Efficacia e Tollerabilità della Terapia
Ipolipemizzante dopo SCA:
Ruolo dell’Ezetimibe nei Programmi
Integrati di Prevenzione Secondaria
Furio Colivicchi
Dipartimento Cardiovascolare
ACO S.Filippo Neri
Roma
Relative risk reduction for major coronary events
La riduzione del Rischio
Relativo risulta
indipendente dai livelli
iniziali di LDL-C e dalle
caratteristiche cliniche
del paziente
Ogni riduzione di LDL-C di
38 mg/dl si associa ad una
riduzione del Rischio
Relativo del 24%
LDL Cholestrol reduction (mmol/l)
Baigent C, et al, Cholesterol Treatment Trialists’ (CTT) Collaborators.
Lancet 2005;366:1267–1278.
2011 ESC/EAS Guidelines for the management
of Dyslipidaemias: General Indications
Every 1.0 mmol/L (38-40 mg/dL)
reduction in LDL-C is associated with a
corresponding 20-25% reduction in CVD
events.
An absolute reduction to an LDL-C level
<1.8 mmol/L (<70 mg/dL) or at least a
50% relative reduction in LDL-C provides
the best benefit in terms of CVD
reduction.
a: class of recommendation
b: level of evidence
European Heart Journal 2011;32:1769–1818
Moderate-intensity therapy reduces LDL by
30% to 49% and high-intensity therapy
reduces LDL by 50% or more.
According to the new guidelines, and
considering statin efficacy, only 40 to 80 mg
of atorvastatin daily or 20 to 40 mg of
rosuvastatin daily may provide such highintensity LDL reduction.
Nuova Nota 13 AIFA
Nuova Nota 13 AIFA
2011 ESC/EAS Guidelines
Meta-analysis on the therapeutic equivalence of
statins.
European Heart Journal 2011; 323: 1769-1818. Addenda doi:10.1093/eurheartj/ehr169
Risultati
Preliminari
3056 pazienti consecutivi con SCA con follow-up di almeno 90 giorni
Colivicchi F, Eur Heart J 2013; 34 (abst.suppl.):164.
Risultati
Preliminari
27% dei Pazienti dimessi
In terapia con statine
1876 pazienti
dose media quotidiana 53 mg
66% dose necessaria a ridurre 50%
C-LDL
Colivicchi F, Eur Heart J 2013; 34 (abst.suppl.):164.
Risultati
Preliminari
Colivicchi F, Eur Heart J 2013; 34 (abst.suppl.):164.
Risultati
Preliminari
Il «destino» della terapia ad alto dosaggio con
Atorvastatina 80 mg/die a 90 giorni dalla dimissione
779 dimessi con prescrizione di A 80mg/die
398 (51%)
continuano Atorvastatina
139 (18%)
interrompono il trattamento
80 mg/die
242 (31%) passano ad altra terapia
161 a
dose minore di
41 a
Atorvastatina
Simvastatina
16 ad
associazione
Eze-Simva
24 a
Rosuvastatina
Colivicchi F, Eur Heart J 2013; 34 (abst.suppl.):164.
Sindromi Coronariche Acute
Profilo lipidico durante il ricovero ed a 90 giorni dalla dimissione in 3056
pazienti consecutivi con SCA dal Registro Regionale del Lazio Net.Sca
22% con C-LDL≤ 70 mg/dl
mg/dl
Reported causes of Switch form Intensive Statin
Therapy after ACS
1. “Dosage too high”
2. “Afraid of major
adverse reactions”
Medical
Decision
44%
Reported Side Effects
Dyspepsia
Fatigue
56%
Side effects
Headache
Myalgias
0%
20%
40%
60%
80% 100%
eGFR < 60 ml/min: HR 1.4 (95% CI, 2.9-1.2)
Colivicchi F, et al. Int J Cardiol (2011), 152: 56-60
Asymptomatic increase in
liver enzymes
Asymptomatic increase in
total CK
ACC/ AHA Advisory on Safety of Statin Therapy
Most adverse events associated with
statins appear to occur in patients who are
at risk for the condition.
For this reason, physicians should be
aware of several caveats when prescribing
statin therapy.
Adverse reactions are more likely to occur
at higher statin doses than at lower doses.
Consequently, doses should not exceed
those required to attain the recommended
goal of therapy. As a rule, statin therapy
should be employed more cautiously in
older persons.
Circulation 2002;106:1024-1028.
Sindromi Coronariche Acute
Funzionalità renale (eGFR stimato con formula MDRD) in 3056 pazienti
consecutivi con SCA dal Registro Regionale del Lazio Net.Sca
Nuova Nota 13 AIFA
Variazione % media dal
basale del C-LDL calcolato (settimana 12)
Ezetimibe associato con atorvastatina:
Risultati dell’efficacia sul C-LDL
Ezetimibe 10 mg
+
atorvastatina 10 mg
Atorvastatina
10 mg
20 mg
40 mg
80 mg
0
–10
–20
–30
–37*
–42*
–40
–50
–53
–60
*p<0,01 terapia di associazione vs. statina da sola
Ballantyne CM et al Circulation 2003;107:2409-2415.
–45*
–54
Intensive LLT in a Comprehensive Secondary Prevention Program
863 ACS patients discharged on atorvastatin
80mg/day* followed for 90 days after discharge
535 (62%)
continued atorvastatin
80mg/day
61 (6%)
discontinued statin therapy
for Major Side effects
switched to Ezetimibe 10 mg
277 (32%)
with minor side effects or unwilling to continue
113 (13%)
switched to a lower
dose of atorvastatin
164 (19%)
switched to a lower dose of
20-40mg/day
20-40mg/day + Ezetimibe 10 mg
atorvastatin
*consecutive patients (586 men, mean age 68 ± 13 years) discharged on atorvastatin 80mg/day after an ACS
in 2.5 year period
Colivicchi F, Eur Heart J 2013; 34 (abst.suppl.):136.
Intensive LLT in a Comprehensive Secondary Prevention
Lipid Profile at 90 days
mg/dl
* P<0.001 versus A80;.
*
Colivicchi F, Eur Heart J 2013; 34 (abst.suppl.):136.
Intensive LLT in a Comprehensive Secondary Prevention
Lipid Profile at 90 days
Admission
Patients
LDL-C, mg/dl
(mean±SD)
Patients with
LDL-C <70 mg/dl
124±35
A80
E10
A20-40
A20-40 +
E10
535
51
113
164
76±21
104±23
87±31
64±19
213 (39.8%)
6 (11.7%)
27 (23.8%)
108 (65.8%)
Colivicchi F, Eur Heart J 2013; 34 (abst.suppl.):136.
IMProved Reduction of
Outcomes: Vytorin Efficacy
International Trial
A Multicenter, Double-Blind, Randomized Study to
Establish the Clinical Benefit and Safety of Vytorin
(Ezetimibe/Simvastatin Tablet) vs Simvastatin
Monotherapy in High-Risk Subjects Presenting
With Acute Coronary Syndrome
Study Design
Patients stabilized post ACS ≤ 10 days:
LDL-C 50–125*mg/dL (or 50–100**mg/dL if prior lipid-lowering Rx)
N=18,144
*3.2mM
**2.6mM
Standard Medical & Interventional Therapy
Simvastatin
40 mg
Uptitrated to
Simva 80 mg
if LDL-C > 79
(adapted per
FDA label 2011)
Ezetimibe / Simvastatin
10 / 40 mg
Follow-up Visit Day 30, every 4 months
90% power to detect
~9% difference
Duration: Minimum 2 ½-year follow-up (at least 5250 events)
Primary Endpoint: CV death, MI, hospital admission for UA,
coronary revascularization (≥ 30 days after randomization), or stroke
Cannon CP AHJ 2008;156:826-32; Califf RM NEJM 2009;361:712-7; Blazing MA AHJ 2014;168:205-12
Baseline Characteristics
Simvastatin
(N=9077)
%
EZ/Simva
(N=9067)
%
Age (years)
64
64
Female
24
25
Diabetes
27
27
MI prior to index ACS
21
21
STEMI / NSTEMI / UA
29 / 47 / 24
29 / 47 / 24
Days post ACS to rand (IQR)
5 (3, 8)
5 (3, 8)
Cath / PCI for ACS event
88 / 70
88 / 70
35
36
95 (79, 110)
95 (79,110)
Prior lipid Rx
LDL-C at ACS event (mg/dL, IQR)
LDL-C and Lipid Changes
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
∆ in mg/dL
-16.7
-19.3
-16.7
+0.6
-0.5
Median Time avg
69.5 vs. 53.7 mg/dL
Primary Endpoint — ITT
Cardiovascular death, MI, documented unstable angina requiring
rehospitalization, coronary revascularization (≥30 days), or stroke
HR 0.936 CI (0.887, 0.988)
p=0.016
Simva — 34.7%
2742 events
NNT= 50
EZ/Simva — 32.7%
2572 events
7-year event rates
Individual Cardiovascular
Endpoints and CVD/MI/Stroke
All-cause death
HR
0.99
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
0.6
Ezetimibe/Simva
Better
1.0
1.4
Simva
Better
Simva* EZ/Simva* p-value
15.3
15.4
0.782
*7-year
event rates (%)
Major Pre-specified
Subgroups
Simva† EZ/Simva†
Male
Female
34.9
34.0
33.3
31.0
Age < 65 years
Age ≥ 65 years
30.8
39.9
29.9
36.4
No diabetes
Diabetes
30.8
45.5
30.2
40.0
Prior LLT
No prior LLT
43.4
30.0
40.7
28.6
LDL-C > 95 mg/dl
LDL-C ≤ 95 mg/dl
31.2
38.4
29.6
36.0
*
0.7
1.0
Ezetimibe/Simva
Better
1.3
Simva
Better
†7-year
event rates
*p-interaction = 0.023, otherwise > 0.05
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
Relative risk reduction for major coronary events
La riduzione del Rischio
Relativo risulta
indipendente dai livelli
iniziali di LDL-C e dalle
caratteristiche cliniche
del paziente
Ogni riduzione di LDL-C di
38 mg/dl si associa ad una
riduzione del Rischio
Relativo del 24%
IMPROVE-IT
LDL Cholestrol reduction (mmol/l)
Baigent C, et al, Cholesterol Treatment Trialists’ (CTT) Collaborators.
Lancet 2005;366:1267–1278.
Sindromi Coronariche Acute
Intervento farmacologico ipolipemizzante alla dimissione e durante il
follow-up – Ruolo dell’Ezetimibe
• Ezetimibe è il farmaco di prima scelta in caso di
intolleranza assoluta alle statine.
• Ezetimibe è utile per favorire il raggiungimento del target
lipidico raccomandato. In particolare è consigliabile il suo
impiego in associazione a statine ad elevata efficacia
nelle seguenti condizioni:
1.Fin dalla dimissione in pazienti con disfunzione renale in
associazione a dosi più contenute (20-40 mg) di
atorvastatina.
2.Durante il follow-up nei pazienti che non tollerano i
dosaggi più elevati di statina