et al. Angiol Sosud Khir. 2006;12(3):53-60.
29. Pokrovsky AV, Saveljev VS, Kirienko AI, et al. Angiol Sosud Khir. 2007;13(2):47-55.
30. Haas R. Available at: http://www.lef.org/magazine/mag2009/sep2009_A-Prescription-for-Beautiful-Healthy-Legs_01.htm?source=search&key=A%20Prescription%20for%20Beautiful%20and%20Healthy%20Legs%20Life%20Extension
31. Savel’ev VS, Pokrovskiî AV, Sapelkin SV, et al. Angiol Sosud Khir. 2006;12(3):53-60.