Epidemiologic data on progression in venous pathology: where are we today?



Armando MANSILHA, MD, PhD and Joel SOUSA, MD

Department of Angiology and Vascular Surgery Hospital CUF Porto – PORTUGAL and Faculty of Medicine of the University of Porto – PORTUGAL

Address for correspondence: Armando Mansilha, Department of Angiology and Vascular Surgery, Faculty of Medicine of the University of Porto, Alameda Prof. Hernâni Monteiro, 4200-319, Porto, Portugal (email: vascular.mansilha@gmail.com)

 

Abstract

Chronic venous disease (CVD) comprises a set of conditions that cause long-term suffering in the population, with known negative effects on mood and well-being documented in multiple quality of life assessment studies. Given its high prevalence, the management of this pathology is also very expensive, particularly when venous ulceration is present, making proper identification of at-risk patients an increasing necessity. Several risk factors, such as older age, female sex, family history, long periods in the upright position, and obesity, have been positively linked with higher disease prevalence, although data regarding disease progression is still sparse. Recent long-term longitudinal studies such as the Bonn Vein Study and the Edinburgh Vein Study have provided some insight into this matter, with documented yearly progression rates as high as 4.3%. Also, risk factors identified in the Edinburgh Vein Study—family history, previous deep venous thrombosis, and presence of venous reflux—were associated with higher progression rates. Nevertheless, prediction of which patients will develop aggravated disease based on baseline risk factors remains impossible; consequently, the benefit of early intervention is unknown. Considering the current demographic characteristics of the Western world, an increase in CVD prevalence in the near future can be expected; therefore, data on CVD progression is now more important than ever. Further studies are required.
 

Introduction

Chronic venous disease (CVD) comprises a set of conditions that cause longterm suffering in the population.1 The majority of these conditions impair quality of life but do not cause a threat to life. This somewhat influences public opinion in that the problem is frequently considered more of a cosmetic embarrassment than a burdening disease. This belief is reflected in the policies of public health systems, ultimately leading to less attention and funding directed to this disease1
 
Nonetheless, CVD is one of the most commonly reported chronic medical conditions2 and represents a substantial source of morbidity in the Western world, consuming up to 1% to 2% of the health care budgets of European countries.3 Little epidemiological data regarding the progression of this pathology in the general population is known, partially due to the lack of uniformity in venous terminology, which makes it difficult to compare and analyze data in different epidemiological studies. This lack of knowledge about the natural history and prognostic factors has meant that few advances have been made in identifying patients who might benefit from early intervention, as well as in evaluating preventive measures. Fortunately, introduction of a consensus on venous terminology and recent longitudinal studies have improved the understanding of this pathology’s natural history. Here, we review the current data on the progression of venous pathology.
 

Primary venous insufficiency: current epidemiological data on patterns and progression

For many years, the management of CVD was mainly empirical, given that its pathophysiology, distribution, and natural history were not fully understood. More recently, with the advent of Doppler ultrasound (DUS), the study of venous insufficiency, as well as its progression, has been possible, and the historical perceptions of the venous disease patterns have been challenged.
 
In fact, according to the traditional “retrograde theory,” it was believed that primary venous insufficiency starts in the saphenofemoral junction, with distal retrograde sequential progression due to an increase in the hydrostatic pressure in the upright position.4 This common notion was challenged by Labropoulos et al, who, in 1997, studied 125 limbs by DUS in order to assess patterns of insufficiency. His group demonstrated that although reflux could be found in all segments of the saphenous veins and their tributaries, the below-knee segment of the greater saphenous vein was the most common site for reflux (68%), with saphenofemoral junction insufficiency present in only 32% of the cases.5 Later, Engelhorn et al, in a larger cohort of patients with CVD (472 limbs with reflux), confirmed Labropoulos’ study findings, reporting single or multiple great saphenous vein segmental reflux without saphenofemoral junction involvement in 53% of the patients.6 These findings changed current lines of thought and influenced several studies that were later undertaken. From here, two theories on venous insufficiency progression have emerged, with some authors defending a segmental to multisegmental progression, whereas others believe in an ascending disease progression. Evidence supporting both theories is available.
 
In 2012, Engelhorn et al repeated duplex investigations in 92 women (184 limbs) with previous known C1 or C2 disease (according to the CEAP classification system stratifying patients according to severity of presentation; C, clinical; E, etiologic; A, anatomic; P, pathophysiologic), after a mean follow-up period of 33 months. Segmental reflux, which was present in 41% of the patients in the first examination, decreased to 28% at follow-up DUS. On the other hand, a significant increase in multisegmental reflux on control DUS was noted (26% in the first DUS; 40% at follow-up), suggesting that CVD progresses with a pattern of progression from segmental to multisegmental. In this study, the progression was slow: in approximately 3 years of follow-up, there was no significant progression of reflux in about two-thirds of the great saphenous veins.7 On the other hand, and supporting the ascending theory, Bernardini et al studied 99 patients (104 limbs) with varicose veins for a mean follow-up period of 4 years. During this period, 94% of the patients had evidence of progression of reflux, and all the progressions, when present, extended to reach one or more venous segments at an upper level uninvolved before.8
 
Although CVD progression was confirmed in several other studies, there has been conflicting evidence regarding the rate of progression of the disease, as well as the risk factors influencing it. This is partly a consequence of the lack of uniform venous terminology, which is essential for epidemiological studies, as it serves as a framework for consistency and standardization. The unstandardized use of the term chronic venous insufficiency (CVI), for example, often leads to confusion in epidemiological studies. This clinical venous term was defined in the terminology consensus document as “advanced chronic venous disorder, which is applied to functional abnormalities of the venous system, producing moderate or severe edema, skin changes, or venous ulcers.”9 Therefore, patients with CEAP C1 to C2 varicose veins do not fit this definition.1 The indiscriminate use of this term in certain publications regardless of clinical severity, as well as unrepresentative study populations and variable follow-up periods, leads to misinterpretation of epidemiological data. Nevertheless, some population-based studies performed during this period provided more solid information on CVD prevalence and progression.
 
In the Basel study, 1441 workers in the chemical industry in the 1970s were observed for a period of 11 years. In this study, one-third of the patients with “mild” varicose veins (trunk, reticular, or hyphenweb) progressed to more severe varicosities or CVI at a rate of 2.9% annually. On the other hand, the rate of progression in patients with “pronounced” varicose veins was higher, with 50% progressing to CVI at a rate of 4.7% annually.10 Although this study provided some insight on CVD progression, no uniform venous terminology was available at the time, and the investigated population was not based on a random sample of the general population, which of course deeply limits this study’s epidemiological value, as previously stated.
 
More recently, another population-based study was performed, the Bonn Vein Study.11 In Bonn Vein Study I, conducted in the year 2000, 3072 participants (1350 men, 1722 women) of the general population of the city of Bonn and two rural townships (Germany), aged 18 to 79 years, took part. Participants were selected by simple random sampling from the registries of residents. In Bonn Vein Study II, the same population was investigated again 6.6 years later in order to determine the incidence of newly developed CVD, as well as the progression of the preexisting one. It was observed that, for the considered follow-up period, the prevalence of varicose veins rose from 22.7% to 25.1% and the prevalence of CVI from 14.5% to 16%.11 This resulted in an incidence of varicose veins and CVI of about 2% per year and suggested that, if left untreated, a significant proportion of patients will move along the spectrum of venous disease from varicose veins to edema, progressing to skin changes and, ultimately, ulceration.12
 
In 2015, the Edinburgh Vein Study accurately reported the progression of CVD during a 13-year follow-up period, granting new insights on disease progression in a larger cohort of patients.10 This was a population-based cohort study, in which an ageand sex-stratified random sample of adults aged from 18 to 64 years old were first examined at baseline from 1994 to 1996, and later underwent a follow-up examination from 2007 to 2009. The response rate was 52.8%, with 1566 subjects taking part in the study. Participants had a social class distribution similar to that of residents in Edinburgh but were slightly older, from more affluent areas, and more likely to be female than were nonresponders. From the 1566 subjects that were initially assessed, 880 underwent follow-up examination, of whom 334 had trunk varicose veins or CVI at baseline; these made up the study sample. Progression was found in 57.8% of the patients, with an annual progression rate of 4.3%, similar to previous studies. It was noted that progression happened regardless of the baseline CEAP C classification, with 31.9% of the patients with baseline varicose veins (CEAP C1-C2) developing CVI (2.4% annually), and 98% of the subjects with previous varicose veins and concomitant CVI experiencing clinical deterioration.10 These findings were broadly similar to the Bonn Vein Study and indicated that in around one-third to one-half of the patients with CVD, disease progresses during a 10-year period.10
 

Risk factors for CVD progression

Throughout the years, several risk factors have been related to the development of CVD.
In 2007, the San Diego Population Study revealed that age, sex, and ethnicity were important risk factors for venous disease,13 confirming previous findings by Adhikari et al14 and Criqui et al.2 Several other studies also revealed that female sex,15 family history,15,16 standing occupation, obesity, and multiparity17 were also associated with the development of this condition. Even smoking was found to be a risk factor for varicose veins, first described exclusively in men in the Framingham study,18 and later confirmed in both sexes by Gourgou et al,19 particularly in patients from the CEAP C4-C6 category.20
Although various risk factors for CVD have been identified, most of the available information came from cross-sectional studies with target populations, therefore deeply limiting conclusions regarding the impact of these risk factors in disease progression. Also, improper control of potential predisposing factors represents a major methodological issue in some of these studies.15 Fortunately, more solid data from recent longitudinal studies regarding this subject is also available, although sparse and often conflicting.
 
In 2010, Kostas et al21 evaluated the long-term characteristics of CVD progression and its correlation with the modification of specific risk factors. In his work, the contralateral limbs of 73 patients undergoing unilateral varicose vein surgery were prospectively evaluated during a 5-year follow-up period, by use of physical as well as color duplex examination. In about 50% of the patients, CVD developed in the contralateral limb during the considered period. Obesity, orthostatism, and nonadherence to treatment with compression elastic stockings were found to be independent risk factors for disease progression, as previously stated in cross-sectional studies, but multiparity was not.21 Although a longitudinal study, the sample was not population-based, and therefore generalization of the findings of this study to all patients with CVD was not possible.
 
The Edinburgh Vein Study later overcame these limitations.10 In this study, as in previous ones, family history of varicose veins was found to be strongly and independently related to worse prognosis, as well as with the development of CVI in subjects with varicose veins, reinforcing the possibility of a strong genetic predisposition to progression (although family environmental factors could also be involved). History of deep venous thrombosis (DVT) was also found to be independently related to CVD progression, as previously stated by Labropoulos et al,22 who concluded that progression of CVD was more rapid in postthrombotic limbs than in those with primary CVD, due to the probable combination of reflux and obstruction, as well as multisegmental venous involvement. More importantly, the Edinburgh Vein Study demonstrated that several other factors that were considered to be related to CVD development were not significantly related to CVD progression. In this study, obesity was not related to progression of CVD, although it is considered a risk factor for CVI. The same was found for multiparity, as in this study, there was no relation to progression. Cigarrete smoking, bowel habits, and mobility at work were also not related to progression, in accordance with the lack of well-established evidence for their roles in CVD development. Finally, this same study also demonstrated that in patients with varicose veins, the presence of superficial venous reflux was more than twice as likely to induce progression than in patients with varicose veins and no reflux. The risk of progression was related to the number of venous segments affected, with reflux in small saphenous veins being particularly important, as progression was found in 85.7% of the cases.10 Similar evidence had been identified in a previous study by Labropoulos et al,23 although in a smaller sample with shorter follow-up. These findings strongly suggest that duplex scanning could be a useful prognostic tool in selected patients.
 

Risk factors in predicting benefit of early intervention

CVD is an expensive and burdensome pathology, with high economic costs and a great impact on general quality of life. Evidence demonstrates that this pathology progresses in more than 50% of the patients,10 and several clinical risk factors for progression have been identified. Some of these risk factors are immutable, such as family history or female sex, but others are modifiable, eventually changing the disease’s natural history. Also, hemodynamic risk factors such as superficial venous reflux were found to be associated with higher disease progression, although with a variable risk, depending on the number of insufficient venous segments present.10
 
Knowing that CVD progresses in certain subgroups of patients when left untreated has important implications in terms of health care planning and raises the obvious question of potential for benefit of early intervention. Nonetheless, it is still difficult to predict which patients will develop aggravated disease and, more importantly, how fast it will occur. In 2012, Engelhorn et al7 reported that a subset of patients with segmental saphenous reflux (CEAP C1-C2) did not need treatment for an average of at least 3 years, but more solid evidence regarding this matter is still lacking.
 
Maybe one day we will be able to accurately predict which patients with CVD are at higher risk of progression and would benefit from an early intervention, but for now, more longitudinal long-term follow-up studies are required to better understand this subject.

 

Etiology of venous insufficiency and varicose veins—ongoing debate and future perspectives

The pathogenesis of primary venous reflux and the etiologic mechanism of morphologic changes in the vein wall still haven’t been totally explained.
 
Evidence states that venous pathology develops when venous pressure is increased and return of blood is impaired. These phenomena can be a consequence of valvular insufficiency, venous obstruction, or a combination of both and when present, determine global or regional venous hypertension that when left untreated can ultimately lead to the diverse clinical manifestations traditionally associated with CVD.24
 
Many authors believe that valvular insufficiency is the principal cause for the development of varicosities, in line with what Moore et al25 had previously stated in 1951. Nonetheless, conflicting evidence exists and has lead to frequent debate regarding the scientific value of this theory. In fact, we now know that veins are exposed to various biomechanical forces other than the traditional intraluminal pressure. Extraluminal pressure, flowing blood, and longitudinal tensile load originating from the presence of different blood volumes in different valveseparated vein segments also influence the biomechanical properties of veins.26 Depending on their magnitude, these physical determinants may either stabilize the architecture of the vessel wall or stimulate maladaptive remodeling processes. In the latter case, a chronic rise in biomechanical load may induce pathophysiological responses of the venous wall, promoting its weakening and eventually leading to the development of venous insufficiency and/or varicose veins, which, as we know, predominantly occurs in the lower extremities.26
 
Taking into account these observations, one must consider that although the development of venous insufficiency may be associated with varicose veins, these venous diseases may simply be coincidental and not necessarily causally related. In fact, there is an ongoing discussion as to whether valve dysfunction initiates these venous diseases or is a secondary event to venous remodeling, since, for example, the weakening of the structural integrity of the venous wall may simultaneously be a consequence of and the cause for dysfunction of the venous valves.27,28The mechanisms that induce these maladaptive responses are also now coming to light, with particular importance being placed on inflammatory markers. In fact, there is increasing evidence to support the notion that among several possible trigger mechanisms, CVI is to a considerable degree a blood-pressure–driven inflammatory disease.29 Elevated venous pressure and a shift in fluid shear stress generate an abnormal biomechanical environment in venules, in their walls and in valves. This may induce the activation of lytic enzyme activity, with the production of matrix metalloproteinases, as well as set in motion a chronic inflammatory cascade that ultimately leads to the degenerative process involved with venous insufficiency. Certain genetic polymorphisms can also be involved in this process, increasing the susceptibility to these biomechanical changes in affected individuals and therefore serving as risk factors for CVD.29
 
Despite detailed knowledge regarding CVD clinical presentation and treatment options, still not much is known about the underlying cellular mechanisms that ultimately trigger its onset. Better understanding of these phenomena is therefore essential, as targeted pharmacologic anti-inflammatory treatments might one day allow for the blockage of the inflammatory cascades involved in these processes, therefore stopping the chronic progression of this debilitating disease.

 

Conclusion

CVD is a common, progressive, and burdening disease, often overlooked by health care providers because of an underappreciation of the magnitude and impact of the problem, as well as incomplete recognition of their various presenting manifestations. Several risk factors, such as older age, female sex, family history, long periods in the upright position, and obesity, have been positively linked with higher disease prevalence, although data regarding risk factors for disease progression are still sparse. Recent long-term longitudinal follow-up studies gave some insight on this matter, by demonstrating that family history, previous DVT, and presence of venous reflux were associated with higher disease progression rates, although it is still difficult to determine which patients will develop aggravated disease and how fast it will happen. Nonetheless, taking into account the current demographic characteristics of the Western world, with an aging population and an ongoing obesity epidemic, it is predictable that the prevalence of CVD will rise, and therefore, better awareness for this condition is necessary in order to prevent patient morbidity and excessive economic costs. More long-term longitudinal studies are needed in order to assess the benefit of early intervention in CVD patients, as well as to assess the risk of deterioration from varicose veins to more advanced stages of venous disease, such as leg ulcers. Better understanding of the etiologic mechanisms causing morphologic vein wall changes is also necessary, as targeted pharmacological treatments could one day be used in at-risk patients in order to block inflammatory cascades that ultimately cause CVD.

 

References

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    11. Rabe E, Pannier F, Ko A, Berboth G, Hoffmann B, Hertel S. Incidence of varicose veins, chronic venous insufficiency, and progression of the disease in the Bonn Vein Study II [Abstract]. J Vasc Surg. 2010;51(3):791.

    14. Adhikari A, Criqui MH, Wooll V, et al. The epidemiology of chronic venous diseases. Phlebology. 2000;15:2-18.

    24. Eberhardt RT, Raffetto JD. Chronic venous insufficiency. Circulation. 2014;130(4):333-346.

    28. Cooper DG, Hillman-Cooper CS, Barker SG, Hollingsworth SJ. Primary varicose veins: the sapheno-femoral junction, distribution of varicosities and patterns of incompetence. Eur J Vasc Endovasc Surg. 2003;25(1):53-59.

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