Risk factors for symptomatic chronic venous disorders: results from the international Vein Consult Program




1Djordje J. RADAK, MD, PhD
2Vuk A. SOTIROVIC, MD
1,2Vascular surgery Clinic
“Dedinje” Cardiovascular
Institute, Belgrade, SERBIA
1School of Medicine
University of Belgrade
SERBIA

Risk factors for symptomatic chronic venous disorders: results from the international Vein Consult Program


by D. J. Radak and V. A. Sotirovic, Serbia



Venous symptoms are very frequently mentioned during general practitioner or vascular surgeon consultations. Even so, the amount of research conducted on venous sensations is inversely proportional to the frequency of reported symptoms. Today, there is a lack of epidemiological studies concerning this issue. The Vein Consult Program (VCP) was started with a clear mission, with the aim to raise awareness and to deal with a chronic disease that has reached almost pandemic proportion—chronic venous disease (CVD). The most worrying finding of the VCP is that the majority of subjects with or without any clinical signs of CVD have symptoms that significantly affect their daily activities and deteriorate quality of life. Several factors have been proposed as risk factors for the development of symptomatic CVD: age, body mass index, sex, family history of CVD, history of previous venous thromboembolism, hours spent standing, smoking, and lack of daily exercise. Also, aside from traditional risk factors, several comorbidities such as high blood pressure, diabetes mellitus, heart failure, and chronic obstructive pulmonary disease could have an influence on the development and progression of the symptoms in patients with CVD. Most of these risk factors cannot be changed, but a significant number of them could easily be modified. In this article, we present the latest facts related to venous-related symptoms and risk factors for the development of such symptoms, based on the results of the VCP.

Medicographia. 2015;35:85-91 (see French abstract on page 91)



Leg pain, heaviness, and swelling are symptoms that are very frequently mentioned during general practitioner (GP) or vascular surgeon consultations.1 Even so, the amount of research conducted on venous sensations is inversely proportional to the frequency of reported symptoms. The risk factors connected to the development of venous symptoms are still a real mystery. A lack of epidemiological studies is frustrating and adds to the unease in the community regarding venous leg symptoms.

The Vein Consult Program (VCP) is a large international observational prospective survey investigating chronic venous disease (CVD) in twenty countries, developed under the auspices of the Union Internationale de Phlébologie (UIP; International Union of Phlebology). The VCP includes the clinical files of approximately 100 000 subjects, who consulted their GP between October 2009 and July 2011. The VCP results have helped in resolving many crucial issues and also in initiating further research in the field of CVD.

In this article, we present the latest facts related to venousrelated symptoms and risk factors for the development of such symptoms, based on the results of the VCP.

The prevalence of CVD and lower-limb symptoms before the VCP

As there is not yet an established relationship between symptoms and signs of CVD, opinions diverge, with some believing that symptoms such as venous pain, cramps, etc, simply do not exist, while others believe that all these symptoms should be treated.

The first step in determining the prevalence of lower-limb symptoms related to CVD should be to exclude all patients with symptoms of nonvenous origin. This approach is more than complex, especially in the group of patients without clear signs of CVD, or in patients with early stages of visible disease.

Before the first results of the VCP, the prevalence rate of CVD and venous-related leg symptoms was based mainly on crosssectional epidemiological studies, which were limited to one region or a single country.2-10 Most of the studies have inhomogeneous prevalence rates, due to the different classification systems used. Today, epidemiological surveys have adopted the universal clinical, etiological, anatomical, pathophysiological (CEAP) classification,10-11 whose purpose is to achieve a better definition of each disease stage. In addition, by using this classification system it is much easier to assess the respective frequency of each disease stage. The international character of the CEAP classification allows precise comparisons between countries and between continents.

However, through our daily practice we observed a large number of limiting factors in the current classification systems. The CEAP classification does not include any assessment of the level of the pain, with the classes only categorized as “symptomatic” or “asymptomatic.” Due to that, symptoms and their levels are often underestimated by physicians. These limitations require additional questionnaires to incorporate levels of symptoms and their change during the time period. In addition, very few epidemiological studies have actually taken venous symptoms into account.

Both the Italian 24-cities cohort study6 and the Bonn Vein Study12 found that patients very frequently reported some venous symptoms (approximately 56% of subjects). However, both studies marked one very worrying finding: the vast majority of subjects with leg symptoms could not be given a medical explanation for their condition (up to 80% in the 24- cities cohort study population). Together, these and results of other studies emphasized a very complex issue of the origin of venous-type leg symptoms, especially in patients without any other clinical signs of CVD (C0s) or venous reflux/obstruction. 6,7,13

The VCP was organized within the framework of ordinary consultations, with GPs properly trained in the use of the CEAP classification. First results show that CVD affects a significant part of the population worldwide, highlighting the importance of adequate screening for CVD, and training of both GPs and specialist physicians. The VCP revealed some key facts, as presented in the following text.

Better identification of subjects who are more
likely to present with one or several venous leg
symptoms

CVD could be associated with a whole range of symptoms such as pain, heaviness, restless legs, tingling, aching, burning, night muscle cramps, swelling, sensations of throbbing or itching skin, leg tiredness, and/or fatigue (Table I).1,14 In addition, these symptoms could be a part of other nonvenous chronic and acute conditions, such as obesity, neurological disease, a standing or sitting profession, or arterial occlusive disease.15

Results of the VCP show that venous pain could be found in approximately 70% of adults, where heaviness and pain were the most frequent symptoms, mostly affecting women. Once there are visible signs of CVD (C1 class or higher), associated symptoms can be more easily assigned to a venous cause. The risk of developing symptoms increased significantly with disease severity. Individuals with chronic venous insufficiency, C3 to C6, were 16-fold more likely to be symptomatic than individuals in class C0.14

It is rational to believe that symptoms of CVD will correlate with Doppler ultrasound findings. However, Chiesa et al6 reported that the occurrence of venous symptoms is independent of venous reflux, but also that symptoms correlated positively in both sexes with the CEAP grade, with the exception of pain (no significant correlation was observed in men). Still, a Serbian group of authors16 found a significant presence of both reflux and obstruction in VCP patients in classes C0s to C1. These findings could justify recommendations for color duplex ultrasound in all patients with symptoms of CVD, regardless of clinical signs.





Patients with no visible sign of disease, but who are reporting venous-like symptoms, represent a real “nightmare” for both GPs and vascular surgeons.1,11,17 Identification of C0s patients could be crucial from a diagnostic and therapeutic point of view and deserves special attention. Revision of the CEAPclassification brought to the professional public a new profile of patients; those in the C0s class.11 For the first time, the results of the VCP13 show a global prevalence of C0s patients. Approximately 20% of patients with CVD are in the C0s class. Also, within the new results from the VCP we expect a detailed clinical profile of patients in the C0s class, including information on the quality of life (QoL) of C0s patients, risk factors, etc.


Table I
Table I. Distribution of the prevalence of chronic venous disease (CVD) symptoms
according to clinical, etiological, anatomical, pathophysiological (CEAP) class.

After reference 14: Phlebolymphology. 2013;20(3):138. © 2013, Les Laboratoires Servier.


The question still remains: if there is no clinical evidence and functional sign of CVD, do the subjective symptoms have an objective origin, and if so, are we able to find and treat this origin? Several hypotheses have been proposed. Vincent at al18 analyzed valvular competence in amputated legs without signs of CVD, or evidence of reflux in the deep and superficial venous system (within the great saphenous vein [GSV]). The authors showed that microvalvular incompetence could exist in the small superficial veins of the leg, independent of incompetence in the GSV or its accessories. These findings raise some additional arguments for ascending incompetence, rather than the traditional descending theory and reflux in the saphenofemoral junction.18 Incompetence in the microcirculation along with activation of the inflammatory response and nociceptors could be the very first manifestation of CVD. Identification of these patients seems to be crucial, because not only could we identify patients in the early stage of disease, but we could also start with some of the treatment options.

Van der Velden et al19 tried to distinguish which symptoms are specific for CVD. However, their results did not have statistical power due to the low number of patients investigated, and the approach and design of the study. This supports the need for future large multicenter studies.

Identification of risk factors that
influence the appearance of
symptoms

Risk factors connected to symptomatic CVD are important, from a therapeutic and prognostic point of view. Some risk factors can easily be modified in order to slow the development and progression of CVD.

The VCP is the first international program that has involved a large and varied range of countries and geographical zones. In total, 91 545 subjects were involved; 36 004 from Western Europe; 32 225 from Central and Eastern Europe; 12 686 from Latin America; 3518 from the Middle East; and 7112 from the Far East (Table II).13

The results of the VCP show that CVD is a global phenomenon not solely limited to Western countries, as is often believed.20,21 The prevalence of symptoms in the VCP is high in all geographical areas studied. Moreover, the distribution of symptom prevalence (by decreasing frequency: heavy legs, pain, sensation of swelling, night cramps, etc) was similar, whatever the area considered. Heaviness and leg pain were found in up to 72% and 68% of VCP participants, respectively. Symptoms, such as the “sensation of swelling,” show the greatest increase between C0s and C4 to C6, and this suggests that the perception of pain is similar in all studied countries and is likely to be disconnected from any cultural phenomenon.13 Furthermore, the VCP shows that the classification system of CVD is applicable worldwide and this classification allows the generation and design of a whole battery of new questionnaires, for better identification of patients and for symptom measurement.


Table II
Table II. Vein Consult Program (VCP) study zones with number
of subjects.

After reference 13: Rabe E et al. Int Angiol. 2012;31:105-115. © 2012, Edizioni
Minerva Medical.



In the VCP population, 56% of patients in the C0s class had leg pain, while almost 90% of patients in C5 to C6 had significant leg pain. Still, it is quite interesting that even though there is a significant increase of symptom prevalence with CEAP class, some patients with severe forms of CVD (C6 and C7) do not report any symptoms (Table I).14

Results of the VCP show that risk factors connected to symptomatic CVD are: age, body mass index (BMI), sex, family history of CVD, and the patient’s history of previous venothromboembolism (Table III).14 In addition, patient habits play a significant role in the development of venous symptoms, such as hours spent in an upright position, smoking, and lack of daily exercise (Table IV).14 Together, all of these facts are traditionally recognized as risk factors for the development of CVD in numerous earlier published studies.5,20,22-26 The results of the VCP, for the first time, show the distribution of risk factors on a global level, and in populations with different social habits and economical standards, sometimes living in diametrically different time and weather zones. As we can see from Table III,14 the sex and age of subjects are two very important factors for symptomatic CVD. In the VCP, screened subjects were divided into four age groups: ≤18 to 34 years, 35 to 50 years, 51 to 64 years, and ≥65 years. When the CEAP profile was analyzed according to the age and sex, the authors observed that whatever the age group, there was a significant difference between men and women in the classes C0s to C3. With the exception of the C0s class, which was more frequent in men than in women after the age of 35, other categories were more prevalent among women. Next, the prevalence of severe CVD (C4 to C6) was found to be similar, whatever the sex and age, and to drastically increase with age in both sexes. C2 and C3 increased with age in both sexes, but stabilized after the age of 64 years.13,14

A number of studies reported an association between obesity and CVD.13,14,27 In the VCP population, mean BMI is significantly higher in men compared with women (P<0.0001). Higher values of BMI are reported in Eastern and Central Europe (27.34±5.64) whereas smaller figures appear among patients in the Far East (22.89±3.59; P<0.0001). In a part of the VCP population, Vlajinac et al28 showed that the CEAP “C” categories of CVD were significantly related to being overweight or obese, and this association was independent of age, sex, and some other postulated risk factors in this study. Several other habits were confirmed as very strong CVD risk factors, such as smoking and physical inactivity.26 The last three mentioned factors (obesity, smoking, and physical inactivity) deserve special attention, since these factors can be easily modified. Standing time increases the risk of symptomatic CVD, especially if that period is more than 10 hours. On the other hand, it seems that sitting time is not a risk factor for symptomatic CVD. Lack of regular exercise has been observed in 67.4% of subjects. Up to 42% of subjects were smokers. The appearance of symptoms was strongly connected to the period of day (end of day) and seasons (summer). Even some regions (Middle and Far East) showed a higher presence of symptoms during the night (52.5% of subjects) and a significantly lower presence of venous symptoms during the summer (only 5.4% of subjects).14


Table III
Table III. Occurrence of venous symptoms and risk factors in the
Vein Consult Program (VCP) population (P<0.05).

Abbreviations: CVD, chronic venous disease, VT, venothromboembolism.
After reference 14: Phlebolymphology. 2013;20(3):138. © 2013, Les Laboratoires

Servier.


Table IV
Table IV. Occurrence of venous symptoms and risk factors in the
Vein Consult Program (VCP) population (P<0.05).

Abbreviation: NS, nonsignificant.
After reference 14: Phlebolymphology. 2013;20(3):138. © 2013, Les Laboratoires

Servier.


Up to 65% of participants with CVD in the VCP had a positive maternal history of CVD. Also, the role of hormonal factors in the development of CVD has been suggested by several investigations. Under the VCP, a Serbian group of authors26 showed that the average number of births was significantly higher in women in classes C2 to C3 and C4 to C6 in comparison with those without the disease. The higher number of births was a risk factor for CVD, independent of other observed factors, including age. Menopause was also independently related to all clinical classes, especially C4 to C6.24 The same study showed no existing relationship between CVD and either oral contraceptive use or hormonal replacement therapy. On a global level, use of birth control pills is significantly more frequent in Western Europe (45.8%, vs 31.1% for the total population of survey), while that of hormone replacement therapy is significantly higher in Latin America (23.2%, vs 8.2% for the total population; P<0.0001); in the Far East, HRT use is significantly less frequent than in the other participating countries (2.3%, vs 8.2% for the overall population of the survey; P=0.0008).13

The risk of developing symptoms increased significantly with disease severity. When considering individual symptoms according to CEAP clinical class, “heaviness” and “sensation of swelling” appeared more related to the C3 class (edema), while itching was related to skin changes.

Comorbidities as risk factors for symptomatic CVD

There is a lack of evidence on how comorbidities affect the development and progression of CVD and venous symptoms. CVD is still often associated with chronic conditions such as diabetes mellitus, high blood pressure, heart failure, chronic obstructive pulmonary disease, renal insufficiency, peripheral arterial disease, and many others.

Our preliminary results of the VCP show that other chronic diseases are found in a large number of patients with CVD, primarily in elderly patients. For example, arterial hypertension can be found in up to 70% of patients aged above 65 years in CEAP classes C4 to C6. Presence of arterial hypertension, simultaneously with congestive heart failure, contributes to edema development and the decrease in local defense capabilities of already damaged skin and subcutaneous tissue in patients with severe CVD.

The presence of comorbidities could potentially be a very important risk factor for symptom development in patients with CVD, not only in severe cases, but also in the early stages (C0s to C3). These factors could mislead GPs and vascular surgeons, especially in subjects without visible signs of CVD (C0s ). Thus, early recognition and quick treatment of comorbidities is essential, and could dramatically reduce symptoms and slow progression of CVD.

The attitude of patients and GPs who manage
venous symptoms

The results of the VCP gave us a clearer picture of how GPs deal with patients who have CVD, through every stage of the disease. Two facts have left the strongest impression. Firstly, subjects with symptoms only are not considered by their GPs to have CVD. Globally, 63% of screened subjects in the VCP were considered to have CVD by their GPs. Subjects with symptoms only (C0s) were less likely to be considered as having CVD and to be liable for treatment than those with signs. The presence of a symptom was not the trigger for starting CVD treatment. Secondly, while 63% of screened subjects were considered to have CVD by GPs, only 22% (one-third) were referred to venous specialists. Despite this, it appears that a systematic search for venous symptoms, as was performed in the VCP, could help detect CVD in 6 out of 10 subjects (it is of note that 50% of these were C0s or C1s).13

Even when venous symptoms are recognized by GPs, the question still remains: should all symptomatic patients be treated? The decision is particularly difficult in patients without visible signs of disease. Yet, it is acknowledged that venous pain greatly worsens patients’ QoL. Several questionnaires have been created to compare the effects of different types of CVD therapy, as well as for discriminative purpose, and show very promising results.29-36

In the VCP, subjects diagnosed with CVD after a GP examination, were requested to complete a self-administered questionnaire reporting features about their professional activities and QoL (using the ChronIc Venous Insufficiency quality of life Questionnaire [CIVIQ]–14; 0=poor QoL, 100=very good QoL). A total of 35 495 questionnaires from 17 countries were analyzed. A total of 7% of patients were hospitalized and 4% changed their professional activities as a result of CVD. Loss of work days was reported in 15% of patients.14

Besides the traditional venous leg symptoms, some authors have identified depression, anxiety, and hypochondria among patients with CVD.12 The authors concluded that a specially designed questionnaire, applied to individuals with venous type leg symptoms, allows the subjects or patients who have a distinct psychiatric condition to be distinguished from those with a true venous disorder.12 The rate of patient referrals to specialists increases with disease severity: 4.1% at C0s stage vs 60.2% at C6. In Central and Eastern Europe as well as in Latin America and the Middle East, patients are referred more frequently, starting at the C2 stage, than in the Far East, where even C6 patients are rarely referred.

Conclusion

In conclusion, CVD is a global phenomenon that reaches almost pandemic proportions. To deal with this problem, the VCP was established. The most worrying finding of the VCP is that the majority of subjects with or without clinical signs of CVD have symptoms that significantly affect their daily activities and deteriorate QoL. However, several factors and comorbidities have been identified as risk factors for the development of venous symptoms, and some of these can be easily modified, such as BMI, hours spent in an upright position, smoking, and lack of daily exercise. Results of the VCP also show the importance of the role of GPs in early recognition and management of CVD. Venous symptoms may be encountered in numerous fields and calls for a multidisciplinary approach (scientific, eg, neurology, molecular biology, psychometrics, etc; clinical, eg, surgery, dermatology, phlebology, etc) and raised awareness amongst patients and the community as a whole. ■


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Keywords: chronic venous disease; chronic venous disorder; comorbidity; prevalence; symptom; risk factor