novedades en tratamiento hipolipemiante · novedades en tratamiento hipolipemiante miguel Ángel...
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NOVEDADES EN TRATAMIENTO
HIPOLIPEMIANTE
Miguel Ángel Cobos Gil. H Clínico San Carlos. Madrid
• Sharlayne Tracy
• 40 años.
• Reside en Dallas con
sus dos hijos
• Instructora de aerobic,
estudia empresariales
• Sin patología relevante
• Sharlayne Tracy
• 40 años.
• Reside en Dallas con sus dos
hijos
• Instructora de aerobic, estudia
empresariales
• Sin patología relevante
• Col LDL de 14
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5
LDL Receptor Function
and Life Cycle
LDL=low-density lipoprotein; LDLR=LDL receptor; SREBP2=sterol regulatory element-binding protein-2.Source: Semenkovich CF et al. In: Williams Textbook of Endocrinology. 12th ed. Philadelphia, PA: Elsevier Saunders; 2011:1633-1674.
8
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The Role of PCSK9 in the Regulation of
LDL Receptor Expression
LDL=low-density lipoprotein; LDLR=LDL receptor; PCSK9=proprotein convertase subtilisin/kexin type 9; SREBP2=sterol regulatory element-binding protein-2. Source: Lambert G et al. J Lipid Res. 2012;53:2515–2524.
9
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Impact of PCSK9 inhibition
on LDL Receptor Expression
LDL=low-density lipoprotein; LDLR=LDL receptor; PCSK9=proprotein convertase subtilisin/kexin type 9; SREBP2=sterol regulatory element-binding protein-2. Source: Catapano AL and Papadopoulos N. Atherosclerosis. 2013;228(1):18-28.
1
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LDL-CLDLR
proteinPCSK9
LDL-CLDLR
proteinPCSK9 X
PCSK9 Promotes Degradation of LDLRs
LDL-C=low-density lipoprotein cholesterol; LDLR=low-density lipoprotein receptor.
10
LDL-CLDLR
proteinPCSK9
LDL-CLDLR
proteinPCSK9 X
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The Statin Decade:For LDL: “Lower is Better”
0
5
10
15
20
25
30R² = 0.9029p < 0.0001
LDL Cholesterol (mg/dl)
CH
D E
ven
ts (
%)
Adapted and Updated from O’Keefe, J. et al., J Am Coll Cardiol 2004;43:2142-6.
30 50 70 90 110 130 150 170 190 210
4S
CARE
LIPID
HPS
PROVE IT –TIMI 22
TNT
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Control de la concentración de c-LDL
0
20
40
60
80
100
TotalCoronario
DiabéticoMixto
86,07 88,4 8781,06
cLDL > 70…
Po
rce
nta
je(%
)
Grupos de pacientes
Pérez de Isla L, et al. Rev Clin Esp. 2012;212(10):475-81.
The Statin Decade:
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EUROASPIRE IV: A ESC survey on the lifestyle, risk factor and
therapeutic management of coronary patients from 24
European countries
European Journal of Preventive Cardiology 2015
DOI: 10.1177/2047487315569401
Proportions (%) at low-density lipoprotein cholesterol target
80%
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C-LDL y modificaciones lipídicas
1 Yr Mean LDL-C TC TG HDL hsCRP
Simva 69.9 145.1 137.1 48.1 3.8
EZ/Simva 53.2 125.8 120.4 48.7 3.3
Δ in mg/dL -16.7 -19.3 -16.7 +0.6 -0.5
Median Time avg
69.5 vs. 53.7 mg/dL
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Endpoint primario — ITT
Simva — 34.7%
2742 events
EZ/Simva — 32.7%
2572 events
HR 0.936 CI (0.887, 0.988)
p=0.016
Muerte cardiovascular, IMA, Angina inestable que requiere
hospitalización, revascularización coronaria (≥30 días), o ictus
7-year event rates
NNT= 50
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Hasta el infinito y más allá
Hasta el infinito y más allá
Hasta el infinito y más allá
Hasta el infinito y más allá
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Study Design: Observational Study
Intervention: N/A
Length of Study: 12 years
# of Participants: 225,000
# of Countries: 25
El futuro ha empezado
The Statin Decade:For LDL: “Lower is Better”
0
5
10
15
20
25
30R² = 0.9029p < 0.0001
LDL Cholesterol (mg/dl)
CH
D E
ven
ts (
%)
30 50 70 90 110 130 150 170 190 210
4S
CARE
LIPID
HPS
PROVE IT –TIMI 22
IMPROVE IT6652
TNT
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Cuanto antes mejor
Conclusiones
GRACIAS
GRACIAS
The Statin Decade:For LDL: “Lower is Better”
0
5
10
15
20
25
30R² = 0.9029p < 0.0001
LDL Cholesterol (mg/dl)
CH
D E
ven
ts (
%)
Adapted and Updated from O’Keefe, J. et al., J Am Coll Cardiol 2004;43:2142-6.
30 50 70 90 110 130 150 170 190 210
4S
CARE
LIPID
HPS
PROVE IT –TIMI 22
TNT
Recent Coronary IVUS Progression Trials
-1.2
-0.6
0
0.6
1.2
1.8
50 60 70 80 90 100 110 120
MedianChange
In PercentAtheroma
Volume(%)
Mean Low-Density Lipoprotein Cholesterol (mg/dL)
REVERSALpravastatin
REVERSALatorvastatin
CAMELOTplacebo
A-Plusplacebo
ACTIVATEplacebo
Relationship between LDL-C and Progression Rate
ASTEROIDrosuvastatin
r2= 0.95p<0.001
Nissen S. JAMA 2006
Regresión
Progresión
Control de la concentración de c-LDL
0
20
40
60
80
100
TotalCoronario
DiabéticoMixto
86,07 88,4 8781,06
cLDL > 70…
Po
rce
nta
je(%
)
Grupos de pacientes
Pérez de Isla L, et al. Rev Clin Esp. 2012;212(10):475-81.
The Statin Decade:
EUROASPIRE IV: A ESC survey on the lifestyle, risk factor and
therapeutic management of coronary patients from 24
European countries
European Journal of Preventive Cardiology 2015
DOI: 10.1177/2047487315569401
Proportions (%) at low-density lipoprotein cholesterol target
80%
• Potencia limitado de las estatinas.
• Ningún fármaco añadido a las estatinas ha demostrado
impacto sobre eventos cv.
• Dudas sobre la seguridad. Problemas de tolerancia
• Los pacientes siguen en riesgo.
The Statin Decade:
80%
Now this is not the end, it
is not even the beginning
of the end. But it is,
perhaps, the end of the
beginning.
2014…..
Ezetimibe: Background
➢ Ezetimibe inhibits Niemann-Pick C1-like 1 (NPC1L1)
protein
– located primarily on the epithelial brush border of
the GI tract
– resulting in reduced cholesterol absorption
➢ When added to statin, produces ~20% further
reduction in LDL-C
C-LDL y modificaciones lipídicas
1 Yr Mean LDL-C TC TG HDL hsCRP
Simva 69.9 145.1 137.1 48.1 3.8
EZ/Simva 53.2 125.8 120.4 48.7 3.3
Δ in mg/dL -16.7 -19.3 -16.7 +0.6 -0.5
Median Time avg
69.5 vs. 53.7 mg/dL
Endpoint primario — ITT
Simva — 34.7%
2742 events
EZ/Simva — 32.7%
2572 events
HR 0.936 CI (0.887, 0.988)
p=0.016
Muerte cardiovascular, IMA, Angina inestable que requiere
hospitalización, revascularización coronaria (≥30 días), o ictus
7-year event rates
NNT= 50
The Statin Decade:For LDL: “Lower is Better”
0
5
10
15
20
25
30R² = 0.9029p < 0.0001
LDL Cholesterol (mg/dl)
CH
D E
ven
ts (
%)
Adapted and Updated from O’Keefe, J. et al., J Am Coll Cardiol 2004;43:2142-6.
30 50 70 90 110 130 150 170 190 210
4S
CARE
LIPID
HPS
PROVE IT –TIMI 22
IMPROVE IT6652
TNT
Reduction of LDL-C to <50mg/dL reduces CV risk by 10% vs ≥50mg/dL
Giugliano et al. Presented at the European Society of Cardiology, London, 2015 (preliminary data).
-0.6
-0.7
-1.1
-0.8
-0.9
-1.0
0 25 50 75 100 125 150
Od
ds o
f th
e p
rim
ary
en
dp
oin
t
(log s
cale
)
Achieved LDL-C on study drug (mg/dL) at Month 1
Adjusted HR 0.90 (0.85–0.96)
P=0.002
50mg/dL
(2.3mmol/L)
Primer estudio que demuestra un beneficio adicional cuando se añade un fármaco no estatínico (ezetimiba) al tratamiento con estatina:
SI: Reducción de C-LDL con tratamiento no-estatina EZETIMIBA reduce los eventos CV
SI: Incluso el C-LDL cuanto más bajo mejorC- LDL 53 vs. 70 mg/dL a 1 año
SI: Confirma el perfil de seguridad de Ezetimiba
- Reafirma la hipótesis del C-LDL, reduciendolo se previenen eventoscardiovasculares
Conclusiones
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54
The Heart Outcomes Prevention Evaluation
(HOPE) – 3 Trial
Eva Lonn, Jackie Bosch, Salim Yusuf
For the HOPE-3 Investigators
Population Health Research Institute, (PHRI)
McMaster University and Hamilton Health Sciences,
Hamilton, Canada
Unique Aspects of Cholesterol Lowering Arm
• No entry criteria based on lipid level. No CVD
• No routine monitoring
• No dose titration
• Low dose of rosuvastatin
CV Death, MI, Stroke, Cardiac Arrest, Revasc, Heart Failure
Years
Cu
mu
lati
ve H
azard
Ra
tes
0.0
0.0
20
.04
0.0
60
.08
0.1
0
0 1 2 3 4 5 6 7
Placebo
Rosuvastatin
HR (95% CI) = 0.75 (0.64-0.88)
P-value = 0.0004
6361 6241 6039 2122
6344 6192 5970 2073
Rosuva
Placebo23
Cholesterol Lowering: Conclusions
• Rosuvastatin 10mg/day reduced:
– LDL-C by 34.6 mg/dl (0.9 mmol/l; i.e. 27% in LDL-C)
– CVD by 25%
• Consistent benefits regardless of:
– LDL-C
– SBP
– Risk
– CRP
– Ethnicity
• Excess in muscle pain/weakness (reversible) and
perhaps cataract surgery
• No excess in rhabdomyolysis, myopathy or new diabetes27
Interpretation of the evidence for the efficacy and safety of statin therapy
Rory Collins, Christina Reith, Jonathan Emberson, Jane Armitage, Colin Baigent, Lisa Blackwell, Roger Blumenthal, John Danesh, George Davey Smith, David DeMets, Stephen Evans, Malcolm Law, Stephen MacMahon, Seth Martin, Bruce Neal, Neil Poulter, David Preiss, Paul Ridker, Ian Roberts, Anthony Rodgers, Peter Sandercock, Kenneth Schulz, Peter Sever, John Simes, Liam Smeeth, Nicholas Wald, Salim Yusuf, Richard Peto
Published Online: 08 September 2016
Probable excepción de Pitavastatina
10,9
14,9
18,2
5,1
0
10
20
Pravastatin Atorvastatin Simvastatin Fluvastatin
PA
TIE
NT
S W
ITH
MU
SC
UL
AR
S
YM
PT
OM
S (
%)
Trial details1 Myalgia1
Trial Total No. Agent Dose, mg Duration, yr Statin Placebo
4S 4,444 Simvastatin 20–40 5.4 3.7% 3.2%
WOSCOPS 6,595Pravastatin 40
4.9 3.5% 3.7%
PROSPER 5,804 3.2 1.2% 1.1%
CARDS 2,838
Atorvastatin10
3.9 4.0% 4.8%
ASPEN 2,410 4.0 3.0% 1.6%
SPARCL 4,731 80 4.9 5.5% 6.0%
JUPITER 17,802 Rosuvastatin 20 1.9 7.9% 6.9%
Statin intolerance may be less common than the
5–18% suggested by observational data
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65
LDLR
PCSK9
3. C-terminus2. Prodomain1. Catalytic
domain
PCSK9
• A serine proprotein convertase1
• Expressed in hepatocytes,
kidney mesenchymal cells,
intestinal ileum and colon
epithelia, CNS2
• Regulates hepatic LDLRs, which
bind and internalise LDL
particles3
1. Abifadel et al. Hum Mutat 2009;30:520–529.
2. Seidah et al. Proc Natl Acad Sci USA 2003;100:928–933.
3. Horton et al. J Lipid Res 2009;50:S172–S177.
1
2
3
LDL Receptor Function
and Life Cycle
LDL=low-density lipoprotein; LDLR=LDL receptor; SREBP2=sterol regulatory element-binding protein-2.Source: Semenkovich CF et al. In: Williams Textbook of Endocrinology. 12th ed. Philadelphia, PA: Elsevier Saunders; 2011:1633-1674.
8
The Role of PCSK9 in the Regulation of
LDL Receptor Expression
LDL=low-density lipoprotein; LDLR=LDL receptor; PCSK9=proprotein convertase subtilisin/kexin type 9; SREBP2=sterol regulatory element-binding protein-2. Source: Lambert G et al. J Lipid Res. 2012;53:2515–2524.
9
Impact of Alirocumab
on LDL Receptor Expression
LDL=low-density lipoprotein; LDLR=LDL receptor; PCSK9=proprotein convertase subtilisin/kexin type 9; SREBP2=sterol regulatory element-binding protein-2. Source: Catapano AL and Papadopoulos N. Atherosclerosis. 2013;228(1):18-28.
1
LDL-CLDLR
proteinPCSK9
LDL-CLDLR
proteinPCSK9 X
PCSK9 Promotes Degradation of LDLRs
LDL-C=low-density lipoprotein cholesterol; LDLR=low-density lipoprotein receptor.
1
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72
Loss-of-Function PCSK9 Mutations in AA Are Associated
with Low LDL-C and Low Prevalence of CHD Events
Adapted from Cohen JC. N Engl J Med 2006;354:1264-72 ARIC=Atherosclerosis Risk in the Community
30
20
10
09.7%
PCSK9142x or PCSK9679X
No Yes
12
8
4
0
0 50 100 150 200 250 300
30
20
10
00 50 100 150 200 250 300
No Nonsense Mutation
(N = 3278)50th Percentile
Plasma LDL Cholesterol in Black Subjects (mg/dL)
Fre
qu
en
cy (
%)
1.2%
PCSK9142x or PCSK9679X
(N=85)
Co
ron
ary
He
art
Dis
ea
se
(%
)
Mean 138 mg/dL
Mean 100 mg/dL
(-28%)
Reduction in the risk of
CHD events during 15-
year follow-up
RRR 88%
LDL-C reductions were maintained over 1 year
Sabatine et al. N Engl J Med 2015;372:1500–1509.
LD
L–
C (
mg/d
L)
Standard therapy
Weeks
Evolocumab
Baseline
1,219
2,508 n =394
864
Standard therapy
Evolocumab
– LDL-C ↓ from baseline maintained with alirocumab:
• significantly greater ↓ vs PBO in COMBO I (48% vs 2% placebo; P<0.0001)
• significantly greater ↓ vs ezetimibe in COMBO II at week 24 (51% vs 21% with ezetimibe;
P<0.0001)
– Mean achieved LDL-C levels of 53.3 mg/dL in COMBO I and 53.3 mg/dL in COMBO II at
week 52 with alirocumab
– Consistent effects of alirocumab vs comparator through 52 weeks
Consistent LDL-C Reductions Over 52 Weeks
24
COMBO I COMBO II
Evolocumab is not associated with adverse CV events
60 adjudicated events of death, MI, unstable angina requiring
hospitalisation, heart failure requiring hospitalisation or coronary
revascularisation, stroke or transient ischaemic attack
0 30 60 90 120 150 180 210 240 270 300 330 365
Days since randomisation
0
1
2
HR 0.47
95% CI 0.28–0.78
P=0.003
Evolocumab plus standard of
care (n=2,976)
Standard of care alone
(n=1,489)
0.95%
2.18%
3
Cum
ula
tive C
V e
vent
incid
ence (
%)
Sabatine et al. N Engl J Med 2015;372:1500–1509.
*Based on primary endpoint for the ODYSSEY OUTCOMES trial, including CHD death, non-fatal MI, fatal and non-fatal
ischemic stroke, and unstable angina requiring hospitalization.
Unstable angina requiring hospitalization was considered based on strict criteria / clear progression of ischemia.
Post hoc Analysis of Adjudicated
Major Adverse Cardiovascular Events*
Placebo + maximally
tolerated statin ±
Alirocumab + maximally
tolerated statin ±
Cu
mu
lati
ve
pro
bab
ilit
y o
f e
ve
nt
Time (weeks)
Cox model analysis
HR = 0.52 (95% CI 0.31 to 0.90)
Nominal p-value = 0.02
No. at riskPlacebo
Alirocumab
788 776 731 700 670 653 644 597
1550 1533 1445 1392 1342 1306 12661170
1.0
0.8
0.6
0.4
0.2
0.0
0 12 24 36 52 64 78 86
0.06
0.04
0.02
0.00
0 12 24 36 52 64 7886
J. Robinson et al., N Engl J Med 2015;372(16):1489-1499
RECOMENDACIONES USO Inhibidores PCSK9SEC
DOCUMENTO SEC 2016. NECESIDADES NO CUBIERTAS CON EL TRATAMIENTO HIPOLIPEMIANTE:
IDENTIFICACIÓN DE PACIENTES PRIORITARIOS EN EL ÁMBITO DE LA ENFERMEDAD CORONARIA
….los dioses perciben el futuro,
los hombres el presente, y los sabios
lo que se avecina.
Filostrato
Pathobiological Determinants of
Atherosclerosis in Youth
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Conclusiones
• Debemos optimizer el uso de las estatinas y otros
fármacos hipolipemiantes (ezetimibe) para disminuir los
eventos cardiovasculares de nuestros pacientes.
• La incorporación de los anticuerpos anti PCSK9 supone
un cambio cualitativo en el tto hipolipemiante. Podemos
curar la arteriosclerosis !!
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89
Tasa de ocurrencia de síntomas musculares con estatinas
individuales. Estudio PRIMO
Bruckert E et al. Mild to Moderate Muscular Symptoms with High-Dosage Statin Therapy in Hyperlipidemic Patients
—The PRIMO Study. Cardiovasc Drugs Ther 2005; 19:403-14.
0%
5%
10%
15%
20%
25%
30%
35%
40%
45%
50%
Fluvastatin XLn=3121
Pravastatinn=1901
Simvastatinn=1027
Atorvastatinn=1844
5,10%
10,90%
18,20%14,90%
% p
ac
ien
tes
en
tra
tam
ien
to c
on
es
tati
na
s a
alt
as
do
sis
co
n
sín
tom
as
mu
sc
ula
res
7924 pacientes dislipémicos tratados con estatinas a dosis altas
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…AND PHYSIOLOGICALLY NORMAL.
Tomado de O’Keefe JH, et al. Optimal low-density lipoprotein is 50 to 70 mg/dL. Lower is better and physiologically normal. Journal of the American College of Cardiology 2004;43(11):2142-6.
Las cifras de C-Total en cazadores-recolectores, primates salvajes y mamíferos salvajes, oscilan generalmente entre 70 y 140 mg/dL, que corresponde a concentraciones de c-LDL de aproximadamente 35 a 70 mg/dL
SERES HUMANOSCAZADORES RECOLECTORES
Hazda
Esquimales
Ikung
Pigmeos
San
Babuino
Mono aullador
Mono de noche
Caballo
Jabalí
Pécari
Rinoceronte negro
Elefante africano
PRIMATES SALVAJES
MAMÍFEROS SALVAJES
SERES HUMANOS MODERNOS
Colesterol total medio (mg/dL)
50 70 80 110 130 150 170 190 210
Norteamericano adulto
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Patients stabilized post ACS ≤ 10 days:LDL-C 50–125*mg/dL (or 50–100**mg/dL if prior lipid-lowering Rx)
Standard Medical & Interventional Therapy
Ezetimibe / Simvastatin
10 / 40 mg
Simvastatin
40 mg
Duration: Minimum 2 ½-year follow-up (5314 events)
Primary Endpoint: CV death, MI, hospital admission for UA,
coronary revascularization (≥ 30 days after randomization), or stroke
N=18,144
Diseño del estudio
Cannon CP AHJ 2008;156:826-32; Califf RM NEJM 2009;361:712-7; Blazing MA AHJ 2014;168:205-12
HR Simva* EZ/Simva* p-value
All-cause death 0.99 15.3 15.4 0.782
CVD 1.00 6.8 6.9 0.997
CHD 0.96 5.8 5.7 0.499
MI 0.87 14.8 13.1 0.002
Stroke 0.86 4.8 4.2 0.052
Ischemic stroke 0.79 4.1 3.4 0.008
Cor revasc ≥ 30d 0.95 23.4 21.8 0.107
UA 1.06 1.9 2.1 0.618
CVD/MI/stroke 0.90 22.2 20.4 0.003
Ezetimibe/Simva
Better
Simva
Better
Eventos CV:Endpoints
0.6 1.0 1.4*7-year
event rates (%)
Safety — ITT
No statistically significant differences in cancer or muscle- or gallbladder-related events
Simva
n=9077
%
EZ/Simva
n=9067
% p
ALT and/or AST≥3x ULN 2.3 2.5 0.43
Cholecystectomy 1.5 1.5 0.96
Gallbladder-related AEs 3.5 3.1 0.10
Rhabdomyolysis* 0.2 0.1 0.37
Myopathy* 0.1 0.2 0.32
Rhabdo, myopathy, myalgia with CK elevation* 0.6 0.6 0.64
Cancer* (7-yr KM %) 10.2 10.2 0.57
* Adjudicated by Clinical Events Committee % = n/N for the trial duration
IMPROVE-IT vs. CTT: Ezetimibe vs. Statin Benefit
CTT Collaboration.
Lancet 2005; 366:1267-78;
Lancet 2010;376:1670-81.
IMPROVE-IT
Novedades ACC 2015
Risk Stratification for Cardiovascular Events in the IMPROVE-IT Trial
E.A. Bohula May, J.A. White, M.A. Blazing, R.P.
Giugliano, T.A. Musliner, A.M. Tershakovec, A. McCagg,
D.L. Bhatt, C.P. Cannon, R.M. Califf & E. Braunwald
on behalf of the IMPROVE-IT Investigators
Risk Prediction by Quartiles -Pooled Treatment Groups
CV death/MI/Stroke/UA/Cor Revasc
Q4Q3
p-value7yr KM (%)
<0.00133.7<0.00141.5
Q2 0.01530.7
Hazard Ratio (95% CI) with REACH Q1 Score as Referent0.81.0 8.0
1.261.63
1.09
HR
Q1 -30.8Ref
CV death
Q4Q3 <0.0017.0
<0.00115.3
Q2 <0.0014.32.476.27
1.68Q1 -3.2Ref
MI
Q4Q3 <0.00114.3
<0.00116.2
Q2 0.2912.01.311.56
1.06Q1 -12.7Ref
Stroke
Q4Q3 <0.0014.9
<0.0018.3
Q2 0.0033.52.093.87
1.44Q1 -2.7Ref
Unstable Angina
Q4Q3 0.272.1
0.172.0
Q2 0.541.91.231.24
1.10Q1 -1.9Ref
Coronary Revasc ≥ 30d
Q4Q3 0.8021.6
0.8421.5
Q2 0.8522.21.010.99
0.99Q1 -24.0Ref
1.6 2.4 3.2 4.4
Subgroup Analysis by Randomized Treatment
0.7 1.0 1.2
Hazard Ratio (95% CI)
Favors EZ/simva Favors simva
CV death/MI/Stroke/UA/Cor Revasc
Q4
Q3
Simva
34.2
43.0
Q2 32.3
0.95
0.91
0.90
HR
Q1 30.90.99
Overall 34.70.94
33.2
39.9
29.1
30.7
32.7
EZ/S p-int
0.58
7yr KM (%)
EZETIMIBE ES IGUAL DE EFICAZ INDISTINTAMENTE DEL RIESGO BASAL
DEL PACIENTE
Reduction in Total (First and Recurrent) Cardiovascular Events with Ezetimibe/Simvastatin compared with Simvastatin Alone post ACS in the IMPROVE-IT Trial
Sabina A. Murphy, Christopher Cannon, Robert Giugliano, Michael
Blazing, Thomas Musliner, Andrew Tershakovec, Jennifer White, Kelly Im,
Naveen Deenadayalu, Haral Darius, Witold Ruzyllo, Andrew Tonkin, Uma
Kher, Robert Califf, Eugene Braunwald
On behalf of the IMPROVE IT Investigators
Ezetimibe en el paciente ESTABLE
Total Primary Endpoint Events
# E
ve
nts
Ezetimibe
Simvastatin
Simvastatin
Alone
45624983
Total Events
RR 0.91
P=0.007
Additional
Events
RR 0.88
(0.79-0.98)
1st Event
HR 0.936
P=0.016
-421
-251
-170
Conclusiones
➢ These data provide further support of the benefit
of continuation of intensive combination lipid
lowering therapy after a recurrent CV event
➢ Analyses of recurrent events are important as total
events have implications:
– Patient morbidity
– Need for recurrent hospitalizations
– Costs
➢ These considerations not always accounted for
when analyzing first events only
RP Giugliano1, CP Cannon1, MA Blazing2, JA
White2, SA Murphy1,
AM Tershakovec3, TA Musliner3, RM Califf2, E
Braunwald1
Baseline LDL-C and Clinical Outcomes With Addition of Ezetimibe to Statins
in18,144 Patients Post ACS:
An Analysis From IMPROVE IT†
Preliminary Results – Presented at ACC 2015 by R Giugliano
LDL-C at Admission and after 4 Monthsof Therapy by Quartiles of Admission LDL-C
Admission LDL-C (mg/dL)
63
4549
69
50
72
53
69
Me
dia
n L
DL
-C a
t 4
Mo
nth
s
(mg
/dL
)
Q1 Q2 Q3 Q4
Simvastatin Ezetimibe + Simvastatin
69
88
102118
All
≤79 79-95 95-110 ≥110Range 10-253
Median 69 88 102 118 95
95
68
49
Preliminary Results – Presented at ACC 2015 by R Giugliano
Hazard Ratios for the Primary Endpointby Quartiles of LDL-C at Admission
0.91
0.95
0.95
0.8 1.0 1.25
FavorsEzetimibe+Simvastatin
FavorsSimvastatin
EZ/S(%) HR
Simvastatin(%)
0.93
32.7 34.7 0.936
HR
PrimaryEndpoint
69
88
102
118
2
3
1
4
Overall
Quartile
MedianLDL-c
(mg/dL)P
Value
0.33
0.068
0.38
0.24
0.017
38.0 39.0
34.0 37.1
32.0 33.0
27.1 29.4
AdjPint
0.85
0.58
0.70
Ref
95
Adj Pint= 0.77 for
Rx* LDL in quartiles
Adj Ptrend = 0.76
Preliminary Results – Presented at ACC 2015 by R Giugliano
Early or high-intensity lipid lowering in FH patients delays onset of CHD
Nordestgaard et al. Eur Heart J 2013;34:3478–3490.
00
Age in years
Cum
ula
tive L
DL
-C (
mm
ol)
200
150
100
50
Threshold
for CHD
603 6 9 12 15 18 21 24 27 30 33 36 39 42 45 48 51 54 57
Without FH
55 years
35 years
Heterozygous FH
12.5 years
Homozygous FH
48 years
Start high
dose statin
53 years
Start low
dose statin
Presentaciones
Atorvastatina + Ezetimibe
¿Qué vamos a conseguir?
Weng TC et al. J Clin Pharm Ther 2010; 35:139-151Mukhtar RY et al. Int J Clin Practice; 2005; 59 (2): 239-252
• Atorvastatina 20 mg/ Ezetimibe 10mg
• Atorvastatina 40 mg/ Ezetimibe 10mg
• Atorvastatina 80 mg/ Ezetimibe 10mg
N Engl J Med 2014; 371:2072-2082
Novedades COLESTEROL Y GENÉTICA
N Engl J Med 2015;372:1500-9.