Estudio SHARP
1
Implicaciones en la Prevención 2ª de la
Cardiopatía Isquémica
1
José R. González Juanatey
Área Cardiovascular. Hospital Clínico Universitario de Santiago de
Compostela
J.R.G. JUANATEY
C.H.U.Santiago
Ezetimibe 2011
Cuestiones pendientes
Eficacia
Seguridad
Nefroprotección
J.R.G. JUANATEY
C.H.U.Santiago
J.R.G. JUANATEY
C.H.U.Santiago
EU, Total Cholesterol Goal
% patients in 2P Total
cholesterol >4.5 mMol/L (175
mg/dL)
EUROASPIRE III
J.R.G. JUANATEY
C.H.U.Santiago
J.R.G. JUANATEY
C.H.U.Santiago
J.R.G. JUANATEY
C.H.U.Santiago
Intima-Media Thickness of the Carotid Artery
during 24 and 14 Months of Therapy
ENHANCE-Trial
ARBITER-6 HALTS
Kastelein J et al. N Engl J Med 2008;358:1431-1443
J.R.G. JUANATEY
C.H.U.Santiago
Taylor A et al. N Engl J Med 2009;361:2113-2122
Ezetimibe
“During the trial, investigators reported an increased number of cancers and cancerrelated 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
C.H.U.Santiago
FDA Statement 22. 12. 2009
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
Eficacia
Seguridad
Nefroprotección
J.R.G. JUANATEY
C.H.U.Santiago
SHARP: Principales eventos isquémicos
25
Ratio de riesgo 0.83 (0.74 – 0.94)
Logrank 2P=0.0022
Porcentaje de eventos (%)
20
Placebo
15
Eze/simv
10
5
0
0
1
2
3
Años de seguimiento
J.R.G. JUANATEY
C.H.U.Santiago
4
5
CTT: Efectos sobre los eventos isquémicos
Reducción de riesgo relativo
de eventos isquémicos (95% CI)
30%
Estatinas vs control
(21 estudios)
Tratamiento
hipolipemiante
intensivo
vs
convencional
(5 estudios)
25%
20%
SHARP
17% de
reducción
SHARP de riesgo
15%
10%
32 mg/dL
5%
0%
0
J.R.G. JUANATEY
C.H.U.Santiago
10
20
30
Diferencia media de cLDL
entre los grupos tratados (mg/dL)
40
Intensive Lipid Lowering with Simvastatin and Ezetimibe in Aortic Stenosis
Kaplan–Meier Curves for Primary and Secondary Outcomes and Death
Death from Any cause
Placebo
Hazard ratio,
0.78
Simvastatin
plus ezetimible
P=0.02
Percentage of Patients
Percentage of Patients
Ischemic Cardiovascular Events
Simvastatin plus
ezetimible
Hazard ratio, 1.04
P=0.80
Placebo
Years in Study
Years in Study
No. at Risk
No. at Risk
Simvastatin plus
ezetimible
917
867
823
769
76
Simvastatin plus
ezetimible
930
912
884
855
89
Placebo
898
838
788
729
76
Placebo
916
890
865
835
94
J.R.G. JUANATEY
C.H.U.Santiago
Rossebo AB et al. N Engl J Med 2008;359
Meta-análisis Hipolipemiantes
Reducción Proporcional en Índice
de Enfermedades (SE)
Ez/Sim - Eficacia
Enfermedades Coronarias Mayores
50
40
Enfermedades Vasculares Mayores
50
SPARCL-A
-35
40
30
SHARP
Ez/Sm
(26.3%)
30
SPARCL-A
-20
20
20
SHARP
Ez/Sm
(16.1%)
10
10
Ictus
-16
-1.58
-1.58
0
-10
0
0,5
1,0
1,5
2,0
0,5
1,0
1,5
-10
Reducción colesterol LDL (mmol/L)
Lancet 2006, 2010
J.R.G. JUANATEY
C.H.U.Santiago
2,0
CTT: Efectos sobre los eventos isquémicos
CV Protection in CKD Pt
Reducción de riesgo relativo
de eventos isquémicos (95% CI)
30%
25%
20%
Estatinas vs control
(21 estudios)
Tratamiento
hipolipemiante
intensivo
vs
convencional
(5 estudios)
SHARP
17% de
reducción
SHARP de riesgo
15%
10%
32 mg/dL
5%
Baseline:
0%
CT 0189+45 mg/dl
10
J.R.G. JUANATEY
C.H.U.Santiago
20
30
Diferencia media de cLDL
LDL-C 108+34 mg/dl
entre los grupos tratados (mg/dL)
40
AURORA
4% de
reducción
de riesgo
Alternativas en práctica clínica
SHARP
J.R.G. JUANATEY
C.H.U.Santiago
Ezetimibe 2011
Cuestiones pendientes
Eficacia
Seguridad
Nefroprotección
J.R.G. JUANATEY
C.H.U.Santiago
Porcentaje de pacientes que desarrollan cácer (%)
SHARP: Incidencia de Cáncer
25
20
Risk ratio 0.99 (0.87 – 1.13)
Logrank 2P=0.89
15
Eze/simv
Placebo
10
5
0
0
1
2
3
Años de seguimiento
J.R.G. JUANATEY
C.H.U.Santiago
4
5
SHARP: Seguridad
Miopatía
CK >10 x y ≤40 x ULN
CK >40 x ULN
Hepatitis
Aumento continuado ALT/AST >3x ULN
Complicaciones por cálculos biliares
Otras hospitalizaciones por cálculos
biliares
Pancreatitis sin cálculos biliares
J.R.G. JUANATEY
C.H.U.Santiago
Eze/simv
Placebo
(n=4650)
(n=4620)
17 (0.4%)
4 (0.1%)
21 (0.5%)
30 (0.6%)
85 (1.8%)
21 (0.5%)
16 (0.3%)
5 (0.1%)
18 (0.4%)
26 (0.6%)
76 (1.6%)
30 (0.6%)
12 (0.3%)
17 (0.4%)
Ezetimibe
“During the trial, investigators reported an increased number of cancers and cancerrelated 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
C.H.U.Santiago
FDA Statement 22. 12. 2009
Ezetimibe 2011
Cuestiones pendientes
Eficacia
Seguridad
Nefroprotección
J.R.G. JUANATEY
C.H.U.Santiago
SHARP: Datos sobre parámetros Renales
Eventos
Evento renal principal
Estadío final de Enfermedad
Renal (ESRD)
Eventos renales secundarios
ESRD o muerte
ESRD o 2x Cr
Eze/simv
(n=3117)
Placebo
(n=3130)
1057 (33.9%)
1084 (34.6%)
0.97 (0.89-1.05)
1477 (47.4%)
1513 (48.3%)
0.97 (0.90-1.04)
1190 (38.2%)
1257 (40.2%)
0.94 (0.86-1.01)
Risk ratio & 95% CI
0.6
0.8
1.0
Eze/simv
mejor
J.R.G. JUANATEY
C.H.U.Santiago
1.2
1.4
Placebo
mejor
Alternativas en práctica clínica
SHARP
J.R.G. JUANATEY
C.H.U.Santiago
Ezetimibe 2011
Cuestiones pendientes
Eficacia
Seguridad
Nefroprotección
J.R.G. JUANATEY
C.H.U.Santiago