Making the right choice in cvd management

1. Making the Right
Choice
in CVD Management
Armando Mansilha MD, PhD,
FEBVS
Porto, Portugal

2. Each situationEach situation
Each diseaseEach disease
has different perspectiveshas different perspectives

3. Society’s perspectiveSociety’s perspective
25-33% adult women have
varicose veins
3-11% prevalence of edema
and skin changes
1% prevalence venous
ulcers (active and healed)
30% of adult women have
CVD
Loss 1 million working days
21% patients change jobs
8% patients have pension
beforehand
Estudo multicêntrico; Nicolaides A.N., et al.; Int Angiol.; 2008;27:1-

4. 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.

5. Epidemiology of chronic venous disease
CEAP clinical
class (%
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)

6. Epidemiology of chronic venous disease
CEAP clinical
class (%
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.

7. The frequency of varicose veins
increases 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.

8. The prevalence of venous ulcer also
increases with age
Cornwall JV et al. Br J Surg. 1986;73:693-696.

9. 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.

10. Assessing the costs of chronic venous
disease
in the Vein Consult Program
Events related to venous leg problems in the last 5 years Patients (%)
Surgery or sclerotherapy 12%
Change in professional activities or job 5%
Hospitalizations 7%
If yes,
number of times
once
40%
twice
29%
3 times
11%
20%
> 3 times
If yes,
duration of lost work days
Less than
1 week
41%
21%
Between 1 week
and 1 month
13%
More than
1 month
25%
Not known
Loss of work days: 15.0%

11. 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’ PerspectivePhysicians’ Perspective

12. 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 1,2Signs 1,2
Symptoms 1Symptoms 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
• 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
• Tingling
• Aching, Burning
• Pain
• Muscle cramps, Swelling
• Throbbing
• Heaviness
• Itching skin
• Restless legs
• Leg-tiredness
• Fatigue
Chronic venous disease-related symptoms
and signs are clearly described
(from consensus documents)
ConclusionConclusion
Clinical aspectsClinical aspects

13. ◦ Quantitative measurement tools
Pain assessment tool Remarks
Analgesic consumption
Only 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
SymptomsSymptoms
Physicians’ PerspectivePhysicians’ Perspective

14. ◦ Assessing treatment effect on signs:
Which end points?
End point Need for a consensus about
Edema
How great a decrease in leg volume constitutes a clinical
improvement?
Varicose veins
Cosmetic 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?
SignsSigns
Physicians’ PerspectivePhysicians’ Perspective

15. Instrument Purpose Remarks
CEAP classification,
the AVF Ad-hoc Committee,
1995, 2004
For patient’s description only
Not 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
SignsSigns
Physicians’ PerspectivePhysicians’ Perspective

16. Patient’s PerspectivePatient’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)

17. Quality of Life (QoL)Quality of Life (QoL)
WHO definitionWHO definition
 Multidimensional concept, including:
 Physical
 Psychological
 Social
 Patient perception about disease (subjective state of health)
 Information – illness burden
“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

18. Quality of Life (QoL)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:

19. Disease-specific instrumentsDisease-specific instruments
Instrument
Number of
languages validated
Number of items,
dimensions
Tested indications
Aberdeen Varicose Veins Q,
AVVQ, Garratt, 1993
1 13 C2
ChronIc Venous disease
quality of lIfe Q,
CIVIQ, Launois, 1996
13
20
Physical, psychological,
social, and pain
C0s-C4, venous stenting,
C2 (stripping vs Closure®
)
Charing Cross Venous
Ulceration Q,
CXVUQ, Smith, 2000
1
Venous ulcer
VEINES-QoL/Sym,
Lamping, 2003
4
35
Physical aspects,
disease effect coupled
with symptoms
C0s-C6, DVT
Adapted from Vasquez MA. Phlebology. 2008;23:259-75
CIVIQ is the gold standard!

20. Jantet, 2000; Alliot-Launois, 2003
1996 – Prof. Robert Launois (France)
Adopted in 18 countries (incl. Portugal)
Disease-specific instruments (20 items)
4 dimensions studied:
 Physical (4 items)
 Psychological (9 items)
According with WHO QoL group recommendations
Properties validated:
 Relevance
 Acceptability
 Reliability
Specific evaluation for CVD patients
 Social (3 items)
 Pain (4 items)
 Construct validity
 Sensitivity
CIVIQ questionnaireCIVIQ questionnaire

21. World College of Vascular Disease
International coordinators:
 Prof. J. Jimenez Cossio (Spain)
 Prof. J. Ulloa (Columbia)
Scientific advisor:
 Dr. G. Jantet (France)
Assessment of patient’s QoL after aAssessment of patient’s QoL after a
venoactive drug treatmentvenoactive drug treatment
2002 – CONSOLIDATED RESULTS
Reflux assEssment and QuaLity of LIfe improvEment with
micronized Flavonoids in Chronic Venous Insufficiency - RELIEF
Jantet G, and the RELIEF Study Group. Angiology. 2002;53:245-256

22. Multicenter and International Study
23 Countries
5 052 patients (classes C0 to C4 – CEAP classification)
2 Years
Patients treated Micronized Purified Flavonoid Fraction*
(MPFF) over 6 months
Evaluations:
 QoL – CIVIQ questionnaire (patient perspective)
 CEAP classification (physician perspective)
RELIEF StudyRELIEF Study
Jantet G, and the RELIEF Study Group. Angiology. 2002;53:245-256

23. Jantet G, and the RELIEF Study Group. Angiology. 2002;53:245-256; Arnould B, et al. Phlebology. 2004;19:146-147.
High
Quality of Life
Low
Quality of Life
ResultsResults
MPFF
(2 tables/daily)
5.052 patients

24. 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.

25. Quality of life impairment associated with
CVD
diabetes, cancer, and heart failure using SF-
36
• QOL in class C3= QoL in diabetes or cancer
• QOL in classes C5-C6= QoL in heart failure
Andreozzi GM et al. Int Angiol 2005;24:272-7
C3 C3
C5
C6
C5
C6

26. Vein Consult Program
The frequency of venous symptoms
increases with increasing CEAP
class

27. Vein Consult Program
Quality of life deteriorates
with escalating numbers of symptoms
Number ofNumber of
symptomssymptoms GIS*GIS*
0 92.5
1 86.9
2 80.8
3 75.1
> 3 62.7
P-P-value <.0001value <.0001 (N=47 149)(N=47 149)
* GIS - Global Index Score; GIS= 100 means optimal quality of life

28. CIVIQ-14 scores according to venous
symptoms
N=31320
CIVIQ global index score
100 = optimal Quality of Life score
* P≤0.0001
N=35 495 (C0s to C6 patients)
* * * *

29. Vein Consult Program
Quality of life deteriorates
with
increasing CEAP class
N=31230
GISofCIVIQ-14

30. Understanding
Chronic Venous
Disease

32. MACRO circulationMACRO circulation MICRO circulationMICRO circulation
Progression of chronic venous disease:
venous hypertension 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
SymptomsSymptomsSymptomsSymptomsC0sC0s SymptomsSymptoms SymptomsSymptoms
VaricoseVaricose
Veins (C2)Veins (C2)
Reflux Edema (C3)Edema (C3)
SkinSkin
Changes (C4)Changes (C4)
Vein wall
remodeling
Valve
damage
Capillary
leakage
Capillary
damage
VenousVenous
Ulcer (C5,6)Ulcer (C5,6)

33. 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

34. “ 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 »

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

36. Leukocytes and changes in venous valves
Courtesy Schmid Schönbein G
flow direction

37. Increased Capillary Permeability
Adapted from Schmid-Schönbein G N. The Vein Book 2007 Academic PressAdapted from Schmid-Schönbein G N. The Vein Book 2007 Academic Press
Hypertension is transmitted to capillaries
EDEMA
SKIN
CHANGES

38. Lymphatic overload
Adapted fromAdapted from Perrin M, Ramelet AA. Eur J Vasc Endovasc Surg. 2011; 41:117-125.
Lymphatic drainage is disturbed

39. A review of the
efficacy
of Daflon 500 mg
on venous symptoms

40. Significant improvement of
the quality of life in symptomatic
patients
# 100 = optimal Quality of Life score
Jantet G; RELIEF Study group. Angiology 2002;53:245-256.
In C0s to C4s patients
N=3948 *P =.0001
CIVIQglobalindexscore#
64.6
Day 0
73.1*
Day 60
78.2*
Day 120
82.1*
Day 180
50
60
70
80
90
Time of study with Daflon 500

41. 82.03
63.38
N=3948
GIS evolution (D180-D0):
– Each group, P <.0001
– Between groups: P <.001
GlobalIndexScore
Day -15 Day 0 Day 60 Day 120 Day 180
Symptomatic patients had significantly
greater improvement in QoL score than
asymptomatic patients
Perrin M. Medicographia 2006;28:146-152.

42. Quality-of-life improvement
parallels symptom
improvement
ParameterParameter
N=3995N=3995
Change inChange in
symptomssymptoms
Patients with symptomPatients with symptom
improvement, N (%)improvement, N (%)
Increase in CIVIQ scoreIncrease in CIVIQ score
between Day 0 and Day 180between 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 improved 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

43. ReferenceReference
RegimenRegimen
(nb of enrolled patients)(nb of enrolled patients)
Changes inChanges in
PainPain
FunctionalFunctional
discomfortdiscomfort
SensationSensation
of swellingof swelling
LegLeg
heavinessheaviness
Chassignolle
et al. 1
Daflon 500 mg (18)
vs placebo (18)
Not
assessed

Not
assessed

Gilly
et al. 2
Daflon 500 mg (76)
vs placebo (74)
   
Cospite
et al. 3
Daflon 500 mg (43)
vs single diosmin (45)

Not
assessed
NS 
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 of
venous symptoms in well-designed trials

44. Significant reduction of leg pain
associated with venous ulcer
%Patientswithoutpain
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

45. 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.

46. Group A: Daflon 500 mg: 0-6 months / Vitamins: 6-12 months
Group B: Vitamins: 0-6 months / Daflon 500 mg: 6-12 months
Adapted from Simsek M, Burak F, Taskin O. Clin Exp Obstet Gynecol. 2007;34(2):96-98.
A significant reduction of pain associated with
pelvic congestion syndrome using Daflon 500
mg
#
Crossover
0
1
2
3
4
5
6
0 2 4 6 8 10 12
Months
Pelvic Pain Score
Group A
Group B
P<0.05

47. Pokrovsky AV et al. Angiol Sosud Khir. 2007;13(2):47-55 and Pokrovsky AV et al. Phlebolymphology 2008; 15: 45-51.
A significant reduction of post-surgery
pain
with Daflon 500 mg
In C2 patients undergoing stripping surgery, within the 30 days following stripping
P<0.05
Control (n=45)
Adjunctive
Daflon 500 mg
(n=200)
0.0
0.5
1.0
1.5
2.0
2.5
3.0
3.5
4.0
3.8 3.7
Day 0
3.5
2.9
Day 7
0.8
0.4
Day 30
Pain on VAS
P<0.05

48. In C2 patients undergoing stripping surgery, within the 14 days following stripping
Veverkova L et al. Rozhl Chir. 2005; 84:410-12 and Veverkova L et al. Phlebolymphology 2006; 13: 195-201
D0 D2 D4 D6 D8 D10 D12 D14
Days after stripping
Daflon 500 mg (n=92)
Control (n =89)
* P=0.023
% patients with analgesics
35
0
30
25
20
15
10
5
Less patients consume analgesics with
Daflon 500 mg after stripping surgery
12.5
3.3

49. Other indications (MPFF- Daflon 500): in
association with endovenous ablation
Significantly decreases
severity scores (VCSS)
Significantly improves
Quality of life (CIVIQ-14)

50. Assessment of venous symptoms on the VAS
(VAS, Visual Analogue Scale; 0 = 'No symptoms' and 100 = 'Unbearable
symptoms')
21.5 ± 20.4 ( ∆ = 22.8 ± 23.3)
19.3 ± 21.0 ( ∆ = 16.1 ± 22.2)
7.9 ± 15.2 ( ∆ = 12.5 ± 22.7)
6.4 ± 13.1 ( ∆ = 9.3 ± 18.7)
4.2 ± 11.5 ( ∆ = 6.0 ± 16.3)
11.8 ± 11.6 ( ∆ = 13.4 ± 13.4)
25.2 ± 17.0
44.4 ± 36.9
15.7 ± 23.5
10.2 ± 20.2
20.3 ± 26.5
35.4 ± 28.3
A significant decrease of venous
symptoms after treatment associating
sclerotherapy + Daflon 500 mg
RR.
- 52%
- 54%
- 54%
- 62%
- 60%
- 59%

51. QoL evolution in the 4 dimensions of the CIVIQ-20
100 = Optimum QoL
Inclusion
Suivi
18.6 ± 18.2
12.5 ± 14.6
∆ = 6.0 ± 12.4
40.9 ± 21.5
26.7 ± 17.8
∆ = 14.2 ± 18.1
31.4 ± 23.5
22.0 ± 20.1
∆ = 9.1 ± 16.4
22.0 ± 23.3
14.9 ± 19.7∆ = 6.7 ± 15.2
Quality of Life is improved after treatment
associating sclerotherapy + Daflon 500 mg
Psychological
Physical Pain
Social
Inclusion visit
Follow-up visit

52. Patient satisfaction
(0=‘Not satisfied at all’ and 100=‘very satisfied’)
Average: 68.5 mm ± 22.3
80% of patients satisfied and very satisfied
with a treatment associating sclerotherapy
+ Daflon 500 mg

53. Understanding
Daflon 500 mg’s
benefits
on venous symptoms
and quality of life

54. Leg pain of venous origin
• Venous pain must intensify under the following
conditions:
– At the end of the day
– After prolonged standing or sitting conditions
– In warm conditions
• …but be relieved:
– In the morning, after rest, or after lying down with the leg raised
– When walking
– In cold environment or with cold water

55. Venous pain is a nociceptive response
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 responseNociceptive response
via C-fibersvia C-fibers 33
Probably express
the same symptom 1
=
Diffuse pain 2

56. Vein-specific anti-inflammatory action
Adapted from Shoab SS et al. Eur J Vasc Endovasc Surg .1999;17:313-318.
Leukocyt
e
ICAM-1
Daflon 500
mgDaflon 500
mg
CD11b/CD18
VLA-4
VCAM-1

57. Powerful analgesic
effect
Adapted from Bergan JJ et al. N Engl J Med 2006;355:488-498 and Danziger N. J Mal Vasc. 2007;32:1-7.
Daflon 500 mg’s specific action
reduces activation of
C-nociceptors in capillary and vein walls
Leg pain
Heaviness
Sensation of swelling
Diffuse pain

58. Venoactive Drugs
Evidence and
Guidelines

59. 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.

60. Mode of action of the main VADs
Category Drug Effect on:
venous tone venous wall
and valve
capillary
leakage
lymphatic
drainage
haemorheologic
al disorders
free radical
scavengers
Flavonoids
(gamma-
benzopyrones)
MPFF-Daflon 500 + + + + + +
Other diosmins*
Rutin and rutosides,
(troxerutin, HR)
+ + + + +
Alpha-
benzopyrones
Coumarin + +
Saponins
Horse chestnut seed
extract; escin
+ + +
Ruscus extract + +
Other plant
extracts
Anthocyans +
Proanthocyanidins + +
Gingko extracts*
Synthetic
products
Calcium dobesilate + + + + +
Benzarone*
Naftazon*
* No data available

61. Chemical group Substance
Venous tone
(n° studies)
Capillary network
(n° studies)
Lymphatic network
(n° studies)
Studies on Venous
Valve
(n° studies)
γ-benzopyrones
Micronised purified
flavonoid fraction
Ibegbuna 1997;
Juteau 1995;
Struckmann 1994;
Tsouderos 1991;
Gargouil 1989;
Duperray 1984. (6)
Korthuis 1997; Bouskela
1997; Nolte 1997;Valensi
1996; Bouskela 1995; Galley
1993; Stucker 1989; Balas
1989; Behar 1988; Godfraind
1988; Pickelmann 1999; Nolte
1999; Korthuis 1999;
Bouskela 1999; Michiels
1991;.Cyrino 2004. (16)
Labrid 1995; Behar
1989; Cotonat 1989.
(3)
Takase 2004,
Pascarella 2007,
Bergan
2006.Bergan 2008
(4)
Diosmin
Rutin and
rutosides
Araujo 1985.
Patwardhan 1995;
Neumann 1992.
(3)
Blazso 1994; Sim 1981. (2)
Saponins
Ruscus extract
Jäger 1999;
Bouskela 1994;
Bouskela 1993;
Rubanyi 1984;
Marcelon 1983 (5)
Svensjo 1997; Bouskela
1994; Bouskela 1993. (3)
Escin
Annoni 1979;
Longiave
1978;10:145-52.
(2)
Other herbal
extracts
Proanthocyanidins
Zafirov 1990. (1)
Synthetic products
Calcium dobesilate
Androulakis 1989;
Urai 1985. (2)
Van Bijsterveld 1981; Brunet
1998; Mestres 1975. (3)
Piller 1988; Piller 1986;
Casley-Smith 1985.
(3)
Naftazone
Coumarin
Borzeix 1995. (1) Laemmel 1998; Casley-Smith
1975. (2)
Casley-Smith 1992;
Borzeix 1995. (2)
EvidenceEvidence

62. Venoactive drugs (VADs):
a significant benefit in Cochrane
review
Venoactive drug
Significant and homogeneous
results on
All venoactive drugs1
Edema reduction (RR 0.72)
Restless legs (RR 0.88)
Trophic disorders (RR 0.84)
Micronized purified flavonoid fraction1
(MPFF)
Swelling, edema
Trophic disorders
Cramps
Heaviness
Global improvement for patients
Rutosides1
Edema
Calcium dobesilate1
Swelling
Cramps
Restless legs
Horse chestnut seed extract2
No homogeneity test performed
1. Martinez MJ et al. Cochrane Database Syst Rev 2005, Issue 3. CD003229.
2. Pittler MH, Ernst E. Cochrane Database Syst Rev 2006, Issue 9. CD003230
RR: Relative Risk

63. 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)

64. GRADE:
a new system to rate the
strength
of recommendation
Grade of
recommendation
1 = strong
2 = weak
Based on the author’s opinion depending
on the balance between
desirable/undesirable effects, cost of
treatment and patients’ preferences
Quality of evidence A, B, C
Depending on the methodological quality
of supporting evidence
Adapted from Guyatt G et al. Chest 2006;129:174-181
Abbreviation: GRADE, ‘Grading of Recommendations Assessment, Development and Evaluation’

65. Updated recommendations for VADs
according to the GRADE system
Indication Venoactive drug Recommend
ation
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.

66. 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 inflammation
May provide an explanation for MPFF’s benefits
on venous pain and quality of life
May provide an explanation for MPFF’s benefits
on venous pain and quality of life

67. 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.

68. Quality of Life and Varicose Vein Surgery:Quality of Life and Varicose Vein Surgery:
a single protocol treatmenta single protocol treatment
Mansilha, 2012/2013
D-7 D0 D+7 D+14
Surgical Procedure Protocol
SF junction Iigation and VGS stripping just below the
knee with Invisigrip Vein StripperR
, with or without
concomitant tributary stab avulsion
Doctor’s evaluation
•Clinical examination
•Duplex ultrasonography
(reflux and GSV diameter)
•Inclusion and exclusion criteria
•CEAP classification
•Calculate BMI
•CIVIQ-14
•CIVIQ-3 pain items
•Pain (10 cm VAS)
•Informed consent for surgery
Doctor’s evaluation
•Clinical examination
•CIVIQ-14
•CIVIQ-3 pain items
•Pain (10 cm VAS)
Patient’s evaluation
•Paracetamol daily intake
D+28D+21
Antithrombotic stockings (during night)
Compression stockings
Micronized Purified
Flavonoid Fraction
500 mg (2 tables/daily)
Doctor’s evaluation
•Clinical examination
•CIVIQ-14
•CIVIQ-3 pain items
•Pain (10 cm VAS)
Paracetamol 500 or 1000 mg
(if needed)
Enoxaparin 20 mg SC
Cefazolin 1g IV
D+360
•Clinical examination
•Duplex ultrasonography
•CEAP classification
•CIVIQ-14

69. Making the Right
Choice
in CVD Management
Armando Mansilha MD, PhD,
FEBVS
Porto, Portugal