september 8 , 2015 - jh-comm.eu. prevention of cvd evolution... · v-cam selectins mmps i-cam...

2015 – G.M. ANDREOZZI - PADUA (Italy) www.angio-pd.it

September 8th, 2015

Material for internal use only


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



Symposium Chronic Venous Disease



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



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


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



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



Pr-C Pr-STX-A2 b-TG

t-PAPAI-1

INTEGRINSSELECTINS

TFPIAT - vW

NO PGI2ET1

PAF

V-CAMI-CAM

THROMBO-MODULIN

& PGH2 CYTOKINES

MMPsTIMPs



TGF-b1& SMCs

BALANCED DYNAMICEQUILIBRIUM

PHYSIOLOGICALVENOUS REMODELING

UNBALANCED DYNAMICEQUILIBRIUM

PATHOLOGICALVENOUS REMODELING



Pr-C Pr-STX-A2 b-TG

t-PAPAI-1

INTEGRINSSELECTINS

TFPIAT - vW

NO PGI2ET1

PAF

V-CAMI-CAM

THROMBO-MODULIN

& PGH2 CYTOKINES

MMPsTIMPs



TGF-b1& SMCs

SDX

SDX

SDX

SDX

SDX

SDX



SDX acts on SEVERAL NODES of the Network, involving the WHOLE SYSTEM, with a “wide-ranging” effect



“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



SDX: improvement of Endothelial Function

Significant increase of FMDin patients with EndothelialDysfunction



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).



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)



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



* 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



IMPACT of SDX PLEIOTROPIC EFFECTon VENOUS ULCERS



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



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



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



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



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



Risk Factors

Primary CVD Secondary CVD



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


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.



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



Obesity – Prolonged Standing or Seating

LIFE STYLE CORRECTION: Diet and adequate exercise



Geater Height

Greater Height could be a risk factor because of mesenchymal laxity.

AVOID OTHER RISK FACTORSESPECIALLY OVERWEIGHT

COMPRESSION THERAPYIF NEEDED



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.)



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



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



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



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)



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



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



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)



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



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



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)



Chronic Venous Disease


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