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