CAMPAGNA EDUCAZIONALE REGIONALE ANMCO TOSCANA

“Difendiamo il Cuore”

Casciana Terme 12 Gennaio 2008

Dai grandi Trials con Statine al razionale del target terapeutico del Colesterolo

in Prevenzione Secondaria

Dr. Stefano VianiUO Malattie Cardiovascolari

Ospedale di PontederaUSL 5 Pisa

La mortalità per malattia ischemica del cuore (IHD) è alta e aumenterà

0

500

1000

1500

2000

2500

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EME FSE India Cina OAI SSA LA MedioOriente

1990 2020

Mo

rtal

ità

per

IH

D (

mig

lia

ia)

EME=mercati con economie stabili; FSE=economia ex socialiste; OAI=altri paesi asiatici e isole del Pacifico; SSA=Africa sub-sahariana; LA=America Latina; Mid East=Medio Oriente.

Yusuf S et al. Circulation. 2001;104:2746-2753.

La mortalità regionale per IHD tra il 1990 e il 2020

… chi presenta tutti i nove fattori ha una probabilità di infarto che è più di 330 volte superiore a quella di chi non ne ha nessuno (90% probabilità) !!!!!!

Studio INTERHEART (15.152 casi e 14.820 controlli)

Lancet 3 settembre 2004

Nove fattori di rischio, facilmente misurabili, “spiegano” oltre il 90% degli infarti in tutte le regioni del mondo”

L’associazione di più fattori di rischio moltiplica la probabilità di infarto: …

1. Fumo

2. Ipertensione

3. Diabete

4. Dislipidemia

5. Obesità addominale

6. Stress

7. Inattività fisica

8. Scarsa assunzione di frutta e verdura

9. Nulla assunzione di alcool

3

RISCHIO CARDIOVASCOLARE E COLESTEROLEMIA

Adapted from Ray KK et al. J Am Coll Cardiol. 2005;46:1425-1433.

EFFETTI NON IPOLIPEMIZZANTI (effetto precoce/rapido)

EFFETTI IPOLIPEMIZZANTI (effetto lento/ritardato)

Effetti delle Statine

Disfunzione/attivazione endoteliale

Coagulazione/attivazione piastrine

inibitorioinibitorio

inibitorio

inibitorio

Infiammazione/attivazione immunologica

Statine

FegatoFegatoSintesi Sintesi

colesterolo colesterolo epaticoepatico

Rottura della placca/occlusione trombotica

Placca aterosclerotica ricca di lipidi

trombotrombo

Nucleo lipidicoNucleo lipidico

Statine

Inibizione HMG-CoA reduttasi

4

Evoluzione nella gestione Evoluzione nella gestione delldell’’ipercolesterolemiaipercolesterolemia

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

UPDATE2004

UPDATE2004

HPS, PROVE-IT , ASCOT, ALLHAT, PROSPER

NCEPNCEP: : NNationalational CCholesterolholesterol EEducationducation PProgramrogram

ATP: ATP: AdultAdult Treatment PanelTreatment Panel

HPS2002

TNT2005

LIPID1998

CARE1996

4 S1994

IDEAL2005

Trials di Prevenzione Secondariacon Statine

•Coronaropatia

•Elevati valori di LDL-C

•Valori di LDL-C nella media

•Popolazione ad“Alto Profilo di Rischio”

•Definizione del target LDL-C

•Alte dosi vs basse dosi

NCEP-ATP III 2001

UPDATE 2004

•4444 pts

•Pregresso Infarto del Miocardio/Angina Stabile

•Colesterolo totale medio 272+23 mg/dl (in terapia dietetica)

•Simvastatina 20 mg/die (40 mg/die 37%) vs Placebo

Riduzione LDL-C 38% nel gruppo trattato

•Follow-up: 5.6 anni-30% mortalità totale-34% mortalità per CHD

4S Scandinavian Simvastatin Survival Study

Lancet 1994

•4159 pts (M 86%)

•Pregresso Infarto del Miocardio (media 10 mesi dalla randomizzazione)

•Colesterolo totale < 240 mg/dl(in terapia dietetica)

•Colesterolo LDL tra 115 e 174 mg/dl (media 139 mg/dl)

•Pravastatina 40 mg/die vs Placebo

•Follow-up: 5 anni

•End point I: evento coronarico fatale o infarto miocardico non fatale

CARECholesterol and Recurrent Events Trial

Sacks FM et al. NEJM 1996

Mean LDL-C level reduced by 32% 97 to 98 mg/dl throughout the 5 yr FU

LIPIDThe Long-term Intervention with Pravastatin in Ischaemic Disease Study

•9014 pts (M 83%)

•Pregresso Infarto del Miocardio/Pregressa Angina Instabile (64%/36%)

•Colesterolo totale medio 218 mg/dl (in terapia dietetica)

•Colesterolo LDL tra 130 e 170 mg/dl (media 150 mg/dl)

•Pravastatina 40 mg/die vs Placebo

•Follow-up: 6.1 anni

•End point I: mortalità per evento coronarico Lipid Study Group. NEJM 1998

NCEP-ATP III Risk Categories

High RiskHigh Risk

CHD, PVD, DiabetesCHD, PVD, Diabetes2 + RF (10 yr risk > 20%)2 + RF (10 yr risk > 20%)

LDL-C goal < 100 mg/dlLDL-C goal < 100 mg/dl

Moderately High RiskModerately High Risk

2 + RF (10 yr risk 10-20%)2 + RF (10 yr risk 10-20%)

LDL-C goal < 130 mg/dlLDL-C goal < 130 mg/dl

Moderate Risk

2 + RF (10 yr risk > 10%)

LDL-C goal < 130 mg/dl

Lower Risk

0-1 RF (10 yr risk > 20%)

LDL-C goal < 160 mg/dl

JAMA 2001

(www.cuore.iss.it/valutazione/carte.asp)

NCEP-ATP III Treatment AlgorithmIn High Risk Patients

2001

LDL-C > 130

LDL-C 100-129

LDL C < 100

TLC and Statin

TLC/Statin/Fibrates/Nicotinic Acid

No LoweringTherapy

TherapeuticIndication

TherapeuticOptions

LDL-CGoal

JAMA 2001

60 100 LDL-C mg/dl

Threshold: unnecessaryThreshold: unnecessaryto go very lowto go very low

Curvilinear: the lower the betterwith diminishing returns

Linear: the lower the better

Possible Relationship between LDL-C and CHD Risk(2001)

CHDRisk

HPS Study(Heart Protection Study Investigators)

•20536 UK pts (40-80 yr)

•High Risk pts CHD, PVD, Diabetes

•Variable LDL-C at baseline (TLC)

•Simvastatin 40 mg/die vs Placebo (also vitamins arm)

•Follow-up: 5 yr

Results

•13% reduction all cause death•24% reduction major vascular events•27% reduction major coronary events•25% reduction stroke•24% reduction revascularization Lancet 2002

-27-30

-22

-50

-40

-30

-20

-10

0LDL-C >

130LDL-C100-130

LDL-C <100

% REDUCTION

P<0.00001

HPS: Reduction of Major Cardiovascular Events according to baseline LDL-C (mg/dl)

Lancet 2002

60 100

LogCVDRisk

LDL-C mg/dl

22% reduction CVD

26% reduction CVD

HPS Study: CVD Risk reductionaccording to LDL-C level

“The lower the better”

Lancet 2002

*In high-risk patients with high TG (>200 mg/dl) or low HDL-C consider fibrates/nicotinic acid

High Risk

CHD or CHD risk equivalents

ACS

LDL-

C level

100 -

160 -

130 -

190 -

Lower RiskModerately

High Risk

Target <160mg/dL

Target <130mg/dL

70 -

Target <100 mg/dL

Optionalgoal <70

mg/dL*

Moderate Risk

Target <130 mg/dL

Optionalgoal <100 mg/dL

NCEP ATP III: LDL-C Goals(2004 proposed modifications)

Grundy SM et al. Circulation 2004

Considerations and Limitations for achieving very lowLDL-C levels

•Dangers from very low LDL-C (unlikely)

•High baseline LDL-C levels (> 150 mg/dl, max drug lowering about 50%)

•Side effects of high drug doses

•10001 pts (M 81%)

•Clinically evident, stable CHD (58.5% previous myocardial infarction)

•LDL-C < 130 mg/dl (mean 98+18/97+18 mg/dl, after a 8 w open-label treatment with Atorva 10 mg/die)

•Atorvastatin 10 mg/die vs Atorvastatin 80 mg/die

•Follow-up: 4.9 yrs

•End point I: occurrence of a first major CV event (death from CHDnon fatal myocardial infarction, resuscitation after cardiac arrest, fatalor nonfatal stroke)

TNT Study(Treating to New Targets Investigators)

La Rosa JC et al. NEJM 2005

34

77mg/dl77mg/dl

101 mg/dl101 mg/dl

•8888 pts (M 81%)

•Previous Myocardial Infarction

•LDL-C < 130 mg/dl (mean 121.4+0.5/121.6+0.5 mg/dl)

•Simvastatin 20 mg/die vs Atorvastatin 80 mg/die

•Follow-up: 4.8 yrs

•End point I: occurrence of a first major CV event (death from CHDnon fatal myocardial infarction, resuscitation after cardiac arrest)

IDEAL Study(Incremental Decrease in End Points Through Aggressive Lipid Lowering)

Pedersen TR et al. JAMA 2005

…intensive lowering of LDL-C did not result in a significant reduction ofthe primary outcome of major coronary events, but did reduce the risk ofother secondary end points and nonfatal acute MI. Pts with MI may benefitfrom intensive lowering of LDL-C without an increase in non-CV mortalityor other serious adverse reaction

Adverse Events resulting in 5.8 8.1 p<.001 4.2 9.6 p<.001permanent discontinuation of study drug (%)

ALT > 3 ULN on 2 consecutive 0.2 1.2 p<.001 0.11 0.97 p<.001 measurements (%)

Myalgia (%) 4.7 4.8 p: NS 1.1 2.2 p<.001

Rhabdomyolysis (%) 0.06 0.04 p: NS 0.07 0.05 p: NS

A10 A80 S A80

TNT IDEAL

Low-density lipoprotein cholesterol (LDL-C) levels of trials comparing high-dose to standard-dose statin therapy

Cannon C. P. et al. J Am Coll Cardiol 2006

Individual trials and pooled analysis showing a highly significant 16% reduction in the risk of coronary death or any cardiovascular event (myocardial infarction, stroke,

hospitalization for unstable angina, or revascularization) (p < 0.0001)

Cannon C. P. et al. J Am Coll Cardiol 2006

Cannon C. P. et al. J Am Coll Cardiol 2006

Individual trials and pooled analysis showing a highly significant 16% reduction in the risk of coronary death or myocardial infarction (p < 0.0001)

Individual and pooled analyses showing: A) non-significant trend in reduction of cardiovascular death

B) no increased risk of non-cardiovascular mortality

C) a non-significant trend toward decreased overall mortality with high-dose statins

Cannon C. P. et al. J Am Coll Cardiol 2006

-30-31

-20

-27-25

-13

-35

-30

-25

-20

-15

-10

-5

0

4S CARE LIPID HPS TNT IDEAL

Risk reduction

High dose vs Standard doseStatin standard dose vs Placebo

Stroke Risk reduction in High Risk Patients

Prevenzione con Statine nei Soggetti ad Alto Rischio (= Prevenzione Secondaria)

•Le modificazioni “terapeutiche” dello stile di vita sono una componente essenzialedel trattamento di questi pazienti

•La riduzione del LDL-C determina un significativo beneficio in termini di mortalità e morbilità cardiovascolare

•Tanto più si riducono i valori di LDL-C tanto maggiore è il beneficio in termini di riduzione del rischio (the lower the better). In particolare la terapia con statine èragionevole anche in soggetti ad alto rischio con LDL-C < 100 mg/dl con un targetterapeutico < 70 mg/dl

•La terapia con alte dosi conferisce un significativo vantaggio se confrontata conquella a dosi standard particolarmente nella prevenzione degli eventi cardiovascolarinon fatali (ogni milione di pts trattati con alte dosi si eviterebbero 35000 eventi CV,più di 14000 morti coronariche o infarto del miocardio, con un NNT di 29 per 2 aanei pazienti con SCA, per 5 aa nei pazienti con coronaropatia stabile)

Ford ES et al. NEJM 2007;356:2388-2398

Special Article Explaining the Decrease in U.S. Deaths from Coronary Disease, 1980-2000

Approximately half the decline in U.S. deaths from coronary heart disease from 1980 through 2000may be attributable to reductions in major risk factors and approximately half to evidence-based medical therapies

Remember…….

Guidelines that are not followedare of no value !

Risk Category Goal Initiation level Consideration level forfor TLC drug therapy

High Risk <100 > 100 > 100 (optional < 70) (optional < 100)

Moderately High Risk <130 > 130 > 130 (optional < 100) (optional 100-129)

Moderate Risk < 130 > 130 > 160

Low Risk < 160 > 160 > 190(optional 160-189)

LDL-C mg/dl

Updated ATP III LDL-C Goals and Cutpoints for Therapy

Grundy SM et al. Circulation 2004