Aterosclerosi, Colesterolo, Statine e Rischio … · Aterosclerosi, Colesterolo, Statine e Rischio...
Transcript of Aterosclerosi, Colesterolo, Statine e Rischio … · Aterosclerosi, Colesterolo, Statine e Rischio...
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