dai grandi trials con statine al razionale del target terapeutico del colesterolo in prevenzione...
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Dai grandi trials con statine al razionale del target terapeutico del
colesterolo in prevenzione secondaria
Angelo Pucci
Cardiologia-UTIC Carrara
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“Difendiamo il cuore”Pontremoli 19 gennaio 2008
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Source: CDC/NCHS 2004
Prevalence of Cardiovascular Diseases (A) and coronary artery disease (B) in adults by age and sexNHANES: 1999–2004
A B
CVD= CAD,stroke,HF, hypertension
Age Age
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CV
DC
ance
r
CO
PD
Oth
ers
CV
DC
ance
r
CO
PD
Oth
ersSource: CDC/NCHS 2004
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Source: CDC/NCHS 2004
Percentage Breakdown of Deaths From Cardiovascular Diseases
United States 2004
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Malattie cardiovascolari 240.072 43.92%
Tumori 156.572 28.64%
Altre malattie 63.440 11.61%
Malattie App. Respiratorio 32.279 5.90%
Traumatismi e avvelenamenti 28.036 5.13%
Malattie App. Digerente 26.162 4.78%
Mortalità in Italia nel 2001(Osservatorio Epidemiologico del Ministero della
Sanità)
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Serum cholesterol (mg/dl)
MRFIT (n=361,662)
Serum cholesterol (mg/dl)
Framingham Study (n=5209)
10
year
CH
D d
eath
rate
(D
eath
s/10
00)
150 200 250 3000
50
40
30
20
10
0
25
50
75
100
125
150
CH
D e
ven
ts x
1000
205-234
235-264 265-294
295
Relationship Between Cholesterol and CHD Risk Epidemiologic trials-1
<204
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Relationship Between Cholesterol and CHD Risk Epidemiologic trials-2
from Verschuren WM, JAMA 1995;274:131-136.
n=12467Follow up 25 aa
“Seven Countries Study”
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1994 - 4S (Scandinavian) (Simvastatina)
1996 - CARE (Chol and Recurrent Event) (pravastatina)
1998 - LIPID Trial (long-term intervention) (pravastatina)
1995 - WOSCOP (West of Scotland) (prava)
1998 - AFCAPS / TexCAPS (lova)
I Grandi trials degli anni 90
seco
nd
ari
ap
rim
ari
a
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Studio n Durata farmaco LDL-C basaleriduzione%
4S 4444 5.4y Simva(10-40mg) 188(mg/dl)
-35%
CARE 4159 5y Prava(40 mg) 139(mg/dl) -27%
LIPID 9014 5y Prava(40 mg) 150(mg/dl) -25%Studio Eventi Mort.tot. Mort.coron Rivasc. Stroke
4S -35%* -30%* - 42 %* -37%* -27%*
CARE -25%* -9% - 24 %* -27%* -31%*
LIPID -29%* -23%* - 24%* -24%* -19%** p<0.05
I Grandi trials in prevezione secondaria (anni 90)
NCEP-ATP III Circulation 2002;106:3143.
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Il rischio di eventi coronarici si riduce del 15% per ogni riduzione del 10% di LDL-C
Gould AL, Circulation 1998
Benefici sono validi anche per sottogruppi di pazienti (donne1, anziani, diabetici3..)
1 Lewis SJ, JACC 1998 , Miettinen TA C, Circulation 19972.Lewis SJ Ann Intern Med 1998
3 Goldberg RB, Circulation 1998, PyoralaK Diabetes Care 1997
Dimostrato effetto preventivo anche sullo stroke.Blauw GJ, Stroke 1997
Dai Grandi trials in prevezione secondaria (anni 90)
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LDL C(mg/dl)
rela
tive r
isk
Studi epidemiologici
4S LIPID, CARE
Modified from Rouleau J, Am J Med. 2005; 118:28S
effetto soglia?
Relazione LDL-C - eventi CVS
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AFCAPS 50
WOSCOPS 42
CARE 33
LIPID 28
4S 14
NNT
The patients who benefited most were those at highest risk
Number needed to treat to save 1 MI =1/ARR
188
150
139
150
192
LDL-C (mg/dl)Modified from Isles CG et al 2000
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NCEP ATP III: target C-LDLCategorie di rischio
da NCEP, ATP III. JAMA 2001:285;2486–2497.
Prevenzione secondaria
< 2 fattori di rischio
≥ 2 fattoridi rischio
Livello
C-L
DL
(mg
/dL)
100 -
160 -
130 -
190 -
Target 100
mg/dL
Target 130
mg/dL
Target 160
mg/dL
(2001)C
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Framingham
MRFIT
LRC-CPPT
Coronary Drug Project
Helsinki Heart
CLAS (angio)
Angiographic Trials (FATS, POSCH, SCOR, STARS, Ornish, MARS)
Meta-Analyses(Holme, Rossouw)
4S, WOSCOPS, CARE, LIPID, AFCAPS/TexCAPS, VAHIT, others
1970s
NCEPATP IGuidelines1988
NCEPATP IIGuidelines1993
NCEPATP IIIGuidelines2001
Evoluzione delle linee guida
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HPS,PROSPER ALLHAT ASCOT-LLA, PROVE IT
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HPS Heart Protection study 2002
Randomizzato, controllato, doppio cieco vs placebo
n= 20536 pz, eta’ 40-80 aaCAD nota, arteriopatia periferica, diabete LDL-C medio 131 mg/dlSimvastatina 40 mg vs placebofollow up 5 aaEnd-point primaio: mortalita’ tot
HPS colaborative Group Lancet 2002; 360:7
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HPS Heart Protection study 2002
Riduzione LDL-C 29.4%Riduzione mortalita’ tot: -13% (p=0.0003)
HPS colaborative Group Lancet 2002; 360:7
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HPS Heart Protection study 2002
IM non fatale: -27%mort. coronarica: -18%Eventi CVS maggiori: -24%
Stroke : -25%
Rivascolarizzazione: -24%
Eventi CVS maggiori: -24%
HPS colaborative Group Lancet 2002; 360:7
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LogCHDRisk
Modified from Heart Protection Study Collaborative Group. Lancet 2002;360:7–22.
116 mg/dl
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100 LDL-C (mg/dL)
Simvastatin40 mg
60
26% Reduction in CVD
22% Reduction in CVD
Simvastatin40 mg
HPS Heart Protection study 2002
Non esiste valore soglia …..
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PROSPER 2002
Shepherd J et al. Lancet 2002;360:1623
5804 pazienti (70–82 anni) vasculopatia coronarica, cerebrale, periferica, >3 fattori di rischio CVS
Follow up 3.5 aa
Terapia: pravastatina 40 mg vs. placebo
19% di riduzione di eventi coronarici maggiori
24% riduzione di mortalità cardiovascolare
25% riduzione TIA (p=0.051)
<131
131-158>158
Valori LDL-C(mg/dl)
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PROSPER 2002
Shepherd J et al. Lancet 2002;360:1623
0 0.5 1 1.5 2 2.5 3 3.5 4
years
CHD death, non-fatal MI, or fatalor non-fatal stroke.
CHD death or non-fatal MI
Riduzione LDL-C 34%
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PROSPER 2002
Shepherd J et al. Lancet 2002;360:1623
Riduzione LDL-C 34%
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ALLHAT- LLT2002
10355 pazienti (>55 anni) ipertensione + 1fattore di rischio (14% CAD nota, 35% diabete)
Follow up 4.8 aa
LDL-C 146 mg/dl (<130 mg/dl nel 61%)
Riduzione LDL-C: 17%
Terapia: pravastatina 20-40 mg + antiipertensivi
Endpoint primario: mortalita’ tot.
JAMA. 2002;288:2998
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ALLHAT- LLT2002
JAMA. 2002;288:2998
All-Cause Mortality CHD Death Plus Nonfatal MI
ns
Non differenze significative negli end points
Riduzione LDL-C: 17%
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ASCOTT- LLA 2003
19342 pazienti (40-79 anni) >3 fattori di rischio CVS
Follow up 5 aa previsti (interrotto 3.3 aa)
LDL-C 132 mg/dl (<130 mg/dl nel 61%)
Riduzione LDL-C: 29%
Terapia: atorvastatina 10 mg + antiipertensivi
Endpoint primario: mortalita’ CAD e IMA non fatale Sever PS, Lancet. 2003;361:1149
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-27%
-27%-29%
-13%, ns
ASCOTT- LLA 2003
Sever PS, Lancet. 2003;361:1149
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LDL-C <100 mg/dl (sotto i valori proposti dalle linee guida)
=Ulteriore beneficio?Sicurezza nel lungo periodo?
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“Is higher dose statin better?”Ong HT. 2005
Terapia aggressiva
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Terapia aggressiva
MIRACL JAMA 2001
PROVE IT NEJM 2004
A to Z JAMA 2004
ACS
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Scwartz GG JAMA 2001; 285:1711
N=3086 paz. 65±12aa con angina instabile /IM non Q Farmaco: atorvastatina 80 mg vs placebo (1% inib IIbIIIa, 11% clopidogrel)Follow up: 16 settimaneLDL-C 124 mg/dl, riduzione LDL fino a 72 mg/dlend point primario combinato: morte/IM non fatale/arresto cardiaco/ reospedalizzazione per ischemia.
Risultati: End point primario: 14.8 (atorva) vs 17,4%(placebo) p=0.048Riduzione reospedalizzazioni (6.2 vs 8.4%, p= 0 02)Safety non gravi eventi avversi livelli transaminasi (X3) 2.5 vs 0.6 (p<0.001)
2001MIRACL
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P=0.048
20
15
10
5
0
Placebon=1548
Tempo dalla randomizzazione (settimane)4 8 12 160
Incid
en
za t
ota
le(%
)
Atorvastatina
(80 mg) n=1538
16%
Occorrenza dell'endpoint primario combinato
da Scwartz GG JAMA 2001; 285:1711
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2001MIRACL
riduzione LDL-C 52% fino a 72 mg/dl
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da Scwartz GG JAMA 2001; 285:1711
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2001MIRACL
ns
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2004PROVE IT
N=4162 paz. 58±11aa con SCA, 69% effettuata PTCA Farmaco: atorvastatina 80 mg vs pravastatina 40mg (1% inib IIbIIIa, 11% clopidogrel)Follow up: 18-36 mesiLDL-C 106 mg/dl (mediana), riduzione LDL : 95 mg/dl prava vs 62 mg/dl atorva end point primario combinato: morte/IM /reospedalizzazione per ischemia/rivascolarizzazione precoce/ictus
Risultati: End point primario: riduzione 16% Sospensione terapia: 21.4%- 33% a 2 aa (ns), nno rabdomiolisi, mialgia e aum CPK (2.7-3.3% ns) livelli transaminasi (X3) 1.1(prava) vs 3.3% atorva) 0.6 (p<0.001) from Cannon CP N Engl J Med
2004;350:1495.
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2004PROVE IT
from Cannon CP N Engl J Med 2004;350:1495.
Death
or
majo
r C
V e
ven
ts %
Months of follow up
-16%
LDL-C medio 62 (atorva) vs 95mg/dl (prava): riduzione 16% end point primario
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2004PROVE IT
from Cannon CP N Engl J Med 2004;350:1495.
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2004A to Z
de Lemos JA, JAMA 2004; 292:1307.
N=4497 paz. 58±11aa con SCA Farmaco:
1. terapia aggressiva precoce: simva 40 mg x1m. poi 80 mg
2. Terapia ritardata placebo x4 m poi simva 20 g Follow up: 24 mesi LDL-C 124 mg/dl (mediana), riduzione LDL : 62 mg/dl End point primario combinato: morte CVS/IM /nuova
SCA/ictus
Risultati: End point primario: 16,6% nel braccio 2 vs 14%nel
braccio 1 (ns) Safety: 0.4% miopatie vs 0% (p=0.02)
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2004A to Z
de Lemos JA, JAMA 2004; 292:1307.
“The early initiation of an aggressive simvastatin regimen resulted in a favorable trend toward reduction of major cardiovascular events.”
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-25% (p=0,02)
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de Lemos JA, JAMA 2004; 292:1307.
In a post-hoc analysis, from month 4 through the end of the study the primary endpoint was reduced by 25% (p=0,02) in the early intensive group
Post-hoc analysis
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Ray KK Am J Cardiol 2006; 98:18P.
PROVE IT
0 1 4 8 16 final months
0 1 4 8 24 months
media
n c
LDL
Riduzione LDL-C nei trials con statine nelle SCA
<100mg/dl <100mg/dl
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Benefici della terapia con statine nelle ACS
Effetti precoci Effetti pleiotropici (antiinfiammatorio, antiproliferativo, anti trombotico, miglioramento funzione endoteliale= stabilizzazione della placca (PROVE IT, A to Z)
Effetti tardivi legati alla riduzione del LDL-C (CARE, 4S, LIPID)
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“Is higher dose statin better?”Ong HT. 2005
Effetti della Terapia aggressiva sulla progressione della ATS
ASAP Lancet 2001
ARBITER Circulation 2002
ATS carotidea
REVERSALAm.J.Cardiol 2005
ASTEROID JAMA 2006
studi IVUS
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Card
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2005REVERSAL
Nissen SE . JAMA. 2004;291:1071
N= 502 paz. 56±9 aa, 73% M, stenosi coronariche 20-50%Farmaco:
Pravastatina 40 mg/dlAtorvastatina 80 mg/dl
Controllo IVUS: 0 e +18 moLDL-C 150 mg/dl , riduzione LDL : 79 (atorva 80) vs 110 mg/dl
(prava 40)End point : variazioni dimensioni ateroma (IVUS)
Risultati: End point : progressione ATS con prava, non progressione
con atorva
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2,7
-0,4
-1
-0,5
0
0,5
1
1,5
2
2,5
3
prava atorva
Prava 40 atorva 80% c
han
ge in
ath
ero
ma v
olu
me
p 0.001 vs base
+2.7%
2005REVERSAL
Nissen SE . JAMA. 2004;291:1071
p=0.02
LDLc 110mg/dl LDLc 79mg/dl
-0.4%
p=0.98 vs base
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n=349
Rosuvastatin 40 mg for two years
Statin naïve : No use of lipid lowering agentsfor > 3 months within the previous 12 months.
Angiographic CAD: > 20% stenosis in any major coronary artery.
A “target vessel” with no more than 50% stenosis throughout at least 40 mm in length:
No prior PCI or MI in the target vessel
IVUS examination screened for image qualityin the Cleveland Clinic Core Laboratory. C
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Nissen SE . JAMA. 2006;291:1071
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Lipid Values and Percent Change (n=349)
Mean
Baseline During
treatment* Percent Change
p value
Total Cholesterol (mg/dL)
204 133.8 -33.8 <0.001
LDL-C (mg/dL)
130.4 60.8 -53.2 <0.001
HDL-C (mg/dL)
43.1 49.0 +14.7 <0.001
Triglycerides (mg/dL)
152.2 121.2 -14.5 <0.001
LDL-C/HDL-C ratio
3.2 1.3 -58.5 <0.001
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2006REVERSAL
Nissen SE . JAMA. 2006;295:1556
2006ASTEROID
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IVUS Efficacy Parameters
-0,79
-1
-0,75
-0,5
-0,25
0
-5,6
-8
-6
-4
-2
0
Median Change in %Atheroma Volume
Median Change in Most Diseased Subsegment
Regressionp<0.001*
*Wilcoxon signed rank test for comparison with baseline
Regressionp<0.001*
ChangeIn
AtheromaVolume(mm3)
ChangeIn
PercentAtheromaVolume
(%)
Card
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2006REVERSAL
Nissen SE . JAMA. 2006;295:1556
2006ASTEROID
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TNT NEJM 2005
IDEAL JAMA 2005
SEARCHongoing
Stable CAD
Terapia aggressivaC
ard
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gia
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Card
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2005TNT
LaRosa JC,NEJM 2005; 352:1425.
N=10001 paz. 61±9 aa con CAD stabile (pregresso IM, angina stab. pregr. rivascolarizzazione)
Farmaco: Atorvastatina 10 mg/dlAtorvastatina 80 mg/dl
Follow up: 4,9 aaLDL-C <130 (98 ±18) mg/dl , riduzione LDL : 101 (atorva 10) vs
77 mg/dl (atorva 80)End point primario combinato: morte CHD/IM/ictus
Risultati: End point primario combinato: riduzione 2.2% (p<0.01) safety: eff. coll. globali 8.1 (atorva 80) vs 5.8 (atorva 10)
x3 transaminasi 1.2 vs .2
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Card
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2005TNT
LaRosa JC,NEJM 2005; 352:1425.
Riduzione dei livelli di LDL-Criduzione LDL : 101 (atorva 10) vs 77 mg/dl (atorva 80)
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Card
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2005TNT
LaRosa JC,NEJM 2005; 352:1425.
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Card
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2004TNT
LaRosa JC,NEJM 2005; 352:1425.
2005TNT
LaRosa JC,NEJM 2005; 352:1425.
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Card
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2005
Pedersen TR. JAMA 2005; 294:2437.
IDEAL
N=8888 paz. 61±9 aa con pregresso IMFarmaco:
Simva 20-40 mgAtorva 80-40 mg
Follow up: 4,8 aaLDL-C 121.4 mg/dl , riduzione LDL : 81 (atorva 80) vs 104
mg/dl (simva 20-40)End point primario combinato: morte CHD/IM/arresto cardiaco
Risultati: End point primario combinato: riduzione 11% (p=0.07 ns)Safety: X3 transaminasi e mialgie in gruppo atorva 80
(p<0.01)
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2005
Pedersen TR. JAMA 2005; 294:2437.
IDEAL
ns
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Card
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2005
Pedersen TR. JAMA 2005; 294:2437.
IDEAL
ns
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Card
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2007SEARCH
N=12064 paz. 64±9 aa con pregresso IMFarmaco:
Simva 20 mgSimva 80 mg
Follow up: 7 aa
End point primario combinato: morte CVD Ongoing trial (fine 2008)
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“Lower Is Better and Physiologically Normal”The normal low-density lipoprotein
(LDL) cholesterol range is 50 to 70 mg/dl for:
native hunter-gatherers neonates free-living primates
All of whom do not develop atherosclerosis
Card
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James H. O’Keefe,JACC 2004;43:2142.
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“Lower Is Better”C
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James H. O’Keefe,JACC 2004;43:2142.
Studi sulla “progressione della placca”
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2
Change in Percent
AtheromaVolume*
(%)
†ASTEROID and REVERSAL investigated active statin treatment; A-PLUS, ACTIVATE AND CAMELOT investigated non-statin therapies but included placebo arms who received background statin therapy (62%, 80% and 84% respectively).
*Median change in PAV from ASTEROID and REVERSAL; LS mean change in PAV from A-PLUS, ACTIVATE AND CAMELOT
1 Nissen S et al. N Engl J Med 2006;354:1253-1263. 2 Tardif J et al. Circulation 2004;110:3372-3377. 3 Nissen S et al. JAMA 2006;295 (13):1556-1565 4 Nissen S et al. JAMA 2004;292: 2217–2225. 5 Nissen S et al. JAMA 2004; 291:1071–1080
-1
-0.5
0
0.5
1
1.5
50 60 70 80 90 100 110 120
ASTEROID3 rosuvastatin
A-Plus2 placebo
ACTIVATE1 placebo
CAMELOT4 placebo
REVERSAL5 pravastatin
REVERSAL5 atorvastatin
Mean LDL-C (mg/dL)
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“Lower Is Better”
Studi sulla “progressione della placca”
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James H. O’Keefe,JACC 2004;43:2142.
I grandi trials in prevenzione primaria
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I grandi trials in prevenzione secondaria
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James H. O’Keefe,JACC 2004;43:2142.
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Adapted from Fonarow GC, Chest. 2005;128:3641.
•TNT•IDEAL•SEARCH
Secondary prevention
Cointinuum della prevenzione CVS
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70*
100*
2004
Alto CHD o equivalenti o rischio CVS a 10 aa. >20%
C-
LD
L (
mg
/dl)
100
160
130
190
Basso< 2 fattori di
rischio
160
Medio- alto
≥ 2 fattori di rischio(rischio a 10 aa. 10-20%)
130
7070
100
Moderato
≥ 2 fattori di rischiorischio a 10 aa. <10%)
130
NCEP ATP III: I nuovi target per il colesterolo LDL
* opzionale
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2001
NCEP, ATP III. JAMA 2001:285;2486.Grundy SM Circulation 2004;110:227.
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Equivalenti di CHD
1. Arteriopatia periferica2. Aneurisma aorta addominale3. Aterosclerosi carotidea4. Diabete tipo 25. Rischio CAD > 20% a 10 anni
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ATP III 2001
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Candidati per target di LDL < 70 mg/dl< 70 mg/dl
1. Sindrome coronarica acuta
2. CAD nota (pregresso IM, angina stabile, rivascolarizzazione etc.
+diabete Sindrome metabolica (TG alti e basso HDL)Fattori di rischio multipli o mal controllati
(fumo)Card
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ATP III update 2004
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Percentage of patients who reached goal (col. tot. <190 mg/dl) at interview among those using lipid-lowering medication
EUROASPIRE II (1999-2000): Only Half of Patients With CHD Achieved TC Goals
EUROASPIRE Study Group. Eur Heart J. 2001;22:554-572.
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SloveniaGreece
ItalySpain
United KingdomIreland
Sweden
Finland
0 20 40 60 80
The Netherlands
Poland
Czech Republic
HungaryFrance
GermanyBelgium
All
Statins-real world
49%
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0
10
20
30
40
50
60
70
80
90
100
CHD Diabetes CHD equivalentsCHD Diabetes Equivalent
Card
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Statine-real world
n=4885
1322 1030 356
62 5540
% o
f pt s
ach
ievin
g L
DL-
C t
reatm
ent
goal
Davidson MH, Am J Cardiol. 2005;96:556.
2003
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37%
37%
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0
10
20
30
40
50
60
70
80
90
100
0 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36
Durata di trattamento (in mesi completati)
%
Probabilità cumulata di continuazione del trattamento con statine (Dati regione Umbria 1997-2000)
5
50%
Statine-real world
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Grazie
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- M
ass
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arr
ara