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