This document summarizes the best medical treatment of venous insufficiency in 2013. It discusses the epidemiology, etiology, socioeconomic aspects, and management of chronic venous disorders. It provides details on medical therapeutic methods, including venoactive drugs, compression therapy, and lifestyle adaptations. It evaluates the efficacy of various venoactive drugs like calcium dobesilate, MPFF, and hydroxyethyl rutosides in treating symptoms and venous leg ulcers based on clinical trials and meta-analyses. It also explains the effects of drugs on the macrocirculation, microcirculation, and leukocyte-endothelium interaction in attenuating venous inflammation.

1. The Best Medical Treatment of
Venous Insufficiency in 2013
Dr. Fatih İslamoğlu
Department of Cardiovascular Surgery,Department of Cardiovascular Surgery,
Ege University MedicalEge University Medical FacultyFaculty,,
Izmir, TurkeyIzmir, Turkey

2. Epidemiology of Chronic Venous Disorders
Age 35-40 yo
- M % 7-35
- F % 20-60
Age > 60 yo;
- M % 15-55
- F % 40-78
Framingham Study
Management of chronic venous disorders of lowew limps: Guidelines according to scientific
evidence Nicolaides et. al. İnt.Ang.Vol:27 2008

3. Etiological and Anatomical Aspects of
Chronic Venous Disorders
• Primary etiology; 77.4 %
• DVT prevalance ; 25 %
• Superficial system disease; 88.7 %
• Reflux ; 97.5 %
• Reflux combined with obstruction ; 11 %

4. Socioeconomic Aspects
• Estimations of the overall annual costs of CVD vary
from 600 to 900 million € (US$720 million-1 billion) in
Western European countries
• 2.5 billion € (US$3 billion) in the USA.
• 1-3 % of total health care budget .
• In France, 41% of total expenditure for CVD is for
drugs.
1-McGuckin M. et al. Validation of venous leg ulcer guidelines in the United States and
United Kingdom AmJ Surg 2002; 183
2-Levy E. et al.(Management of venous leg ulcer by French physicians, diversity and
related costs. A prospective medicoeconomic observational study), j Mal Vasc 1994;19

5. Management
Story
Clinical examination
Duplex scanning
DVT Venous reflux Normal
Treatment Sclerotherapy
Operation Medical Treatment
Ligation Stripping, Ablations Sclerotherapy

6. Management Options According to CEAP
C A: S, D, P P: R, O, O+R Management
C0-2 S
S R Medical Treatment
Sclerotharpy
Surgery
Mild C3 S
D O Medical Treatment
Severe C3 S
D (above
inguinal
level)
O Medical Treatment
Angioplasty-stent
C 4-6
D (above
inguinal
level)
O Medical Treatment
Angioplasty-stent
C 6 active or
repeating venous
ulcer
D R+O Medical Treatment
Cerrahi
Management of chronic venous disorders of lowew limps: Guidelines according to scientific evidence
Nicolaides et. al. İnt.Ang.Vol:27 2008

7. MEDICAL THERAPEUTIC METHODS
• Venoactive drugs
• Compression therapy
• Adaptation of lifestyle

8. The care of patients with varicose veins and associated chronic
venous diseases: Clinical practice guidelines of the Society for
Vascular Surgery and the American Venous Forum
Gloviczki P, Comerota AJ, Dalsing MC, Eklof BG, Gillespie DL, Gloviczki ML, Lohr JM,
McLafferty RB, Meissner MH, Murad MH, Padberg FT, Pappas PJ, Passman MA,
Raffetto JD, Vasquez MA, Wakefield TW; Society for Vascular Surgery; American
Venous Forum.
J Vasc Surg. 2011 May;53(5 Suppl):2S-48S. doi:
10.1016/j.jvs.2011.01.079.
Guidelines for the management of
varicose veins.
Gloviczki P, Gloviczki ML.
Phelobology 2012 Mar;27 Suppl 1:2-9. doi:
10.1258/phleb.2012.012S28.

9. Guideline No. 8. Medical treatment
We suggest venoactive drugs (diosmin, hesperidin, rutosides,
sulodexide, micronized purified flavonoid fraction, or horse chestnut
seed extract [aescin]) for patients with pain and swelling due to
chronic venous disease, in countries where these drugs are
available..
We suggest using pentoxifylline or micronized purified flavonoid
fraction, if available, in combination with compression, to accelerate
healing of venous ulcers..
Guideline No. 9. Compression treatment
We suggest compression therapy using moderate pressure (20 to 30
mm Hg) for patients with symptomatic varicose veins
We recommend against compression therapy as the primary
treatment of symptomatic varicose veins in patients who are
candidates for saphenous vein ablation
We recommend compression as the primary therapeutic modality for
healingvenous ulcers. .
We recommend compression as an adjuvant treatment to superficial
vein ablation for the prevention of ulcer recurrence.
2 B
8.1
8.2
2 B
9.1
2 C
9.2 1 B
9.3
9.4
1
1 A
B
Grade of
Recommend
.
Level of
evidence

10. Classification of the main venoactive drugs
• Benzopyrones
- Alpha benzopyrones
• Coumarin
- Gamma benzopyrones
• Diosmin
• Micronized purified flavonoid fraction (MPFF)
• Rutin and rutosides
• 0-(b-hydroxyethyl)-rutosides (troxerutin, HR)
• Saponins
• Escin
• Ruscus extract
• Other plant extracts
• Anthocyan Proanthocyanidins (oligomers), Extracts of Ginkgo,
heptaminol and troxerutin, Total triterpene fraction
• Synthetic products
– Calcium dobesilate
– Benzaron
– Naftazone

11. Mode of Action of Venoactive Drugs
Effect on Venous
Tone
Effect on capillary
Leakage
Lymphatic
Network
Anti-inflammatory
effect
Micronized purified
flavanoid fractions
(MPFF)
Increases venous tone by
prolonging noradrenergic
activity
Reduces capillary
hyperpermeability by
inhibition of leukocyte
adhesion
Increases
lymphatic flow
and number of
lymphatics
Reduces release of
inflammatory mediators
by inhibiting adhesions of
leukocytes
Rutin and
Rutosides
Increases venous tone by
bhlocking the inactivation
of noradrenalin
Reduces capillary
hyperpermeability
_ Inhibits free radical
generation
Coumarin and rutin Increase of venous flow Beneficial effects on the
microcirculation
Increases high-
protein edema
proteolysis and
lymphatic flow
_
Escin Increases venous wall
tone
Decreases capillary
filtration
_ Free radical scavenging
anti-elastase and anti-
hyaluronidase properties,
Ruscus extract Increases venous tone by
venous α1 adrenergic
receptors
Antipermeability effect _ _
Proantocyanidines _ Reduces
hyperpermeability
_ Free radical scavenging
effect
Gingko biloba _ _ _ _
Calcium dobesilate Increases venous tone Increases capillary
resistance by mitigating
reactive O2 species and
histamine effect
Improves
lymphatic
drainage
Anti-oxidant and
angioprotective effects,
enhances nitric oxide
synthetase activity
Naftazone _ Same Same Same ?

12. The Effects of Venoactive Drugs on Symptoms
Positıve results on the
following indications
Recommendation Trials and Meta-
analyses
Micronized purified
flavanoid fractions
(MPFF)
Pains, cramps, heaviness,
sensation of swelling,
edema
Grade A Coleridge-Smith etal.
2005
Hydroxethyl-
rutosides
Itching, edema Grade A Unkauf et al. 1996
Krenendo et al. 1993
Grossman 1997
Coumarin and rutin
(troxerutin)
_ Grade C Vanscheidt, et al, 2002
Escin Pain, edema Grade B Diehm et al, 1996
Pittler and Ernst, 2006
Siebert et al, 2002
Ruscus extract Pain, edema Grade B Boyle et al. 2003.
Proantocyanidines Pain Grade C Kiesswetter et al. 2000
Gingko biloba _ Grade C _
Calcium dobesilate Cramps, restless legs,
sensation of swelling,
edema
Grade A Labs et al. 2004
Ciapponi et al. 2004
Naftazone _ Grade C Vayssairat et al, 1997

13. Indication VAD Recommendation Level of
evidence
code
Relief of
symptoms
associated
with CVD
In patients
with C0s and
C6s and with
CVD related
oedema
MPFF Strong Moderate 1B
Nonmicronized
Flavanoid
Moderate Poor 2C
Oxerutin Moderate High 2A
Ca Dobesilate Moderate High 2A
Escin Moderate Moderate 2B
Ruscus Ext Moderate Moderate 2B
Gingko Biloba Weak Poor 2C
Venous ulcer
healing
MPFF Strong Moderate 1B
Updated recommendations foUpdated recommendations forr VADsVADs

14. Drug:Drug: CalciuCalciumm dobesilatedobesilate
Symptoms: Cramps, restlessSymptoms: Cramps, restless
legs, sensation of swelling,legs, sensation of swelling,
edemaedema
Number of RCT: 4Number of RCT: 4
Meta-analyses: 2Meta-analyses: 2
Grade of recommendation: 2AGrade of recommendation: 2A
Venoactive drugs: EfficacyVenoactive drugs: Efficacy

15. Drug:Drug: MPFFMPFF
Symptoms: Pain, cramps, heaviness,Symptoms: Pain, cramps, heaviness,
sensation of swelling, trophic changessensation of swelling, trophic changes
and ulcerationand ulceration
Number of RCT: 5Number of RCT: 5
Meta-analyses: 1Meta-analyses: 1
Grade of recommendation: 1BGrade of recommendation: 1B
Venoactive drugs: EfficacyVenoactive drugs: Efficacy

16. Drug:Drug: Hydroxyethyl rutosidesHydroxyethyl rutosides
Symptoms: Itching, edemaSymptoms: Itching, edema
Number of RCT: 11Number of RCT: 11
Meta-analyses: 4Meta-analyses: 4
Grade of recommendation: 2Grade of recommendation: 2AA
Venoactive drugs: EfficacyVenoactive drugs: Efficacy

17. Drug:Drug: Ruscus extract(Cyclo-3R)Ruscus extract(Cyclo-3R)
Symptoms: EdemaSymptoms: Edema
Number of RCT: 2Number of RCT: 2
Meta-analyses: 1Meta-analyses: 1
Healing of ulcers: RCT 1Healing of ulcers: RCT 1
Grade of recommendation 2BGrade of recommendation 2B
Venoactive drugs: EfficacyVenoactive drugs: Efficacy

18. Mode of Action of Venoactive Drugs
1- Effects on Macrocirculation
Most VADs increase the venous tone by a
mechanism related to noradrenaline pathway.
Especially. MPFF and hydroxyethylruosides
have more affinity to venous wall.
Last studies show that CVD is closely related to
primary insufficiency of venous valves origined
from inflammation.
MPFF: Potential anti-inflammatory effect on an
animal model of acute venous HT. The
protective effect on venous valves in CVD..

19. 2-Effects on Microcirculation
Capillary resistance:: To increase capillary resistance
and to decrease capillary filtration.
Especially MPFF enhanced inhibition of
adhesion of leukocytes on capillariees by
micronisation..
Lymphatic drainage
Coumarin and rutin edema lysis effect by proteolysis.
MPFF: increase both lymphatic flow and lymphatic
channels
Ca dobesilate: increases lymphatic drainage.

20. Protection against inflammation: The attenuation of
inflammatory response by free radical scavenging,
anti-elastase and anti-hyaluranidase properties of
VADs (rutosides, escin, ruscus extracts,
proanthocyanidines, Ca dobesilate, MPFF).
Hemorrheological disorders: Inflammation
increased fibrinogen, plasma volume contraction,
increased blood viscosity accumulation of
huge red cell aggregates around the venules,
reduced blood flow and poor O2 delivery
lipodermatosklerosis.
Decrease in viscosity: MPFF, Ca dobesilate,
Increase in red cell velocity: MPFF

21. Efficacy on edema of Venous Origin
The confirmed efficacy by meta analyses: MPFF, Ca
debosilate, rutosides, escin, proanthocyanidine and
coumarin rutin..
Pharmacological Treatment of Leg Ulcers
Only MPFF: This efficacy was confirmed in 2005 by a
meta-analysis of 5 trials using MPFF as an adjunct
to standard treatment in 723 patients of stage 6 of
the CEAP classification.

22. Leukocyte-Endothelium Interaction:
The cause of venous inflammation and
following damage
Leukocyte-endothel interactionLeukocyte

23. At the level of microcirculation: Hyperpressure at the capillary level induces capillary leakage
allowing the accumulation of fluids, protein, and red blood cells in the interstitial space, forming
edema. Red blood cell degradation products and protein extravasations are the initial inflammatory
signals that result in leukocyte migration into the interstitial space..
Leukocyte Endothelium Capillary
adhesion changes hyperpressure
Inflammation
Plasma
leakage
Adhesion
molecules
Free
radicals
Proteolytic
enzymes
Red blood
cell
Leukocyte
Venous hypertension is transmitted to the microcirculation causing an
inflammatory state and damage to capillaries. This leads to complications
ranging from edema to open leg ulceration.
1 - Nicolaides AN. Angiology. 2003;54:533-544. 2 - Adapted from Bergan J et al. Microcirculation. 2000;7:S23-S28. 3 - Boisseau MR. Angéiologie. 2000;52:71-

24. Leukocytes and changes inLeukocytes and changes in
venous valvesvenous valves

25. Venous inflammation is the first step in
progression of early-term leg symptoms
1
1 - Boisseau MR. Medicographia. 2006;28:128-136.
Inflammatory mediators
released after the
leukocyte/endothelium
interaction may
stimulate nociceptors
in the venous wall,
causing venous pain
and leg symptoms.

26. New England Journal of Medicine:
The importance of early treatment of CVD1
1 - Bergan JJ, et al. N Engl J Med. 2006;355:488-498.
1-“Early treatment aimed at
preventing venous hypertension,
reflux, and inflammation could
alleviate symptoms of chronic
venous disease and reduce the risk
of ulcers.”
2-“Treatment to inhibit inflammation
may offer the greatest opportunity to
prevent disease–related
complications.”

27. • Among the medical therapy options, especially
MPFF has a confirmed protective effect on
mıcrocirculation against the ambulatory venous
hypertension.
• MPFF attenuates the leukocyte/endothelium
interaction by inhibiting and/or reducing the
release of endothelial intercellüler adhesion
molecule I, vasculary cell adhesion molecule
and some other leukocyte adhesion molecules.

28. • The healing effect of MPFF is most evident in
patients with leg ulcers.
• The patients who were treated with MPFF and
compression combination showed 32% better
healing rate than the patients who were treated
topical care and compression alone during 6-
month follow-up.

29. Other Drugs Having Effect on Venous System
• Pentoxifilline: Reduces leukocyte adhesion and erythrocyte
aggregation, and a mild fibrinolytic action. Although it is relatively
well tolerated, its value for treating leg ulcers remain debatable
until new data become available.
• Stanozolol: Stanozolol (stanazol), an anabolic steroid, stimulates
blood fibrinolysis and has been evaluated with several
randomized trials for the treatment of the more advanced skin
changes associated with lipodermatosclerosis. and it possibly
faster ulcer healing rates.
• Prostoglandins E: Augments blood flow in the capillaries,
increases fibrinolytic activity, reduces platelet and leukocyte
aggregation and adhesion to endothelium. A significant
improvement in the status of leg ulcers with intra-venous
systemic application. (No recommendation can be made)
• Topical prostacyclin-Iloprost: Local application to the ulcer edge
and surrounding skin. No clear benefit.

30. VAD Adverse Events
• Safety of VADs is in general good and well
tolerated,
• Hepatotoxicity: Coumarin and benzarone,
• Gastrointestinal and autonomic adverse
events, 5%,
• Usage in pregnancy: Some VADs have
been used without any problem during 2.
and 3. trimester of pregnancy, but there
are no long-term series documenting this.
• Caution is recommended during breast
feeding also.

31. INDICATIONS FOR VADs
• Symptomatic CVD: Heavy legs, pain, resless legs, night
cramps, itching, numbness. If there is no symptom
recurrence; max. 3-month usage. Combined usage of VADs
is not appropriate.
• Anti-edema effecti: A clear effect proved by double-blind
studies
• Lymphedema, MPFF, Coumarine and rutin, Ca dobesilate
• Venous ulcer treatment: MPFF,
• Additive effect in combination with sclerotherapy, surgery
and compression.
• Compression + VAD > compression,
• Compression necessary but contra-indicated (arterial
insufficiency, neuropathies),
• Topical treatment: VADs + heparinoids (anti-inflammatory
effect + analgesic effect by inactivating histamine and anti-
thrombotic effect),
• Prevention of venous hypertension and inflammation,
protection of venous valves; MPFF

32. Compression Therapy
• Bandages
– Short strech bandages
– Four layer bandages
– Hard-stiff bandages (Unna Bout)
• Compression stockings
• İntermittant pneumotic compression devices

33. Effects of Compression Therapy
• Reduces edema
• Reduces venous volume
• Increases venous flow
• Reduces venous reflux
• Improves venous pump
• Increases lymphatic flow

34. Recommendations for Compression Stockings
Indication Grade of
recommendation
and evidence
A (10-14 mmHg) C0S, C1S B
I (15-21 mmHg ) C2S
C2S (cerrahi sonrası)
C2S (skleroterapi sonrası)
B
B
C
II (23-32 mmHg) C3 C4
DVT sonrası
B
A
III (34-46 mmHg) C5 C6 A
CEN pressure gradings

35. Compression Bandaging
• There is no proved superiority in comparison of different
bandaging styles (i.e, circular, figure of eight or spiral).
• Only, the superiority of multi-layer (four layer) bandaging
was shown in treatment of active venous ulcers.

36. Intermittant pneumatic compression devices
• Shortens the healing time in treatment of active
venous ulcers. (recommendation and evidence
level B)
Caution in arterial insufficiency:
Can not be used if the patient
has ABI<0,4, or can be used
after revascularization
Should not be used in dermatitis
origined from synthetic
materials used for compression.

37. Adaptation of lifestyle
There is no evidence-based recommendation
about their efficacy.
• Walking exercises
• Avoiding from long-time stand up position
• Avoiding from obesity
• Leg elevation and bed rest
• Avoiding from heat, hot water

38. Ineffective adjuncts to ulcer care
• Hyperbaric oxygen —
• Electromagnetic therapy — .
• Therapeutic ultrasound —
• Medical management of lower extremity chronic venous disease
Literature review current through: Sep 2013.

39. Conclusion
• The combination of medical treatment with
compression provides considerably superior healing
results and better life quality than the compression
alone.
• Medical treatment has a considerable efficacy in
almost every stages of CVD by both alleviating the
symptoms and preventing the progression of
symptoms as well as complications.