Best Strategy to Improve Patient’s Quality of Life

PATRIANEF

Vascular and Endovascular Division

Department of Surgery – FMUI – Ciptomangunkusumo Hospital

September 6nd 2014

Chronic Venous Disease (CVD)-Definition

“Chronic Venous Disease (CVD) is defined as an

abnormally functioning venous system due to

venous valvular incompetence with or without

associated venous outflow obstruction, which

may affect the superficial venous system, the

deep venous system, or both.”

Each situation

Each diseasehas different perspectives

Evaluation of:

Symptoms

◦ Consumption of analgesic – Pain

◦ Visual scale – Pain

◦ Numeric scale – Pain, Leg heaviness, Cramps, Swelling, Heat sensation

◦ Reduction in the number of patients presenting a specific symptom

Signs

◦ Edema – Perimeter (Leg-o-meter); Volume (Water displacement)

◦ Leg Ulcer – Size + Time to Healing

Physicians’ Perspective

1 - Eklof B et al. J Vasc Surg 2009;49:498-501; 2 - Eklof B. et al. J Vasc Surg 2004;40:1248-1252.

Signs 1,2Symptoms 1

• C0: No visible signs

• C1: Telangiectasia, reticular veins

• C2: Varicose veins

• C3: Edema

• C4: Skin changes

C4a: pigmentation, eczema,

C4b: lipodermatosclerosis,

atrophie blanche.

• C5: Healed Venous ulcer

• C6: Active Venous ulcer

• Tingling

• Aching, Burning

• Pain

• Muscle cramps, Swelling

• Throbbing

• Heaviness

• Itching skin

• Restless legs

• Leg-tiredness

• Fatigue

Chronic venous disease-related symptomsand signs are clearly described(from consensus documents)

Con

clu

sion

Clinical aspects

◦ Quantitative measurement tools

Pain assessment tool Remarks

Analgesic consumptionOnly practitioner-reported data are

reliable

10-cm visual analogue scale (VAS) Good reproducibility

Numerical scale (usually from 0 to 5) Good reproducibility

Others:

McGill Pain Questionnaire

Brief Pain Inventory

Multidimensional Pain Inventory

Impractical in routine

Close to a quality-of-life scale

Skewed towards back pain

Adapted from Allaert FA. Medicographia 2006;28:137-140

Symptoms

Physicians’ Perspective

◦ Assessing treatment effect on signs:

Which end points?

End point Need for a consensus about

EdemaHow great a decrease in leg volume constitutes a clinical

improvement?

Varicose veinsCosmetic satisfaction of patients? Absence of pain?

Absence of reflux? No recurrence? Quality of life?

Cost effectiveness?

Venous ulcer

Complete re-epithelization of the wound? Time to healing?

Ability to walk without reopening of the wound? Frequency

of dressing change? Frequency of admission to hospital?

Signs

Physicians’ Perspective

Instrument Purpose Remarks

CEAP classification,

the AVF Ad-hoc Committee, 1995,

2004

For patient’s description onlyNot for scoring

(not sensitive to changes)

• Venous Clinical

Severity Score (VCSS)

• Venous Disability

Score (VDS)

• Venous Segmental

Disease Score (VSDS)

Rutherford, 2000

• To assess changes over time or

in response to therapy

f

• To assess the ability to work an

8-hour day with or without a

“support device”

• To generate a grade based on

reflux or obstruction

• Imperfect tool for

evaluation of the early

stages

• Daily activities not taken

into consideration

f

• Arbitrary and difficult to

grade

Adapted from Vasquez MA. In press

◦ From the CEAP to its adjuncts

Signs

Physicians’ Perspective

Patient’s Perspective

Type of instruments:

Preference about care received

Health behaviours

Subjective symptoms

Patient satisfaction

Health related quality of life

PRO – Instruments that measures perceived health

outcomes or endpoints assessed by patients

reports (questionnaires)

Quality of Life (QoL)

WHO definition

Multidimensional concept, including:

Physical

Psychological

Social

Patient perception about disease (subjective state of health)

Information – burden illness

“The product of the interplay between social, health, economic and

environmental conditions which affect human and social development”

Alliot-Launois, 2003; Pitsch, 2008; Kahn, 2008; Vasquez , 2008

Quality of Life (QoL)

Pitsch, 2008; Vasquez , 2008; Alliot-Launois, 2003

Generic instruments:

Nottingham Health Profile (NHP)

Short Form 36 Health Survey (SF-36)

Disease-specific instruments

Charing Cross Venous Ulceration Questionnaire (CXVUQ)

Aberdeen Varicose Vein Questionnaire (AVVQ)

Venous Insufficiency Epidemiological and Economic Study (VEINES)

Chronic Venous Insufficiency Questionnaire (CIVIQ)

Evaluation:

Symptoms and quality of life

• The % of symptomatic patients increases with increasing CEAP class.1-

3

• There is a significant association between increasing CEAP class and

reduced quality of life (QOL),4 even after adjustment for confounding

variables.5

• The QOL impairment associated with CVD is equal to the QOL

impairment associated with other chronic and severe diseases

(C3=cancer and diabetes6; C5-C6= heart failure7).

1. Rabe E. Int Angiol. 2012;31:105-15. - 2. Chiesa R. J Vasc Surg. 2007; 46:322-330.

3. Carpentier P. J Vasc Surg. 2003; 37:827-833. - 4. Franks PJ. Qual Life Res. 2001;10:693-700.

5. Kahn Sr. J Vasc Surg. 2004;39:823-828. - 6. Andreozzi GM et al. Int Angiol. 2005;24:272-277.

7. Ware JE. 1994. New England Medical Center.

Burden of Chronic Venous Disease

• CVD (C1 to C6) affects 75 % of adults in the USA1 and around 64% worldwide.2

• CVI (C3 to C6) affects 16% of adults in the USA1 and 24% worldwide.2

• Venous ulcers (C6) affect 2.5 million patients/year in the USA.3

• 70% of venous ulcers recur within 5 years of healing.4

1- Passman MA. J Vasc Surg 2011;54:2S-9S 2- Rabe E. Int Angiol 2012;31:105-115.

3- Eklof B. J Vasc Surg 2004;40:1248-1252. 4- Callam MJ. BMJ. 1987;294:1389-1391.

Epidemiology of chronic venousdisease

CEAP clinicalclass (%

individuals)

USA1 Germany2 Worldwide3

C0 26 10 36

C1 33 59 22

C2 24 14 18

C3 9 13 15

C4 7 3 7

C5 0.5 0.6 1.4

C6 0.2 0.1 0.6

1- McLafferty RB et al. J Vasc Surg. 2008;48:394-399.

2- Rabe E et al. Phlebologie. 2003;32:1-14.

3- Rabe E et al. Int Angiol. 2012;31:105-115.

In the USA, more than 50% of adults present with telangiectases or varices(not adjusted for age, gender, or BMI)

Epidemiology of chronic venousdisease

CEAP clinicalclass (%

individuals)

USA1 Germany2 Worldwide3

C0 26 10 36

C1 33 59 22

C2 24 14 18

C3 9 13 15

C4 7 3 7

C5 0.5 0.6 1.4

C6 0.2 0.1 0.6

In the USA, more than 50% of adults present with telangiectases or varices(not adjusted for age, gender, or BMI)

1- McLafferty RB et al. J Vasc Surg. 2008;48:394-399.

2- Rabe E et al. Phlebologie. 2003;32:1-14.

3- Rabe E et al. Int Angiol. 2012;31:105-115.

The frequency of varicose veinsincreases with older age

1- Abramson JH et al. J Epidemiol Community Health. 1981; 35: 213-217.

2- Coon WW et al. Circulation 1973 ; 48:839-846.

The prevalence of venous ulceralso increases with age

Cornwall JV et al. Br J Surg. 1986;73:693-696.

Socioeconomic aspects of chronic venous disease

• Overall annual costs:

– 900 million € in Western Europe (2% of health care budget)1

– Equivalent to 2.5 billion € in the USA

– Greater than the amount spent for treatment of arterial disease

• Annual loss of work days:

– 2 million work days lost due to venous ulcers in the USA2

– 4 million work days lost due chronic venous disease (C1-C6) in France

– Ranked 14th for work absenteeism in Brazil

– Cost for loss of work days varies between 270 million € (Germany), 320 million € (France), and 3 billion USD per year in the USA2

• CVD is progressive, increases with age, and has a propensity to recur.

This further increases costs.

1- Ruckley CV. Angiology. 1997;48:67-9. 2- McGuckin M. Am J Surg. 2002;183:132-137.

Etiology

• Reflux 80%

• Venous obstruction 18-28%

– Resultant edema and skin changes = Postthrombotic syndrome

• Muscle Pump Dysfunction

Risk factors

• Age: Aging causes wear and tear. Eventually, that wear causes the valves to malfunction.

• Sex: Women > Men. Hormonal changes during pregnancy or menopause. Progesterone relaxes venous walls. HRT / OCP may increase the risk of varicose veins.

• Genetics

• Obesity: Increases venous HTN.

• Standing for long periods of time. Prolonged immobile standing impairs venous return.

Fowkes, FG, Lee, AJ, Evans, CJ, et al. Lifestyle risk factors for lower limb venous reflux in the general population: Edinburgh Vein Study.

Int J Epidemiol 2001; 30:846.

Sadick, NS. Predisposing factors of varicose and telangiectatic leg veins. J Dermatol Surg Oncol 1992; 18:883.

Iannuzzi, A, Panico, S, Ciardullo, AV, et al. Varicose veins of the lower limbs and venous capacitance in postmenopausal women:

relationship with obesity. J Vasc Surg 2002; 36:965.

Evans, CJ, Fowkes, FG, Hajivassiliou, CA, et al. Epidemiology of varicose veins. A review. Int Angiol 1994; 13:263.

Incidence

25-50% of adult women

15-30% of adult men

1-2% with Active or Healed Ulceration

Patrick H. Carpentier, Hildegard R. Maricq, Christine Biro, Claire O. Poncot-Makinen, Alain Franco, Prevalence, risk factors, and clinical patterns of chronic venous disorders of lower limbs: A population-based study in France, Journal of Vascular Surgery, Volume 40, Issue 4, October 2004, Pages 650-659, ISSN 0741-5214, DOI: 10.1016/j.jvs.2004.07.025. Coon WW, Willis PW III, Keller JB. Venous thromboembolism and other venous disease in the Tecumseh community health study. Circulation 1973; 48: 839–846.Franks PJ, Wright DD, Moffatt CJ, Stirling J, Fletcher AE, Bulpitt CJ et al. Prevalence of venous disease: a community study in west London. Eur J Surg 1992; 158: 143–147.Bradbury A, Evans C, Allan P, Lee A, Ruckley CV, Fowkes FG. What are the symptoms of varicose veins? Edinburgh vein study cross sectional population survey. BMJ 1999; 318: 353–356

Chronic venous disease

• Most common vascular disorder

• 3 Billion US dollars spent a year for treatment

• 3 % of the total Heath care Budget

• 2 million USA work days lost per year

Class C0s:

Symptoms without visible or palpable signs of venous disease

Class C1a,s:

Telangiectasias or reticular veins

a = asymptomatic

s = symptomatic

Class C2a,s: Varicose veins

Class C3a,s: Edema

Class C4a,s:Skin changes ascribed to venous disease,eg, pigmentation, venous eczema, lipodermatosclerosis

Class C5a,s: Skin changes with healed ulceration

Class C6a,s: Skin changes with active ulceration

The CEAP* classification – Identification ofCVD patient profiles8

8. Allegra C, Antignani PL, Bergan J, Carpentier P, et al. J Vasc Surg. 2003;37:129-313.* CEAP: Clinical, Etiological, Anatomical, Pathophysiological.

C1

C4

C2 C3

C6 C5

MACRO circulation MICRO circulation

Progression of chronic venous disease: venoushypertension is key

Adapted from Bergan JJ et al. N Engl J Med. 2006;355:488-498, and from Eberhardt RT et al. Circulation. 2005; 111:2398-2409

SymptomsSymptomsC0s Symptoms Symptoms

Varicose Veins (C2)

Reflux Edema (C3)Skin Changes (C4)

Vein wall remodeling

Valve damage

Capillary leakage

Capillary damage

Venous Ulcer (C5,6)

Altered patterns of blood flow,

Change in shear stress

Genetic predisposition,

obesity, pregnancy, ..

Environmental factors

repeated over time

Chronic inflammation in vein wall and valve

Remodeling in venous wall and valves

Valve failure, reflux

Chronic hypertension

Adapted from JJ Bergan et al. N Engl J Med 2006 355:488-498

Shear stress dependent leukocyte-endothelial interaction

Activation

of

C nociceptors

Pain

Venous hypertension is linked to venous inflammation

“ Treatment to inhibit inflammation may offer the greatest opportunity to prevent

disease-related complications.

Drugs can attenuate various elements of the inflammatory cascade, particularly the

leukocyte–endothelium interactions that are important in many aspects of the disease »

Am J Pathol. 1983; 113:341-358.

Leukocytes and changes in venous valves

Courtesy Schmid Schönbein G

flow direction

Increased Capillary Permeability

Adapted from Schmid-Schönbein G N. The Vein Book 2007 Academic Press

Hypertension is transmitted to capillaries

EDEMA

SKIN

CHANGES

Lymphatic overload

Adapted from Perrin M, Ramelet AA. Eur J Vasc Endovasc Surg. 2011; 41:117-125.

Lymphatic drainage is disturbed

Pitting edema

(Lymphedema)

Examination

1. Valsava test and The Trendelenburg test Used to assess the competence of SFJ

2. Tourniquet test Similar as trendelenburg test, uses a tourniquet Assess perforator vein

3. Perthes Test Indicated deep venous incompetence. This is a painful and rarely used test.

All of these examination are rarely used, only when duplex scanning or doppler are not available

J Vasc Surg 2011;53:2s-48s

Non invasive measurement

Ultrasound 1980, gold standard

method instead of phlebography

1990, color dopplerimproved the reliability

Diagnostic and interventional guided treatment

Photophletysmography Ambulatory venous

pressure measurement

Van der Bremmer et al. Ann Vasc Surg 2010; 24: 426-432

J Vasc Surg 2011;53:2s-48s

Therapy

• Education

• Compression

• Drugs

• Physioterapy

TREATMENT

• Limit the disease progression

• Lifestyle changes

• Compression stocking is the basic and the most used ( Grade I A,B & Grade 2 C)

• Exercise

Conservative

Leopardi et al. Systematic Review of Treatments for Varicose Veins. Ann Vasc Surg 2009

Medicine

• Venoactive drugs ( Grade 2 B)

– Pentoxiphylline

– Saponins

– Flavonoids: • rutoside,

• diosmin,

• hesperidin,

• MPFF

– Synthetic • Calcium dobesilate, naftazone, benzarone

• Reduce edema and restless leg syndrome, improve healing of venous ulcer

J Vasc Surg 2011;53:2s-48s

The most effective venoactive drugs

according to Cohranereview

Quality-of-life improvement parallels symptom improvement

Parameter

N=3995

Change in

symptoms

Patients with symptom

improvement, N (%)

Increase in CIVIQ score

between Day 0 and Day 180

Sensation of swelling

Improved* 2134 (69) 21.1 + 16.8

Heaviness Improved* 2778 (74) 20.1 + 16.2

Cramps Improved* 2189 (79) 21.1 + 16.4

Pain

Improved§ 1560 (80) 23.8 + 16.2

Very much improved**

442 (23) 29.2 + 16.9

* Improved: decrease of one class on 5-point scale. §Improved pain: decrease of 2.5 to 5 cm on VAS.** Very much impoved pain: decrease of ≥5 cm on VAS.

Launois R, Mansilha A et al. Eur J Vasc Endovasc Surg. 2010;40:783-789.

In C0s to C4s patients

ReferenceRegimen

(nb of enrolled patients)

Changes in

PainFunctional

discomfort

Sensation

of swelling

Leg

heaviness

Chassignolle

et al. 1Daflon 500 mg (18)

vs placebo (18)

Not

assessed

Not

assessed

Gilly

et al. 2Daflon 500 mg (76)

vs placebo (74)

Cospite

et al. 3Daflon 500 mg (43)

vs single diosmin (45)

Not

assessedNS

NS, not significant; + P<.05; ++ P<.01; +++ P<.001 Daflon 500 mg vs comparator

1. Chassignolle J-F et al. J Int Med 1987;99 (Suppl.):32-7. - 2. Gilly R et al. Phlebology 1994;9 (2): 67-70.

3. Cospite M et al. Int Angiol 1989; 8 (4 suppl): 61-65.

Significant improvement ofvenous symptoms in well-designed trials

Significant reduction of leg painassociated with venous ulcer

% P

atie

nts

wit

ho

ut

pai

n

N=459 * P =.0023 **P <.001

* **

**

23

28

37

Lok C. Abstract presented at the 7th meeting of the EVF, London, UK, 29th June- 1st July, 2006

Significant reduction of leg edema which is often associated with venous pain

Population size

N=463

N=165

N=90

N=45

N=497

Allaert FA. Int Angiol 2012;31:310-5.

Venous pain is a nociceptiveresponse

to venous inflammation and therefore difficult to express• Heaviness • Pain, aching• Sensation of swelling• Burning• Night cramps• Tingling• Itching• Restless legs• Leg tiredness, fatigue

1. Eklof B et al. J Vasc Surg. 2009;49:498-501. - 2. Strigo IA et al. Pain. 2002;97:235-246.

3. Vital A et al. Angiology. 2010;19:73-77.

Nociceptive responsevia C-fibers 3

Probably expressthe same symptom 1

=Diffuse pain 2

Vein-specific anti-inflammatory action

Adapted from Shoab SS et al. Eur J Vasc Endovasc Surg .1999;17:313-318.

Leukocyte

ICAM-1

Daflon 500 mgDaflon 500 mg

CD11b/CD18

VLA-4

VCAM-1

Adapted from Coleridge Smith P. In Ruckley, Fowkes, Bradbury, eds. London, UK: Springer-Verlag; 1999:51-70.

Damage induced by leukocyte migration at the level

of the venous valves is present at the onset of the disease

The leukocyte – A central role in thepathogenesis of CVD

Venoactive Drugs: Action

Macrocirculation: Increase venous tone, attenuate leucocyte-endothelial interaction

Microcirculation: Increase capillary resistance and reduce capillary filtration, increase lymphatic drainage, reduce inflammation, decrease blood viscosity.

Document developed under the auspices of:

•The European Venous Forum

•The International Union of Angiology

•The Cardiovascular Disease Educational and Research Trust, UK

•L’Union Internationale de Phlébologie

On the initiative of the European Venous Forum

International Guidelines for management of CVD (2013)

Updated recommendations for VADs according to the GRADE system

Indication Venoactive drug Recommen

dation

Quality of

evidence

Code

Relief of symptoms in C0s to

C4s patients, when no other

anatomical lesions and/or

pathophysiological anomalies

are present

• MPFF (Daflon 500)

• Non micronized diosmins

• Rutins (Venoruton)

• Calcium dob. (Doxium)

• Horse chestnut

• Ruscus extracts

• Strong

• Weak

•Weak

•Weak

•Weak

• Weak

•Moderate

•Poor

•Moderate

•Moderate

• Low

• Low

1B

2C

2B

2B

2B

2B

Healing of primary ulcer, as

an adjunct to local therapy and

compressive or/and operative

treatment

(Coleridge Smith, 2009)

• MPFF (Daflon 500) • Strong •Moderate 1B

To be published by end 2013.

Treatment

Sclerotherapy (Grade1 B) Small non-saphenous varicose veins (less

than 5 mm), Perforator veins Residual or recurrent varicosities following

surgery Telangiectasia Reticular veins

To initiate Inflammation, Occlusion and Scarring

US guided Foam sclerotherapy ( Grade 1 B )

Catheter directed Complication: blistering and ulceration

7.1%, phlebitis 15.4%, staining 7.7%

Leopardi et al. Systematic Review of Treatments for Varicose Veins. Ann Vasc Surg 2009

Surface /skin laser therapy

• Telangiectasias, reticular veins, small varicose veins <5mm

Treatment• Ambulatory

phlebectomy

( Grade 1 B)

• For larger veins

• Below SFJ and SPJ

• Not including the GSV or SSV

• Without reflux

• Complication: blistering 31%, phlebitis 12%, hematoma

• Junction ligation with or without vein stripping

• When GSV and SSV have reflux

• Ligation alone high recurrence

• Ligation and stripping treatment of choice ( Grade 2 B)

Leopardi et al. Systematic Review of Treatments for Varicose Veins. Ann Vasc Surg 2009

TIPP-Transilluminated powered phlebectomy ( Grade 2 C)

“LIPOSUCTION OF VEIN”

Safe and effective for vein

excision

Complication: cellulitis 2.2%;

abscess 0.4%; hematoma

3.4%; residual varicose

1.1%; cutaneous nerve

damage 2.2%, seroma 2.9%

The Vein Book 2007

Kiw JW, Surgery Today 2013;43:62-66

Subfascial endoscopic perforator vein ligation (SEPS) ( grade 2 C)

• Refractory symptoms, ulceration, recurrent ulceration.

• Perforators divided electrocautery, harmonic scalpel or clipped.

• 1140 limbs overall ulcer healing in 88%

Kalra, M, Gloviczki, P. Surgical treatment of venous ulcers: role of subfascial endoscopic perforator vein ligation. Surg Clin North Am 2003; 83:671.

Treatment

• RFA and EVLT ( Grade 1 B)

• Heat-generating laser fiber via catheter

• Heat source: Laser or radiofrequency

• Endothelial and vessel wall damage

J Vasc Surg 2011;53:2s-48s

Mechanicochemical endovenousablation

• A new alternative treatment

• Endovenous mechanical and chemical sclerotherapy

• Technical success rate: initial 100%; after 1 year 94%

• No major complication

ESVS 2012.jejvs.2012.12.004

Van Eekeren et al. J Endovasc Ther 2011;18:328-334

Take Home Messages

• The mechanisms resulting in venous pain involve:

– The presence of nerve structures (C-fibers) in the vein wall and perivenous space close to the capillaries

– Local inflammation mediated by activated leukocytes

• MPFF inhibits:

– Leukocyte activation

– Subsequent venous inflammationMay provide an explanation for MPFF’s benefits on venous pain and quality of life

Practical use

• Treatment of symptoms and edema likely to be of venous origin.1

• May be combined with sclerotherapy, endovenous treatment or open surgery for the treatment of varicose veins.2-4

• Adjunctive treatment in venous leg ulcer (VLU) healing and for relief of VLU-associated symptoms.5

1. Lyseng-Williamson K et al. Drugs. 2003;63:71-100 - 2. Veverkova L et al. Phlebolymphology. 2006;

13:195-201 - 3. Pokrovsky AV et al. Angiol Sosus Khir. 2007; 3:47-55 - 4. Cazaubon M et al. Angiologie.

2011;15: 554-560 - 5. Coleridge-Smith P et al. Eur J Vasc Endovasc Surg. 2005;30:198-208.

Suggestion

• Varicose:

– phlebectomy

– GSV varices not related to reflux sclerotherapy

– GSV plus reflux surgery or foam sclerotherapy

• Ligation without stripping is more effective than phlebectomy alone.

• EVLT and RFA are better than surgery in regard to QOL, return to work etc

• EVLT and RFA are considered as an effective alternative to surgery, as safe as surgery with long-term safety supported by case evidence.

Healthy leg is our aim

• Varicose is not just a cosmetic problem, but ….

• Varicose is a disease entity which can reduce the QOL

Thank You