José R. González Juanatey
Área Cardiovascular. Hospital Clínico Universitario de Santiago de Compostela
1
1
Estudio SHARP
Implicaciones en la Prevención 2ª de la
Cardiopatía Isquémica
J.R.G. JUANATEY
Ezetimibe 2011
Cuestiones pendientes
Seguridad
Nefroprotección
Eficacia
J.R.G. JUANATEY
EU, Total Cholesterol Goal
EUROASPIRE III
% patients in 2P Total cholesterol >4.5 mMol/L (175
mg/dL)
J.R.G. JUANATEY
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
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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
Alternativas en práctica clínica
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de qué estamos pendientes…
Ezetimibe 2011
Cuestiones pendientes
Seguridad
Nefroprotección
Eficacia
J.R.G. JUANATEY
0 1 2 3 4 5
Años de seguimiento
0 5 10 15 20 25
Porcentaje de eventos (%)
Ratio de riesgo 0.83 (0.74 – 0.94) Logrank 2P=0.0022
Placebo Eze/simv
SHARP: Principales eventos isquémicos
CTT: Efectos sobre los eventos isquémicos
Reducción de riesgo relatvo de eventos isquémicos (95% CI)
0%
5%
10%
15%
20%
25%
30% Estatnas vs control
(21 estudios) Tratamiento
hipolipemiante intensivo
vs
convencional (5 estudios)
SHARP SHARP 32 mg/dL 32 mg/dL
0 10 20 30 40
Diferencia media de cLDL
SHARP 17% de reducción
de riesgo
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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
Percentage of Patients
Hazard ratio, 1.04 P=0.80
Simvastatin plus ezetimible
Placebo
Years in Study
Percentage of Patients
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
R ed u c ci ó n P ro p o rc io n a l en Í n d ic e d e E n fe rm ed ad es ( S E )
Enfermedades Coronarias Mayores Enfermedades Vasculares Mayores
Reducción colesterol LDL (mmol/L)
Meta-análisis Hipolipemiantes
Ez/Sim - Eficacia
SPARCL-A
-1.58 -35
SPARCL-A
-1.58 -20
-16 Ictus
Lancet 2006, 2010
SHARP Ez/Sm (16.1%)
SHARP Ez/Sm (26.3%)
J.R.G. JUANATEY
CTT: Efectos sobre los eventos isquémicos CV Protection in CKD Pt
Reducción de riesgo relatvo de eventos isquémicos (95% CI)
0%
5%
10%
15%
20%
25%
30% Estatnas vs control
(21 estudios) Tratamiento
hipolipemiante intensivo
vs
convencional (5 estudios)
SHARP SHARP 32 mg/dL 32 mg/dL
0 10 20 30 40
Diferencia media de cLDL entre los grupos tratados (mg/dL)
SHARP 17% de reducción
de riesgo
Baseline:
CT 189+45 mg/dl LDL-C 108+34 mg/dl
AURORA 4% de reducción
de riesgo
Alternativas en práctica clínica
SHARP
J.R.G. JUANATEY
Ezetimibe 2011
Cuestiones pendientes
Seguridad
Nefroprotección
Eficacia
SHARP: Incidencia de Cáncer
0 1 2 3 4 5
0 5 10 15 20 25
Porcentaje de pacientes que desarrollan cácer (%)
Placebo Eze/simv Risk ratio 0.99 (0.87 – 1.13)
Logrank 2P=0.89
Años de seguimiento
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SHARP: Seguridad SHARP: 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%)
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.”?
J.R.G. JUANATEY
Ezetimibe 2011
Cuestiones pendientes
Seguridad
Nefroprotección
Eficacia
Risk rato & 95% CI
Eventos Eze/simv Placebo
Eze/simv mejor
Placebo mejor (n=3130)
(n=3117)
Evento renal principal
Estadío final de Enfermedad Renal (ESRD)
1057 (33.9%) 1084 (34.6%) 0.97 (0.89-1.05)
Eventos renales secundarios
ESRD 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
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