Post on 26-Mar-2015
Nuove evidenze sull’impiego di antiaggreganti e anticoagulanti nello
STEMI e nelle SCA NSTE
Francesco Bovenzi
Dipartimento Cardio-RespiratorioU.O. di Cardiologia, Ospedale “Campo di Marte” Lucca LUCCA
CARDIOLOGIA
SYNERGY
LMWH
ESSENCE
1997
CURE
Clopidogrel
Ischemic risk
GP IIb/IIIa blockers
PRISM-PLUS
PURSUIT
ACUITYTACTICS TIMI-18
Early invasive
PCI ~ 5% stents ~85% stents Drug-eluting stents
ISAR-REACT 2
Milestones in ACS Management
OASIS-5
FondaparinuxAnti-Thrombin Rx
Anti-Platelet Rx
Treatment Strategy
Heparin
Aspirin
Conservative
ICTUS
Bivalirudin
REPLACE 2
Bleeding risk
19941994 19951995 19961996 19971997 19981998 19991999 20002000 20022002 20032003 20042004 20052005 2006 20102006 20102001200119901990
TRITON Timi 38
Prasugrel
CURRENT OASIS-7
PLATO
Ticagrenor
The result is 80 different combinations!
Extreme attention should be paid to the use of drugs or drug combinations and
dosages that may favour bleeding
Atalanta ACC 2010Eugene Braunwald
“I più potenti inibitori delle piastrine sono stati studiati nel TRITON TIMI-38 e nel PLATO che hanno posto le basi per l’alba di una nuova era della terapia antipiastrinica.
Finora non c’è stato nulla di “free lunch”, perché quando interveniamo sulla coagulazione troveremo associato, in ogni modo, un eccesso di sanguinamento.
La nostra futura sfida sarà trovare uno “sweet spot” nella ricerca di bilanciare l’efficacia con la sicurezza.”
Primary Therapeutic Goal for ACS
•Prevent the development of occlusive thrombus
•Arrest procoagulant activity and inflammation
•Attenuate platelet activation and aggregation
•Promote platelet disaggregation
•Facilitate perfusion
The Key Platelet Transmembrane Receptors
AA
ADP PGI2
IP
TXA2
TP
PLCCa++
ADP
Gq
+
IP3
Ca++
Ca++
AC
GS
+Gi
-
ATP
cAMP+ -
P2X1 P2Y1
ADP
P2Y12
Activation of GPIIb/IIIa
Binding of soluble fibrinogen
Aggregation
PGH2
TAX2
COX
TAXS
PAR
TRAP
AA
ADP PGI2
IP
TXA2
TP
PLCCa++
ADP
Gq
+
IP3
Ca++
Ca++
AC
GS
+Gi
-
ATP
cAMP+ -
P2X1 P2Y1
ADP
P2Y12
Activation of GPIIb/IIIa
Binding of soluble fibrinogen
Aggregation
PGH2
TAX2
COX
TAXS
PAR
TRAP
Conventional Antiplatelet Agents
ASA
ClopidrogelTiclopidina
ReoproTirofibanEptifibatide
AA
ADP PGI2
IP
TXA2
TP
PLCCa++
ADP
Gq
+
IP3
Ca++
Ca++
AC
GS
+Gi
-
ATP
cAMP+ -
P2X1 P2Y1
ADP
P2Y12
Activation of GPIIb/IIIa
Binding of soluble fibrinogen
Aggregation
PGH2
TAX2
COX
TAXS
PAR
TRAP
Conventional Antiplatelet Agents
ASA
ClopidrogelTiclopidina
ReoproTirofibanEptifibatide
PrasugrelTicagrelorCangrelor
AA
ADP PGI2
IP
TXA2
TP
PLCCa++
ADP
Gq
+
IP3
Ca++
Ca++
AC
GS
+Gi
-
ATP
cAMP+ -
P2X1 P2Y1
ADP
P2Y12
Activation of GPIIb/IIIa
Binding of soluble fibrinogen
Aggregation
PGH2
TAX2
COX
TAXS
PAR
TRAP
Conventional Antiplatelet Agents
ASA
ClopidrogelTiclopidina
ReoproTirofibanEptifibatide
PrasugrelTicagrelorCangrelor
SCH530348
P2Y12 inhibitors
AC+
Gi
-
ATP
cAMP
P2Y12
Ticlopidine and clopidogrel
• Prodrugs, converted in vivo by the hepatic cytochrome P-450 enzymatic pathway to active metabolites, 85% inactive metabolite
• Irreversibly inhibiting the receptor
• Because of the toxicity of ticlopidine (neutropenia, thrombotic thrombocytopenic purpura), ticlopidine has been almost completely replaced by clopidogrel in clinical practice.
P2Y12 inhibitors
AC+
Gi
-
ATP
cAMP
P2Y12
Ticlopidine and clopidogrel
• Prodrugs, converted in vivo by the hepatic cytochrome P-450 enzymatic pathway to active metabolites, 85% inactive metabolite
• Irreversibly inhibiting the receptor
• Because of the toxicity of ticlopidine (neutropenia, thrombotic thrombocytopenic purpura), ticlopidine has been almost completely replaced by clopidogrel in clinical practice.
Prasugrel
• Prodrugs, Prasugrel is a thienopyridine with 10-fold more potent anti-P2Y12 receptor inhibitory activity than clopidogrel. Conversion to its active metabolite is less dependence on CYP enzymes than clopidogrel
• Irreversibly inhibiting the receptor
• More rapid and consistent inhibitory effects on platelet aggregation than Clopidogrel
P2Y12 inhibitors
AC+
Gi
-
ATPcAMP
P2Y12
Ticlopidine and clopidogrel
• Prodrugs, converted in vivo by the hepatic cytochrome P-450 enzymatic pathway to active metabolites, 85% inactive metabolite
• Irreversibly inhibiting the receptor
• Because of the toxicity of ticlopidine (neutropenia, thrombotic thrombocytopenic purpura), ticlopidine has been almost completely replaced by clopidogrel in clinical practice.
Prasugrel
• Prodrugs, Prasugrel is a thienopyridine with 10-fold more potent anti-P2Y12 receptor inhibitory activity than clopidogrel. Conversion to its active metabolite is less dependence on CYP enzymes than clopidogrel
• Irreversibly inhibiting the receptor
• More rapid and consistent inhibitory effects on platelet aggregation than Clopidogrel
Ticagrelor
• Not a prodrug
• Rapid onset of inhibitory effect
•Reversibly bound with faster offset of effect and functional recovery of all circulating platelets
P2Y12 inhibitors
AC+
Gi
-
ATPcAMP
P2Y12Ticlopidine and clopidogrel
• Prodrugs, converted in vivo by the hepatic cytochrome P-450 enzymatic pathway to active metabolites, 85% inactive metabolite
• Irreversibly inhibiting the receptor
• Because of the toxicity of ticlopidine (neutropenia, thrombotic thrombocytopenic purpura), ticlopidine has been almost completely replaced by clopidogrel in clinical practice.
Prasugrel
• Prodrugs, Prasugrel is a thienopyridine with 10-fold more potent anti-P2Y12 receptor inhibitory activity than clopidogrel. Conversion to its active metabolite is less dependence on CYP enzymes than clopidogrel
• Irreversibly inhibiting the receptor
• More rapid and consistent inhibitory effects on platelet aggregation than Clopidogrel
Ticagrelor
• Not a prodrug
• Rapid onset of inhibitory effect
•Reversibly bound with faster offset of effect and functional recovery of all circulating platelets
Cangrelor
• ATP analogue
• Reversible binds to and inhibits the P2Y12 ADP receptor
• Immediately active after i.v. infusion
New P2Y12 inhibitors
AC+
Gi-
ATPcAMP
P2Y12
Elinogrel
Direct-acting, reversible P2Y12 inhibitor that can be administeredboth intravenously and orally
A Phase 2 Safety and Efficacy Study of Elinogrel a Novel Intravenous and Oral P2Y12 Inhibitor in Non-Urgent PCI (INNOVATE-PCI) is a multicenter, randomized, double-blind, triple-dummy,clopidogrel-controlled study of intravenous and oral elinogrelcompared with clopidogrel in patients undergoing nonurgent (including elective) PCI. After diagnostic angiography, patientsscheduled for nonurgent PCI will be randomized to clopidogrel or 1 of 3 doses of elinogrel.
The Early Rapid Reversal of Platelet Thrombosis With Intravenous Elinogrel Before PCI to Optimize Reperfusionin Acute MI (ERASE-MI) is a randomizedtrial evaluating the safety and tolerability of intravenous elinogrel (10, 20, 40,and 60 mg) before PCI in patients with STEMI
I ragionevoli dubbi con terapia anticoagulante e antiaggregante• Quale è il rischio e l’impatto degli eventi aterotrombotici
nelle SCA?• Quale è il rischio e l’outcome dei sanguinamenti nelle
SCA?• Esiste un compromesso clinico tra rischio emorragico e
beneficio della doppia antiaggregazione?• Quanto incide la biodiversità sulle scelte?• Quale è il timing del rischio di sanguinamento• Come affrontare il rischio di sanguinamento correlato ad
altre procedure invasive
Partiamo dalle evidenze dei tre ultimi grandi trial
Factorial Randomized Trial (2X2) of Optimal Clopidogrel and Aspirin Dosing in Patients with ACS Undergoing an Early Invasive Strategy with Intent For PCI
Factorial Randomized Trial (2X2) of Optimal Clopidogrel and Aspirin Dosing in Patients with ACS Undergoing an Early Invasive Strategy with Intent For PCI
Non ancora pubblica
to!
OASIS-7
2007
2009
ESC 2009
Study Design, Flow and Compliance25,087 ACS Patients (UA/NSTEMI 70.8%, STEMI 29.2%)
Planned Early (<24 h) Invasive Management with intended PCIIschemic ECG Δ (80.8%) or ↑cardiac biomarker (42%)
25,087 ACS Patients (UA/NSTEMI 70.8%, STEMI 29.2%)Planned Early (<24 h) Invasive Management with intended PCIIschemic ECG Δ (80.8%) or ↑cardiac biomarker (42%)
PCI 17,232(70%)
Angio 24,769(99%)
Angio 24,769(99%)
No PCI 7,855 (30%)
No Sig. CAD 3,616 CABG 1,809 CAD 2,430
Randomized to receive (2 X 2 factorial):
CLOPIDOGREL: Double-dose (600 mg then150 mg/d x 7d then 75 mg/d) vs Standard dose (300 mg then 75 mg/d)
ASA: High Dose (300-325 mg/d) vs Low dose (75-100 mg/d)
Efficacy Outcomes: CV Death, MI or stroke at day 30Stent Thrombosis at day 30
Safety Outcomes: Bleeding (CURRENT defined Major/Severe and TIMI Major)Key Subgroup: PCI v No PCI
Efficacy Outcomes: CV Death, MI or stroke at day 30Stent Thrombosis at day 30
Safety Outcomes: Bleeding (CURRENT defined Major/Severe and TIMI Major)Key Subgroup: PCI v No PCI
Complete Follow up
99.8%
Complete Follow up
99.8%
Clopidogrel: Double vs Standard DosePrimary Outcome and Components
Standard Double HR 95% CI P Intn P
CV Death/MI/Stroke
PCI (2N=17,232) 4.5 3.9 0.85 0.74-0.99 0.0360.016
No PCI (2N=7855) 4.2 4.9 1.17 0.95-1.44 0.14
Overall (2N=25,087) 4.4 4.2 0.94 0.84-1.07 0.370
MI
PCI (2N=17,232) 2.6 2.0 0.78 0.64-0.95 0.0120.025
No PCI (2N=7855) 1.4 1.7 1.25 0.87-1.79 0.23
Overall (2N=25,087) 2.2 1.9 0.86 0.73-1.03 0.097
CV Death
PCI (2N=17,232) 1.9 1.9 0.96 0.77-1.19 0.681.0
No PCI (2N=7855) 2.8 2.7 0.96 0.74-1.26 0.77
Overall (2N=25,087) 2.2 2.1 0.96 0.81-1.14 0.628
Stroke
PCI (2N=17,232) 0.4 0.4 0.88 0.55-1.41 0.590.50
No PCI (2N=7855) 0.8 0.9 1.11 0.68-1.82 0.67
Overall (2N=25,087) 0.5 0.5 0.99 0.70-1.39 0.950
Days
Cu
mu
lati
ve H
azar
d
0.0
0.01
0.02
0.03
0.04
0 3 6 9 12 15 18 21 24 27 30
Clopidogrel: Double vs Standard Dose Primary Outcome: PCI Patients
Clopidogrel Standard
Clopidogrel Double
HR 0.8595% CI 0.74-0.99
P=0.036
15% RRR15% RRR
CV Death, MI or StrokeCV Death, MI or Stroke
Days
Cu
mu
lati
ve H
azar
d
0.0
0.00
40.
008
0.01
2
0 3 6 9 12 15 18 21 24 27 30
Clopidogrel Standard Dose
Clopidogrel Double Dose
42% RRR
HR 0.5895% CI 0.42-0.79
P=0.001
Clopidogrel: Double vs Standard DoseDefinite Stent Thrombosis (Angio confirmed)
ConclusionsClopidogrel Dose Comparison
1. Double-dose clopidogrel significantly reduced major CV events in PCI (CV death, MI or stroke) and stent thrombosis
2. In patients not undergoing PCI double dose clopidogrel was not significantly different from standard dose
3. There was a modest excess in CURRENT-defined major bleeds but no difference in severe: TIMI major bleeds, ICH, fatal bleeds or CABG-related bleeds
Trial to Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition with Prasugrel Thrombolisis in MI
TRITON-TIMI 38: Balance of efficacy and safety
15
10
5
00 30 60 90 180 270 360 450
1.8
2.4
9.9
12.1
138 events
HR 0.81(0.73-0.90)p=0.0004NNT=46
35 events
HR 1.32(1.03-1.68)p=0.03NNH=167
Wiovitt SD et al. NEJM 2007
(6795 pts)
(6813 pts)
Diabetic SubgroupDiabetic Subgroup
0
2
4
6
8
10
12
14
16
18
0 30 60 90 180 270 360 450
HR 0.70P<0.001
Days
En
dp
oin
t (%
)
CV Death / MI / Stroke
TIMI Major NonCABG Bleeds
NNT = 20 (46)
N=3146N=3146
17.0
12.2
Prasugrel
Clopidogrel
Prasugrel
Clopidogrel 2.6
2.5
Montalescot G et al. Lancet 2008;372:1-9; Wiviott SD, N Engl J Med 2007;357(20):2001-15
TRITON-TIMI 38: Timing of benefit
0
2
4
6
8
0 1 2 3 3060 90 180 270 360 450 Days0
Loading Dose Maintenance Dose
Prim
ary
End
poin
t (%
)
Wiovitt SD et al. NEJM 2007
(6795 pts)
(6813 pts)
TRITON-TIMI 38: Stent Thrombosis (ARC Definite + Probable)
0 30 60 90 180 270 360 4500
1
2
3
Days
En
dpo
int (
%)
Wiovitt SD et al. NEJM 2007
TRITON-TIMI 38: Bleeding
0
2
4
Eve
nts
(%)
TIMI MajorBleedsARD 0.6%HR 1.32p=0.03NNH=167
LifeThreateningARD 0.5%HR 1.52p=0.01
Non fatal
ARD 0.2%p=0.23
Fatal
ARD 0.3%p=0.002
ICH
ARD 0%p=0.74
Wiovitt SD et al. NEJM 2007
OVERALL
>=60 kg
< 60 kg
< 75
>=75
No
Yes
0.5 1 2
Prior Stroke / TIA
Age
Wgt
Risk (%)
+ 37
-16
-1
-16
+3
-14
-13
Prasugrel Better Clopidogrel BetterHR
Pint = 0.006
Pint = 0.18
Pint = 0.36
Wiovitt SD et al. NEJM 2007
TRITON-TIMI 38: Bleeding risk subgroups
Safety
Significant increase in
serious bleeding(32% increase)
Avoid in pts with prior CVA/TIA
Efficacy
1. A significant reduction in: CV Death/MI/Stroke 19% Stent Thrombosis 52% uTVR 34%
MI 24%
2. An early and sustained benefit
3. Across ACS spectrum
Prasugrel 60 mg LD/10mg MD vs Clopidogrel 300 mg LD/ 75 mg MD
Higher IPA to Support PCI
Net clinical benefit significantly favored Prasugrel
Optimization of Prasugrel maintenance dosing in a minority of patients
may help improve the benefit: risk balance
Bleeding Risk SubgroupsTherapeutic Considerations
Significant Net Clinical Benefit
with Prasugrel80%
MD MD 10 mg10 mg
Reduced MD
Guided by PK
Age > 75 or
Wt < 60 kg
16%
Avo
id
Prasu
grel
Prio
r
CV
A/T
IA4%4%
Antman EM, AHA 2007
Study of Platelet Inhibition and Patient Outcomes: PLATO Study Design
Days after randomisation
Cum
ulat
ive
inci
denc
e (%
)
PLATO: Primary efficacy endpoint(CV death,MI or stroke)
Wallentin L et al. NEJM 2009
0 60 120 180 240 300 360
0
2
4
6
8
10
12 11.7
9.8
(9.291 pts)
(9.333 pts)
0 60 120 180 240 300 360 0 60 120 180 240 300 360
0
1
2
3
4
5
6
7
0
1
2
3
4
5
6
7
Days after randomization Days after randomization
Cum
ulat
ive
inci
denc
e (%
)
Cum
ulat
ive
inci
denc
e (%
)
Myocardial Infarction Cardiovascular death
PLATO: Secondary efficacy endpoints
Wallentin L et al. NEJM 2009
0 60 120 180 240 300 360
0
5
10
15
K-M
est
imat
ed r
ate
(% p
er y
ears
)
Days from first IP doseWallentin L et al. NEJM 2009
PLATO: Primary safety event (total major bleeding)
(9.235 pts)
(9.186 pts)
0
1
2
3
4
5
6
7
8
9
Non-CABGTIMI major bleeding
Non-CABGPLATO major bleeding*
CABGPLATO major bleeding*
CABGTIMI major bleeding
K-M
est
imat
ed r
ate
(% p
er y
ears
)PLATO: Non CABG and CABG major bleeding
Wallentin L et al. NEJM 2009
*Bleeding with clinically significant disability or associated with hemoglobin declive at least 3.0 g/dl but less 5.0 g/dl trasfusion of 2 to 3 units
No. at risk
Clopidogrel
Ticagrelor
6,676
6,732
6,157
6,268
6,062
6,173
5,917
Days after randomization
4,849
4,924
3,706
3,766
2,987
3,078
0 60 120 180 240 300 360
8
6
4
2
0
Cu
mu
lati
ve i
nci
de
nce
(%
)
Clopidogrel
Ticagrelor
5.3
6.6
6,010
0 60 120 180 240 300 360
8
4
2
0
Clopidogrel
Ticagrelor3.4
4.3
6
6,676
6,732
6,376
6,439
6,332
6,375
6,209
Days after randomization
5,114
5,141
3,917
3,591
3,164
3,2336,241
Myocardial infarction Cardiovascular death
Cu
mu
lati
ve i
nci
de
nce
(%
)
HR 0.80 (95% CI = 0.69–0.92), p=0.002 HR 0.82 (95% CI = 0.68–0.98), p=0.025
PLATO-invasive
Cannon PC et al. Lancet 2010
TicagrelorClopidogrel
NS
NS
NS
0
K-M
est
imat
ed r
ate
(% p
er y
ear)
PLATO major bleeding*
1
2
3
4
5
6
7
8
9
10
12
11
13
TIMI major bleeding
11.5 11.6
8.0 8.0
2.93.2
GUSTO severe bleeding*
4.7
4.1
2.8 2.3
1.9
1.7
No
n-C
AB
GC
AB
G
PLATO-invasive: Non-CABG and CABG-related major bleeding
Cannon PC et al. Lancet 2010
*Bleeding with clinically significant disability or associated with hemoglobin declive at least 3.0 g/dl but less 5.0 g/dl trasfusion of 2 to 3 units
- Inibisce in modo diretto la trombina legata al coagulo e circolante con uno specfico legame bivalente ai due siti - Non richiede la presenza dell'antitrombina- Inibisce la trombina mediata dall'attivazione piastrinica- Ha un'emivita plasmatica di 25 minuti- Non richiede monitoraggio
Luci e ombre della bivaliridina
Fibrina
Sito catalitico
Trombina
TrombinaTrombina
Trombina
Bivalirudina
1 2
Sito esterno
Study Design – Patient Flow
Moderate-high risk unstable angina or NSTEMI undergoing an invasive strategyModerate-high risk unstable angina or NSTEMI undergoing an invasive strategy
UFH/Enox+ GP IIb/IIIa(N=4,603)
Bivalirudin+ GP IIb/IIIa(N=4,604)
BivalirudinAlone(N=4,612)
R*
GPI upstream (N=2294)
GPI CCL for PCI (N=2309)
GPI upstream (N=2311)
GPI CCL for PCI (N=2293)
Aspirin in allAspirin in allClopidogrelClopidogreldosing and timingdosing and timingper local practiceper local practice
Aspirin in allAspirin in allClopidogrelClopidogreldosing and timingdosing and timingper local practiceper local practice
Moderate-high riskACS
ACUITY
Primary Endpoint Measures (ITT)
UFH/Enoxaparin + GPI vs. Bivalirudin AloneUFH/Enoxaparin + GPI vs. Bivalirudin Alone
11,7%
7,3%5,7%
3,0%
10,1%
7,8%
Net clinicaloutcome
Ischemiccomposite
Major bleeding
30 d
ay e
vent
s (%
)
UFH/Enoxaparin+GPI (N=4603) Bivalirudin alone (N=4612)
PNI <0.0001PSup = 0.015
PNI = 0.011PSup = 0.32
PNI <0.0001PSup <0.0001
ACUITY
Stone GW et al. N Engl J Med. 2006;355:2203–2216.
3602 randomized pts undergoing primary PCI3602 randomized pts undergoing primary PCI
Hypothesis: Use of the polymer-based slow-Use of the polymer-based slow-release release paclitaxel-eluting paclitaxel-eluting TAXUS stent will TAXUS stent will safely reduce the 1-year rate of ischemia-safely reduce the 1-year rate of ischemia-driven TLRdriven TLR
Hypothesis: Bivalirudin compared to UFH Bivalirudin compared to UFH + routine IIb/IIIa will r+ routine IIb/IIIa will reduce the composite educe the composite rate of death, reinfarction, TVR, stroke and rate of death, reinfarction, TVR, stroke and major bleeding at 30-daysmajor bleeding at 30-days
HORIZONS AMI Trial
UFH + UFH + IIb/IIIaIIb/IIIa
inhibitorinhibitor
BivalirudinBivalirudin++
bail-outbail-outIIb/IIIa IIb/IIIa
Randomize 1:1Randomize 1:1
Target vessel Target vessel stentingstenting
TAXUSTAXUSstentstent
Bare metal Bare metal Express stentExpress stent
Randomize 3:1Randomize 3:1
Anti-thrombotictherapy
HHarmonizing armonizing OOutcomes with utcomes with RRevascularevascularizizatiationon and and SStents in AMItents in AMI
UFH +GP IIb/IIIaN=1802
BivalirudinMonotherapyN=1800
R 1:1
RandomizedRandomized
30 day FU*30 day FU*
* Range ±7 days* Range ±7 days
ITT populationITT population
N=1778(98.7%)
N=1777(98.7%)
N=1802 N=1800
• • • • • • Withdrew • • •Withdrew • • •
• • • • • • Lost to FU • • •Lost to FU • • •99
15151010
1313
3602 pts with STEMI3602 pts with STEMI
Diff = Diff = 0.0% [-1.6, 1.5] RR = 0.99 [0.76, 1.30]
PPsupsup = 1.00 = 1.00
Primary Outcome Measures
Diff = Diff = -3.3% [-5.0, -1.6] RR RR = = 0.60 [0.46, 0.77]
PPNINI ≤ 0.0001 ≤ 0.0001
PPsupsup ≤ 0.0001 ≤ 0.0001
Diff = Diff = -2.9% [-4.9, -0.8]RR = RR = 0.76 [0.63, 0.92]
PPNINI ≤ 0.0001 ≤ 0.0001
PPsupsup = 0.006 = 0.006
1 endpoint 1 endpoint
Stone GW, et al. N Engl J Med. 2008;358(21):2218-2230.
Conclusioni- I nuovi farmaci che bloccano il recettore P2Y12 (prasugrel, ticagrelor) sono risultati più efficaci del clopidogrel grazie ad una migliore farmacocinetica e farmacodinamica. Ad essi si associa tuttavia un certo grado di rischio emorragico.
- La bivalirudina riduce i sanguinamenti locali e d’organo nei pazienti con SCA sottoposti a PCI, soprattutto in quelli a maggior rischio emorragico (anziani), ma per un’efficace copertura anti-ischemica deve essere associata ad un regime di doppia anti-aggregazione piastrinica.
- L’analisi di efficacia e di rischio in particolari sottogruppi di pazienti con SCA potrà permettere di utilizzare il farmaco più vantaggioso per quel dato contesto clinico.