HEARTLINE HSM Genoa
Cardiology Meeting
NUOVI ORIZZONTI FARMACOLOGICI NELLA CARDIOPATIA ISCHEMICA
Cardiopatia ischemica: nuovi orizzonti nella
terapia con antiaggreganti orali
Giancarlo Casolo
Genova, Hotel NH Marina
21/22 Ottobre 2011
ESC Guideline 2010
Guidelines on myocardial revascularization
Prasugrel
Ticagrelor
Guidelines on myocardial revascularization
ESC Guideline 2011
STUDIO PLATO
STUDIO TRITON TIMI 38
Current Oasis 7
STUDIO TRITON TIMI 38
STUDIO PLATO
TRITON: Results
Balance of
Efficacy and Safety
15
138
events
Clopidogrel
Endpoint (%)
12.1
CV Death / MI / Stroke
9.9
10
HR 0.81
(0.73-0.90)
P=0.0004
NNT = 46
Prasugrel
5
TIMI Major
NonCABG Bleeds
Prasugrel
0
0 30 60 90
180
Adapted with permission from Wiviott SD et al
NEJM 357:2007
270
Days
35
events
2.4 HR 1.32
1.8 (1.03-1.68)
Clopidogrel
P=0.03
NNH = 167
360
450
ACC/AHA 2009 Joint STEMI/PCI Guidelines Focused Update
10
Timing of Benefit
(Landmark Analysis)
Primary Endpoint (%)
8
Clopidogrel
6
5.6
4
4.7
5.6
Prasugrel
Prasugrel
HR 0.82
P=0.01
2
6.9
Clopidogrel
HR 0.80
P=0.003
1
0
0
1
2
Loading Dose
3
0
30 60 90
Days
180
270
360
Maintenance Dose
450
Principali risultati nello studio
TRITON TIMI 38
ACC/AHA 2009 Joint STEMI/PCI Guidelines Focused Update
TRITON: Previous STOKE or TIA (3.8%)
Wiviot SD et al. N Engl J Med 2007;357:2001-2015
PLATO study design
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)
Clopidogrel
If pre-treated, no additional loading dose;
if naive, standard 300 mg loading dose,
then 75 mg qd maintenance;
(additional 300 mg allowed pre PCI)
Ticagrelor
180 mg loading dose, then
90 mg bid maintenance;
(additional 90 mg pre-PCI)
6–12-month exposure
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 mortality
Primary safety:
• Total major bleeding
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)
Cumulative incidence (%)
Completeness of follow-up 99.97% = five patients lost to follow-up
13
12
11
10
9
8
7
6
5
4
3
2
1
0
9.8
Ticagrelor
HR 0.84 (95% CI 0.77–0.92), p=0.0003
0
No. at risk
Ticagrelor
11.7
Clopidogrel
60
120
180
240
300
360
Days after randomisation
9,333
8,628
8,460
8,219
6,743
5,161
4,147
Clopidogrel 9,291
8,521
8,362
8,124
6,743
5,096
4,047
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
Ticagrelor
(n=9,333)
Clopidogrel
(n=9,291)
HR for
ticagrelor
(95% CI)
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
901 (10.2)
1,065 (12.3)
0.84 (0.77–0.92)
<0.001
1,290 (14.6) 1,456 (16.7)
0.88 (0.81–0.95)
<0.001
All patients*
CV death + MI + stroke +
ischaemia + TIA + arterial
thrombotic events
P Value†
Myocardial infarction
504 (5.8)
593 (6.9)
0.84 (0.75–0.95)
0.005
CV death
353 (4.0)
442 (5.1)
0.79 (0.69–0.91)
0.001
Stroke
125 (1.5)
106 (1.3)
1.17 (0.91–1.52)
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
13
12
Ticagrelor
Clopidogrel
NS
11.6
11.2
K-M estimated rate (% per year)
11
NS
10
8.9
NS
9
7.9
8
8.9
7.7
NS
7
5.8
6
5.8
5
4
3
2
NS
1
0.3
0.3
0
PLATO major
bleeding
TIMI major
bleeding
Red cell
transfusion *
PLATO lifethreatening/
fatal bleeding
Fatal bleeding
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
Wallentin L et al. N Engl J Med. 2009 Sep 10;361(11):1045-57
Dyspnoea
Ticagrelor
All patients
Clopidogrel HR for ticagrelor
(n=9,235)
(n=9,186)
(95% CI)
P Value
Any dyspnoea adverse event
13.8
7.8
1.84 (1.68–2.02)
<0.001
Discontinued due to dyspnoea
0.9
0.1
6.12 (3.41–11.01)
<0.001
Dyspnoea*, %
* 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
Ticagrelor
(n=1,451)
Clopidogrel
(n=1,415)
P Value
Ventricular pauses ≥3 seconds, n (%)
84 (5.8)
51 (3.6)
0.01
Ventricular pauses ≥5 seconds, n (%)
29 (2.0)
17 (1.2)
0.10
Ticagrelor
(n= 985)
Clopidogrel
(n=1,006)
P Value
Ventricular pauses ≥3 seconds, n (%)
21 (2.1)
17 (1.7)
0.52
Ventricular pauses ≥5 seconds, n (%)
8 (0.8)
6 (0.6)
0.60
Ticagrelor
Clopidogrel
P Value
(n=89)
(n=62)
4 (4.5)
8 (12.9)
Holter monitor first week
Holter monitor at 30 days
Patients with Ventricular Pauses ≥3 seconds
Patients with symptomatic pauses, n (%)
Wallentin L et al. N Engl J Med. 2009 Sep 10;361(11):1045-57
0.06
Risultati principali
TRITON
morte CV, IM, CVA
9.9 vs 12.1%, RRR -19%
NNT 46
CABG related bleeding NNH 10
PLATO
morte cause vascolari, IM,CVA
9.8 vs 11.7%, RRR -16%
NNT 53
Platelets and Coronary Thrombosis
Coronary plaque
Erosion/rupture
Thrombotic occlusion
Davies MJ. Am J Cardiol. 2001 Aug 16;88(4A):2F-9F
Meccanismi di attivazione piastrinica
Wallentine L. Eur Heart J 2009
Limitations of clopidogrel
 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)
Clopidogrel Response Variability
Baseline - 2hr (5mol ADP)
24
Resistance = 63%
Number of patients
20
16
12
8
4
0
≤ -30
-20, -10
-30, -20
-10, 0
0, 10
20, 30
10, 20
40, 50
30, 40
∆ percent aggregation
Gurbel PA et al. Circulation 2003; 107:2908
60, 70
50, 60
> 80
70, 80
Attività piastrinica residua ed eventi
cardiovascolari
Price M et Al. Circulation 2011
Kaplan Meier Survival Curves
1789 Pazienti consecutivi
14% HRPP
14.6%
8.7%
9.7%
4.3%
Parodi G et Al. JAMA 2011
Cardiac death, myocardial infarction,
any urgent coronary revascularization,
and stroke at 2-year follow up
Verify-now
LTA ADP
WDA ADP
PFA 100
ESC Guideline 2011
Antiplatelets Drug metabolism
Ticagrelor
O
F
O
O
N
S
Prasugrel
O
CI
N
S
O
Clopidogrel
N
O
O
N
O
S
O
N
N
N
N
No in vivo
biotransformation
Active compoud
Intermediate metabolite
Prodrug
F
F
Ticagrelor
Prasugrel
Clopidogrel
CYP-dependent
oxidation
CYP3A4/5
CYP2B6
CYP2C19
CYP2C9
CYP2D6
Hydrolysis
by esterase
Binding
Platelet
P2Y12
CYP-dependent
oxidation
CYP1A2
CYP2B6
CYP2C19
CYP-dependent
oxidation
CYP2C19
CYP3A4/5
CYP2B6
Diverso meccanismo d’azione degli
inibitori del recettore P2Y12
Becker RC, Gurbel PA Thromb Haemost 2010
New Antiplatelet Agents
Greater and More Consistent IPA
with AZD6140 than Clopidogrel
Final Extent
Mean percent inhibition
100
AZD6140 100 mg bd
100
80
80
60
60
40
40
20
20
0
0 2 4 8 12
Day 1
2 4 8
12
Day 14
Hours
Clopidogrel
24
0
0 2 4 8 12
Day 1
2 4 8
12
Day 14
Hours
24
Circulation 2010
Inhibition of Platelet Aggregation (IPA) percent
Onset and Offset of the Antiplatelet Effects
Ticagrelor vs Clopidogrel
100
Gurbel PA et al,
Last
maintenance
dose
Loading
90 dose
Ticagrelor (n=54)
Clopidogrel (n=50)
Placebo (n=12)
80
70
60
50
40
30
20
10
0
0
0.5
1
2
4
Onset
Circulation 2009; 120: 2577-2585
8
24
6 weeks
0
2
Maintenance
Time (hours)
4
8
24
48
Offset
72 120 168 240
Quale antiaggregante?
• Non esistono studi di confronto tra
Prasugrel e Ticagrelor
• E’ possibile identificare una tipologia di
paziente specifica per ciascun farmaco
Recent Meta-Analyses
Adjusted 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 e
avviato 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