j.r.g. juanatey c.h.u.santiago josé r. gonzález juanatey Área cardiovascular. hospital clínico...

J.R.G. JUANATEY C.H.U.Santiago

José R. González JuanateyÁrea Cardiovascular. Hospital Clínico Universitario de

Santiago de Compostela

1

1

Estudio SHARPImplicaciones en la Prevención 2ª de la

Cardiopatía Isquémica

J.R.G. JUANATEY C.H.U.Santiago

Ezetimibe 2011

Cuestiones pendientes

Seguridad

Nefroprotección

Eficacia

J.R.G. JUANATEY C.H.U.Santiago

J.R.G. JUANATEY C.H.U.Santiago

EU, Total Cholesterol Goal

EUROASPIRE III

% patients in 2P Total cholesterol >4.5 mMol/L (175

mg/dL)

J.R.G. JUANATEY C.H.U.Santiago

J.R.G. JUANATEY C.H.U.Santiago

J.R.G. JUANATEY C.H.U.Santiago

Kastelein J et al. N Engl J Med 2008;358:1431-1443 Taylor A et al. N Engl J Med 2009;361:2113-2122

Intima-Media Thickness of the Carotid Artery during 24 and 14 Months of Therapy

ENHANCE-Trial

ARBITER-6 HALTS

J.R.G. JUANATEY C.H.U.Santiago

Ezetimibe

“During the trial, investigators reported an increased number of cancers and cancer-related deaths in patients using Vytorin compared to placebo. Cancer was reported in 105 patients (11.1%) in the Vytorin group and in 70 patients (7.5%) in the placebo group. The number of deaths from cancer was also higher in the Vytorin group, with 39 deaths compared to 23 deaths in the placebo group.

A large body of long-term clinical data indicates that simvastatin is not associated with an increased risk of cancer, but long-term clinical data on ezetimibe is insufficient to definitely rule out a cancer risk at this time.”

FDA Statement 22. 12. 2009

J.R.G. JUANATEY C.H.U.Santiago

Alternativas en práctica clínica

J.R.G. JUANATEY C.H.U.Santiago

de qué estamos pendientes…

J.R.G. JUANATEY C.H.U.Santiago

Ezetimibe 2011

Cuestiones pendientes

Seguridad

Nefroprotección

Eficacia

J.R.G. JUANATEY C.H.U.Santiago

0 1 2 3 4 5 Años de seguimiento

0

5

10

15

20

25

Porc

enta

je d

e ev

ento

s (%

)

Ratio de riesgo 0.83 (0.74 – 0.94) Logrank 2P=0.0022

Placebo

Eze/simv

SHARP: Principales eventos isquémicos

J.R.G. JUANATEY C.H.U.Santiago

CTT: Efectos sobre los eventos isquémicos

Redu

cció

n de

ries

go re

lativ

ode

eve

ntos

isqu

émic

os (9

5% C

I)

0%

5%

10%

15%

20%

25%

30% Estatinas vs control(21 estudios)

Tratamientohipolipemiante

intensivovs

convencional(5 estudios)

SHARPSHARP32 mg/dL32 mg/dL

0 20 4010 30Diferencia media de cLDL

entre los grupos tratados (mg/dL)

SHARP17% de

reducción de riesgo

J.R.G. JUANATEY C.H.U.Santiago

Intensive Lipid Lowering with Simvastatin and Ezetimibe in Aortic Stenosis

Rossebo AB et al. N Engl J Med 2008;359

Kaplan–Meier Curves for Primary and Secondary Outcomes and Death

Ischemic Cardiovascular Events Death from Any cause

Hazard ratio, 0.78

P=0.02

Simvastatin plus ezetimible

Placebo

Years in Study

Per

cen

tag

e o

f P

atie

nts

Hazard ratio, 1.04

P=0.80

Simvastatin plus ezetimible

Placebo

Years in Study

Per

cen

tag

e o

f P

atie

nts

No. at Risk

Simvastatin plus ezetimible

917 867 823 769 76

Placebo 898 838 788 729 76

No. at Risk

Simvastatin plus ezetimible

930 912 884 855 89

Placebo 916 890 865 835 94

J.R.G. JUANATEY C.H.U.Santiago

-10

0

10

20

30

40

50

0,5 1,0 1,5 2,0

-10

0

10

20

30

40

50

0,5 1,0 1,5 2,0

Red

ucc

ión

Pro

po

rcio

nal

en

Ín

dic

e d

e E

nfe

rmed

ades

(S

E)

Enfermedades Coronarias Mayores Enfermedades Vasculares Mayores

Reducción colesterol LDL (mmol/L)

Meta-análisis HipolipemiantesEz/Sim - Eficacia

SPARCL-A

-1.58

-35

SPARCL-A

-1.58

-20

-16Ictus

Lancet 2006, 2010

SHARP Ez/Sm (16.1%)

SHARP Ez/Sm (26.3%)

J.R.G. JUANATEY C.H.U.Santiago

CTT: Efectos sobre los eventos isquémicos CV Protection in CKD Pt

Redu

cció

n de

ries

go re

lativ

ode

eve

ntos

isqu

émic

os (9

5% C

I)

0%

5%

10%

15%

20%

25%

30% Estatinas vs control(21 estudios)

Tratamientohipolipemiante

intensivovs

convencional(5 estudios)

SHARPSHARP32 mg/dL32 mg/dL

0 20 4010 30Diferencia media de cLDL

entre los grupos tratados (mg/dL)

SHARP17% de

reducción de riesgo

Baseline:

CT 189+45 mg/dl

LDL-C 108+34 mg/dl

AURORA4% de

reducción de riesgo

J.R.G. JUANATEY C.H.U.Santiago

Alternativas en práctica clínica

SHARP

J.R.G. JUANATEY C.H.U.Santiago

Ezetimibe 2011

Cuestiones pendientes

Seguridad

Nefroprotección

Eficacia

J.R.G. JUANATEY C.H.U.Santiago

SHARP: Incidencia de Cáncer

0 1 2 3 4 5 0

5

10

15

20

25

Porc

enta

je d

e pa

cien

tes

que

desa

rrol

lan

cáce

r (%

)

Placebo Eze/simv

Risk ratio 0.99 (0.87 – 1.13) Logrank 2P=0.89

Años de seguimiento

J.R.G. JUANATEY C.H.U.Santiago

SHARP: SeguridadSHARP: Seguridad

Eze/simv(n=4650)

Placebo(n=4620)

Miopatía

CK >10 x y ≤40 x ULN 17 (0.4%) 16 (0.3%)

CK >40 x ULN 4 (0.1%) 5 (0.1%)

Hepatitis 21 (0.5%) 18 (0.4%)

Aumento continuado ALT/AST >3x ULN 30 (0.6%) 26 (0.6%)

Complicaciones por cálculos biliares 85 (1.8%) 76 (1.6%)

Otras hospitalizaciones por cálculos biliares

21 (0.5%) 30 (0.6%)

Pancreatitis sin cálculos biliares 12 (0.3%) 17 (0.4%)

J.R.G. JUANATEY C.H.U.Santiago

Ezetimibe

“During the trial, investigators reported an increased number of cancers and cancer-related deaths in patients using Vytorin compared to placebo. Cancer was reported in 105 patients (11.1%) in the Vytorin group and in 70 patients (7.5%) in the placebo group. The number of deaths from cancer was also higher in the Vytorin group, with 39 deaths compared to 23 deaths in the placebo group.

A large body of long-term clinical data indicates that simvastatin is not associated with an increased risk of cancer, but long-term clinical data on ezetimibe is insufficient to definitely rule out a cancer risk at this time.”?

FDA Statement 22. 12. 2009

J.R.G. JUANATEY C.H.U.Santiago

Ezetimibe 2011

Cuestiones pendientes

Seguridad

Nefroprotección

Eficacia

J.R.G. JUANATEY C.H.U.Santiago

Risk ratio & 95% CIEventos PlaceboEze/simv

Eze/simvmejor

Placebomejor

(n=3130)(n=3117)

Evento renal principalEstadío final de Enfermedad Renal (ESRD)

1057 (33.9%) 1084 (34.6%) 0.97 (0.89-1.05)

Eventos renales secundariosESRD o muerte 1477 (47.4%) 1513 (48.3%) 0.97 (0.90-1.04)

ESRD o 2x Cr 1190 (38.2%) 1257 (40.2%) 0.94 (0.86-1.01)

0.6 0.8 1.0 1.2 1.4

SHARP: Datos sobre parámetros Renales

J.R.G. JUANATEY C.H.U.Santiago

Alternativas en práctica clínica

SHARP

J.R.G. JUANATEY C.H.U.Santiago

Ezetimibe 2011

Cuestiones pendientes

Seguridad

Nefroprotección

Eficacia