Post on 31-Mar-2015
Cardiopatia ischemica: nuovi orizzonti nella terapia con antiaggreganti orali
Giancarlo Casolo
Genova, Hotel NH Marina21/22 Ottobre 2011
HEARTLINE HSM GenoaCardiology Meeting
NUOVI ORIZZONTI FARMACOLOGICI NELLA CARDIOPATIA ISCHEMICA
ESC Guideline 2010
Guidelines on myocardial revascularization
Guidelines on myocardial revascularization
PrasugrelTicagrelor
ESC Guideline 2011
STUDIO PLATO
STUDIO TRITON TIMI 38
Current Oasis 7
STUDIO TRITON TIMI 38
STUDIO PLATO
ACC/AHA 2009 Joint STEMI/PCI Guidelines Focused Update
10
0
5
10
15
0 30 60 90 180 270 360 450
HR 0.81(0.73-0.90)P=0.0004
Prasugrel
Clopidogrel
Days
En
dp
oin
t (%
)
12.1
9.9
HR 1.32(1.03-1.68)
P=0.03
Prasugrel
Clopidogrel1.82.4
138 events
35 events
Balance of Balance of Efficacy and SafetyEfficacy and Safety
CV Death / MI / Stroke
TIMI Major NonCABG Bleeds
NNT = 46
NNH = 167Adapted with permission from Wiviott SD et al NEJM 357:2007
TRITON: Results
0
2
4
6
8
0 1 2 3
1
0
3060 90 180 270 360 450
HR 0.82P=0.01
HR 0.80P=0.003
5.6
4.7
6.9
5.6
Days
Pri
ma
ry E
nd
po
int
(%)
Prasugrel
Clopidogrel
Prasugrel
Clopidogrel
Loading Dose Maintenance Dose
Timing of BenefitTiming of Benefit(Landmark Analysis)(Landmark Analysis)
ACC/AHA 2009 Joint STEMI/PCI Guidelines Focused Update
Principali risultati nello studio TRITON TIMI 38
TRITON: Previous STOKE or TIA (3.8%)
Wiviot SD et al. N Engl J Med 2007;357:2001-2015
PLATO study design
Primary endpoint: • CV death + MI + Stroke Key secondary: • CV death + MI + Stroke in patients intended for invasive management • Total mortality + MI + Stroke • CV death + MI + Stroke + recurrent ischaemia + TIA + arterial thrombotic events • MI alone / CV death alone / Stroke alone / Total mortalityPrimary safety: • Total major bleeding
6–12-month exposure
ClopidogrelIf pre-treated, no additional loading dose;if naive, standard 300 mg loading dose,
then 75 mg qd maintenance;(additional 300 mg allowed pre PCI)
Ticagrelor180 mg loading dose, then
90 mg bid maintenance;(additional 90 mg pre-PCI)
UA/NSTEMI (moderate-to-high risk) STEMI (if primary PCI)All receiving ASA; clopidogrel-treated or -naive;
randomised within 24 hours of index event (N=18,624)
UA = unstable angina; PCI = percutaneous coronary intervention; ASA = acetylsalicylic acid; CV = cardiovascular; TIA = transient ischaemic attack
James S et al. Am Heart J 2009;157:599-605
K-M estimate of time to first primary efficacy event (Composite of CV death, MI or stroke)
No. at risk
Clopidogrel
Ticagrelor
9,291
9,333
8,521
8,628
8,362
8,460
8,124
Days after randomisation
6,743
6,743
5,096
5,161
4,047
4,147
0 60 120 180 240 300 360
121110
9876543210
13C
um
ula
tive
inci
den
ce (
%)
9.8
11.7
8,219
HR 0.84 (95% CI 0.77–0.92), p=0.0003
Clopidogrel
Ticagrelor
Completeness of follow-up 99.97% = five patients lost to follow-up
K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval
Wallentin L, Harrington R et al. New Engl J Med 2009;361 (10.1056/NEJMoa0904327).
Hierarchical testing of major efficacy endpoints
All patients*Ticagrelor(n=9,333)
Clopidogrel(n=9,291)
HR for ticagrelor(95% CI) P Value†
Primary objective, n (%)
CV death + MI + stroke 864 (9.8) 1,014 (11.7) 0.84 (0.77–0.92) <0.001
Secondary objectives, n (%)
Total death + MI + stroke
CV death + MI + stroke + ischaemia + TIA + arterial thrombotic events
Myocardial infarction
CV death
Stroke
901 (10.2)
1,290 (14.6)
504 (5.8)
353 (4.0)
125 (1.5)
1,065 (12.3)
1,456 (16.7)
593 (6.9)
442 (5.1)
106 (1.3)
0.84 (0.77–0.92)
0.88 (0.81–0.95)
0.84 (0.75–0.95)
0.79 (0.69–0.91)
1.17 (0.91–1.52)
<0.001
<0.001
0.005
0.001
0.22
Total death 399 (4.5) 506 (5.9) 0.78 (0.69–0.89) <0.001
*The percentages are K-M estimates of the rate of the endpoint at 12 months. Patients could have had more than one type of endpoint. Death from CV causes included fatal bleeding and only traumatic fatal bleeds were excluded from the CV death category; †By Cox regression analysis
Wallentin L, Harrington R et al. New Engl J Med 2009;361 (10.1056/NEJMoa0904327).
PLATO Conservative Arm
James et Al. BMJ 2011
Total major bleeding
NS
NS
NS
NS
NS
0
K-M
est
ima
ted
rat
e (%
per
ye
ar)
PLATO major bleeding
1
2
3
4
5
6
7
8
9
10
12
11
13
TIMI major bleeding
Red cell transfusion *
PLATO life-threatening/
fatal bleeding
Fatal bleeding
TicagrelorClopidogrel
Major bleeding and major or minor bleeding according to TIMI criteria refer to nonadjudicated events analyzed with the use of a statistically programmed analysis in accordance with definition described in (Wiviott SD et al. NEJM. 357:2001-2015); *Proportion of patients (%); NS = not significant
11.611.2
7.9 7.7
8.9 8.9
5.8 5.8
0.3 0.3
Wallentin L et al. N Engl J Med. 2009 Sep 10;361(11):1045-57
Dyspnoea
All patients
Ticagrelor
(n=9,235)
Clopidogrel
(n=9,186)
HR for
ticagrelor
(95% CI) P Value
Dyspnoea*, %
Any dyspnoea adverse event
Discontinued due to dyspnoea
13.8
0.9
7.8
0.1
1.84 (1.68–2.02) 6.12 (3.41–11.01)
<0.001
<0.001* Combined incidence of dyspnoea, dyspnoea at rest, dyspnoea exertional, dyspnoea paroxysmal nocturnal and nocturnal dyspnoea
Wallentin L et al. N Engl J Med. 2009 Sep 10;361(11):1045-57
Holter monitoring program
Holter monitor first weekTicagrelor(n=1,451)
Clopidogrel(n=1,415) P Value
Ventricular pauses ≥3 seconds, n (%)
Ventricular pauses ≥5 seconds, n (%)
84 (5.8)
29 (2.0)
51 (3.6)
17 (1.2)
0.01
0.10
Holter monitor at 30 days Ticagrelor(n= 985)
Clopidogrel(n=1,006)
P Value
Ventricular pauses ≥3 seconds, n (%)
Ventricular pauses ≥5 seconds, n (%)
21 (2.1)
8 (0.8)
17 (1.7)
6 (0.6)
0.52
0.60
Patients with Ventricular Pauses ≥3 seconds Ticagrelor
(n=89)
Clopidogrel
(n=62)
P Value
Patients with symptomatic pauses, n (%) 4 (4.5) 8 (12.9) 0.06
Wallentin L et al. N Engl J Med. 2009 Sep 10;361(11):1045-57
Risultati principali
TRITON morte CV, IM, CVA9.9 vs 12.1%, RRR -19%NNT 46CABG related bleeding NNH 10
PLATO morte cause vascolari, IM,CVA
9.8 vs 11.7%, RRR -16%NNT 53
Platelets and Coronary Thrombosis
Davies MJ. Am J Cardiol. 2001 Aug 16;88(4A):2F-9F
Coronary plaque Erosion/rupture Thrombotic occlusion
Meccanismi di attivazione piastrinica
Wallentine L. Eur Heart J 2009
Slow onset of action (steady state platelet
inhibition: 4 - 5 hour after 300-600 mg load)
Modest inhibition of platelet aggregation
(steady state mean platelet inhibition 30 - 40%)
Slow offset of effect (at least 5 – 7 days)
Large interindividual variability in inhibition of platelet aggregation (poor platelet inhibition
response in 15 - 40% of pts)
Limitations of clopidogrel
Clopidogrel Response VariabilityBaseline - 2hr (5mol ADP)
∆ percent aggregationGurbel PA et al. Circulation 2003; 107:2908
Num
ber o
f pat
ient
s
0
4
8
12
16
20
24
≤ -30
-30, -20
-20, -10
-10, 0
0, 10
10, 20
20, 30
30, 40
40, 50
50, 60
60, 70
70, 80
> 80
Resistance = 63%
Attività piastrinica residua ed eventi cardiovascolari
Price M et Al. Circulation 2011
Kaplan Meier Survival Curves
Parodi G et Al. JAMA 2011Cardiac death, myocardial infarction, any urgent coronary revascularization, and stroke at 2-year follow up
14.6%
8.7% 9.7%
4.3%
1789 Pazienti consecutivi14% HRPP
Verify-nowLTA ADPWDA ADPPFA 100
ESC Guideline 2011
N
S
O
O
O
F
N
F
F
S N
O
O
N
NN
N
O
O
N
S
OCI
O
Ticagrelor
Prasugrel
Clopidogrel
ClopidogrelPrasugrelTicagrelor
Hydrolysisby esterase
CYP-dependentoxidation
CYP1A2CYP2B6
CYP2C19
CYP-dependentoxidationCYP2C19CYP3A4/5CYP2B6
Binding
P2Y12
CYP-dependentoxidationCYP3A4/5CYP2B6
CYP2C19CYP2C9CYP2D6
No in vivobiotransformation
Active compoud
Intermediate metabolite
Prodrug
Platelet
Antiplatelets Drug metabolism
Diverso meccanismo d’azione degli inibitori del recettore P2Y12
Becker RC, Gurbel PA Thromb Haemost 2010
New Antiplatelet Agents
Greater and More Consistent IPAwith AZD6140 than Clopidogrel
Final Extent
Mea
n pe
rcen
t inh
ibiti
on
Hours
AZD6140 100 mg bd
0
20
40
60
80
100
0 2 4 8 12 242 4 8 12Day 1 Day 14
Hours
Clopidogrel
0
20
40
60
80
100
0 2 4 8 12 242 4 8 12Day 1 Day 14
Circulation 2010
Onset
0
10
20
30
40
50
60
70
80
90
100
0 0.5 1 2 4 8 24 0 2 4 8 24 48 72 120 168 240
Onset and Offset of the Antiplatelet EffectsTicagrelor vs Clopidogrel
Time (hours)
Inhi
bitio
n of
Pla
tele
t Agg
rega
tion
(IPA
) per
cent
Gurbel PA et al, Circulation 2009; 120: 2577-2585
Ticagrelor (n=54)Clopidogrel (n=50)Placebo (n=12)
OffsetMaintenance
Loadingdose
Lastmaintenance
dose
6 weeks
Quale antiaggregante?
• Non esistono studi di confronto tra Prasugrel e Ticagrelor
• E’ possibile identificare una tipologia di paziente specifica per ciascun farmaco
Recent Meta-AnalysesAdjusted comparison of Prasugrel vs. Ticagrelor
Biondi-Zoccai G et al. Int J Cardiol 2010
Prasugrel
• Azione rapida, legame irreversibile
. soggetto “giovane”, nessuna storia di accidenti CV, peso > 60Kg,*
. paziente con STEMI avviato alla PCI
. ACS con anatomia coronarica nota eavviato alla PCI
*Non indizi di malattia che meriti BPAC
Ticagrelor
• Azione rapida , legame reversibile
. Paziente con ACS
. Quadro angiografico ignoto
. Clearance Creat >30 ml/min/1.73m2
Effetto dello switching tra farmaci
Gurbel et Al. Circulation,2010
Conclusioni
• Una moderna terapia antiaggregante dei pazienti con malattia coronarica consente di ridurre gli eventi ischemici e la mortalità nei pazienti con SCA
• I nuovi antiaggreganti sono più potenti, risentono poco o nulla delle differenze individuali, e sono più efficaci rispetto al clopidogrel
• Poiché si associano ad un rischio emorragico maggiore la selezione dei pazienti diventa molto importante nella scelta del farmaco da utilizzare e richiede un utilizzo giudizioso soppesando il rischio trombotico e quello emorragico
Eseguito con il WASP