Transcript Diapositiva 1

Prasugrel
The Third Generation Thienopyridine
•Epidemiology and patterns of care of patients admitted to
Italian Intensive Cardiac Care Units:The BLITZ-3 registry
•Role of platelets in ACS
•The thienopyridine family evolution, P2Y12 receptor and its
role in platelets inhibition
•TRITON TIMI 38: Study Objectives and Hypothesis, Design,
Key Enrollment Criteria
•Kaplan-Meier Curves: Efficacy of Prasugrel Versus
Clopidogrel, Landmark analisys
•Cohort Study: STEMI
•TARGET POPULATION Balance of Efficacy/Safety in patients
<75 yrs, ≥60 kg, No prior TIA/stroke
•RCP
Codice ITEFF00049
Data di deposito AIFA 12-05-20101
Epidemiology : the BLITZ-3 registry
( N=6986 consecutive patients admitted to 81% of Italian ICCUs )
N (6986)
Different proportions of
discharge diagnosis for the
study population
2
Casella Journal of Cardiovascular Medicine 2010, 11:000–000
Epidemiology and patterns of care of patients
Complications
during
hospitalization
in ICCUs
admitted
to Italian
intensive
cardiac care
units:
the BLITZ-3
registry
Global study
population
(N=6986)
STEMI ACS
(N=1492)
NSTEMI ACS
(N=2144)
0.9
1
1
1
0.6
3
5
6
2
0.8
6
6
5
10
5
4
6
2
4
3
2
3
1
0.8
3
0.5
0.6
0.6
0.8
0.3
9
12
10
12
5
Shock or Killip IV (%)
6
6
2
20
2
Cardiac arrest (%)
3
5
2
4
2
Sepsis (%)
Other complications
(%)
Acute renal
dysfunction (%)
Modified TIMI major
bleeding (%)
Length of stay in ICCU
[median (IQR)]
In-ICCU crude global
mortality
0.8
0.2
0.6
2
0.7
7
9
6
9
6
11
13
11
18
8
0.4
1
0.2
0.1
0.2
4 (2–5)
4 (3–5)
4 (3–6)
4 (3–6)
3 (2–4)
3.3
5.1
2
5.4
2.6
Reinfarction or
infarction (%)
Angina or recurrent
ischemia (%)
Supraventricular
arrhythmias (%)
Major ventricular
arrhythmias (%)
High grade AV block
(%)
Fatal or nonfatal stroke
(%)
Heart failure or
worsening (%)
Other acute
Acute heart failure
cardiac
(N=966)
diseases(N=2384)
3
Casella Journal of Cardiovascular Medicine 2010, 11:000–000
Epidemiology and patterns of care of patients
admitted
to Italian
intensive cardiac care units:
Treatment
utilization
the BLITZ-3
registry
Global study
population
(N=6986)
Other acute
ST-elevation ACS Non-ST-elevation Acute heart
cardiac diseases
(N=1492)
ACS (N=2144) failure (N=966)
(N=2384)
Aspirin (%)
Aspirin and clopidogrel
association (%)
Oral anticoagulation
therapy (%)
71
94
90
51
48
45
77
69
13
16
9
2
3
20
14
Beta-blockers (%)
53
69
69
42
34
2b/3a inhibitors (%)
16
39
21
0.8
3
ACE inhibitors (%)
50
59
57
51
39
Statins (%)
57
80
77
34
34
Nitrates intravenous (%)
41
52
61
41
17
Inotropes intravenous (%)
8
10
4
22
7
Diuretics intravenous (%)
47
35
39
93
43
Insulin subcutaneous (%)
15
13
17
22
11
Insulin intravenous (%)
4
5
4
6
2
Transfusions (%)
4
3
4
7
3
Coronary reperfusion (%)
NA
60
NA
NA
NA
Primary PCI (%)
NA
45
NA
NA
NA
Thrombolysis (%)
NA
15
NA
NA
NA
4
Casella Journal of Cardiovascular Medicine 2010, 11:000–000
Progression of a Coronary Atherosclerotic Plaque
Development and Rupture of an Atherosclerotic Lesion
Normal
Fatty Streak
Occlusive
Plaque
Rupture and
thrombus
formation
Unstable
Angina
MI
Sudden
Coronary
Death
Plaque rupture
Time
Platelet activation,
aggregation, and
thrombus formation
Libby P. Circulation 2001;104:365-3725
Platelet Activation Pathways
Thromboxane A2
Collagen
5HT
Coagulation
TPα
Thrombin
GPV1
ADP
ATP
5HT2A
P2Y1
Par4
Thienopyridine
P2X1
Par1
Platelet
Activation
Thrombin
generation
Shape change
Dense
granule
P2Y12 is critical
for amplification
P2Y12
Alpha
granule
Amplification
Aggregation
αIIbβ3
Coagulation factors
Inflammatory mediators
αIIbβ3
αIIbβ3
Fibrinoge
n
Adapted and modified from Storey RF. Curr Pharm Des 2006;12:1255-1259
7
The Thienopyridine Family
O
C
O
N
N
S
S
Cl
Ticlopidine
(1st generation)
CH
3
Cl
Clopidogrel
(2nd generation)
O
O
CH O
3
N
S
F
Prasugrel (CS-747) (LY640315)
(3rd generation)
8
Meadows et al. Circulation Res. 2007;100:1261-1275.
Active Metabolite Formation:
Prasugrel and Clopidogrel
Clopidogrel4–8
Prasugrel1-3
Prodrug
Hydrolysis
hCE1
Esterase
(mainly
hepatic)
1st Oxidation
CYP hepatic
1A2,2B6,2C19
Intermediate
85%
Inactive
Metabolite8
2nd
Oxidation
CYP hepatic
3A, 2B6,
2C9, 2C19
Active Metabolite
DRUGS and Genetic variation in CYP2C19
can impair metabolism
1. Rehmel et al. Drug Metab Dispos. 2006;34:600-607.
2. Williams et al. Drug Metab Dispos. 2008;36:1227-1232.
3. Farid et al. J Clin Pharmacol. 2009 Nov 30. [Epub ahead of print].
4. Savi et al. Thromb HaemostRUGS 000;84:891-896.
Prodrug
Esterase
( mainly
intestinal)
Hydrolysis
hCE2
Intermediate
Intestinal CYPs
(3A, 2C9, 2C19)
CYP hepatic:
(3A, 2B6, 2C9,
2C19)
Oxidation
CYP 3A,
2B6, 2C9,
2C19
Active Metabolite
Prasugrel has no clinically relevant interactions
with CYP2C19 variants or inhibitor
5. Kurihara et al. Drug Metab Rev. 2005;37(S2):99.
6. Lagorce et al. J Chromatogr B Biomed Sci Appl. 1998;720:107-117.
7. Tang et al. J Pharmacol Exp Ther. 2006;319:1467-1476.
9
In comparison to clopidogrel, prasugrel appears to be well absorbed
and/or metabolized more efficiently to its active metabolite, resulting in
the rapid formation of relatively high concentrations of active metabolite,
accounting for its rapid onset of activity
20 µM ADP
Interpatient Variability
100
90
80
70
60
50
40
30
20
10
0
-10
-20
Response to
clopidogrel 300 mg
Interpatient
Variability
Individual Levels of IPA 24 hrs after
Loading Dose Clopidogrel and Prasugrel
64 Healthy volunteer crossover study IPA (20 M ADP) at 24 hours
Background Variability
Response to
prasugrel 60 mg
Brandt et al. Am Heart J 2007;153(66)e9-e16
10
Prasugrel 60 mg LD was associated with more rapid,
more consistent, and significantly greater inhibition of
platelet aggregation than was clopidogrel 300 mg LD.
64 Healthy volunteer crossover study IPA (20 M ADP) at 24 hours
Background Variability
μM ADP
20
5 μM ADP
IPA Frequency Distribution
4 h Post-LD
60
BV
20 µM ADP
40
30
20
40
30
20
10
10
0
0
-10 0
10 20 30 40 50 60 70 80 90 100
5 µM ADP
BV
50
Percentage (%)
Percentage (%)
50
60
-10 0
10 20 30 40 50 60 70 80 90 100
IPA (%)
IPA (%)
IPA (%)
Clopidogrel
Clopidogrel
Prasugrel
Prasugrel IPA (%)
Frequency distribution of IPA 4 hours after prasugrel 60 mg or clopidogrel 300 mg in response to 5  mol/L ADP and 20  mol/L ADP
Clopidogrel
Prasugrel
Clopidogrel
Prasugrel
Brandt et al. Am Heart J 2007;153(66)e9-e16
11
Greater exposure to prasugrel’s active metabolite results
in faster onset, higher levels, and less variability of
platelet inhibition compared with high-dose clopidogrel in
healthy subjects
Loading Dose
100
Inhibition of Platelet Aggregation (%) (20 μM ADP)
Data are expressed as mean ± SEM.
*p < 0.001 versus clopidogrel 300-mg/75-mg and 600-mg/75-mg regimen;
†P < 0.05 versus clopidogrel 300-mg/75-mg; ‡p < 0.001 versus clopidogrel 300-mg/75-mg.
Arrows (↓) indicate day of dose administration
Prasugrel pharmacodynamics and pharmacokinetics after a 60-mg loading dose (LD) and daily 10-mg maintenance doses (MD) were
compared in a 3-way crossover study to clopidogrel 600-mg/ 75-mg and 300-mg/75-mg LD/MD in 41 healthy, aspirin-free subjects.
90
*
*
80
Maintenance Doses
*
‡
70
‡
‡
*
60
*
*
‡
*
*
*
*
*
*
*
†
50
40
†
▲ Clopidogrel 300-mg/75-mg
 Clopidogrel 600-mg/75-mg
● Prasugrel 60-mg/10-mg
30
20
10
0
Pre-dose
IPA
-10
Time
0.25
0.5
1
2
Day 1, Hours
4
6
2
3
4
5
6
Days
7
8
9
12
Payne CD et al. J Cardiovasc Pharmacol 2007; 50: 555-562
Conclusions
• In aspirin-treated subjects with coronary artery disease, prasugrel 60/10 mg
provides faster onset and greater inhibition of P2Y12 receptor-mediated platelet
aggregation than clopidogrel 600/75 mg, because of greater and more efficient
generation of the active metabolite (1)
• Compared to clopidogrel, the more rapid onset and greater inhibition of P2Y12mediated platelet aggregation, with prasugrel was associated with earlier and
higher peak levels and greater exposure to the active metabolite (1)
• Prasugrel 60 mg LD results in more rapid, potent, and consistent inhibition of
platelet function than clopidogrel 300 mg LD. Lower IPA responses to
clopidogrel were associated with lower concentrations of its active metabolite (2)
• The faster onset of platelet inhibition after prasugrel was evident in a number of
parameters (2)
1. Wallentin et al. Eur Heart J 2008;29:21-30
2. Brandt et al. Am Heart J 2007;153(66):e9-e1613
TRial to Assess Improvement in Therapeutic
Outcomes by Optimizing Platelet Superiority
InhibitioN With
Prasugrel (TRITON)-TIMI 38 Trial
ACS (UA/NSTEMI or STEMI) and Planned PCI
N=13,608
Randomized
Double-blind
Prasugrel
60-mg LD/10-mg MD
+ Aspirin
Clopidogrel
300-mg LD/75-mg MD
+ Aspirin
Median duration of follow up = 14.5 months
• Primary efficacy endpoint:
– Composite CV death, nonfatal MI, or nonfatal stroke
• Safety endpoints:
– TIMI major or minor bleeding
14
Wiviott et al. N Engl J Med. 2007;357:2001-2015.
TRITON-TIMI 38:
Key Enrollment Criteria
Inclusion Criteria
Planned PCI for :
Known
Anatomy
Mod-High Risk UA/NSTEMI (TIMI Risk Score > 3)
STEMI: >12 hrs to < 14 days (ischemia or Rx strategy)
STEMI: Primary PCI < 12 hrs
Esclusion Criteria
•
•
•
•
•
•
•
•
Cardiogenic shock
Severe comorbidity
Increased bleeding risk
Prior hemorrhagic stroke or any stroke < 3 mos
Any thienopyridine within 5 days
Fibrin-specific lytic <24 hours
Nonfibrin-specific lytic <48 hours
No exclusion for advanced age or renal function
15
Wiviott et al. N Engl J Med. 2007;357:2001-2015.
TRITON-TIMI 38:
baseline Caracteristic
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
UA/NSTEMI
74
74
STEMI
26
26
Age, median
(IQR)
61 (53,69) y
61 (53, 70) y
13
13
> 75 y
TRITON-TIMI 38:
Index Procedure
Clopidogrel
(N=6795)
%
Prasugrel
(N=6813)
%
PCI / CABG
99 / 1
99 / 1
Any Stent
95
94
BMS
47
48
DES
47
47
14
Wgt, median
(IQR)
< 60 kg
83 kg (72, 92)
5.3
84 kg (73, 93)
4.6
Multivessel PCI
14
Female
27
25*
UFH / LMWH /
Bival
65 / 8 / 3
Diabetes
23
23
GP IIb/IIIa
55
54
Prior MI
18
18
LD of Study Rx
Pre PCI
During
PCI
Post PCI
25
74
1
26
73
1
*P<0.05
CrCl (ml/min)
>60
<60
88
12
89
11
66 / 9 / 3
*P<0.05
Wiviott et al. N Engl J Med 2007;357:2001-2015
16
TRITON-TIMI 38:
Primary Efficacy Endpoint
Cardiovascular Death, Nonfatal Myocardial Infarction, Nonfatal Stroke
23 %
RRR
p<0.001
20 %
RRR
p<0.001
*
19 %
RRR
p=0.008
RRR
32%
P=0.03
* composite of the rate of death from cardiovascular causes,
nonfatal myocardial infarction or nonfatal stroke
Wiviott et al. N Engl J Med 2007;357:2001-201517
TRITON-TIMI 38:
Primary Efficacy Endpoint
Wiviott et al. N Engl J Med 2007;357:2001-201518
TRITON-TIMI 38:
Bleeding Events (Safety Choort) n=13.457
Wiviott et al. N Engl J Med 2007;357:2001-201519
TRITON-TIMI 38:
Primary Efficacy Endpoint
(Landmark analysis - 3 days - 450 days)
Cardiovascular Death, Nonfatal Myocardial Infarction, Nonfatal Stroke
18 %
RRR
20 %
RRR
p=0.003
p=0.01
20
Wiviott et al. N Engl J Med 2007;357:2001-2015
TRITON-TIMI 38:
Myocardial Infarction
(Landmark analysis - 3 days - 450 days)
19 %
RRR
p=0.008
31 %
RRR
p=0.0001
Loading dose
Maintenance dose
Antman et al. JACC 2008;51:2028–33
21
TRITON-TIMI 38:
Stent Thrombosis
(Landmark analysis
TRITON-TIMI
38:- 3 days - 450 days)
(Landmark analysis - 3 days - 450 days)
51 %
RRR
p=0.006
55 %
RRR
p=0.0001
Loading dose
Maintenance dose
Antman et al. JACC 2008;51:2028–33
22
TRITON-TIMI 38:
Urgent Target Vessel Revascularisation
(Landmark analysis - 3 days - 450 days)
35 %
RRR
p=0.0003
34 %
RRR
p=0.0047
Loading dose
Maintenance dose
Antman et al. JACC 2008;51:2028–33
23
TRITON-TIMI 38:
CONCLUSIONS
(Landmark analysis - 3 days - 450 days)
Conclusions Wiviott
A significant reduction in the primary end point was seen in the prasugrel
group by the first prespecified time point, 3 days (5.6% in the clopidogrel
group vs. 4.7% in the prasugrel group; hazard ratio, 0.82; 95% CI, 0.71 to
0.96; P = 0.01), and persisted throughout the follow-up period. From 3 days
to the end of the study, the primary end point had occurred in 6.9% of
patients receiving clopidogrel and in 5.6% of patients receiving prasugrel
(hazard ratio, 0.80; 95% CI, 0.70 to 0.93; P = 0.003).(1)
Conclusions Antman
The reduction in the HR for MI in favor of the prasugrel group was 19% in
the first 3 days and 31% from 3 days to the end of the trial. (2)
Reductions in the HR were observed with prasugrel for stent thrombosis
(51% reduction by 3 days [p 0.006] and 55% reduction from 3 days
to the end of the trial [p 0.0001]) and (2)
urgent target vessel revascularization (34% reduction by 3 days [p
0.047] and 35% reduction from 3 days to the end of the trial [p
0.0003]). (2)
1 Wiviott et al. N Engl J Med 2007;357:2001-2015
24
2 Antman et al. JACC 2008;51:2028–33
TRITON-TIMI 38 EFFICACY:
Conclusions:
In patients with acute coronary syndromes with scheduled percutaneous coronary
intervention, prasugrel therapy was associated with significantly reduced rates of ischemic
events, including stent thrombosis, but with an increased risk of major bleeding, including
fatal bleeding.
A significant reduction in the primary end point was seen in the prasugrel group by the first
prespecified time point, 3 days (5.6% in the clopidogrel group vs. 4.7% in the prasugrel
group; hazard ratio, 0.82; 95% CI, 0.71 to 0.96; P = 0.01) (Fig. 1B), and persisted
throughout the follow-up period
We also found significant reductions in the prasugrel group in the rates of myocardial
infarction (9.7% for clopidogrel vs. 7.4% for prasugrel; P<0.001), urgent target-vessel
revascularization (3.7% vs. 2.5%; P<0.001), and stent thrombosis (2.4% vs. 1.1%;
P<0.001).
Prasugrel showed superior efficacy in major prespecified subgroups, without significant
interactions between the characteristics of the patients and the treatment group
Wiviott et al. N Engl J Med 2007;357:2001-2015
25
TRITON-TIMI 38 SAFETY:
Conclusions:
• Among patients treated with prasugrel, 146 (2.4%) had at least one TIMI major hemorrhage that was not related
to CABG, as compared with 111 patients (1.8%) treated with clopidogrel (hazard ratio, 1.32; 95% CI, 1.03 to
1.68; P = 0.03) (Table 3). This excess of TIMI major bleeding included a higher rate of life-threatening bleeding
in the prasugrel group (1.4%, vs. 0.9% in the clopidogrel group; hazard ratio, 1.52; 95% CI, 1.08 to 2.13; P =
0.01) at the end of the study, as well as from the time of randomization to day 3 (0.4% vs. 0.3%; hazard ratio,
1.38; 95% CI, 0.79 to 2.41; P = 0.26) and from day 3 to the end of the study (1.0% vs. 0.6%; hazard ratio, 1.60;
95% CI, 1.05 to 2.44;P = 0.03).
• A higher rate of TIMI major bleeding related to instrumentation and a significantly higher rate of spontaneous
TIMI major bleeding were seen in the prasugrel group than in the clopidogrel group.
• There was also a significant interaction between the presence or absence of any of these three risk factors and
the degree of net clinical benefit for prasugrel as compared with clopidogrel (P = 0.006), though no significant
harm was evident. Among patients without any of these three risk factors, there was greater efficacy with
prasugrel (hazard ratio, 0.74; 95% CI, 0.66 to 0.84; P<0.001), no significant difference in the rate of major
bleeding in the prasugrel group and the clopidogrel group (hazard ratio, 1.24; 95% CI, 0.91 to 1.69; P = 0.17),
and a substantially favorable net clinical benefit for the use of prasugrel.
• These included patients with a history of stroke or transient ischemic attack before enrollment, the elderly (age
≥75 years), and those with a body weight of less than 60 kg, risk factors that have been previously identified as
being associated with an increased risk of adverse outcomes from the use of antiplatelet or antithrombotic
agents.2
Wiviott et al. N Engl J Med 2007;357:2001-2015
26
In patients with STEMI undergoing PCI, Prasugrel is more eff ective
than clopidogrel for prevention of ischaemic events, without an
apparent excess in bleeding.
21 %
RRR
p=0.0221
27
Wiviott et al. N Engl J Med 2007;357:2001-2015
TRITON-TIMI 38:
STEMI Cohort (N=3534)
28
Montalescot Lancet 2009; 373: 723–31
TRITON-TIMI 38:
STEMI Cohort (N=3534)
29
Montalescot Lancet 2009; 373: 723–31
TRITON-TIMI 38:
STEMI Cohort (N=3534)
Primary study
endpoint
(cardiovascular
death, non-fatal
MI, or non-fatal
stroke).
32 %
RRR
p=0.0017
21 %
RRR
p=0.0221
30
Montalescot Lancet 2009; 373: 723–31
TRITON-TIMI 38:
STEMI Cohort (N=3534)
Key secondary
Endpoint:
cardiovascular
death, nonfatal MI, or
urgent TVR
25 %
RRR
p=0.0205
21 %
RRR
p=0.0250
31
Montalescot Lancet 2009; 373: 723–31
TRITON-TIMI 38:
STEMI Cohort (N=3534)
51 %
RRR
p=0.0084
Stent
thrombosis
42 %
RRR
p=0.0232
32
Montalescot Lancet 2009; 373: 723–31
TRITON-TIMI 38:
STEMI Cohort (N=3534)
TIMI major
bleeding
unrelated
to CABG
surgery.
33
Montalescot Lancet 2009; 373: 723–31
TRITON-TIMI 38: STEMI Cohort (N=3534)
MORTALITY, NET CLINICAL BENEFIT 30 Days
34
Montalescot Lancet 2009; 373: 723–31
TRITON-TIMI 38: STEMI Cohort (N=3534)
MORTALITY, NET CLINICAL BENEFIT 15 Months
35
Montalescot Lancet 2009; 373: 723–31
TRITON-TIMI 38: STEMI Cohort N (3534)
CONCLUSIONS
In patients with STEMI undergoing PCI, Prasugrel is more effective than
clopidogrel for prevention of ischaemic events, without an apparent excess
in bleeding.
Compared with clopidogrel, prasugrel was not associated with any
significant increase in major bleeding, life-threatening bleeding, or major or
minor bleeding
This analysis of STEMI patients in TRITON-TIMI 38 shows that, for the specific
regimens that were administered, prasugrel-when compared with clopidogrel- was
associated with a significant risk reduction in the primary composite
endpoint of cardiovascular death, non-fatal myocardial infarction, or nonfatal stroke for the trial duration.
A significant reduction in the key secondary composite endpoint of
cardiovascular death, non-fatal myocardial infarction, or urgent target
vessel revascularisation at 30 days was also recorded.
36
Montalescot Lancet 2009; 373: 723–31
The Efficacy and Safety of Prasugrel With and Without a
Glycoprotein IIb/IIIa Inhibitor in Patients With ACS
Undergoing PCI
Researchers in the TRITON–TIMI 38
randomized 13,608 subjects with acute
coronary syndrome undergoing PCI to
prasugrel versus clopidogrel. The use
of a GP IIb/IIIa inhibitor was at the
physician’s discretion.
For the current analysis, end points
were examined at 30 days and were
stratified by use of a GP IIb/IIIa inhibitor.
A total of 7,414 subjects (54.5%)
received a GP IIb/IIIa inhibitor during
their index hospitalization.
O’Donoghue Anerican College Vol. 54, No. 8, 2009 37
The Efficacy and Safety of Prasugrel With and Without a
Glycoprotein IIb/IIIa Inhibitor in Patients With ACS
Undergoing PCI BASELINE CHARACTERISTICS
O’Donoghue Anerican College Vol. 54, No. 8, 2009 38
The Efficacy and Safety of Prasugrel With and Without a
Glycoprotein IIb/IIIa Inhibitor in Patients With ACS
Undergoing PCI
22%
RRR
p=0.026
O’Donoghue Anerican College Vol. 54, No. 8, 2009 39
The Efficacy and Safety of Prasugrel With and Without a
Glycoprotein IIb/IIIa Inhibitor in Patients With ACS
Undergoing PCI
24%
RRR
p=0.01
O’Donoghue Anerican College Vol. 54, No. 8, 2009 40
Safety Outcomes Stratified by the Use of
GP IIb/IIIa Inhibitors
GP IIb/IIIa
inhibitor
used
Prasugrel
(%)
Clopidogrel
(%)
Hazard Ratio
(95% CI)
p value for
interaction
TIMI major or minor bleed
Yes
No
3.3
1.7
2.9
1.1
1.16 (0.89, 1.50)
1.63 (1.05, 2.52)
0.19
TIMI major bleed
Yes
No
1.2
0.9
1.1
0.6
1.06 (0.69, 1.64)
1.47 (0.81, 2.66)
0.39
TIMI life-threatening
bleed
Yes
No
0.7
0.5
0.6
0.2
1.25 (0.70, 2.22)
2.61 (1.02, 6.67)
0.19
Procedure-related TIMI
major bleed
Yes
No
0.6
0.4
0.6
0.3
0.93 (0.52, 1.66)
1.20 (0.50, 2.89)
0.64
Intracranial hemorrhage
Yes
No
0.1
0.0
0.1
0.0
1.01 (0.14, 7.15)
0.98 (0.06, 15.66)
0.99
Need for blood
transfusion
Yes
No
2.2
1.5
2.0
1.1
1.11 (0.81, 1.52)
1.34 (0.85, 2.09)
0.50
Endpoint at 30 days
41
O’Donoghue M, et al. J Am Coll Cardiol 2009;54:678-685
The Efficacy and Safety of Prasugrel With and Without a
Glycoprotein IIb/IIIa Inhibitor in Patients With ACS
Undergoing PCI CONCLUSIONS
The current findings suggest that prasugrel compared with clopidogrel significantly reduces
the risk of CV events in patients undergoing PCI after ACS, regardless of whether a GP
IIb/IIIa inhibitor is used during index hospitalization.
Importantly, the use of a GP IIb/IIIa inhibitor does not appear to accentuate the relative
increase in bleeding observed with prasugrel versus clopidogrel when a loading dose of
thienopyridine is administered shortly before or at the time of PCI.
Prasugrel appears to be both safe and effective in the setting of GP IIb/IIIa inhibitor use in
patients with ACS undergoing PCI. These data also support the concept tha inhibition of
platelet activation and aggregation are complementary and that there is additive value for
enhanced targeting of the P2Y12 receptor in the setting of GP IIb/IIIa receptor blockade.
Efforts should continue to be made to help identify those individuals who will have the
potential to achieve the greatest benefit from treatment with prasugrel without a significant
excess in bleeding.
Prasugrel significantly reduces the risk of cardiovascular events in patients with acute
coronary syndromes after percutaneous coronary intervention regardless of whether or not a
GP IIb/IIIa inhibitor is used. The use of a GP IIb/IIIa inhibitor does not accentuate the relative
risk of bleeding with prasugrel as compared with clopidogrel.
O’Donoghue Anerican College Vol. 54, No. 8, 2009 42
TRITON TIMI 38
The Balance of Efficacy and Safety in Selected Subgroups
Additional work to define populations with an increased risk of bleeding,
in association with oral regimens yielding high degrees of inhibition of
platelet aggregation, is likely to be helpful in guiding therapy
43
Wiviott et al. N Engl J Med 2007;357:2001-2015
Indicazioni
Efient, somministrato in associazione con acido acetilsalicilico (ASA), è
indicato per la prevenzione di eventi di origine aterotrombotica in
pazienti con sindrome coronarica acuta (ACS) (cioè angina instabile,
infarto miocardico senza sopraslivellamento del tratto ST [UA/NSTEMI]
o infarto miocardico con sopraslivellamento del tratto ST [STEMI])
sottoposti a intervento coronarico percutaneo (PCI) primario o
ritardato.
Efient SPC 44
Controindicazioni
•Ipersensibilità al principio attivo o ad uno qualsiasi degli
eccipienti.
•Sanguinamento patologico in atto.
•Storia clinica di ictus o di attacco ischemico transitorio (TIA).
•Disfunzione epatica grave (classe Child-Pugh C).
Efient SPC 45
Posologia
Adulti
• Efient deve essere iniziato con una singola dose di carico di 60 mg e
quindi continuato con 10 mg una volta al giorno. I pazienti che
assumono Efient devono assumere anche acido acetilsalicilico (ASA)
75 mg - 325 mg al giorno.
• In pazienti con sindrome coronarica acuta (ACS) sottoposti a intervento
coronarico percutaneo, l’interruzione anticipata di qualsiasi farmaco
antiaggregante piastrinico, incluso Efient, potrebbe portare a un
aumentato rischio di trombosi, infarto miocardico o morte dovuta alla
situazione patologica di base del paziente. Si raccomanda un
trattamento di durata fino a 12 mesi, a meno che l’interruzione del
trattamento con Efient sia clinicamente indicata.
Efient SPC 46
Posologia in pz ≥ 75 anni
• L’impiego di Efient in pazienti di età ≥ 75 anni non è generalmente
raccomandato.
• Se, dopo attenta valutazione del rapporto beneficio/rischio individuale da
parte del medico che prescrive la terapia, il trattamento con Efient viene ritenuto
necessario in pazienti nella fascia di età ≥ 75 anni, allora dopo la dose di carico
di 60 mg si dovrà prescrivere una dose di mantenimento ridotta pari a 5 mg.
I pazienti di età ≥ 75 anni hanno una maggiore sensibilità al sanguinamento
e una maggiore esposizione al metabolita attivo di prasugrel.
• I dati a sostegno della dose di 5 mg si basano solamente su analisi
farmacodinamiche / farmacocinetiche e attualmente non esistono dati clinici sulla
sicurezza di questa dose nei pazienti della fascia di età ≥ 75 anni.
Efient SPC 47
Posologia in pazienti < 60 kg
• Efient deve essere somministrato con una singola dose di carico
di 60 mg seguita da una dose di 5 mg una volta al giorno.
• Una dose di mantenimento di 10 mg non è raccomandata. Ciò è
dovuto ad un aumento dell’esposizione al metabolita attivo di
prasugrel, e ad un aumento del rischio di sanguinamento nei
pazienti con peso <60 kg che assumono una dose di 10 mg una
volta al giorno in confronto a pazienti di peso ≥60 kg.
Efient SPC 48
Incidenza di sanguinamento non correlato a
intervento di bypass coronarico (CABG)a (% di Pazienti)
Evento
Intera popolazione di ACS
Prasugrel
b
Clopidogrel
b
Popolazione UA/NSTEMI
Prasugrel
b
Clopidogrel
Popolazione STEMI
b
Prasugrel
b
Clopidogrel
+ASA
+ASA
+ASA
+ASA
+ASA
+ASA
(N=6.741)
(N=6.716)
(N=5.001)
(N=4.980)
(N=1.740)
(N=1.736)
2,2
1,7
2,2
1,6
2,2
2
1,3
0,8
1,3
0,8
1,2
1
0,3
0,1
0,3
0,1
0,4
0,1
ICH sintomatica
0,3
0,3
0,3
0,3
0,2
0,2
Che ha richiesto
medicinali inotropi
Che ha richiesto
intervento chirurgico
Che ha richiesto
trasfusione (≥4 unità)
0,3
0,1
0,3
0,1
0,3
0,2
0,3
0,3
0,3
0,3
0,1
0,2
0,7
0,5
0,6
0,3
0,8
0,8
2,4
1,9
2,3
1,6
2,7
2,6
Sanguinamento
c
maggiore (TIMI)
d
A rischio di morte
Mortale
e
Sanguinamento minore
f
(TIMI)
b
Efient SPC 49
Piano Terapeutico
• CLASSE DI RIMBORSABILITÀ : A
• PRESCRIZIONE del medicinale
soggetta a diagnosi piano
terapeutico
• PREZZO AL PUBBLICO:
• Efient 10 mg, Efient 5 mg: € 72,15.
• REGIME DI DISPENSAZIONE:
Ricetta ripetibile.
Efient SPC 50
Clinical Service Center 24/7
Per ulteriori informazioni o dettagli su EFIENT® il medico potrà contattare il
numero verde:
06-89386013
oppure inoltrare richiesta di informazione via e-mail al seguente indirizzo:
[email protected]
51