Reflux and chronic venous disease – are they linked?

Interview wi th E. Rabe, Germany

Eberhard RABE, MD, PhD
Department of Dermatology
University of Bonn, Bonn

Bringing focus to the discussion about an association of venous reflux and chronic venous disease, Professor Dr med Eberhard Rabe, Emeritus President of the Union Internationale de Phlébologie, from the Department of Dermatology at the University of Bonn, Germany shares his comments on what three important studies in this area bring to the table. Looking particularly at the Bochum studies, the Bonn Vein study, and the Kostas trial, here he discusses the finding that in many cases reflux precedes the development of varicose veins (and may be an early stage of varicose-vein development) and touches briefly on risk factors for such development—such as age and genetics—but also more generally on risk factors for progression of chronic venous disease, factors possibly more amenable to intervention through lifestyle changes and adequate use of compression stockings. We ask Professor Rabe to weigh in on what can be done to prevent varicose veins and what measures may beneficially influence risk factors for progression to chronic venous insufficiency.

Could you summarize the main characteristics and findings of the Bochum study, the Bonn Vein study, and the Kostas trial?
In the initial Bochum study, 740 school children aged 10-12 years were screened for venous abnormalities.1 They underwent clinical and ultrasound follow-up at the ages of 14-16, 18-20, and 29-31 years. None of the participants showed varicose veins during Bochum study I. In the follow-up investigation, it was shown that the manifestation of truncal varicose veins is preceded by venous reflux in the same veins (P=0.039). Venous reflux increased with age (Bochum I: 2.5%, Bochum III: 18.5%, Bochum IV: 25%). The presence of preclinical venous reflux presented a 30% risk (95% confidence interval, 13%-53%) of developing truncal varicose veins within 4 years.

In Bonn Vein study I and II, reflux in the saphenous veins was defined as an insufficient vein in clinical stage C2.2 However, we demonstrated progression of the severity of venous disease from stage C2 with reflux in the saphenous veins to chronic venous insufficiency (stages C3 and C4a) in 31.8% of participants in the 6.6-year follow-up period.3 Kostas et al4 examined the contralateral limbs of 73 patients undergoing varicose vein surgery after 5 years of follow-up. In that study, 48 new sites of reflux were identified and reviewed in 38 patients (52%). During that same period, CEAP (Clinical-Etiology-Anatomy-Pathophysiology clinical class) scores deteriorat- ed significantly. Independent risk factors for progression of chronic venous disease in a binary logistic regression analysis were orthostatism, obesity, and incompliance with compression treatment, whereas multiparity and estrogen therapy were not identified as risk factors.

What did these studies have to say about the cause of varicose veins?
In the Bochum studies, the development of varicose veins was preceded by the detection of reflux.1 However, venous reflux is caused by venous valve dysfunction, which itself is a part of the varicose vein disease. The detection of venous reflux in truncal veins may therefore be an early stage of the development of varicose veins. In addition, truncal veins, eg, the great and small saphenous veins, are located in a duplicature of the muscle fascia, and they are usually not clinically visible even if they have developed reflux and dilatation. This means that a dilated insufficient saphenous vein may not be clinically visible, whereas the more superficially located sidebranch varicosities are clinically diagnosed as varicose veins.

In the Bonn Vein study, we investigated the incidence of varicose veins during a 6.6-year follow-up period.3 The overall incidence for new varicose veins, increasing with age, was 13.7%—so, roughly 2% per year—equally in the male and female population. The only significant risk factors for the incidence of varicose veins were age and family history of varicose veins.Pregnancies showed a trend for a higher incidence, but this did not reach a significant level. This may be due to the fact that the number of pregnancies in our population is low.

Where varicose veins were preceded by reflux, what was the latency period?
This question refers to the Bochum study; in that study, venous reflux in truncal veins preceded the clinical manifestation of varicose veins in most of the cases.1 In 30% of the participants, the progression of reflux toward visible varicose veins was fast, with the latency period between 0 and 4 years. In other cases, this period was longer. In two cases, truncal reflux detected in Bochum study I did not transform into varicose veins during the 19 years of Bochum study IV.

Did these studies identify individuals at risk for developing varicose veins?
In the Bochum study, venous reflux occurred earlier in individuals with a family predisposition for varicose veins and displayed a higher prevalence and longer duration of reflux than in the control group with a family history negative for venous disease.1 Concerning chronic venous disease progression, the Kostas study showed that prolonged orthostatism, obesity, and incompliance with compression-stocking use are risk factors.4 However, this is not specific for progression of varicose veins, but represents risk factors for the overall progression of signs and symptoms in chronic venous disease.

In Bonn Vein study II, higher age and family history for varicose veins were significant risk factors for the development of new varicose veins.3 With regard to progression of the Cstages, the risk factors for progression from C0 and C1 to higher C-stages were higher age, obesity, and superficial and deep venous reflux. Risk factors for progression from C2 to chronic venous insufficiency (C3-C6) were higher age, higher body mass index, and swelling sensation.

On the basis of these studies, are there any preventive measures you would recommend?
To answer this question, we have to differentiate between the development of varicose veins and the development of chronic venous insufficiency with edema, skin changes, or venous ulcers. With regard to the development of varicose veins, it seems that we have no instruments to prevent this, as we cannot change age and genetic risk. Early detection of venous reflux, however, may lead to a higher awareness of signs and symptoms of venous diseases in patients and may also encourage early treatment of developing varicose veins.

Age is also one of the main risk factors for the progression of the disease toward chronic venous insufficiency with edema and skin changes. Additional risk factors for the progression toward chronic venous insufficiency are obesity as well as orthostatism and compliance with treatment measures. These are risk factors that can be influenced by weight loss and a change in working habits, as well as engagement in more sports activities. The Kostas study also showed a protective effect of the use of compression stockings in the progression of chronic venous disease. The same may also be true for the treatment of varicose veins.

Today, we understand varicose veins and chronic venous insufficiency to be inflammatory diseases or diseases with inflammation in the venous wall. In this context, the use of venoactive drugs that are able to reduce the inflammatory reaction of the venous wall may also be protective for the progression of venous diseases.5 However, long-term longitudinal studies showing this protective effect clinically are still missing.

Keywords: chronic venous disease; risk factor; varicose veins; venous reflux

1. Schultz-Ehrenburg U, Reich-Schupke S, Robak-Pawelczyk B, et al. Prospective epidemiological study on the beginning of varicose veins: Bochum Study I-IV. Phlebologie. 2009;38:17-25. 
2. Rabe E, Pannier-Fischer F, Bromen K, et al. Bonner Venenstudie der Deutschen Gesellschaft für Phlebologie - Epidemiologische Untersuchung zur Frage der Häufigkeit und Ausprägung von chronischen Venenkrankheiten in der städtischen und ländlichen Wohnbevölkerung. Phlebologie. 2003;32:1-14. 
3. 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. J Vasc Surg. 2010;51:791. 
4. Kostas TI, Ioannou CV, Drygiannakis I, et al. Chronic venous disease progression and modification of predisposing factors. J Vasc Surg. 2010;51:900-907. 
5. Rabe E, Guex JJ, Morrison N, et al. Treatment of chronic venous disease with flavonoids: recommendations for treatment and further studies. Phlebology. 2013; 28:308-319.