ATC criticas+apresentaçåo cópia cópia

Universidadede São PauloFaculdade de Medicina

Instituto do Coração (InCor)

Colesterol um vilåo cujo controle depende de voces

Jose Antonio F. RamiresProfessor Titular de Cardiologia

[email protected]@yahoo.compubmed : Ramires J A

MAL 2

2 Sets of 2 Sets of LipoproteinsLipoproteins

0.950.95

1.0061.006

1.021.02

1.061.06

1.101.10

1.201.20

Den

sity

(g/

mL

)D

ensi

ty (

g/m

L)

55 1010 2020 4040 6060 8080 10001000Diameter (nm)Diameter (nm)

ApoA1ApoA1 Apo BApo B

MAL 3

Atherogenic Cholesterol LoadAtherogenic Cholesterol Load

0.950.95

1.0061.006

1.021.02

1.061.061.101.10

1.201.20

55 1010 2020 4040 6060 8080 10001000

Den

sity

(g/

ml)

Den

sity

(g/

ml)

Diameter (nm)Diameter (nm)

MAL 4

Non HDL CholesterolNon HDL Cholesterol

0.950.95

1.0061.006

1.021.02

1.061.061.101.10

1.201.20

55 1010 2020 4040 6060 8080 10001000

Den

sity

(g/

ml)

Den

sity

(g/

ml)


MAL 5

Atherogenic LipoparticlesAtherogenic Lipoparticles

0.950.95

1.0061.006

1.021.02

1.061.061.101.10

1.201.20

55 1010 2020 4040 6060 8080 10001000

Den

sity

(g/

ml)

Den

sity

(g/

ml)


Apo B100

Apo B48

MAL 6

On-Treatment LDL-C is Closely Related to CHD Events in Statin Trials

Erhardt L. Atherosclerosis 2006;185:12-20

Translating Today’s Science into Clinical Practice

(LDL≈50) (LDL≈70)

Mean Total Cholesterol (mg/dL)Mean Total Cholesterol (mg/dL)

50 70 90 110 130 150 170 190 210

Ikung ≈120Ikung ≈120

Ikung

Hazda ≈110Hazda ≈110

Hazda

Amer.Men

American men ≈ 208American men ≈ 208

Pygmy

Pygmy ≈100Pygmy ≈100

Inuit ≈140Inuit ≈140

Inuit

San ≈ 120San ≈ 120

San

ATEROSCLEROSE

METABOLISMO do METABOLISMO do COLESTEROLCOLESTEROL

• Sintese Diaria de um AdultoSintese Diaria de um Adulto800 mg

Local de Sintesefigado – 75 a 95%

Intestino – 5 a 25%

Redução do risco relativo de morte por DAC/Redução do risco relativo de morte por DAC/eventos coronarianos nos Estudos de Prevenção Primária ou eventos coronarianos nos Estudos de Prevenção Primária ou

Secundária com vastatinasSecundária com vastatinas

RED

UÇ

ÃO

RELA

TIV

A D

O R

ISC

OR

ED

UÇ

ÃO

RELA

TIV

A D

O R

ISC

O(%

)(%

)

AFCAPS/AFCAPS/TexCAPSTexCAPS++ 4S4S

Estudos independentes, não comparativos, com populações diferentes de pacientesEstudos independentes, não comparativos, com populações diferentes de pacientes

AFCAP/TEXCAPSAFCAP/TEXCAPS= Air Force/texas Coronary Atherosclerosis Prevention Study; = Air Force/texas Coronary Atherosclerosis Prevention Study; WOSCOPSWOSCOPS= West of Scotland Coronary Prevention Study; = West of Scotland Coronary Prevention Study; CARECARE= Cholesterol = Cholesterol and Recurrent Events; and Recurrent Events; HPSHPS= Heart Protection Study; = Heart Protection Study; 4S4S= Scandinavian Simvastatin Survival Study; = Scandinavian Simvastatin Survival Study; LIPIDLIPID= Long-term Intervation with Pravastatin in = Long-term Intervation with Pravastatin in Ischemic Disease; Ischemic Disease; TNTTNT= Treating to New Targets.= Treating to New Targets.++Principais eventos coronarianos; morte relacionada à DAC em todos os outros estudos.Principais eventos coronarianos; morte relacionada à DAC em todos os outros estudos.

Downs JR et al Downs JR et al JAMAJAMA 1998;279(20):1615–1622; Sheperd J et al 1998;279(20):1615–1622; Sheperd J et al N Engl J MedN Engl J Med 1995;333(20):1301–1307; Sacks FM et al 1995;333(20):1301–1307; Sacks FM et al N Engl J MedN Engl J Med 1996;335:1001–1009; 1996;335:1001–1009; Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: A Heart Protection Study Collaborative Group. MRC/BHF Heart Protection Study of cholesterol lowering with simvastatin in 20,536 high-risk individuals: A randomised placebo-controlled trial. randomised placebo-controlled trial. LancetLancet 2002;360: 7-22. 4S study group 2002;360: 7-22. 4S study group LancetLancet 1994;344:1383–1389; LIPID study group 1994;344:1383–1389; LIPID study group N Engl J MedN Engl J Med 1998;339(19):1349–1357; LaRosa JC et al. 1998;339(19):1349–1357; LaRosa JC et al. N Engl J MedN Engl J Med 2005;352:1-11. 2005;352:1-11.

WOSCOPSWOSCOPS CARECARE LIPIDLIPID00

––1010

––2020

––3030

––4040

––5050

––37%37%

––28%28%

––20%20%

––42%42%

––24%24%

PREVENÇÃO PRIMÁRIAPREVENÇÃO PRIMÁRIA PREVENÇÃO SECUNDÁRIAPREVENÇÃO SECUNDÁRIA

––22%22%

TNTTNTHPSHPS

-24%-24%

Risco moderadamente alto: 2 ou+ fatores de risco+ (risco em 10 anos 10–20%)

130 (100–129: considerar

opções farmacológicas)130

<130(opcional:

<100)

190(160–189: medicação p/ reduzir LDL-C opcional)

160<160Baixo risco: 0–1 fator de risco+

160130<130Risco moderado:2 ou + fatores de risco+ (risco em 10 anos <10%)

100100(<100(<100: considerar : considerar

opções farmacológicasopções farmacológicas))100

<100<100((opcional: opcional:

<70)<70)

Alto risco: DAC ou equivalente de risco de DAC (risco em 10 anos >20%)

NÍVEL P/ CONSIDERAR NÍVEL P/ CONSIDERAR

TRATAMENTO FARMACOLÓGICOTRATAMENTO FARMACOLÓGICO

NÍVEL P/NÍVEL P/INICIAR MEVINICIAR MEV

METAMETA

LDL-C (mg/dL)LDL-C (mg/dL)

Metas de LDL-C do ATP III revisadasMetas de LDL-C do ATP III revisadase pontos de corte para o tratamentoe pontos de corte para o tratamento

CATEGORIA DE RISCOCATEGORIA DE RISCO

++Exceto diabetes mellitusExceto diabetes mellitus

Grundy SM. Grundy SM. CirculationCirculation 2004;110:227-239 2004;110:227-239..

Eficácia na redução de LDL-C nas Eficácia na redução de LDL-C nas doses iniciaisdoses iniciais

M.H. Davidson et al. Lipid-Altering Efficacy and Safety of Ezetimibe/Simvastatin Versus Rosuvastatin Patients with Primary Hypercholesterolemia - Pôster apresentado no ISA (International Society of Atherosclerosis) em 18 de Junho de 2006, Roma, Itália. Ballantyne CM et al. Ballantyne CM et al. Am J CardiolAm J Cardiol 2004;93:1487–1494. 2004;93:1487–1494. Ballantyne CM et al. Ballantyne CM et al. Am Heart JAm Heart J 2005;149:464–473. 2005;149:464–473.

4610Rosuvastatina

50-5410/20Ezetimiba/sinvastatina

Redução % de LDL- CDoseMedicação

36-3810Atorvastatina

Goldberg RB, et al. Mayo Clin Proc. 2006;81:1579–1588.

*p<0.001 vs. rosuvastatina

A.L.Catapano, M.H. Davidson et al. Lipid-Altering Efficacy of the Ezetimibe/Simvastatin single tablet Versus Rosuvastatin in Hypercholesterolemic Patients – Curr Med Res Opin, 22 (10), 2006: 2041-2053

Doses Mínimas para Atingir Doses Mínimas para Atingir 50% 50% de Redução de LDL-Cde Redução de LDL-C

M.H. Davidson et al. Lipid-Altering Efficacy and Safety of Ezetimibe/Simvastatin Versus Rosuvastatin Patients with Primary Hypercholesterolemia - Pôster apresentado no ISA (International Society of Atherosclerosis) em 18 de Junho de 2006, Roma, Itália. Ballantyne CM et al. Ballantyne CM et al. Am J CardiolAm J Cardiol 2004;93:1487–1494. Ballantyne CM et al. 2004;93:1487–1494. Ballantyne CM et al. Am Heart JAm Heart J 2005;149:464–473. 2005;149:464–473.

5220Rosuvastatina

50-5110/20Ezetimiba/sinvastatina

Redução % de LDL- CDose (mg/dl)Medicação

51–5480Atorvastatina

Ezetimiba/Sinvastatina Reduziu Ezetimiba/Sinvastatina Reduziu

Significativamente o LDL-C em toda a Faixa PosológicaSignificativamente o LDL-C em toda a Faixa Posológica

0

–50

–55

–45

–65

–60

–51.5%*

–45.8%

–54.8%**–52.3%

–61%*

–56.7%

*p<0.001 **p<0.01AA.L.Catapano, M.H. Davidson et al. Lipid-Altering Efficacy of the Ezetimibe/Simvastatin single tablet Versus Rosuvastatin in Hypercholesterolemic Patients – Curr Med Res Opin, 22 (10), 2006: 2041-2053

Eze/Sinva10/40 mg

(n=477)

Rosuva20 mg(n=478)

Eze/Sinva 10/20 mg

(n=476)

Rosuva10 mg(n=475)

Eze/Sinva 10/80 mg

(n=474)

Rosuva40 mg(n=475)

–55.8%*

–51.6%

Eze/Sinva 10/20 a

10/80 mg(n=1.427)

Rosuva 10 a 40 mg

(n=1428)

Alt

eraç

ão %

méd

ia n

a 6a

. Sem

ana

a

par

tir

do

per

íod

o b

asal

Ezetimiba/SinvastatinaRosuvastatina

Doses agrupadas

81.9%

88.2%*

Mais Pacientes Atingiram a Meta de Mais Pacientes Atingiram a Meta de LDL <100 mg/dL com Ezetimiba/SinvastatinaLDL <100 mg/dL com Ezetimiba/Sinvastatina

*p<0.001 vs. rosuvastatina A.L.Catapano, M.H. Davidson et al. Lipid-Altering Efficacy of the Ezetimibe/Simvastatin single tablet Versus Rosuvastatin in Hypercholesterolemic Patients – Curr Med Res Opin, 22 (10), 2006: 2041-2053

% p

acie

ntes

na

met

a na

6a.

se

man

a

95

85

80

75

70

LDL-C alvo <100 mg/dL0

Ezetimiba/Sinvastatina 10/20–10/80 mg (n=1.427)Rosuvastatina 10–40 mg (n=1.428)

90

29.5%

43.5%*

Mais Pacientes Atingiram a Meta de LDL Mais Pacientes Atingiram a Meta de LDL <70 mg/dL com Ezetimiba/Sinvastatina<70 mg/dL com Ezetimiba/Sinvastatina

*p<0.001 vs. rosuvastatina A.L.Catapano, M.H. Davidson et al. Lipid-Altering Efficacy of the Ezetimibe/Simvastatin single tablet Versus Rosuvastatin in Hypercholesterolemic Patients – Curr Med Res Opin, 22 (10), 2006: 2041-2053

% p

acie

ntes

na

met

a na

6a.

se

man

a

55

45

35

30

20

LDL-C alvo <70 mg/dL0


40

25

50

Ezetimiba/Sinvastatina Melhorou Outros Parâmetros LipídicosEzetimiba/Sinvastatina Melhorou Outros Parâmetros LipídicosA

lter

ação

% m

édia

+ n

a 6a

. sem

ana

a

par

tir

do

per

íod

o b

asal

10

–30

–20

HDL-C

CT

–40%++

–40


0TG

–50

–36.7%

–26.2%++–24.6%

7.6% 7.6%

–25

–35

–45

–45.3%++

–42.3%

–51.3%++

–47.2%

–55

Apo BColesterol não–HDL

+Exceto para os TGs (alterações porcentuais medianas); ++p<0.001 vs. rosuvastatina A.L.Catapano, M.H. Davidson et al. Lipid-Altering Efficacy of the Ezetimibe/Simvastatin single tablet Versus Rosuvastatin in Hypercholesterolemic Patients – Curr Med Res Opin, 22 (10), 2006: 2041-2053

Reduction in Triglyceridesp<0.001

Presented at ACC Scientific Sessions 2004Presented at ACC Scientific Sessions 2004

EASE TrialEASE Trial•A large proportion of patients in the trial had diabetes (38.4%) and metabolic syndrome by NCEP ATP III criteria (60%).

•Baseline LDL levels were 129 mg/dl in the overall population, 123 mg/dl in the coronary heart disease (CHD) or CHD risk equivalent group, 147 mg/dl in the multiple risk factors group, and 167 mg/dl in the <2 risk factors group.

•The ezetimibe arm had a larger reduction in triglycerides and a larger increase in high-density lipoprotein (HDL) levels.

Ezetimibe Placebo

mg/

dl

Increase inHigh-Density Lipoprotein

(HDL)p<0.001

Ezetimibe Placebo

Reduction in LDLp<0.001


EASE TrialEASE Trial•In the overall study population, a larger percent change from baseline in LDL levels occurred in the ezetimibe arm versus placebo.

•The follow-up LDL level in the ezetimibe arm was 95 mg/dl.

•A larger percentage of patients in the ezetimibe arm reached target LDL goals.

•Results were similar across the different statin brands and by the prespecified subgroups of age group, gender, and diabetes status.

Ezetimibe Placebo

Reached Target LDL Goals

p<0.001

mg/

dl

Ezetimibe Placebo

Reduction in LDLp<0.001


EASE TrialEASE TrialReached Target LDL Goals

p<0.001

mg/

dl

•Similar results were observed in the CHD/CHD risk equivalent subgroup, the multiple risk factor subgroup, and the <2 CHD risk factor subgroup.

•There were no increases in the frequency of alanine aminotransferase (ALT) ≥3 times upper limit of normal (ULN) (0.4% for ezetimibe vs. 0.2% for placebo), aspartate aminotransferase (AST) ≥3 times ULN (0.2% vs. 0.1%), or creatine kinase (CK) ≥10 times ULN (0 in both groups).

CHD/CHD Equivalent

Multiple Risk Factor

<2 CHD Risk Factor

CHD/CHD Equivalent

Multiple Risk Factor

<2 CHD Risk Factor

EFEITO do EZETIMIBE + SINVASTATINA EFEITO do EZETIMIBE + SINVASTATINA sobre o ST em Pacientes com DAC e sobre o ST em Pacientes com DAC e

HipercolesterolemiaHipercolesterolemia

0

10

20

30

40

50

60

70

80

90

100

Dieta Sinva+Ezet

Basal

8 sem.

16 sem.

% de redução do infra SST

*

**

*,** =p<0.02

20 10

n 39 41 Ramires JAF,... Mansur AP , 2007

Extenso Programa de Desfechos Clínicos envolvendo mais de 21.000 Pacientes Extenso Programa de Desfechos Clínicos envolvendo mais de 21.000 Pacientes de Alto Risco de Eventos Cardiovascularesde Alto Risco de Eventos Cardiovasculares

N População de estudo Medicamentos Desfecho primário

~725 HFhe Ezetimiba/sinvastatina 10/80 mgSinvastatina 80 mg

Espessura da íntima-média da carótida

~1873 Estenose aórtica assintomática com LDL-C

<230 mg/dl

Ezetimiba/sinvastatina 10/40 mgPlacebo

Morte CV, cirurgia aórtica, desfechos cardiovasculares

~9000 Doença renal crônica Ezetimiba/sinvastatina 10/20 mgPlacebo

Desfechos CVs (IM, AVC, revascularização coronária)

~10,000 Síndrome Coronariana Aguda

Ezetimiba/sinvastatina 10/40 mgSinvastatina 40 mg

Desfechos CVs (morte, IM, SCA, revascularização)

Adaptado de Kastelein JJP, et al. Am Heart J. 2005;149:234–239; Baigent C, Landry M. Kidney Int. 2003;63(suppl 84):S207–S210; Oxford Clinical Trial Service Unit. The Study of Heart and Renal Protection (SHARP). Disponível em: http://www.ctsu.ox.ac.uk/ ~sharp/. Acessado em juho de 2005; Rossebo A, et al, for the SEAS Steering Committee. Apresentado no XIII International Symposium on Atherosclerosis em 23 de setembro a 2 de outubro de 2003, em Kyoto, Japão. Poster 3P-0870; Schering-Plough. IMPROVE-IT: Examining outcomes in subjects with acute coronary syndrome: Vytorin (ezetimiba/sinvastatina) vs sinvastatina (Estudo P04103). Disponível em: http://www.clinicaltrials.gov/ct/show/NCT00202878. Acessado em novembro de 2006.

MAL 26

Kwiterovich P. Am J Cardiol 2000;86:5-10

Lipoprotein Metabolism Consists of 2 Interconnected Cascades

ApoB 48

ApoB 100

MAL 27

Two Types of Lipoproteins are Atherogenic in Two Types of Lipoproteins are Atherogenic in HumansHumans

B48B100

CE TG

TGCE

Apo B100 containing LDL

Apo B100 containing LDL

Apo B48 containing Chylomicron Remnants

Apo B48 containing Chylomicron Remnants

Apolipoprotein B fragmentsApolipoprotein B fragments

Cholesteryl esterCholesteryl ester

TG

Hepatic Intestinal

MAL 28

Oram J. Trends in Molecular Medicine 2002;8:168-173

Catabolism

Apo A1Apo A1

Lipid Removal

Peripheral Tissue

Processing LCATMaturatio

n

Model for the Major Steps in Reverse Cholesterol Transport

MAL 29

HDL Metabolism HDL Metabolism

and Reverse Cholesterol and Reverse Cholesterol

TransportTransport

Rader D. Curr Athero Reports 2004;6:398-405

MAL 30

Cholesterol and Isoprenoid Biosynthesis Network

Schmitz G. Vascular Pharmacology 2006;44:75-89

MAL 31

Major Pathways in the Absorption and Intracellular Traffic of Cholesterol and Plant Sterols in the Mucosa Cell

Von Bergmann K. Am J Cardiol 2005;96(suppl): 10D-14D

MAL 32

Intestinal Cholesterol Absorption is a Multistep Process that is Regulated by Multiple Genes

Sterol Influx Transporter

Lammert F. Gastroenterology 2005;129:718-734

Lumen Enterocyte Lymph

MAL 33

Universidadede São PauloFaculdade de Medicina

Instituto do Coração (InCor)

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