LL’’ AAtteerroosscclleerroossii èè uunnaa ccoonnddiizziioonnee aassssoocciiaattaa aa MMaallaattttiiaa CCVV,, iinn ppaarrttiiccoollaarr mmooddoo aa qquueell llaa CCoorroonnaarriiccaa nneell llaa mmaaggggiioorr ppaarrttee ddeeii ppaazziieennttii ,, eedd èè uunnaa ddeell llee pprriinncciippaall ii ccaauussee ddii mmoorrttee nneeii ppaaeessii ssvvii lluuppppaattii.. LLaa pprrooiieezziioonnee aall ll ’’ aannnnoo 22002200 ddeell WWoorrlldd HHeeaalltt RReeppoorrtt 22000022 ddeell llaa WWoorrlldd HHeeaalltt OOrrggaanniizzaattiioonn pprreevveeddee vvii ssaarraannnnoo cciirrccaa 44 mmii ll iioonnii ddii mmoorrttii ((77%% ddeell llaa mmoorrttaall ii ttàà ttoottaallee)) ccaauussaattee ddaa eelleevvaattii vvaalloorrii ddeell ccoolleesstteerroolloo ssee nnoonn ssii mmeetttteerraannnnoo iinn aattttoo ddeell llee mmiissuurree aaddeegguuaattee.. LL’’ AAtteerroosscclleerroossii,, ssppeessssoo ccoommbbiinnaattaa aa MMaallaattttiiaa CCVV,, èè pprreesseennttee iinn mmoollttee mmaannii ffeessttaazziioonnii ccll iinniicchhee cchhee iinncclluuddoonnoo::

•• PPaattoollooggiiaa CCoorroonnaarriiccaa:: AAnnggiinnaa ppeeccttoorriiss,, IInnffaarrttoo mmiiooccaarrddiiccoo,, MMoorrttee ccaarrddiiaaccaa iimmpprroovvvviissaa •• PPaattoollooggiiaa CCeerreebbrraallee:: AAttttaacccchhii iisscchheemmiiccii ttrraannssiittoorrii ((TTIIAA)),, SSttrrookkee •• PPaattoollooggiiaa VVaassccoollaarree PPeerrii ffeerriiccaa:: CCllaauuddiiccaattiioo iinntteerrmmiitttteennss,, GGaannggrreennaa

LLaa mmaannii ffeessttaazziioonnee ccll iinniiccaa ppiiùù iimmppoorrttaannttee iinn tteerrmmiinnii ddii mmoorrbbii ll ii ttàà ee mmoorrttaall iittàà èè llaa PPaattoollooggiiaa CCoorroonnaarriiccaa.. CCoonn 44 mmii ll iioonnii ddii mmoorrttii ooggnnii aannnnoo,, mmaaggggiioorr ccaauussaa ddii mmoorrttee iinn EEuurrooppaa,, llaa MMaallaattttiiaa CCVV èè aassssoocciiaattaa aadd eelleevvaattii vvaalloorrii ddii ccoolleesstteerroolloo.. VVaarrii TTrriiaallss hhaannnnoo eevviiddeennzziiaattoo cchhee iiddeennttii ff iiccaarree ee ddiimmiinnuuiirree ii ll vvaalloorree ddii qquueessttoo ffaattttoorree ddii rriisscchhiioo CCVV ppuuòò aaiiuuttaarree aa rriidduurrrree llee sseeqquueellee ddeell llaa MMaallaattttiiaa CCVV..

Relationship Between Cholesterol and CHD Risk: Framingham Study

Relationship Between Cholesterol and Relationship Between Cholesterol and

CHD Risk: Framingham StudyCHD Risk: Framingham Study

0

25

50

75

100

125

150

<204

(<5.3)

205-234

(5.3-6.1)

235-264

(6.1-6.8)

265-294

(6.8-7.6)

>295

(>7.6)

CHD incidence per 1000

Serum total cholesterol, mg/dL (mmol/L)

0

25

50

75

100

125

150

<204

(<5.3)

205-234

(5.3-6.1)

235-264

(6.1-6.8)

265-294

(6.8-7.6)

>295

(>7.6)

CHD incidence per 1000

Serum total cholesterol, mg/dL (mmol/L)

Global Burden of Cardiovascular DiseaseGlobal Burden of Cardiovascular DiseaseGlobal Burden of Cardiovascular Disease

In 2002:

� CVD contributed to approximately a third of all global deaths (17 million)

� 80% of burden is in low and middle-income countries

By 2020:

� CHD and stroke will become the leading cause of death and disability worldwide

� Mortality from CVD will increase to 20 million

Clinical care of CVD is costly and prolonged

Cholesterol: A Modifiable Risk FactorCholesterol: A Modifiable Risk FactorCholesterol: A Modifiable Risk Factor

� Plasma cholesterol at levels >200 mg/dL cause 4.4 million deaths a year1

� Incidence of plasma cholesterol >200 mg/dL in:

�51% (107 million) adults in the USA2

�58% of patients with established CHD in EUROASPIRE II3

� 10% reduction in plasma cholesterol results in:

�15% reduction in CHD mortality (p<0.001)

�11% reduction in total mortality (p<0.001)4

� LDL-C is a major target to prevent CHD

1. International CVD Statistics 2005 AHA;

2. Heart and Stroke Statistical Update 2004 AHA;

3. EUROASPIRE II Study Group. Eur Heart J 2001;22:554-572; 4. Gould AL et al. Circulation 1998;97:946–952.

Pathogenesis of Atherosclerotic PlaquesPathogenesis of Atherosclerotic PlaquesPathogenesis of Atherosclerotic Plaques

Protective response results in production of cellular adhesion molecules

Monocytes and T lymphocytes attach to ‘sticky’ surface of endothelial cells

Migrate through arterial wall to subendothelial space

Lipid-rich foam cells

Endothelial damage

Macrophages take up oxidised LDL-C

Fatty streak and plaque

Protective response results in production of cellular adhesion molecules

Monocytes and T lymphocytes attach to ‘sticky’ surface of endothelial cells

Migrate through arterial wall to subendothelial space

Lipid-rich foam cells

Endothelial damage

Macrophages take up oxidised LDL-C

Fatty streak and plaque

Upregulation of endothelial

adhesion molecules

Increased endothelial

permeability

Migration of leucocytes

into the artery wall

Leucocyte adhesion

Lipoprotein infiltration

Increased endothelial

permeability

Migration of leucocytes

into the artery wall

Leucocyte adhesion

Lipoprotein infiltration

Endothelial Dysfunction in AtherosclerosisEndothelial Dysfunction in Atherosclerosis

Formation of foam

cells

Adherence and entry

of leucocytes

Activation of T cells

Migration of smooth

muscle cells

Adherence and

aggregation of platelets

Formation of foam

cells

Adherence and entry

of leucocytes

Activation of T cells

Migration of smooth

muscle cells

Adherence and

aggregation of platelets

Fatty Streak Formation in Fatty Streak Formation in

AtherosclerosisAtherosclerosis

Formation of

the fibrous cap

Accumulation of

macrophages

Formation of

necrotic core

Formation of

the fibrous cap

Accumulation of

macrophages

Formation of

necrotic core

Formation of the Complicated Atherosclerotic PlaqueFormation of the Complicated Atherosclerotic Plaque

Haemorrhage

from plaque

microvessels

Rupture of the

fibrous cap

Thinning of the

fibrous cap

Haemorrhage

from plaque

microvessels

Rupture of the

fibrous cap

Thinning of the

fibrous cap

Rupture of the

fibrous cap

Thinning of the

fibrous cap

The Unstable Atherosclerotic PlaqueThe Unstable Atherosclerotic Plaque

Intraluminal thrombus

Intraplaque thrombus

Lipid pool

Intraluminal thrombus

Intraplaque thrombus

Lipid pool

Atherosclerotic Plaque Rupture and Atherosclerotic Plaque Rupture and

Thrombus FormationThrombus Formation

Clinical Manifestations of Atherosclerosis

Clinical Manifestations of Clinical Manifestations of

AtherosclerosisAtherosclerosis

�Coronary heart disease

�Angina pectoris, myocardial infarction, sudden cardiac death, congestive heart failure (CHF), and arrhythmias

�Cerebrovascular disease

�Transient ischaemic attack, stroke

�Peripheral vascular disease

�Intermittent claudication, gangrene, cold feet, painful feet, impotence

B e n e f i t s o f C h o le s te r o l L o w e r in gB e n e f it s o f C h o le s t e r o l L o w e r in gB e n e f it s o f C h o le s t e r o l L o w e r in g

M e ta -a n a ly s is o f 3 8 p r im a ry a n d s e c o n d a r y in te r v e n t io n t r ia ls

% in c h o le s te r o l r e d u c t io n

T o t a l m o r t a l i ty ( p = 0 .0 0 4 )

C H D m o r t a li t y ( p = 0 .0 1 2 )

Mortality log odds ratio

0 4 8 1 2 1 6 2 0 2 4 2 8 3 2 3 6-1 .0

- 0 .8

- 0 .6

- 0 .4

- 0 .2

- 0 .0

4 0

M e ta -a n a ly s is o f 3 8 p r im a ry a n d s e c o n d a r y in te r v e n t io n t r ia ls

% in c h o le s te r o l r e d u c t io n

T o t a l m o r t a l i ty ( p = 0 .0 0 4 )

C H D m o r t a li t y ( p = 0 .0 1 2 )

Mortality log odds ratio

0 4 8 1 2 1 6 2 0 2 4 2 8 3 2 3 6-1 .0

- 0 .8

- 0 .6

- 0 .4

- 0 .2

- 0 .0

4 0

T o t a l m o r t a l i ty ( p = 0 .0 0 4 )

C H D m o r t a li t y ( p = 0 .0 1 2 )

Mortality log odds ratio

0 4 8 1 2 1 6 2 0 2 4 2 8 3 2 3 6-1 .0

- 0 .8

- 0 .6

- 0 .4

- 0 .2

- 0 .0

4 0

G o u ld A L e t a l . C ir c u la t io n . 1 9 9 8 ;9 7 :9 4 6 -9 5 2 . R e l a t i o n s h i p B e t w e e n C h a n g e s i n

L D L - C a n d H D L - C L e v e l s a n d C H D R i s k

R e l a t i o n s h i p B e t w e e n C h a n g e s i n R e l a t i o n s h i p B e t w e e n C h a n g e s i n

L D LL D L -- C a n d H D LC a n d H D L -- C L e v e l s a n d C H D R i s kC L e v e l s a n d C H D R i s k

1 % d e c r e a s ei n L D L - C r e d u c e s

C H D r i s k b y1 %

1 % i n c r e a s ei n H D L - C r e d u c e s

C H D r i s k b y3 %

Is Lower Better? Relationship between LDL-C and CV Event Rate

Is Lower Better? Relationship between Is Lower Better? Relationship between

LDLLDL--C and CV Event RateC and CV Event Rate

LDL-C achieved mg/dL (mmol/L)

WOSCOPS –Pl

AFCAPS - Pl

ASCOT - Pl

AFCAPS - Rx WOSCOPS - Rx

ASCOT - Rx

4S - Rx

HPS -Pl

LIPID - Rx

4S - Pl

CARE - Rx

LIPID - Pl

CARE - Pl

HPS - Rx

0

5

10

15

20

25

30

40(1.0)

60(1.6)

80(2.1)

100(2.6)

120(3.1)

140(3.6)

160(4.1)

180(4.7)

Event rate (%)

6

Secondary Prevention

Primary Prevention

Rx - Statin therapyPl –PlaceboPra –pravastatinAtv - atorvastatin

200(5.2)

PROVE-IT -Pra

PROVE-IT –Atv

TNT –Atv10

TNT –Atv80

LDL-C achieved mg/dL (mmol/L)

WOSCOPS –Pl

AFCAPS - Pl

ASCOT - Pl

AFCAPS - Rx WOSCOPS - Rx

ASCOT - Rx

4S - Rx

HPS -Pl

LIPID - Rx

4S - Pl

CARE - Rx

LIPID - Pl

CARE - Pl

HPS - Rx

0

5

10

15

20

25

30

40(1.0)

60(1.6)

80(2.1)

100(2.6)

120(3.1)

140(3.6)

160(4.1)

180(4.7)

Event rate (%)

6

Secondary Prevention

Primary Prevention

Rx - Statin therapyPl –PlaceboPra –pravastatinAtv - atorvastatin

200(5.2)

PROVE-IT -Pra

PROVE-IT –Atv

TNT –Atv10

TNT –Atv80

Design of Key Statin Trials (2)Design of Key Statin Trials (2)Design of Key Statin Trials (2)

atorva

10 mg od

Low/average3.4(130)

10,305 40-79 yrs

>3 risk factors

ALLHAT-LLT9prava

40 mg od

HypertensionSome CVD

10,355 >55 yrs

Average3.8(146)

4.8

StatinCVD/risk factors

Patientsage

Mean LDL-C mmol/L (mg/dL)

Follow-up (years)Study

CARDS10atorva

10 mg od

Diabetes + 1 other risk factor

2838 40-75 yrs

Low/average3.0(115)

4.0

3.3 ASCOT-LLA8

PROVE-IT11atorva 80 mg

prava 40 mg

od

Yes 4162>18 yrs

Low/average2.7(106)

3.0

TNT12 Yes 10,001 35-75 yrs

Low/average 2.5(98)

4.9atorva 10 mg

atorva 80 mg

od

1. 4S Study Group. Lancet 1994;344:1383–1389. 2. Shepherd J et al. N Engl J Med1995;333:1301–1307. 3. Sacks FM et al. N Engl J Med.

IDEAL13 Yes

MI

8888<80 yrs

Low/average 3.1(121)

4.8atorva 80 mg

simva 20 mg

od

Design of Key Statin Trials (1)Design of Key Statin Trials (1)Design of Key Statin Trials (1)

4S1

WOSCOPS2

CARE3

LIPID4

AFCAPS/

TexCAPS5

simva

20 mg od

prava

40 mg od

prava

40 mg od

prava

40 mg od

lova

40 mg od

Yes

No MI,

angina

(5% )

Yes

Yes

Low HDL-C

No CHD

5.4

4.9

5.0

6.1

5.2

4444

35–70 yrs

6595

male only

45–64 yrs

4159

21–75 yrs

9014

31–75 yrs

6605

45–73 yrs

Raised 4.9(188)

Raised 5.0(192)

Low/average 3.6(139)

Average 3.8(147)

Average 3.9(150)

StatinCVD/risk factors

Patientsage

Mean LDL-C mmol/L (mg/dL)

Follow-up (years)Study

HPS6Yessimva

40 mg od

20,536 40-80 yrs

Low/average 3.4(130)

5.0

5804 prava 3.2Average

Yes

SummarySummarySummary

�Atherosclerosis is associated with CVD, which is a major cause of death in developed countries

�Dyslipidaemia, in particular elevated LDL-C and low HDL-C, is associated with increased risk for CVD

�Large statin trials have shown that the lower the level of LDL-C achieved the greater the reduction in CV events

�Guidelines recommend lipid levels to reduce the morbidity and mortality caused by dyslipidaemia, and proposed recommendations suggest even more

Aterosclerosi, Colesterolo, Statine e Rischio Cardiovascolare

1Greco Eugenio - 2Greco Raffaella 1Departement of Internal Medicine, Institute Ninetta Rosano-Clinica Tricarico, Belvedere M.mo (CS) - 2Scientific Institute Ospedale San Raffaele, Milan - ITALY