According to the Vein Consult Program (largest global epidemiological study on chronic venous disease), “not having regular exercise” is a statistically significant risk factor of chronic venous disease from 18 to 65 years in both men and women⁵. In this context it is worth questioning on how to help patients with reduced mobility to have healthy veins.

First, patients should be encouraged to avoid prolonged sitting positions and to lose weight in case of concomitant obesity (two well-known risk factors of CVD)⁴. They should be encouraged to have ankle or hips movements as often as possible. Indeed, even small ankle or hip movements increase venous return, avoid blood stagnation in the lower limbs and decrease the intensity of leg oedemas in workers that stand for long periods⁶. One could expect that for patients with reduced mobility, ankle and hip movements should have the same benefits.

Balneotherapy is also a valid therapeutic approach: spa therapy, associating balneotherapy and patient education, is able to improve significantly the skin trophic changes of the CVD patients and their CVD related quality of life and symptoms¹. Of course, spa therapy should be adapted to each patient: for those able to walk, walking sessions in baths are appropriate to reduce oedema of the legs, whereas for those not able to walk, hydromassages could be more appropriate.

Compression therapy, associated or not with balneotherapy, is of very special relevance in patients with reduced mobility, for the same reasons as previously stated: it increases venous return and minimizes blood stagnation in the legs². Compression will prevent oedema, as well as Deep Venous Thrombosis which is of special concern for this category of patients. Appropriate pressure should be chosen with regards to the clinical stage of the CVD.

Some specific medical devices that stimulate calf pump can also be considered, for example the neuromuscular electric stimulation³. In addition, venotonics can be used to help relieving functional symptoms.

To conclude, there are several options to help patients maintain healthy veins healthy leg veins, which should be closely supported by patient education from HCPs.

References:
1. Carpentier, Patrick H., and Bernadette Satger. ‘Randomized Trial of Balneotherapy Associated with Patient Education in Patients with Advanced Chronic Venous Insufficiency’. Journal of Vascular Surgery 49, no. 1 (January 2009): 163–70. https://doi.org/10.1016/j.jvs.2008.07.075.
2. 2010_Dispositifs de compression médicale à usage individuel, utilisation en pathologie vasculaires; Révision de la liste des produits et prestations remboursables.
3. Hajibandeh, Shahab, Shahin Hajibandeh, George A. Antoniou, James Rh Scurr, and Francesco Torella. ‘Neuromuscular Electrical Stimulation for the Prevention of Venous Thromboembolism’. The Cochrane Database of Systematic Reviews 11 (21 2017): CD011764. https://doi.org/10.1002/14651858.CD011764.pub2.
4. Kostas, Theodoros I., Christos V. Ioannou, Ioannis Drygiannakis, Efstratios Georgakarakos, Christos Kounos, Dimitrios Tsetis, and Asterios N. Katsamouris. ‘Chronic Venous Disease Progression and Modification of Predisposing Factors’. Journal of Vascular Surgery 51, no. 4 (April 2010): 900–907. https://doi.org/10.1016/j.jvs.2009.10.119.
5. Vuylsteke ME, et al. An Epidemiological Survey of Venous Disease Among General Practitioner Attendees in Different Geographical Regions on the Globe: The Final Results of the Vein Consult Program. Angiology. 2018 ; 69, I 9.
6. Lin Y-H et al. Effectiveness of leg movement in reducing leg swelling and discomfort in lower extremities.Applied Ergonomics Vol 43, Issue 6, Nov 2012, Pages 1033-1037.

Risk factors of Chronic Venous Disease, such as BMI, age, pregnancy are well identified. However, many patients exposed to these risk factors do not develop the disease and primary varicose veins are also seen in young adults with no specific cause¹. This raises the question of how genetic plays a role in CVD.

CVD is considered as a genetically predisposed disease, but it has multifactorial genetic basis which in addition may be changed by non-genetic factors (as for example lifestyle)³. At current time, unfortunately the precise nature and profile of the genes involved in CVD remain poorly understood^1,3. Identifying the genetic factors involved in the etiology of CVD may translate into better prevention or treatment, which would benefit patients suffering from its clinical sequelae¹

There are several kind of genes thought or known to be involved in CVD (2): those related to vascular development & angiogenesis (ex: FOXC2 gene & VEGF-A gene) are the most well know. The FOXC2 gene encodes a regulatory transcription factor, which plays a role in normal development of the lymphatic and venous system, in particular the development and the maintenance of venous and lymphatic valves function. FOXC2 is needed for interactions between mesenchymal cells during the formation of lymphatic and blood vessels, lymphnode and valve formation. Vascular endothelial growth factor (VEGF)-A gene is also of importance, as VEGF-A is a physiological and pathological angiogenesis regulator that plays a pivotal role in the vascular reactivity and integrity maintenance. VEGF-A increases the expression and production of endothelial nitric oxide synthase and also promotes inflammation by stimulating expression of adhesion molecule-1 (ICAM-1) as well as other molecules involved in the inflammation process of varicose veins².

Other genetic factors such as those related to vein wall integrity, or related to hemochromatosis (as iron can be toxic with a capability of generating reactive oxygen species) could also be of importance in CVD².

Some authors consider that there is an urgent need of fundamental research in this field, in establishing collaborative links and designing a Genome-Wide case-control Association Study (GWAS) as an international consortium to provide a statistically robust paradigm in the field of CVD genetics¹. A GWAS involves the direct genotyping of common genetic variants, usually single nucleotide polymorphisms (SNPs), in hundreds to thousands of DNA samples using microarray technology. Algorithms are utilized which compare the frequency of SNPs between disease and control cohorts, based on the premise that adjacent parts of the chromosome are inherited together with a disease-influencing allele. This permits for unbiased investigation of the entire genome for any phenotypic links¹. It is a tool used to examine genes implicated in disease susceptibility. Few GWAS have been carried out until now on CVD.

Further studies are needed to have a better knowledge of the genetic inputs in the CVD apparition and progression and in order to effectively improve clinical care in this area. One could not that epigenetics should not be forgotten.

References:
1. Grant, Yasmin, Sarah Onida, and Alun Davies. ‘Genetics in Chronic Venous Disease’. Phlebology 32, no. 1 (February 2017): 3–5. https://doi.org/10.1177/0268355515624030.
2. Serra, Raffaele, Lwanga Ssempijja, Michele Provenzano, and Michele Andreucci. ‘Genetic Biomarkers in Chronic Venous Disease’. Biomarkers in Medicine, 13 February 2020. https://doi.org/10.2217/bmm-2019-0408.
3. Nicolaides, Andrew, Stavros Kakkos, Niels Baekgaard, Anthony Comerota, Marianne de Maeseneer, Bo Eklof, Athanasios D. Giannoukas, et al. ‘Management of Chronic Venous Disorders of the Lower Limbs. Guidelines According to Scientific Evidence. Part I’. International Angiology: A Journal of the International Union of Angiology 37, no. 3 (2018): 181–254. https://doi.org/10.23736/S0392-9590.18.03999-8.

A French large pharmaco-epidemiological study has investigated the possible adverse effects of venotonic drugs commercialized in France - and belonging to the French capillary stabilising agents subclass (ATC subclass C05C)- on pregnancy outcome and foetus malformation². This study was exclusively financed by public funds. It compared pregnancy outcomes and new-born health between women exposed to venotonics during their pregnancy (8 998 women) - corresponding to the organogenesis period for 1200 women - and unexposed women (27 963 women). The information of venoactive consumption was based on their prescription during pregnancy; the data related to infant were birth weight and length, APGAR score, diseases, malformations. The assessed pregnancy (negative) outcomes were any miscarriage, elective abortion and foetal death.

The most frequently prescribed venotonic drugs during pregnancy were hesperidin (17.7%), diosmin (16.9%) and troxerutin (4.8%). It is worth saying that the risks of pregnancy termination remained significantly lower in the women exposed to venotonics (an uncertain hypothesis is the action of flavonoids on mediators of inflammation such as PGE2 known to induce myometrical contractions). In the group of new-borns whose mother had a prescription of venotonics during organogenesis, the rate of malformations was similar to that of the unexposed control group. To end, the risk of neonatal diseases was not increased by exposure to venotonic agents in the third trimester. It was concluded that there was no increased risk of adverse pregnancy outcome among women exposed to venotonics compared with unexposed pregnant women. Overall, the authors considered the results are reassuring.

Nevertheless, these data are not enough to affirm that venotonics are fully safe during pregnancy. In addition, safety profiles can differ between venotonics drugs.

Of interest, the CRAT, a French independent public center aimed to inform health care professionals on reproductive effects of drugs, concluded that based on available clinical data, use experience, and on pharmacokinetic profile, the following drugs should be preferred to be used in case where venotonic drugs are deemed necessary during pregnancy and lactation: diosmin, hesperidin, troxerutin and rutoside¹.

In conclusion, despite reassuring data for some drugs, it’s worth reminding that the management of venous disease during pregnancy should be treated in a first instance with daily activities, adequate alimentation (haemorrhoid crisis) and elastic venous compression when appropriate. When not possible, the balance between benefice and risk of the venotonic drug should be closely assessed.

References:
1. CRAT 2019 (French reference center for teratogenic agents or “Centre de Référence pour les Agents Tératogènes”): https://lecrat.fr/
2. Lacroix I., Hurault C., Sarramon M.F., Guitard C., Berrebi A., Grau M., Albouy-Cossard C., Bourrel R., Elefant E., Montastruc J.L., Damase-Michel C. (2009) Prescription of drugs during pregnancy: a study using EFEMERIS, the new French database. Eur J Clin Pharmacol. 2009 Aug;65(8):839-46

CVD progression is defined as a change in clinical signs that indicate an increase in CEAP class, as a change in symptoms, or changes in both. Progression of CVD is highly variable and proceeds along different pathways in different patients, though some patterns are evident5. Chronic venous hypertension and venous dilatation lead to a number of pathophysiologic changes in the vein wall and surrounding tissues. Chronic inflammation alone can have deleterious consequences on venous flow⁵.

Several risk factors have been associated with the development of CVD, including older age, female gender family history, standing occupation, obesity, and multiparity. However, other potential factors that may be involved in CVD progression have not been well studied, such as estrogen treatment and warrant further investigations¹. Consequently dealing with these risk factors is expected to play a role in the disease prevention & progression. Patients should therefore be informed of the risk factors for CVD and its consequences and should be encouraged to reduce risk where possible. In all applicable cases, lifestyle changes are warranted to increase physical activity, and reduce excess bodyweight⁵.

With regards to medical treatments, venoactive drugs, compression therapy and surgical procedures (to remove incompetent veins), as well as endovenous procedures, are the most widely used therapies for managing the CVD symptoms and/or clinical signs.

The following focus on less invasive therapies can be stated:

• First, prevention of CVD progression, such as from lower clinical classes to more severe disease, including venous leg ulcer is one of the main goals of treatment of compression therapy^2,3. At the earliest stages, compression therapy relieves the symptoms but unfortunately there is no clinical study allowing to state that compression delays the disease progression³. Indeed, these clinical studies would be very long and complex to set up, as the disease progresses very slowly. Nevertheless, although at current time there is insufficient information on the prevention of CVD progression by compression therapy, noncompliance with compression has been reported as one of the risk factors for overall CVD progression².
• Secondly, venoactive drugs aim at relieving functional symptoms of CVD. If symptoms progress, venoactive drugs should not be forgotten. They are no reliable data showing that venoactive drugs delays the disease progression. Nevertheless, as venoactive have antiinflammatory properties, one could not exclude that they play a role in the chronic inflammation present in the CVD⁵.

Of note, secondary CVD has been shown to progress faster than primary CVD, which emphasizes the importance of primary and secondary prevention, sufficient anticoagulation (when needed), control of risk factors, and the use of compression stockings, the latter furthermore preventing the deterioration of existing CVD⁴.

References:
1. Kostas, Theodoros I., Christos V. Ioannou, Ioannis Drygiannakis, Efstratios Georgakarakos, Christos Kounos, Dimitrios Tsetis, and Asterios N. Katsamouris. ‘Chronic Venous Disease Progression and Modification of Predisposing Factors’. Journal of Vascular Surgery 51, no. 4 (April 2010): 900–907. https://doi.org/10.1016/j.jvs.2009.10.119.
2. Rabe, Eberhard, Hugo Partsch, Juerg Hafner, Christopher Lattimer, Giovanni Mosti, Martino Neumann, Tomasz Urbanek, Monika Huebner, Sylvain Gaillard, and Patrick Carpentier. ‘Indications for Medical Compression Stockings in Venous and Lymphatic Disorders: An Evidence-Based Consensus Statement’. Phlebology 33, no. 3 (April 2018): 163–84. https://doi.org/10.1177/0268355516689631.
3. HAS_2010_Dispositifs de compression médicale à usage individuel, utilisation en pathologie vasculaires ; Révision de la liste des produits et prestations remboursables. 
4. Labropoulos, Nicos, Antonios P. Gasparis, Dina Pefanis, Luis R. Leon, and Apostolos K. Tassiopoulos. ‘Secondary Chronic Venous Disease Progresses Faster than Primary’. Journal of Vascular Surgery 49, no. 3 (March 2009): 704–10. https://doi.org/10.1016/j.jvs.2008.10.014
5. Labropoulos, Nicos. ‘How Does Chronic Venous Disease Progress from the First Symptoms to the Advanced Stages? A Review’. Advances in Therapy 36, no. Suppl 1 (2019): 13–19. https://doi.org/10.1007/s12325-019-0885-3.

Sclerotherapy is one of the treatment options currently available in CVD treatment among a wide range of therapeutic options: dressing for venous ulcers, compression therapy, physiotherapy/leg massages/leg elevation, medical treatment with drugs (mainly venotonics), transcutaneous laser, endovenous treatments, surgery¹.

Sclerotherapy involves injection of dilated veins, with liquid or foam chemical agents to damage the endothelium and eventually ablate the vein¹.

It is easy to carry out and treatment may be repeated without restriction; it is generally associated with minor side effects and a comparatively short downtime².

Sclerotherapy may be used for trunk incompetence, nevertheless it shows high recurrence rates after five years. It is therefore advisable to treat the saphenous veins with surgical or endovenous procedures. Of note, sole sclerotherapy may exhibit good long-term results in the treatment of isolated tributary or perforator incompetence as well as in recurrent varicose veins. In addition, sclerotherapy may also be successfully employed in the treatment of venous malformations².

Generally speaking, sclerotherapy is is a good alternative in elderly multimorbid patients or individuals who decline surgical and endovenous procedures¹.

Four recommendations were established by Wittens et al. in 2015:
  

Grade A recommendations:

• Liquid or foam sclerotherapy is not recommended as the firstchoice treatment for CVD C2-C6 due to saphenous vein incompetence. It should be used only as primary treatment in selected cases
• Foam sclerotherapy is recommended as a secondchoice treatment of varicose veins (C2) and for more advanced stages of CVD (C3-C6) in patients with saphenous vein incompetence, not eligible for surgery or endovenous ablation.

Grade B recommendations:

• Foam sclerotherapy should be considered as primary treatment in patients with recurrent varicose veins, and in elderly and frail patients with venous ulcers.
• Foam sclerotherapy should be considered for treating telangiectasias and reticular veins (C1).

References: 
1. Santler, Bettina, and Tobias Goerge. ‘Chronic Venous Insufficiency - a Review of Pathophysiology, Diagnosis, and Treatment’. Journal Der Deutschen Dermatologischen Gesellschaft = Journal of the German Society of Dermatology: JDDG 15, no. 5 (May 2017): 538–56. https://doi.org/10.1111/ddg.13242.
2.Wittens, C., A. H. Davies, N. Bækgaard, R. Broholm, A. Cavezzi, S. Chastanet, M. de Wolf, et al. ‘Editor’s Choice - Management of Chronic Venous Disease: Clinical Practice Guidelines of the European Society for Vascular Surgery (ESVS)’. European Journal of Vascular and Endovascular Surgery: The Official Journal of the European Society for Vascular Surgery 49, no. 6 (June 2015): 678–737. https://doi.org/10.1016/j.ejvs.2015.02.007.