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2015 – G.M. ANDREOZZI - PADUA (Italy) www.angio-pd.it
September 8th, 2015
Material for internal use only
2015 – G.M. ANDREOZZI - PADUA (Italy) www.angio-pd.it
PERIOD 2012 -2014
EDUCATIONAL PAPERS WOLTERS KLUWER HEALTH – Milan ItalySINERGIE srl – Milano ItalyHippocrates – Milan Italy
JOURNAL COLLABORATION Minerva Medica TorinoCardiovascular Resource Group, San Jose, CA USA
CONGRESS LECTURES
PAD CIC Roma ItalyPlanning Congress Bologna Italy
CVD Alfa Wassermann Bologna ItalyStaff Italia Incentive & Motivation Roma ItalyGC Congressi – Rome Italy
SCIENTIFIC CONSULTANCY
Alfa Wassermann Bologna ItalySegno & Forma Milano ItalyDroguerie Phenicia LebanonAlfa Wassermann Czech & SlovakiaMediolanum Farmaceutici Milano ItalyLab. Elmor – Caracas Venezuela
TRIALS SURVET Study (OsSC CODE:ALFAWAS_III_2010_001)ALFAWASSERMANN Bologna Italy
G.M. ANDREOZZI
Conflicts of Interest Disclosure
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2015 – G.M. ANDREOZZI - PADUA (Italy) www.angio-pd.it
Symposium Chronic Venous Disease
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2015 – G.M. ANDREOZZI - PADUA (Italy) www.angio-pd.it
CVD PROGRESSION in EDINBURGH VEIN STUDY57.8% in 13 years (4.3% per year)Risk Factors OR CI 95%Family History 1.85 1.14-1.30new-DVT 4.10 1.07-15.71Overweight 1.85 1.10-3.12
Lee AJ, et al.: Edinburgh Vein Study. J Vasc Surg 2015; 3: 18–26Pannier F, Rabe E: Phlebology 2015 30(1S) 95–97
REFLUX BASELINE 33 mo. FUSegmental 41% 28 %Multisegmental 26% 40%
Engelhorn CA, et al.: Phlebology 2012; 27: 25–32
Progression of Chronic Venous Disease
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2015 – G.M. ANDREOZZI - PADUA (Italy) www.angio-pd.it
Biomarkers can befunctional or non-functional, specific or non-specific.They may be quantified to determine the- disease state (diagnosis/prognosis),- progression or regression of disease.Mannello F, Ligi D, Canale M, Raffetto JD: Expert Rev Mol Diagn. 2014 14(6):737-62
MAIN BIOMARKERS OF CVD
IntegrinsV-CAM
Selectins MMPsI-CAM
Cytokines
ENDOTHELIALDYSFUNCTION
INFLAMMATIONMaterial for internal use only
2015 – G.M. ANDREOZZI - PADUA (Italy) www.angio-pd.it
Veins Remodeling
Fiber’s Displacement
in Varicose Veins
VENOUS ULCER
STASIS
ENDOTHELIUMDYSFUNCTION
INFLAMMATIONPRIMED
ENDOTHELIAL CELLS
PRIMED
MONOCYTE
0
10
20
30
40
50
60
70
80
90
mm
Hg
C4
Health C
C5
C6
Venous Hypertension
MMPs ACTIVATION
PATHOPHYSIOLOGY of CVD
Material for internal use only
2015 – G.M. ANDREOZZI - PADUA (Italy) www.angio-pd.it
Pr-C Pr-STX-A2 b-TG
t-PAPAI-1
INTEGRINSSELECTINS
TFPIAT - vW
NO PGI2ET1
PAF
V-CAMI-CAM
THROMBO-MODULIN
& PGH2 CYTOKINES
MMPsTIMPs
Molecular Network of BIOMARKERS
ImbalanceCollagene I/III in dermal fibroblast
TGF-b1& SMCs
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2015 – G.M. ANDREOZZI - PADUA (Italy) www.angio-pd.it
Pr-C Pr-STX-A2 b-TG
t-PAPAI-1
INTEGRINSSELECTINS
TFPIAT - vW
NO PGI2ET1
PAF
V-CAMI-CAM
THROMBO-MODULIN
& PGH2 CYTOKINES
MMPsTIMPs
Molecular Network of BIOMARKERS
ImbalanceCollagene I/III in dermal fibroblast
TGF-b1& SMCs
BALANCED DYNAMICEQUILIBRIUM
PHYSIOLOGICALVENOUS REMODELING
UNBALANCED DYNAMICEQUILIBRIUM
PATHOLOGICALVENOUS REMODELING
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2015 – G.M. ANDREOZZI - PADUA (Italy) www.angio-pd.it
Pr-C Pr-STX-A2 b-TG
t-PAPAI-1
INTEGRINSSELECTINS
TFPIAT - vW
NO PGI2ET1
PAF
V-CAMI-CAM
THROMBO-MODULIN
& PGH2 CYTOKINES
MMPsTIMPs
Molecular Network of BIOMARKERS
ImbalanceCollagene I/III in dermal fibroblast
TGF-b1& SMCs
SDX
SDX
SDX
SDX
SDX
SDX
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2015 – G.M. ANDREOZZI - PADUA (Italy) www.angio-pd.it
SDX acts on SEVERAL NODES of the Network, involving the WHOLE SYSTEM, with a “wide-ranging” effect
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2015 – G.M. ANDREOZZI - PADUA (Italy) www.angio-pd.it
“WIDE-RANGING” EFFECT = PLEIOTROPIC EFFECT
WIDE RANGING EFFECT INDICATES MULTIPLE PHARMACOLOGICAL EFFECTS,
ON DISTINCT AND UNRELATEDBIOLOGICAL PROCESSES OR FUNCTIONS
SDX acts on SEVERAL NODES of the Network, involving the WHOLE SYSTEM, with a “wide-ranging” effect
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2015 – G.M. ANDREOZZI - PADUA (Italy) www.angio-pd.it
SDX: improvement of Endothelial Function
Significant increase of FMDin patients with EndothelialDysfunction
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2015 – G.M. ANDREOZZI - PADUA (Italy) www.angio-pd.it
SDX: Reduction of InflammationCISZEWICZ M, POLUBINSKA A, et al: Translational Research 2009 153:118–123
Dose-dependent reduction of free radicals, interleukin 6, and
the synthesis of prot-1 chemoattractant
Restoring Endothelial Gr. F. depressed by chronic exposure to
glucose (30 mmol/L).
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2015 – G.M. ANDREOZZI - PADUA (Italy) www.angio-pd.it
SDX: Inhibition of MetalloproteinasesMannello F, et al: Curr Vasc Pharmacol. 2013 11(3):354-365
Dose-dependent inhibitory effect of sulodexide on serum MMP-9 formsmimicking the effect of physiological inhibitors of MMPs (TIMP-1)
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2015 – G.M. ANDREOZZI - PADUA (Italy) www.angio-pd.it
FERRERO S: NAM, 6:169-72; 1990
IMPACT of SDX PLEIOTROPIC EFFECTon Clinical Features of CVD
Allegra C: Minerva Angiol 1993 18(s3) 45-49
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2015 – G.M. ANDREOZZI - PADUA (Italy) www.angio-pd.it
* p < 0.05 vs P and Baseline
Pain Prurigo Edema Skin A. Sens. A.
Sulodexide
Placebo
% variation
20
0
-20
-40
-60
-80
-100
*
* *
IMPACT of SDX PLEIOTROPIC EFFECTon Symptoms & Signs of PTS
Haemodynamic Effects of Sulodexide in post-thrombophlebitic syndromesCospite M. et al. Acta Therapeutica 1992
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2015 – G.M. ANDREOZZI - PADUA (Italy) www.angio-pd.it
IMPACT of SDX PLEIOTROPIC EFFECTon VENOUS ULCERS
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2015 – G.M. ANDREOZZI - PADUA (Italy) www.angio-pd.it
SULODEXIDE and Venous Ulcers: surface reduction
COCCHERI S, SCONDOTTO G, AGNELLI G. et al.: Randomised, double-blind, multicentre,placebo controlled study of sulodexide in the treatment of venous leg ulcers.Thromb Haemost, 87: 947-952, 2002
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2015 – G.M. ANDREOZZI - PADUA (Italy) www.angio-pd.it
SULODEXIDE and Venous Ulcers: Time Ratio of Surface Reduction
Time relationship of the ulcer areas (s)
Unna’s boot + occlusive dressing - Unna’s boot + occlusive dressing + sulodexide
Kucharzewski M, Franek A, Koziolek K: Treatment of venous leg ulcers with sulodexide.Phlebologie 2003; 32: 115–20
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Retrospective study on DATABASE ofChair of Angiology (University of Catania) 1988 - 1997
Andreozzi GM: Treatment of CVD with Sulodexide. Retrospective unpublished Study
0
0,5
1
1,5
2
2,5
0 6 12 18 24 30
0
0,5
1
1,5
2
2,5
0 6 12 18 24 30
0
1
2
3
4
0 6 12 18 24 30
DISABILITY PAIN
OEDEMA
112 PATIENTS WITHPRIMARY CVD
CEAP DISABILITY SCORES
P<0,05 P<0,05
P<0,05
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2015 – G.M. ANDREOZZI - PADUA (Italy) www.angio-pd.it
Retrospective study on DATABASE ofChair of Angiology (University of Catania) 1988 - 1997
Andreozzi GM: Treatment of CVD with Sulodexide. Retrospective unpublished Study
0
1
2
3
0 6 12 18 24 30
0
0,5
1
1,5
2
0 6 12 18 24 30
0
1
2
3
4
0 6 12 18 24 30
DISABILITY PAIN
OEDEMA
CEAP DISABILITY SCORES in 92 patients with PTStreated with Sulodexide 250 LSU twice daily for 30 months
92 PATIENTS WITHPTS (SECONDARY CVD)
P<0,05 P<0,05
P<0,05
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2015 – G.M. ANDREOZZI - PADUA (Italy) www.angio-pd.it
Guideline No. 8.1 (page 4S)
“We suggest venoactive drugs (diosmin, hesperidin, rutosides, Sulodexide,
micronized purified flavonoid fraction, or horse chestnut seed extract [aescin])
in addition to compression for patients with pain and swelling due to chronic
venous disease, in countries where these drugs are available.”
“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. et al. J Vasc Surg 2011;53:2S-48S
“GUIDELINES. ITALIAN COLLEGE OF PHLEBOLOGY. REVISION 2013”
G. B. AGUS, C. ALLEGRA, G. ARPAIA, S. DE FRANCISCIS, V. GASBARRO Int Angiol 2013; 32 (4) Suppl.1: 1-139
Recommendations
We recommend the use of phlebotrophic drugs (FFPM, oxerutina, Sulodexide, aescin) forpatients with pain and swelling due to chronic venous disease. — Grade B Ib
We recommend the use of pentoxifylline, FFPM, mesoglycans and Sulodexide, in combination with compression, to accelerate the healing of venous leg ulcers. — Grade B Ib
SULODEXIDE and Guidelines
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2015 – G.M. ANDREOZZI - PADUA (Italy) www.angio-pd.it
Risk Factors
Primary CVD Secondary CVD
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2015 – G.M. ANDREOZZI - PADUA (Italy) www.angio-pd.it
Risk Factors of Primary C.V.D.
FamiliarityHeredityAge
Female GenderPregnancy (number of parity)
Obesity (especially in women)Prolonged Standing
Greater HeightMaterial for internal use only
2015 – G.M. ANDREOZZI - PADUA (Italy) www.angio-pd.it
Familiarity - Heredity
CVD is not a hereditary disease,rather it is inherited a Genetic Predisposition to the Disease
In populations with genetic predisposition,
a primary inflammatory activation(such as pregnancy, ATS, or infections)
can lead to valve remodeling with
development of primary varicose veins!
Takase S et al. Ann Vasc Surg 2000; 14: 427-435.
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2015 – G.M. ANDREOZZI - PADUA (Italy) www.angio-pd.it
Female Gender - PregnancyGenetic Predisposition affects especially female gender,
and it is enhanced by pregnancy and number of parity
PREGNANCY...
... WITH VENOUS SYMPTOMS
... IN WOMEN WITH VENOUS DISEASE
Different Features and Different Strategieswe could talk about during the discussion
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Obesity – Prolonged Standing or Seating
LIFE STYLE CORRECTION: Diet and adequate exercise
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Geater Height
Greater Height could be a risk factor because of mesenchymal laxity.
AVOID OTHER RISK FACTORSESPECIALLY OVERWEIGHT
COMPRESSION THERAPYIF NEEDED
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2015 – G.M. ANDREOZZI - PADUA (Italy) www.angio-pd.it
Age and Gender
Body Mass Index (BMI)
Thrombophilia
Site and Extension of the initial DVT
Intensity, quality and duration of anticoagulation
Recurrent DVT
Residual thrombosis on ultrasound
Persistent elevation of D-Dimer after AVK withdr.
risk of recurrence
LIGHT
INTERMEDIATE
SEVERE
Risk Factors of Secondary C.V.D. (P.T.S.)
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2015 – G.M. ANDREOZZI - PADUA (Italy) www.angio-pd.it
Risk Factors of Secondary C.V.D. (P.T.S.)MAIN PREVENTION is the COMPRESSION THERAPY
Multilayer Bandage-Graduated Elastic Stockings
Reduction of RefluxImprovement of Deep CirculationReduction of edemaImprovement of symptoms
Partsh H: Vasa. 2014 43(4):235-7; Vasa 2014 43(5):305-7;Lancet. 2014 384(9938):129-30
Prandoni, Thromb Haemost 2005Andreozzi GM: 2004 Basi Razionali Terapia (s1) 3-12Cornwall JV et al: Phlebology ’85Libbey, London 1986 676-78Sarin S et al: Br J Surg 1995
Start of Treatment: during acute DVTUntil: 24-36 monthsLong-life: in case of PTS
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Site & Extension of the Initial DVT
BETTER PREVENTION OF PTS IS THEOPTIMAL TREATMENT OF ACUTE DVT
(Intensity, Quality, Duration of anticoagulation)
LONG LIFE ANTICOAGULATION(low risk of bleeding)
ALTERNATIVE TREATMENTASA (Warfasa and Aspire Studies)
SULODEXIDE(San Valentino Study - SURVET Study)
Recurrent DVT
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SAN VALENTINO STUDY (378 patients)
SULODEXIDE and RECURRENT DVT
Available pts
199 control198 sdx
182 control198 sdx
178 control189 sdx
p<0.05
p<0.05
p<0.05
Errichi et al Angiol, 2004
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SULODEXIDE in SECONDARY PREVENTION
of RECURRENT DEEP VEIN THROMBOSIS
SURVET Study
END POINTSPRIMARYCONFIRMED VTE RECURRENCE
New episode of proximal DVT or PEDeath due to documented complications
of new VTE episode
SECONDARYtime to VTE new episodeisolated distal vein thrombosis (under popliteal vein)superficial vein thrombosis of the legsPost-Thrombotic SyndromeIncidence of major CV events (AMI, Stroke)
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617 randomized patients
SDX PLACEBOSafety Analysis 617 308 309
Efficacy Anal. (ITT) 615 307 308
PP Sensitivity Anal.521 263 258
SURVET Study SUBMITTED
I am not allowedto report the results in details,
I can only tell you thatthey confirm the SanVal Data
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2015 – G.M. ANDREOZZI - PADUA (Italy) www.angio-pd.it
Persistent high d-Dimerafter AVK discontinuation, andUS residual thrombosis are considered high risk of DVT-r
Residual Thrombosis & Persistent High d-Dimer Value
Eichinger S, et al: JAMA 2003 290:1071–4
Palareti G, et al: Circulation 2003; 108: 313–8
Palareti G, et al: N Engl J Med 2006; 355: 1780–9
Shrivastava S, et al: JThrombHaemost 2006; 4: 1208–14
Cosmi B, et al: (PROLONG study) J Thromb Thrombol 2009; 28: 381-8
DASH score ≤1 low risk of r-VTEDASH score 3-4 high probability of r-VTELong-life anticoagulation
Tosetto A, et al: J Thromb Haemost 2012 10:1020-5
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Why use SULODEXIDE
in CHRONIC VENOUS DISEASE
- Restoring Endothelial Dysfunction, reducing
inflammation, permeability and
pathological remodeling
- Care of Venous Ulcers
- Potential Prevention
of the progression since CEAP C-3
Reduction of the risk of DVT Recurrence
(main risk factors of PTS)
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ENDOTHELIAL GLYCOCALIX FUNCTIONS
BARRIER EFFECT BLOOD-TISSUE EXCHANGE
ENDOTHELIALGLYCOCALYX
The roles of Glycocalyx (GAGs compounds) are not only ...
Glycocalyx are also the trasducersof hemodynamic signal (venous hypertension) in molecular signal (NO, PGI2, ET1, MMPs, TIMPs, cytokines, V-CAM, I-CAM).
Therefore, an early intervention on them, improving their function, may help to slow the progression of the disease
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2015 – G.M. ANDREOZZI - PADUA (Italy) www.angio-pd.it
SDX increases glycocalyx thickness
in patients and in controls
The GAGs reintegration with SDX is relevant for the
Glycocalix Restoring,
improving the impaired endothelial function, and suggests an indication for SDX even in the
Early stages of C.V.D. to prevent its progression.
ENDOTHELIAL GLYCOCALIX FUNCTIONS
L. N. Broekhuizen, et al: Diabetologia 2010 53 2646-55
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2015 – G.M. ANDREOZZI - PADUA (Italy) www.angio-pd.it
Why use SULODEXIDE
in CHRONIC VENOUS DISEASE
- Restoring Endothelial Dysfunction, reducing
inflammation, permeability and
pathological remodeling
- Care of Venous Ulcers
- Potential Prevention
of the progression since CEAP C-3
Reduction of the risk of DVT Recurrence
(main risk factors of PTS)
- To reduce signs and symptoms
of CVD any grade (C1-C6)
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