Servier – Phlebolymphology

Abstract

Chronic venous disorders (CVD), a highly prevalent problem among populations worldwide, with which both general practitioners and specialists have to deal, include symptoms (leg pain, leg heaviness, and other types of discomfort) and signs as described in the Clinical, Etiological, Anatomical, and Pathophysiological (CEAP) classification. Symptoms appear early in the progression of the disease and with time may be associated with clinical signs of increasing severity. CVD is a chronic disorder that significantly alters the quality of life for the affected patient right from the early symptomatic stages, but may progress toward skin complications. Numerous risk factors have been postulated as possible causes for the development of CVD, but specific and validated instruments to adequately assess the impact that these risk factors may have on CVD progression were lacking. This article presents the steps that were needed to construct a self-assessment tool (Phleboscore®) for patients with leg problems to quantify the risks of developing further CVD complications.

Introduction

Chronic venous disorders (CVD) are common among the general population worldwide,^1,2 and the prevalence of such disorders is likely to increase with population aging.³ For a long time, wide differences have been observed between the reported rates of prevalence, probably due to recruitment bias and to the use of a definition of CVD that has long remained nonhomogenous. The clinical, etiological, anatomical, and pathophysiological (CEAP) classification, updated in 2004,⁴ provides a framework that describes CVD in all its aspects. With the CEAP classification, the multiple variations of CVD can be communicated in a clinically and scientifically meaningful manner, allowing analysis and comparison of treatment modalities for like conditions. It describes the multifactorial nature of the condition that leads to very different rates of progression in different patients and allows comparisons between epidemiological data in various countries. The CEAP classification categorizes limbs into seven classes from C₀ to C₆. Each clinical class is further characterized by either a subscript S or A depending on whether the categorized limb is symptomatic or asymptomatic, respectively. This classification has been used in recent population-based epidemiological surveys.^5-10

Both general practitioners and specialists have to deal with this pathology. The management of CVD is usually based on clinical examination and on complementary investigations when needed. However, such evaluations do not take into account the patients’ lifestyle, genetic inheritance, or family history of CVD–the factors known to be associated with the disease and its aggravation. A specific patient-oriented tool capable of allowing patients to identify the risk factors for CVD and self-assess the impact these factors may have on CVD progression is the key for efficient prevention and management of the disease.

Objective

The objective of this article is to present the steps that were needed to construct a self-assessment tool (Phleboscore®) for a patient with leg problems to quantify the risk for developing more severe stages of CVD.

Methods

The scoring system for “venous” risks was set up in several steps:

1. Listing the prevalence of all symptoms and signs of CVD from epidemiological surveys.

2. Identifying the risk factors for CVD.

3. Finding a relationship between the exposures to identified CVD risk factors and the appearance or aggravation of the symptoms and signs of the disease.

4. Quantifying and “weighting” each risk factor accordingly.

Results

Prevalence of the CVD-related symptoms and signs in epidemiological surveys
Recent population-based surveys that used the CEAP classification reported CVD prevalence rates of 44% in Bulgaria,⁵ 49% in Poland,⁶ 71% in the US,⁷ 77% in Italy,⁸ 85% in Scotland,⁹ and 90% in Germany.¹⁰ The Vein Consult program was a worldwide epidemiological survey involving 20 countries, 5 continents, and 91 545 screened adults consulting for any medical reason, found that the distribution of individuals among the CEAP clinical classes was as follows: 16 901 (21.7%) were C₁ (telangiectases, reticular veins), 13 888 (17.9%) C₂ (varicose veins), and 18 863 (24.3%) C₃ (edema) to C₆ (chronic venous insufficiency) for a total of 46 452 patients. The number of subjects complaining solely of symptoms, the so-called C_0S patients, was 15 290 (19.7%), indicating that almost 20% of the survey population had CEAP grade C_0s. Only 12 774 (16.4%) individuals had no symptoms or signs of CVD and thus were exempt from leg problems (C_0A).^2,11 Figure 1 summarizes the epidemiological data of this program.

Figure 1. Distribution of the clinical, etiological, anatomical, and pathophysiological (CEAP) classifications according to geographical
areas.

Finally, the incidence and prevalence of CVD depend on the age and sex of the surveyed populations. In the US, one branch of the Framingham study found that the annual incidence was 2.6% in women and 2.0% in men,¹² and one Finnish study reported an incidence rate of 13.5 per 1000 person-years (8.5 for men and 19.2 for women).¹³

CVD risk factors in the literature
Based on numerous CVD studies, the main risk factors found to be associated with CVD include age, sex, pregnancy, obesity, positive family history of varicose veins, and previous thrombophlebitis.¹⁴ Environmental or behavioral factors may also be associated with CVD, such as smoking, prolonged standing, and a special sitting posture at work.¹⁵ Moreover, tight clothes, constipation, diet habits, foot posture, or hypermobility showed variable associations with CVD.^6,14,16

Age
A common finding in epidemiological studies is that the prevalence of CVD increases with age.^1-3,9,16 In the Bochum study, examination of a cohort of school children between the ages of 10 and 12 demonstrated the presence of discrete reticular veins in only 10% of the pupils, but 4 years later, this figure had increased to 30% and a few children had developed varicose veins.¹⁷ The underlying mechanisms for changes in the venous system with aging are insufficiently understood. There is evidence for an association between age-related alterations of deep venous valves and high incidences of deep venous thrombosis¹⁸ because deep venous valves change with age and are thicker in older individuals. The increase in valve thickness with age would explain the age gradient seen in the incidence of venous thrombosis. Likewise, in CVD, aging was established as an important factor responsible for changes in the venous wall and valves where inflammatory events play a pivotal role both in the aging process and the development of varicose veins.^19,20 Although the disease and aging processes run a parallel, overlapping course, the aging process may be accelerated in CVD, coinciding with the remodeling of the venous wall and valves that affect both its cellular component^19-22 and its extracellular component, as observed by Buján et al.¹⁹

Sex
Most studies have shown that CVD is more frequent in women.^12,23-26 Sex-related and lifestyle risk factors, such as genetic factors, obstetric history, work, and oral contraceptive use, could be considered partly responsible for the higher frequency of CVD in women. In the Edinburgh Vein Study,^9,26 the prevalence of varicose veins and chronic venous insufficiency was higher in men. Severe stages (C₃ to C₆) of chronic venous insufficiency were also more frequent in men than in women in the study by Scott et al.²⁷ Vlajinac et al²⁸ showed that chronic venous insufficiency was significantly more frequent in men, while more women reported the earlier stages (C_0s-C₁).²⁸ Fiebig et al²⁹ postulated that the higher proportion of women suffering from CVD may be partially explained by different timing in disease progression between the two sexes.

Hormones and pregnancies
It is a widely held view that hormones may be important in the development of postpartum varicose veins. Epidemiological studies have sought to determine whether the number of pregnancies or childbirths is related to the occurrence of CVD. Several studies found that a greater number of pregnancies^12,15,30 and childbirths^16,20 were related to an increasing prevalence of CVD signs, and this association was maintained after age adjustment. In the Serbian Vein Consult Program,²⁸ the average number of births was significantly higher in women with CVD compared with those without the disease. The higher number of births was a risk factor for CVD independently of other observed factors, including age.²⁸ The association of CVD with the use of oral contraceptive pills and hormonal replacement therapy is not clear and controversial results came up from a number of studies.²⁸ It is not well understood why pregnancy might increase the risk of developing CVD. The belief that pregnancy leads to varicose veins due to pressure from the uterus that obstructs venous return from the legs has been refuted because the majority of varices appear during the first trimester of pregnancy when the uterus is not large enough to cause mechanical obstruction. Hormonal factors or the additional burden of increased circulating blood volume could be important.

Obesity
Doubt remains about the relationship between obesity and CVD. Epidemiological studies, including the Basel study,³¹ the Edinburgh Vein Study,⁹ and the study by Jawien et al⁶ observed a relationship between obesity and varicose veins in women, but not in men, while others failed to show an association in either sex.³² Another French epidemiological study did not find any relationship between CVD and obesity in male patients,³³ while the Serbian Vein Consult Program concluded that obesity was a positive risk factor for varicose veins in both sexes, with the exception of a severe form of CVD in men.²⁸ The Framingham Study showed a higher incidence of varicose veins in women who were more likely to be obese than men.¹²

Since obese patients have more severe forms of CVD than nonobese patients with comparable anatomical patterns of venous incompetence, van Rij et al postulated that obesity exacerbates the severity of the varicose disease once venous reflux occurs,³² and that this may be the result of increased intra-abdominal pressure leading to increased reflux, vein diameter, and venous pressures.

Family history of CVD
A strong body of evidence implicates genetics in the etiology of CVD. Cornu-Thenard et al studied the role of the family history in varicose disease in a prospective case-controlled study.³⁴ They showed that the risk of developing varicose veins was 90% for the children when both parents had varicose veins, 25% for men and 62% for women when one parent was affected, and 20% when neither parent was affected.³⁴ A Chinese analysis of nuclear families reported a penetrance between 70% and 92%, while 37% of their cases were sporadic.³⁵ A Finnish longitudinal study showed a 1.6-fold increased risk of developing varicose veins in those with a family history of varicosities.³⁶ Fiebig et al examined heritability of CVD and concluded that the additive genetic component was approximately 17%.²⁹ These studies suggest a strong genetic component in primary venous failure, but the genes involved have yet to be identified.

History of venous thromboembolism
In the Vein Consult Program, history of venous thromboembolism was the most important independent risk factor for CVD.²⁸ This confirmed the results of previous work in which venous thromboembolism was found to be the most important cause of secondary CVD.²⁷ Heit et al³ and Carpentier et al¹⁵ estimated that as many as 20% of CVD cases developed as a consequence of a prior deep venous thromboembolism. Venous thromboembolism would lead to CVD via the development of venous hypertension because of persistent venous outflow obstruction and/or venous valvular incompetence due to damage caused by thromboses.

Lifestyle factors
Smoking was found to be a risk factor for varicose veins in the Framingham study,¹² but only in men, not in women. In the San Diego survey¹⁶ and the Vein Consult Program,²⁸ current smoking was associated with increased rates of chronic venous insufficiency in men. In a recent study from Finland,³⁷ the 5-year incidence of varicose veins in both sexes was higher in smokers compared with nonsmokers.

The mechanisms responsible for the harmful effects of smoking on the venous system might involve the oxidative stress related to the smoke, which causes hypoxia and endothelial damage.²⁸

There are many studies about the effect of prolonged standing on CVD, which has often been blamed for the development of CVD and, more particularly, varicose veins.³⁸ In the San Diego survey, prolonged standing was positively associated with more severe disease and prolonged sitting inversely associated with moderate disease in women. For men, increased daily walking was associated with moderate disease, and men who worked as laborers were more likely to have severe disease than those in positions that typically required more desk time. Regular movement when sitting for long periods was related to lower rates of moderate disease in men.¹⁶ In the Framingham study, the 2-year incidence of varicose veins was higher with the length of time women spent sitting or standing.¹²

In theory, tight undergarments might promote the development of varicose veins by increasing intra-abdominal pressure. The prevalence of varicose veins increased with the stiffness of the corsets being worn in the 1960’s by the female cotton workers in England and Egypt.³⁹

Constipation and a low-fiber diet could be related to an increased CVD prevalence since this produces small, hard stools that are difficult to pass, leading to regular straining and repeated increases in intra-abdominal pressure. Increased intra-abdominal pressure from straining at stool may be transmitted down the veins of the legs, leading to dilation of the veins and nonapposition of the valve cusps, rendering the valves incompetent. Research is currently ongoing to determine the possible relationship between constipation and CVD occurrence (the CHORUS survey [Chronic venous and HemORrhoidal diseases evalUation for improvement of Scientific knowledge] from Servier).

Abnormal static posture of the foot may account for improper emptying of the plantar venous pump while walking. Since the venous pump of the human foot is the first step in venous return from the lower extremity to the heart, it has a role to play in the occurrence of CVD.⁴⁰

The risk factors retained for constructing Phleboscore_ are summarized in Table I.

Table I. Risk factors for chronic venous disorders retained for constructing Phleboscore.

Relationship between risk factors and CVD aggravation
The knowledge of the natural history (progression) of CVD relies on a few longitudinal studies, and much of the available information arises from cross-sectional studies. In patients awaiting surgery for a mean of 19 months, nearly one-third of those with venous reflux had progression in the CEAP clinical stage and either an extension of a preexisting reflux or reflux in a new segment.⁴¹ In a prospective 7-year follow-up on patients with venous reflux, most of the limbs clinically deteriorated at the end of the observation period. Limbs that underwent a superficial or deep venous procedure remained stable or improved over time; those that underwent elastic compression alone had worsening hemodynamic and clinical status.⁴²

The Bochum study, a large cohort investigation in Germany, explored the natural history of preclinical (C₀) and early stages (C₁) of the development of varicosities and the behavior and function of the venous calf pump from childhood to adulthood in subjects with healthy veins. Telangiectasias and reticular veins were noted early on, independently of the presence of reflux. Large varicosities appeared in older subjects, often preceded by reflux in the saphenous veins.¹⁷

In the Bonn Vein Study I that was conducted in 2000, 3072 participants of the general population of the city of Bonn and two rural townships, aged 18 to 79 years old, participated.¹⁰ In the follow-up study (Bonn Vein Study II) that occurred 6.6 years later, the same population was assessed again. The incidence of progress to chronic venous insufficiency (C₃-C₆) was approximately 2.0% per year.43 In a multivariate analysis, the main risk factors for developing severe stages of CVD (C₄-C₆) were age, arterial hypertension, and obesity. The presence of the symptom of a “sensation of swelling” significantly increased the risk for developing chronic venous insufficiency.⁴³

Kostas et al evaluated long-term (5-year) characteristics of CVD progression and its correlation with the modification of specific risk factors. The contralateral (normal) limb of 73 patients undergoing varicose vein surgery for unilateral varicosities was prospectively evaluated using physical and color duplex examination and classified using the CEAP classification. In about half of the patients, CVD (reflux development and clinical deterioration) developed in the contralateral, but initially asymptomatic, limb in 5 years. In these patients, obesity, orthostatism, and noncompliance with the use of elastic stockings were independent risk factors for CVD progression, but estrogen therapy and multiparity were not.⁴⁴

Clinical signs (eg, corona phlebectatica and other skin changes) may warrant early interventions to prevent later ulcer formation. The risk of ulceration is related to the severity of varicosities and venous insufficiency, and this risk is increased following deep vein thrombosis (incompetence). However, the risks may also be increased in those who smoke, are obese, and have restricted ankle movement and reduced power in the calf muscle pump.⁴⁵ Studies show that mechanical dysfunction of the calf muscle pump may enhance the development of leg ulceration.⁴⁶ Therefore, it is important to investigate ankle range of motion, function of the calf muscle pump, and patient activity in relation to disease progression.

Quantification of the CVD risk factors
The multifactorial evaluation of all risk factors for CVD appearance and progression led us to “weight” the factors according to sex (Figures 2 and 3), which allowed us to build the Phleboscore_ questionnaire (Table II).

Table II. Content of Phleboscore, a patient’s self-questionnaire for the assessment of the risk of chronic venous disorder progression.
Version from November 2015, printed with the kind permission of Dr Philippe Blanchemaison.

Figure 2. Multifactorial evaluation of the risk factors for chronic
venous disorders in men.

Figure 3. Multifactorial evaluation of the risk factors for chronic
venous disorders in women.

Advice for CVD patients according to the Phleboscore_ results
The advice for patients depends on the score that women or men with CVD received after filling out the Phleboscore_ questionnaire. CVD patients are divided into 3 classes depending on their risk factors: low risk of CVD (class I), moderate risk of CVD (class II), and high risk of CVD (class III). Actions to take according to the patient’s risk class are summarized in Table III.

Table III. Actions to take by subjects presenting with chronic venous disorders or disease according to their Phleboscore results.
Version from November 2015, printed with the kind permission of Dr Philippe Blanchemaison.

Conclusion

Phleboscore® is a medical tool to assess a patient’s potential risk of developing chronic venous disease. Phleboscore_ should help to more accurately identify the patients at risk of developing a more serious disease so that interventions can be offered at an early stage to those who will gain the most benefit.

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