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Attualità nell’impiego delle statine. Prof. P. Pauletto Dip. di Medicina Clinica e Sperimentale Università degli Studi di Padova U.O. di Medicina Interna I^ U.L.S.S. n° 9, Ospedale di Treviso. Risk Factors and Attributable Mortality Reduction. - PowerPoint PPT Presentation
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Attualità nell’impiego Attualità nell’impiego delle statinedelle statine
Prof. P. PaulettoProf. P. Pauletto
Dip. di Medicina Clinica e SperimentaleDip. di Medicina Clinica e SperimentaleUniversità degli Studi di PadovaUniversità degli Studi di Padova
U.O. di Medicina Interna I^U.O. di Medicina Interna I^U.L.S.S. n° 9, Ospedale di TrevisoU.L.S.S. n° 9, Ospedale di Treviso
Risk Factors and Attributable Mortality Reduction
— which one stands out as best therapeutic target —
Contribution from RF modification
• Cholesterol (LDL/HDL) 37%
• Blood pressure 14%
• Cigarette smoking 6%
Contribution comparators
• Medical Rx of acute MI 21%
• PCI or CABG 16%
Stati Uniti
Europa Meridionale
Dati dallo studio Seven Countries su 12,467 uomini dell’Europa, USA e Giappone.Verschuren WM et al. JAMA 1995;274:131–136.
COLESTEROLO COME FATTORE DI RISCHIO
PER LA CARDIOPATIA ISCHEMICA
Correlazione tra CT e mortalità da CHD in uno studio di 25 anni su 12.467 uomini, abitanti in cinque paesi europei, negli USA e in Giappone (da Verschuren et al 1995).
Colesterolemia totale, mmol/L (mg/dL)
0
5
10
15
20
25
30
35
Tass
i di m
orta
lità
per C
HD
(%
)
2.60(100)
3.25(125)
3.90(150)
4.50(175)
5.15(200)
5.80(225)
6.45(250)
7.10(275)
7.75(300)
8.40(325)
9.05(350)
RA 200 = 8.5%RA 240 = 10.1%RR = 1,18
RA 200 = 11.5%RA 240 = 13.6%RR = 1,18
RA = rischio assolutoRR = rischio relativo
Il contributo del FR è lo stesso, ma si parte da livelli basali diversi
Le Linee Guida
Relationship Between LDL-C Levels and CHD Events
— data derived from epidemiologic studies and clinical trials —
S. Grundy et al. Circulation 2004;110:227-39
40 70 100 130 160 190 220
LDL-Cholesterol (mg/dl)
Relative Riskof
CHD(log scale)
3.7
2.9
2.2
1.7
1.3
1.0
0
“Rule of One” applies when LDL < 100 mg/dl•
•
••
•
•
Lancet November 30, 2002, pag 1783
HEART PROTECTION STUDY
Le Linee Guida: i livelli di LDL-C• NCEP Adult Treatment Panel III update 2004† National Cholesterol Education Program (NCEP) Expert Panel on Detection, Evaluation and Treatment of High Blood Cholesterol in Adults (Adult Treatment
Panel, ATP) *TLC: therapeutic lifestyle change (cambiamenti terapeutici dello stile di vita)Grundy SM, Cleeman JI, Merz CNB, et al. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III
Guidelines. Circulation. 2004;110:227–239
Rischio alto: CHD o equivalenti del rischio di CHD (rischio di CHD a 10 aa >20%)
Obiettivo LDL-C < 100 mg/dl valore ideale opzionale < 70 mg/dl
• Joint British Societes 2005† JBS 2: Joint British Societies’ guidelines on prevention of cardiovascular disease in clinical practice; Formerly British Heart JournalJournal of the British Cardiac Society Volume 91 Supplement V December 2005
Rischio alto: CHD o equivalenti del rischio di CHD (Total CVD risk† ≥ 20%)
Obiettivo LDL-C < 80 mg/dl
• European Guidelines On Vascular Disease Prevention in Clinical Practice 2007
Fourth Joint Task Force of the European Society of Cardiology and Other Societies on Cardiovascular Disease Prevention in ClinicalPractice (Constituted byrepresentatives of nine societies and by invited experts) European Heart Journal (2007) 28, 2375–2414
Rischio alto: CHD o equivalenti del rischio di CHD (rischio di CHD a 10 aa >20%)
Obiettivo LDL-C < 100 mg/dl valore auspicabile < 80 mg/dl
Le opzioni di trattamento farmacologico
Effect of lipid-modifying therapies -
Therapy
TC-total cholesterol, LDL- -low density lipoprotein, HDL- -high density lipoprotein, TG-triglyceride. *Daily dose of 40mg of each drug. This slide does not include rosuvastatin.
TC
20%
LDL HDL TG Patienttolerability
Bile acidsequestrants
Down Down 15–30%
Up 3–5%
Neutralor up
Poor
Nicotinic acid Down 25%
Down 25%
Up 15–30%
Down 20–50%
Poor toreasonable
Fibrates Down 15%
Down 5–15%
Up 20%
Down 20–50%
Good
Probucol Down 25%
Down 10–15%
Down20–30%
Neutral Reasonable
Statins* Down 15–30%
Down 24–50%
Up 6–12%
Down 10-29%
Good
Ezetimibe - Down18%
Up1%
Down 8%
Good
Adapted from Yeshurun D, Gotto AM. Southern Med J1995;88 (4):379-391, KnoppRH. N Engl J Med1999; 341:498 – 511, Ezetimibe Prescribing Information. ,
J.G. Robinson, J Am Coll Cardiol 2005; 46: 1855-
62
Estimated change in the five-year relative risk of non-fatal myocardial
infarction or CHD death associated with mean LDL-C reduction for the diet,
bile-acid sequestrant, surgery, and statin trials (dashed line) along with
the 95% probability interval (dotted line). The solid line has a slope=1
Lancet 367, 69, 2006
CHD EVENTS AND LDL-C IN STATIN TRIALS
L’ intensità del trattamento
con statine e coronaropatia
Published at www.nejm.org March 8, 2005
Published at www.nejm.org March 8, 2005
NEJM 350, 2004
Effect of a 3-month lipid lowering therapyon cell composition of carotid plaque
P. Pauletto et al, AHA meeting 2009
0
4
8
12
16
20
24
Lymphocytes0
4
8
12
16
20
24
Smooth muscle cells
┌ - n.s. - ┐
┌ - n.s. - ┐┌ - - - 0.017 - - - ┐
0
4
8
12
16
20
24
28
32
36
Macrophages
┌ 0.046 ┐
┌ - n.s. - ┐
┌ - - - 0.004 - - - ┐
Perc
enta
ge o
f pla
que
area
(ANOVA p=0.031) (ANOVA p=0.003) (ANOVA n.s.=0.621)
C-S AT-10 AT-80
Plasma LDL-Chol levels before and after a 3-month lipid lowering therapy
0
50
100
150
200
250
300t0t1
Atorva80 Atorva10 Chol+Sitost
mg/
dL
NSNS
Effect of a 3-month lipid lowering therapyon cell composition of carotid plaque
0,000
0,020
0,040
0,060
0,080
0,100
0,120
0,140
SMC MO Linpho
Chol+SitostStatin
Cel
ls p
er a
rea
unit
Il rimodellamento coronarico nei pazienti
trattati con statine
Intravascular Ultrasound Images at Baseline and Follow-up
— an example of plaque regression —
Nissen et al. JAMA 2004;291:1079
JAMA 2004;291:1071-1080
JAMA 2006; 295, 13 March
JAMA 2006; 295, 13 March
Correggendo i livelli di infiammazione si riduce il rischio CV ?
CRP in 3745 patients wiht ACS(PROVE IT-TIMI22)
Ridker PM et al. NEJM 2005
Placebo 251 / 8901
Rosuvastatin 142 / 8901
HR 0.56, 95% CI 0.46-0.69P < 0.00001
Number Needed to Treat (NNT2) = 95Number Needed to Treat (NNT5) = 25
0 1 2 3 4
0.00
0.02
0.04
0.06
0.08
Cum
ulat
ive
Inci
denc
e
Number at Risk Follow-up (years)RosuvastatinPlacebo
8,901 8,631 8,412 6,540 3,893 1,958 1,353 983 544 1578,901 8,621 8,353 6,508 3,872 1,963 1,333 955 534 174
109 Fewer Events
*Extrapolated figure based on Altman and Andersen method
* -44%
Ridker P et al. N Eng J Med 2008;359: 2195-2207
JUPITER - Primary Endpoint MI, Stroke, UA/Revascularization, CV Death
JUPITER - Primary Endpoint Components
Primary Endpoint 251 (1.36) 142 (0.77) 0.56 0.46-0.69 <0.001*
(Time to first occurrence of CV death, MI, stroke, unstable angina, arterial revascularisation)
Non-fatal MI 62 (0.33) 22 (0.12) 0.35 0.22-0.58 <0.001*
Fatal or non-fatal MI 68 (0.37) 31 (0.17) 0.46 0.30-0.70 0.0002
Non-fatal stroke 58 (0.31) 30 (0.16) 0.52 0.33-0.80 0.003Fatal or non-fatal stroke 64 (0.34) 33 (0.18) 0.52 0.34-0.79 0.002
Arterial Revascularization 131 (0.71) 71 (0.38) 0.54 0.41-0.72 <0.0001
Unstable angina† 27 (0.14) 16 (0.09) 0.59 0.32-1.10 0.09
CV death, stroke, MI 157 (0.85) 83 (0.45) 0.53 0.40-0.69 <0.001*
Revascularization or unstable angina 143 (0.77) 76 (0.41) 0.53 0.40-0.70 <0.001*
Placebo Rosuvastatin HR95% CI p-value
[n=8901] [n=8901]
n (rate**) n (rate**)
HR – Hazard Ratio; CI – Confidence Limit
** Rates are per 100 person years; † Hospitalisation due to unstable angina; *Actual p-value was < 0.00001
Ridker P et al. N Eng J Med 2008;359: 2195-2207
PlaceboN=247
Rosuvastatin 20mgN=198
JUPITER - Total Mortality Death from any cause
Hazard Ratio 0.80 (95% CI 0.67-0.97)p=0.02
Ridker P et al. N Eng J Med 2008;359: 2195-2207
0 1 2 3 4
0.00
0.01
0.02
0.03
0.04
0.05
0.06
Cum
ulat
ive
Inci
denc
e
Number at Risk Follow-up (years)RosuvastatinPlacebo
8,901 8,847 8,787 6,999 4,312 2,268 1,602 1,192 683 2278,901 8,852 8,775 6,987 4,319 2,295 1,614 1,196 684 246
-20%
LDL-CT and hs-CRP Levels during the Follow-up PeriodBaseline level: LDL-CT=108 mg/dL both groups; hs-CRP=4.2 vs 4.3 mg/L in placebo
PM Ridker, et al. N Engl J Med 2008;359:2195-207
Cumulative Incidence of Cardiovascular Events According to Study Group
PM Ridker, et al. N Engl J Med 2008;359:2195-207
Relationship of the proportional reduction in cardiovascular event rate and mean LDL cholesterol difference between
treatment groups in published statin trials
PM Ridker, et al. N Engl J Med 2008;359:2195-207 - Online Supplemental Appendix
The results of JUPITER and the primary prevention of CHD
• Should indications for statin treatment be expanded?
• How should measurements of hs-CRP be used?
• Hard cardiac events 1.8% (157 of 8901 subjects) in the placebo group vs 0.9% (83 of 8901 subjects) in the rosuvastatin group: 120 participants were treated for 1.9 years to prevent one event.
• Significantly higher HbA1levels and incidence of diabetes in the rosuvastatin group (3.0%, vs. 2.4% in the placebo group;P=0.01)
• The trial did not compare subjects with and those without hs-CRP measurements
• Since statins lower both LDL cholesterol and hs-CRP we cannot determine whether CT, a reduction in inflammation, or a combination of both are responsible for the benefit
• Meta-regression is not a reliable technique, and the early termination of the trial owing to the efficacy data probably exaggerated the results to some degree
JUPITER: potential limitations / warnings
Statine e cardiopatie non ischemiche
- 61,3%
- 53,6%
-22%p=0,02
ENDPOINT PRIMARIO
GISSI-HF trial: all-cause death (A)and admission for cardiovascular reasons (B)
Terapia di associazione ?
Statine + Niacina• Negli USA è entrata in commercio l’associazione Lovastatina
20 mg + niacina a lento rilascio (Advicor*)
• Possibili vantaggi: maggiore riduzione del colesterolo e trigliceridi, maggior incremento del colesterolo HDL e maggior riduzione delle LDL piccole e dense
• Potenziali rischi: maggior rischio di miopatia e rialzo degli enzimi epatici. Peggioramento del controllo metabolico del diabete o della gotta
Brown BG, NEJM 2001 - Wolfe ML, Am J Cardiol 2001 - Bays HE, Am J Cardiol 2003
Strategie di incremento del colesterolo HDL
• Storiche– Uso dei fibrati (studio VA-HIT, Helsinki Heart Study)
– Uso della niacina (studi CLAS, FATS)
• Future– Infusione di Apo A1 Milano (Nissen JAMA 2003)
– Inibitori della CETP (Brousseau NEJM 2004)
Intervento: misure igienico dietetiche
Benefici del decremento ponderale (2- 9 kg)
• Riduzione dei fattori di rischio:– Riduzione p.a.: 5- 20 mm
Hg/ 10 kg– Riduzione colesterolo LDL
10- 15%• Riduzione della mortalità
totale (16- 65%) (Chaturvedi 1995, Eriksson 1998)
Benefici dell’esercizio fisico moderato
(20’- 30’ al dì / a gg alterni)
• Riduzione dei fattori di rischio:– Aumento HDL– Riduzione p.a.– Riduzione insulino- resistenza
• Riduzione della patologia coronarica del 35-55% (Manson 1992, Lakka 1994)
• Riduzione della mortalità cv (31%) e totale (29%) (Bijnen 1998)
Ezetimibe associato con simvastatina: efficacia sul C-LDL
*p<0.01 terapia di associazione vs. statina da solaTratto da Davidson MH et al J Am Coll Cardiol 2002;40:2125-2134.
–44 –44
–36* –36*
Varia
zion
e %
med
ia d
al b
asal
e
del C
-LD
L c
alco
lato
(set
timan
a 12
)
Ezetimibe 10 mg+
simvastatina 20 mg 80 mg40 mg20 mg
Simvastatina
–50
–40
–30
–20
–10
0
–60
Ezetimibe associato con atorvastatina: efficacia sul C-LDL
*p<0,01 terapia di associazione vs. statina da solaTratto da Ballantyne CM et al Circulation 2003;107:2409-2415.
10 mg
Ezetimibe 10 mg+
atorvastatina 10 mg 80 mg40 mg20 mg
Atorvastatina
–50
–40
–30
–20
–10
0
–60
–54
–45*–42*
–37*
–53
Varia
zion
e %
med
ia d
alba
sale
de
l C-L
DL
cal
cola
to (s
ettim
ana
12)
Studio sull’associazione fra ezetimibe e simvastatina:risultati raggruppati sul C-LDL
–3,0
–2,0
–1,5
–1,0
–0,5
0
Varia
zion
e m
edia
del
C-L
DL
calc
olat
o (m
mol
/l)
Simvastatina (10–80 mg)
(n=263)4,66 mmol/l
Ezetimibe + simvastatina (10–80 mg)
(n=274)4,60 mmol/l C-LDL basale
–2,38
–1,71–0,67 mmol/l (–28,2%)*
Dosi raggruppate
*p<0,01 terapia di associazione vs. statina da sola
Tratto da Davidson MH et al J Am Coll Cardiol 2002;40:2125-2134.
–2,5
Studio sull’associazione fra ezetimibe e atorvastatina: risultati raggruppati sul C-LDL
–2,5
–2,0
–1,5
–1,0
–0,5
0
Varia
zion
e m
edia
del
C-L
DL
calc
olat
o (m
mol
/l)
Atorvastatina (10–80 mg)
(n=248)4,69 mmol/l
Ezetimibe + atorvastatina (10–80 mg)
(n=255)4,70 mmol/l C-LDL basale
–2,66
–2,07
–0,59 mmol/l (–22,2%)*
Dosi raggruppate
–3,0
*p<0,01 terapia di associazione vs. statina da sola
Tratto da Ballantyne CM et al Circulation 2003;107:2409-2415;Ballantyne C et al J Am Coll Cardiol 2002;39(suppl A):227A.
Ezetimibe associato con statine dall’inizio: conformità dei risultati degli studi
Tratto da Dati di Registrazione, MSP; Davidson MH et al J Am Coll Cardiol 2002;40:2125-2134; Melani L et al Eur Heart J 2003;24:717-728.
Ezetimibe più statina ha fornito un C-LDL più basso del 18 - 24%
rispetto alla statina da sola
Studio constatina già iniziata
C-L
DL
med
io (m
mol
/l)al
term
ine
dello
stu
dio
Statina da sola Statina + ezetimibe
2,7
3,43,4
SimvastatinaAtorvastatina LovastatinaPravastatina
2,0
2,62,2
2,9 2,82,7
3,4
23%24%
18% 21% 21%
,5
1,5
2,5
3
3,5
0
1
2
,5
1,5
2,5
3
3,5
0
1
2
Varia
zion
e %
med
ia a
lla
setti
man
a 12
–50
–40
–30
–20
–10
0
–60
Atorvastatina80 mg(n=62)
–54
Ezetimibe10 mg +
atorvastatina 10 mg (n=65)
–53
Simvastatina80 mg(n=67)
–44
Ezetimibe10 mg +
simvastatina 20 mg(n=67)
–44
Pravastatina40 mg(n=69)
–31
Ezetimibe10 mg +
pravastatina 10 mg(n=71)
–34
Statina a dose elevata rispetto ad Ezetimibe associato con statina a dose starter (C-LDL)
Tratto dalla Worldwide Product Circular (ezetimibe), MSP; Dati di Registrazione, MSP; Ballantyne CM et al Circulation 2003;107:2409-2415; Davidson MH et al J Am Coll Cardiol 2002;40:2125-2134.
*Variazione mediana; **p<0,01 ezetimibe + dosi raggruppate delle statine vs. dosi raggruppate delle statine da soleTratto da Ballantyne CM et al Circulation 2003;107:2409-2415; Davidson MH et al J Am Coll Cardiol 2002;40:2125-2134; Melani L et al Eur Heart J 2003;24:717-728; Kerzner B et al Am J Cardiol 2003;91:418-424.
Efficacia sui trigliceridi: Ezetimibe associato con statine - risultati raggruppatiVa
riazi
one
% m
edia
dei
TG
dal
ba
sale
alla
set
timan
a 12
–35
–30
–25
–20
–10
0
–40
Ezetimibe+
atorvastatina(n=255)
Atorvastatina (n=248)
Ezetimibe+
simvastatina(n=274)
Simvastatina(n=263)
Ezetimibe+
lovastatina(n=192)
Lovastatina(n=220)
Ezetimibe+
pravastatina(n=204)
Pravastatina(n=205)
–33*
–25* –24
–17
–22
–11
–18
–8
8%**
7%**
11%**10%**
–15
–5
*p<0,01 ezetimibe + dosi raggruppate della statina vs. dosi raggruppate della statina da sola; **p=0,03 ezetimibe + dosi raggruppate della statina vs. dosi raggruppate della statina da sola.Tratto da Ballantyne CM et al Circulation 2003;107:2409-2415; Davidson MH et al J Am Coll Cardiol 2002;40:2125-2134; Melani L et al Eur Heart J 2003;24:717-728; Kerzner B et al Am J Cardiol 2003;91:418-424.
Efficacia sul C- HDL: Ezetimibe associato con statine – risultati raggruppati
Ezetimibe+
atorvastatina(n=255)
Atorvastatina(n=248)
Ezetimibe+
simvastatina(n=274)
Simvastatina(n=263)
Ezetimibe+
lovastatina(n=192)
Lovastatina(n=220)
Ezetimibe+
pravastatina(n=204)
Pravastatina(n=205)
Varia
zion
e %
med
ia d
el C
-HD
L da
l bas
ale
alla
set
timan
a 12
2
4
6
8
10
0
4
7
9
7
9
4
87
3%*
2%**
5%*1%
Residual CVD RiskNiacin and Simvastatin
P. PaulettoMedicina Interna I^, TrevisoUniversity of Padova - Italy
Time to the first primary clinical end point(death from coronary causes, nonfatal MI, stroke, or revascularization)
Brown BG et al. N Engl J Med 2001;345:1583
Stenosis (%) and minimal luminal diameter for nine proximal lesions, for all lesions, and for lesions in various categories of
base-line severity, according to treatment group.
Brown BG et al. N Engl J Med 2001;345:1583
Dose ranges and efficacy ofstatins, ezetimibe, and bile acid sequestrants
Runhua H et al. Endocrinol Metab Clin N Am 2009;38:79
Residual CVD Risk After Statin Therapy
Alagona P. Am J Manag Care 2009;15:s65
Low HDL-C Is Associated With High CVD RiskEven If LDL-C Levels Are Well-Controlled (TNT Study)
Alagona P. Am J Manag Care 2009;15:s65
Strategies for Reducing CHD Risk
Alagona P. Am J Manag Care 2009;15:s65
Efficacy of niacin ER/simvastatin combination therapy:SEACOAST I
Alagona P. Am J Manag Care 2009;15:s65
Efficacy of niacin ER/simvastatin combination therapy:SEACOAST II
Alagona P. Am J Manag Care 2009;15:s65
Fenofibric Acid and Rosuvastatin Combination Therapy in Patients With Mixed Dyslipidemia
Alagona P. Am J Manag Care 2009;15:s65