The best medical treatment of venous insufficiency in 2013

The Best Medical Treatment of Venous Insufficiency in 2013

Dr. Fatih İslamoğluDepartment of Cardiovascular Surgery, Department of Cardiovascular Surgery,

Ege University Medical Ege University Medical FacultyFaculty,, Izmir, TurkeyIzmir, Turkey

Epidemiology of Chronic Venous Disorders

Age 35-40 yo - M % 7-35 - F % 20-60Age > 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

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 %

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

ManagementStory

Clinical examination

Duplex scanning

DVT Venous reflux Normal

Treatment Sclerotherapy

Operation Medical Treatment

Ligation Stripping, Ablations Sclerotherapy

Management Options According to CEAP

C A: S, D, P P: R, O, O+R Management

C0-2 S S R Medical TreatmentSclerotharpy

Surgery

Mild C3 SD O Medical Treatment

Severe C3 SD (above inguinal level)

O Medical TreatmentAngioplasty-stent

C 4-6D (above inguinal level)

O Medical TreatmentAngioplasty-stent

C 6 active or

repeating venous ulcer

D R+O Medical TreatmentCerrahi

Management of chronic venous disorders of lowew limps: Guidelines according to scientific evidence

Nicolaides et. al. İnt.Ang.Vol:27 2008

MEDICAL THERAPEUTIC METHODS

• Venoactive drugs

• Compression therapy

• Adaptation of lifestyle

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.

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 veinsWe recommend against compression therapy as the primary treatment of symptomatic varicose veins in patients who are candidates for saphenous vein ablationWe 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 B8.1

8.22 B

9.12 C

9.2 1 B

9.3

9.4

1

1 A

B

Grade ofRecommend.

Level ofevidence

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

Mode of Action of Venoactive DrugsEffect 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 ?

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. 1996Krenendo et al. 1993Grossman 1997

Coumarin and rutin (troxerutin)

_ Grade C Vanscheidt, et al, 2002

Escin Pain, edema Grade B Diehm et al, 1996Pittler and Ernst, 2006Siebert 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. 2004Ciapponi et al. 2004

Naftazone _ Grade C Vayssairat et al, 1997

Indication VAD Recommendation Level of evidence

code

Relief of symptoms associated with CVDIn patients with C0s andC6s and withCVD 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 VADs VADs

Drug: Drug: CalciuCalciumm dobesilate dobesilate

Symptoms: Cramps, restless Symptoms: 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

Drug: Drug: MPFF MPFF

Symptoms: Pain, cramps, heaviness, Symptoms: Pain, cramps, heaviness, sensation of swelling, trophic changes sensation of swelling, trophic changes and ulcerationand ulceration



Grade of recommendation: 1BGrade of recommendation: 1B


Drug: Drug: Hydroxyethyl rutosidesHydroxyethyl rutosides

Symptoms: Itching, edemaSymptoms: Itching, edema



Grade of recommendation: 2Grade of recommendation: 2AA


Drug: Drug: Ruscus extract(Cyclo-3R)Ruscus extract(Cyclo-3R)

Symptoms: EdemaSymptoms: Edema



Healing of ulcers: RCT 1Healing of ulcers: RCT 1

Grade of recommendation 2BGrade of recommendation 2B


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..

2-Effects on MicrocirculationCapillary resistance:: To increase capillary resistance

and to decrease capillary filtration. Especially MPFF enhanced inhibition of

adhesion of leukocytes on capillariees by micronisation..

Lymphatic drainageCoumarin and rutin edema lysis effect by proteolysis.MPFF: increase both lymphatic flow and lymphatic

channelsCa dobesilate: increases lymphatic drainage.

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

Efficacy on edema of Venous OriginThe confirmed efficacy by meta analyses: MPFF, Ca

debosilate, rutosides, escin, proanthocyanidine and coumarin rutin..

Pharmacological Treatment of Leg UlcersOnly 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.

Leukocyte-Endothelium Interaction:The cause of venous inflammation and

following damage

Leukocyte-endothel interactionLeukocyte

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 Capillaryadhesion 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;52:71-77.

Leukocytes and changes in Leukocytes and changes in venous valvesvenous valves

Venous inflammation is the first step in

progression of early-term leg symptoms1

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.

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.”

• 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.

• 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.

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.

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.

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

Compression Therapy

• Bandages– Short strech bandages– Four layer bandages– Hard-stiff bandages (Unna Bout)

• Compression stockings• İntermittant pneumotic compression devices

Effects of Compression Therapy

• Reduces edema• Reduces venous volume• Increases venous flow• Reduces venous reflux• Improves venous pump• Increases lymphatic flow

Recommendations for Compression Stockings

Indication Grade of recommendation and evidence

A (10-14 mmHg) C0S, C1S B

I (15-21 mmHg ) C2SC2S (cerrahi sonrası)C2S (skleroterapi sonrası)

BBC

II (23-32 mmHg) C3 C4DVT sonrası

BA

III (34-46 mmHg) C5 C6 A

CEN pressure gradings

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.

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.

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

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.

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.

Presentations & Public Speaking

The best medical treatment of venous insufficiency in 2013