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
— 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%
COLESTEROLO COME FATTORE DI RISCHIO
PER LA CARDIOPATIA ISCHEMICA
Tassi di mortalità per CHD (%)
35
Stati Uniti
RA 200 = 11.5%
RA 240 = 13.6%
30
25
RR = 1,18
20
Europa Meridionale
RA 200 = 8.5%
RA 240 = 10.1%
15
10
RR = 1,18
5
RA = rischio assoluto
RR = rischio relativo
0
2.60
(100)
3.25 3.90 4.50 5.15 5.80 6.45 7.10 7.75 8.40 9.05
(125) (150) (175) (200) (225) (250) (275) (300) (325) (350)
Colesterolemia totale, mmol/L (mg/dL)
Dati dallo studio Seven Countries su 12,467 uomini dell’Europa, USA e Giappone.
Verschuren WM et al. JAMA 1995;274:131–136.
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).
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 —
3.7
•
2.9
•
Relative Risk 2.2
of
1.7
CHD
(log scale)
•
•
1.3
•
“Rule of One” applies
when LDL < 100 mg/dl
1.0 •
0
40
70
100
130
160
190
220
LDL-Cholesterol (mg/dl)
S. Grundy et al. Circulation 2004;110:227-39
HEART PROTECTION STUDY
Lancet November 30, 2002, pag 1783
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 Journal
Journal 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 by
representatives 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
Patient
tolerability
TC
LDL
HDL
TG
Bile acid
sequestrants
Down
20%
Down
15–30%
Up
3–5%
Neutral
or up
Poor
Nicotinic acid
Down
25%
Down
25%
Up
15–30%
Down
20–50%
Poor to
reasonable
Fibrates
Down
15%
Down
5–15%
Up
20%
Down
20–50%
Good
Probucol
Down
25%
Down
10–15%
Down
20–30%
Neutral
Reasonable
Down
15–30%
Down
24–50%
Up
6–12%
Down
10-29%
Good
-
Down
18%
Up
1%
Down
8%
Good
Statins*
Ezetimibe
low density
lipoprotein, HDLhigh density lipoprotein,
TGtriglyceride.
TC- total cholesterol, LDLrosuvastatin.
*Daily dose of 40mg of each drug. This slide does not include
Adapted from Yeshurun D, Gotto AM.
Southern Med J1995;88 (4):379-391,
KnoppRH. N Engl J Med1999; 341:498 –511, Ezetimibe Prescribing Information. ,
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
J.G. Robinson, J Am Coll Cardiol 2005; 46: 1855-62
CHD EVENTS AND LDL-C IN STATIN TRIALS
Lancet 367, 69, 2006
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 therapy
on cell composition of carotid plaque
C-S
AT-10
(ANOVA p=0.031)
Percentage of plaque area
24
┌ - - - 0.017 - - - ┐
┌ - n.s. - ┐
AT-80
(ANOVA p=0.003)
36
(ANOVA n.s.=0.621)
24
┌ - - - 0.004 - - - ┐
32
20
┌ 0.046 ┐
20
28
16
┌ - n.s. - ┐
24
20
12
16
┌ - n.s. - ┐
12
16
8
12
8
8
4
4
4
0
0
Smooth muscle cells
0
Macrophages
Lymphocytes
P. Pauletto et al, AHA meeting 2009
mg/dL
Plasma LDL-Chol levels
before and after a 3-month lipid lowering therapy
300
t0
NS
250
NS
200
150
100
50
0
Atorva80
Atorva10
Chol+Sitost
t1
Effect of a 3-month lipid lowering therapy
on cell composition of carotid plaque
0,140
Cells per area unit
Chol+Sitost
0,120
Statin
0,100
0,080
0,060
0,040
0,020
0,000
SMC
MO
Linpho
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
JUPITER - Primary Endpoint
MI, Stroke, UA/Revascularization, CV Death
HR 0.56, 95% CI 0.46-0.69
P < 0.00001
0.06
Number Needed to Treat (NNT2) = 95
Number Needed to Treat (NNT5) = 25 *
-44%
109 Fewer Events
0.04
*Extrapolated figure based on
Altman and Andersen method
Rosuvastatin 142 / 8901
0.02
Cumulative Incidence
0.08
Placebo 251 / 8901
0.00
Ridker P et al. N Eng J Med 2008;359: 2195-2207
0
1
2
4
Follow-up (years)
Number at Risk
Rosuvastatin
Placebo
3
8,901
8,901
8,631
8,621
8,412
8,353
6,540
6,508
3,893
3,872
1,958
1,963
1,353
1,333
983
955
544
534
157
174
JUPITER - Primary Endpoint Components
Placebo
Rosuvastatin
n (rate**)
n (rate**)
[n=8901]
[n=8901]
HR
95% CI
p-value
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
Fatal or non-fatal MI
62 (0.33)
68 (0.37)
22 (0.12)
31 (0.17)
0.35
0.46
0.22-0.58 <0.001*
0.30-0.70 0.0002
Non-fatal stroke
Fatal or non-fatal stroke
58 (0.31)
64 (0.34)
30 (0.16)
33 (0.18)
0.52
0.52
0.33-0.80
0.34-0.79
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
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*
0.003
0.002
0.09
** Rates are per 100 person years; † Hospitalisation due to unstable angina; *Actual p-value was < 0.00001
HR – Hazard Ratio; CI – Confidence Limit
Ridker P et al. N Eng J Med 2008;359: 2195-2207
0.06
JUPITER - Total Mortality
Death from any cause
0.05
-20%
0.02
0.03
0.04
Rosuvastatin 20mg
N=198
0.00
0.01
Cumulative Incidence
Placebo
N=247
Hazard Ratio 0.80
(95% CI 0.67-0.97)
p=0.02
0
Number at Risk
Rosuvastatin 8,901
Placebo
8,901
1
2
3
4
Follow-up (years)
8,847
8,852
8,787
8,775
6,999
6,987
4,312
4,319
2,268
2,295
1,602
1,614
1,192
1,196
683
684
227
246
Ridker P et al. N Eng J Med 2008;359: 2195-2207
LDL-CT and hs-CRP Levels during the Follow-up Period
Baseline 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?
JUPITER: potential limitations / warnings
• 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
Statine e cardiopatie non ischemiche
- 53,6%
- 61,3%
ENDPOINT PRIMARIO
-22%
p=0,02
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)
Benefici dell’esercizio
fisico moderato
(20’- 30’ al dì / a gg alterni)
• Riduzione dei fattori di
rischio:
• 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)
– 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)
Variazione % media dal basale
del C-LDL calcolato (settimana 12)
Ezetimibe associato con simvastatina:
efficacia sul C-LDL
Ezetimibe 10 mg
+
simvastatina 20 mg
Simvastatina
20 mg
40 mg
–36*
–36*
80 mg
0
–10
–20
–30
–40
–44
–44
–50
–60
*p<0.01 terapia di associazione vs. statina da sola
Tratto da Davidson MH et al J Am Coll Cardiol 2002;40:2125-2134.
Variazione % media dalbasale
del C-LDL calcolato (settimana 12)
Ezetimibe associato con atorvastatina: efficacia
sul C-LDL
Ezetimibe 10 mg
+
atorvastatina 10 mg 10 mg
Atorvastatina
20 mg
40 mg
80 mg
0
–10
–20
–30
–37*
–42*
–40
–50
–45*
–53
–60
*p<0,01 terapia di associazione vs. statina da sola
Tratto da Ballantyne CM et al Circulation 2003;107:2409-2415.
–54
Studio sull’associazione fra ezetimibe e simvastatina:
risultati raggruppati sul C-LDL
Simvastatina
(10–80 mg)
(n=263)
Ezetimibe +
simvastatina (10–80 mg)
(n=274)
Dosi raggruppate
4,66 mmol/l
4,60 mmol/l
C-LDL basale
Variazione media del
C-LDL calcolato (mmol/l)
0
–0,5
–1,0
–1,5
–1,71
–2,0
–2,38
–2,5
–3,0
*p<0,01 terapia di associazione vs. statina da sola
Tratto da Davidson MH et al J Am Coll Cardiol 2002;40:2125-2134.
–0,67 mmol/l (–28,2%)*
Studio sull’associazione fra ezetimibe e
atorvastatina: risultati raggruppati sul C-LDL
Atorvastatina
(10–80 mg)
(n=248)
Ezetimibe +
atorvastatina (10–80 mg)
(n=255)
Dosi raggruppate
4,69 mmol/l
4,70 mmol/l
C-LDL basale
Variazione media del
C-LDL calcolato (mmol/l)
0
–0,5
–1,0
–1,5
–2,07
–2,0
–2,5
–2,66
–0,59 mmol/l (–22,2%)*
–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
Ezetimibe più statina ha fornito un C-LDL più basso del 18 - 24%
C-LDL medio (mmol/l)
al termine dello studio
rispetto alla statina da sola
3,5
Statina da sola
Statina + ezetimibe
3,4
3
2,5
2
3,5
2,9
2,6
24%
18%
2,8
23%
2,0
3,4
21%
2,7
2,2
3
2,5
21%
2,7
2
1,5
1,5
1
1
,5
,5
0
0
Atorvastatina Simvastatina Pravastatina
3,4
Lovastatina
Studio con
statina già iniziata
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.
Statina a dose elevata rispetto ad Ezetimibe associato
con statina a dose starter (C-LDL)
Atorvastatina
80 mg
(n=62)
Ezetimibe
10 mg +
atorvastatina
10 mg
(n=65)
Simvastatina
80 mg
(n=67)
Ezetimibe
10 mg +
simvastatina
20 mg
(n=67)
Pravastatina
40 mg
(n=69)
Ezetimibe
10 mg +
pravastatina
10 mg
(n=71)
Variazione % media alla
settimana 12
0
–10
–20
–31
–30
–40
–50
–44
–54
–34
–44
–53
–60
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.
Efficacia sui trigliceridi: Ezetimibe
associato con statine - risultati raggruppati
Atorvastatina
(n=248)
Variazione % media dei TG dal
basale alla settimana 12
0
Ezetimibe
Ezetimibe
+
+
Simvastatina
atorvastatina
simvastatina
(n=263)
(n=255)
(n=274)
–5
Ezetimibe
+
Pravastatina pravastatina
(n=205)
(n=204)
–8
–11
–10
–20
–30
10%**
–17
–15
–25
Ezetimibe
+
Lovastatina
lovastatina
(n=220)
(n=192)
7%**
–25*
8%**
–18
–24
11%**
–22
–33*
–35
–40
*Variazione mediana; **p<0,01 ezetimibe + dosi raggruppate delle statine vs. dosi raggruppate delle statine da sole
Tratto da Ballantyne CM et al Circulation 2003;107:2409-2415; Davidson MH et al J Am Coll Cardiol 2002;40:21252134; Melani L et al Eur Heart J 2003;24:717-728; Kerzner B et al Am J Cardiol 2003;91:418-424.
Variazione % media del C-HDL
dal basale alla settimana 12
Efficacia sul C- HDL: Ezetimibe associato con
statine – risultati raggruppati
10
2%**
8
1%
7
6
4
9
9
7
7
8
5%*
3%*
4
4
2
0
Atorvastatina Ezetimibe Simvastatina Ezetimibe Pravastatina Ezetimibe Lovastatina Ezetimibe
(n=248)
(n=263)
(n=205)
(n=220)
+
+
+
+
atorvastatina
simvastatina
pravastatina
lovastatina
(n=255)
(n=274)
(n=204)
(n=192)
*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.
Residual CVD Risk
Niacin and Simvastatin
P. Pauletto
Medicina Interna I^, Treviso
University 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 of
statins, 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 Risk
Even 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