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Making the Right Choice
in CVD ManagementArmando Mansilha MD, PhD,
FEBVS Porto, Portugal
Each situationEach situationEach diseaseEach disease
has different perspectiveshas different perspectives
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;27:1-60
Burden of Chronic Venous Disease
• CVD (C1 to C6) affects 75 % of adults in the USA 1 and around 64% worldwide. 2
• CVI (C3 to C6) affects 16% of adults in the USA 1 and 24% worldwide. 2
• Venous ulcers (C6) affect 2.5 mil l ion 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 venous disease
CEAP cl inical 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)
Epidemiology of chronic venous disease
CEAP cl inical 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.
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.
The prevalence of venous ulcer also 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.
Assessing the costs of chronic venous disease
in the Vein Consult ProgramEvents 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 than1 week
41%21%
Between 1 weekand 1 month
13%More than1 month
25%
Not known
Loss of work days: 15.0%
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
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 1,2Symptoms 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 symptomsand signs are clearly described
(from consensus documents)Con
clu
sion
Con
clu
sion
Clinical aspectsClinical aspects
◦ 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
SymptomsSymptomsPhysicians’ PerspectivePhysicians’ Perspective
◦ 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 veinsCosmetic satisfaction of patients? Absence of pain?
Absence of reflux? No recurrence? Quality of life?
Cost effectiveness?
Venous ulcerComplete 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?
SignsSignsPhysicians’ PerspectivePhysicians’ Perspective
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 forevaluation of the earlystages
• Daily activities not taken into consideration f
• Arbitrary and difficult to grade
Adapted from Vasquez MA. In press
◦ From the CEAP to its adjuncts
SignsSignsPhysicians’ PerspectivePhysicians’ Perspective
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)
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
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:
Disease-specific instrumentsDisease-specific instruments
InstrumentNumber of
languages validatedNumber of items,
dimensionsTested indications
Aberdeen Varicose Veins Q,AVVQ, Garratt, 1993
1 13 C2
ChronIc Venous disease quality of lIfe Q,CIVIQ, Launois, 1996
1320
Physical, psychological, social, and pain
C0s-C4, venous stenting,
C2 (stripping vs Closure®)
Charing Cross Venous Ulceration Q,CXVUQ, Smith, 2000
1Venous ulcer
VEINES-QoL/Sym,Lamping, 2003
4
35Physical aspects,
disease effect coupledwith symptoms
C0s-C6, DVT
Adapted from Vasquez MA. Phlebology. 2008;23:259-75
CIVIQ is the gold standard!
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
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 a Assessment 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
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
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
LowQuality of Life
ResultsResults
MPFF(2 tables/daily)
5.052 patients
Symptoms and quality of l i fe
• 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 diabetes 6; C5-C6= heart fai lure 7).
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.
Quality of l i fe 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 C3C5C6
C5C6
Vein Consult ProgramThe frequency of venous symptoms
increases with increasing CEAP class
Vein Consult ProgramQuality of l i fe deteriorates
with escalating numbers of symptoms
Number of Number of symptomssymptoms GIS*GIS*
0 92.5
1 86.9
2 80.8
3 75.1
> 3 62.7
P-P-value <.0001 value <.0001 (N=47 149)(N=47 149)
* GIS - Global Index Score; GIS= 100 means optimal quality of life
CIVIQ-14 scores according to venous symptoms
N=31320
CIVIQ global index score
100 = optimal Quality of Life score
* P≤0.0001N=35 495 (C0s to C6 patients)
* * * *
Vein Consult ProgramQuality of l i fe deteriorates
withincreasing CEAP class
N=31230
GIS
of C
IVIQ
-14
Understanding Chronic Venous
Disease
MACRO circulat ionMACRO circulat ion MICRO circulat ionMICRO circulat ion
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
Varicose Varicose Veins (C2)Veins (C2)Reflux Edema (C3)Edema (C3) Skin Skin
Changes (C4)Changes (C4)
Vein wall remodeling
Valve damage
Capil lary leakage
Capil lary damage
Venous Venous Ulcer (C5,6)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 l inked 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 PressAdapted from Schmid-Schönbein G N. The Vein Book 2007 Academic Press
Hypertension is transmitted to capillaries
EDEMA
SKINCHANGES
Lymphatic overload
Adapted from Adapted from Perrin M, Ramelet AA. Eur J Vasc Endovasc Surg. 2011; 41:117-125.
Lymphatic drainage is disturbed
A review of the eff icacy
of Daflon 500 mgon venous symptoms
Significant improvement ofthe quali ty of l i fe 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
CIV
IQ g
loba
l ind
ex s
core
#
64.6
Day 0
73.1*
Day 60
78.2*
Day 120
82.1*
Day 18050
60
70
80
90
Time of study with Daflon 500
82.03
63.38
N=3948
GIS evolution (D180-D0):– Each group, P <.0001
– Between groups: P <.001
Glo
bal
Ind
ex S
core
Day -15 Day 0 Day 60 Day 120 Day 180
Symptomatic patients had signif icantly greater improvement in QoL score than
asymptomatic patients
Perrin M. Medicographia 2006;28:146-152.
Quality-of-l i fe improvement parallels symptom
improvement
ParameterParameter
N=3995N=3995Change in Change in symptomssymptoms
Patients with symptom Patients with symptom improvement, N (%)improvement, N (%)
Increase in CIVIQ score Increase 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
PainImproved§ 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
ReferenceReference RegimenRegimen(nb of enrolled pat ients)(nb of enrolled pat ients)
Changes inChanges in
PainPain Functional Funct ional discomfortdiscomfort
SensationSensationof swell ingof swell ing
Leg Leg heavinessheaviness
Chassignol leet al. 1
Daflon 500 mg (18)vs placebo (18)
Notassessed
Not
assessed
Gil lyet al. 2
Daflon 500 mg (76)vs placebo (74)
Cospiteet al. 3
Daflon 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
with
out p
ain
N=459 * P =.0023 **P <.001
* **
**
2328
37
Lok C. Abstract presented at the 7th meeting of the EVF, London, UK, 29 th June- 1st July, 2006
Signif icant 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.
Group A: Daflon 500 mg: 0-6 months / Vitamins: 6-12 monthsGroup 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 signif icant reduction of pain associated withpelvic 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
Pokrovsky AV et al. Angiol Sosud Khir. 2007;13(2):47-55 and Pokrovsky AV et al. Phlebolymphology 2008; 15: 45-51.
A signif icant reduction of post-surgery pain
with Daflon 500 mg
In C2 patients undergoing stripping surgery, within the 30 days following stripping
P<0.05Control (n=45)
AdjunctiveDaflon 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
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 D14Days 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 withDaflon 500 mg after stripping surgery
12.5
3.3
Other indications (MPFF- Daflon 500): in association with endovenous ablation
Significantly decreases severity scores (VCSS)
Significantly improves Quality of life (CIVIQ-14)
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 signif icant decrease of venous symptoms after treatment associating
sclerotherapy + Daflon 500 mg
RR.
- 52%
- 54%
- 54%
- 62%
- 60%
- 59%
QoL evolution in the 4 dimensions of the CIVIQ-20100 = 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
SocialInclusion visitFollow-up visit
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
UnderstandingDaflon 500 mg’s
benefits on venous symptoms
and quality of l i fe
Leg pain of venous origin
• Venous pain must intensify under the following condit ions:– 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
Venous pain is a nociceptive response to venous inflammation
and therefore diff icult 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 responsevia C-f ibers via C-f ibers 33
Probably expressthe same symptom 1
=Diffuse pain 2
Vein-specif ic 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
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 actionreduces activation of
C-nociceptors in capillary and vein walls
Leg pain
Heaviness
Sensation of swelling
Diffuse pain
Venoactive DrugsEvidence and
Guidelines
Venoactive Drugs: Action
Macrocirculat ion: Increase venous tone, attenuate leucocyte-endothelial interaction
Microcirculation: Increase capillary resistance and reduce capillary filtration, increase lymphatic drainage, reduce inflammation, decrease blood viscosity.
Mode of action of the main VADsCategory 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
Chemical group SubstanceVenous tone (n° studies)
Capillary network (n° studies)
Lymphatic network(n° studies)
Studies on Venous Valve
(n° studies)
γ -benzopyrones
Micronised purif ied 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
ProanthocyanidinsZafirov 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
Venoactive drugs (VADs):a significant benefit in Cochrane
reviewVenoactive drug Signif icant and homogeneous
results onAll venoactive drugs1 Edema reduction (RR 0.72)
Restless legs (RR 0.88) Trophic disorders (RR 0.84)
Micronized purified flavonoid fraction1 (MPFF)
Swelling, edemaTrophic disordersCrampsHeavinessGlobal improvement for patients
Rutosides1 Edema
Calcium dobesilate1 SwellingCrampsRestless 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
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)
GRADE:a new system to rate the
strengthof recommendation
Grade of recommendation
1 = strong2 = 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’
Updated recommendations for VADs according to the GRADE system
Indication Venoactive drug Recommendation
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.
Take Home Messages
• The mechanisms result ing 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 l i fe
May provide an explanation for MPFF’s benefits on venous pain and quality of l i fe
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.
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 ProtocolSF 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 SCCefazolin 1g IV
D+360•Clinical examination
•Duplex ultrasonography •CEAP classification
•CIVIQ-14
Making the Right Choice
in CVD ManagementArmando Mansilha MD, PhD,
FEBVS Porto, Portugal
