TEMA

1. DRA. LAURA FLORES
RESIDENCIA DE CARDIOLOGIA
SANATORIO NUESTRA SEÑORA DEL ROSARIO
JUJUY - 2013

2. CURE
Shear, PCI
Plaque Rupture
Central Role of Platelets in the Genesis of Thrombosis
Initial
Activation
Thrombin
Tissue Factor
Collagen
vWF
TxA2
ADP
PAR-1
P2Y12
TP
Activation
Granule
Secretion
Amplification
Amplification
Amplification
COX-1
Adapted from Gurbel PA et al. J Am Coll Cardiol. 2007;50:1822-34.
X
X
X
X Platelet
Aggregation
GPIIb/IIIa
Activation
Fibrinogen
Fibrin
+
Platelet -Fibrin
Clot Formation

3. CURE

4. CURE

5. CURE
Unión covalente
irreversible al receptor
P2Y12
Hidrólisis por esterasas
Droga activa 15%
Metabolitos inactivos
eliminados por orina/heces
85%
Meadows TA, et al. Circ Res. 2007;100(9):1261-1275; Beitelshees A, et al. Arterioscler Thromb Vasc Biol. 2006;26:1681-1683; Wiviott S, et al. Circulation. 2010; 122: 394-403; Cattaneo M.
Eur Heart J. 2008;10(Suppl I):I33-I3; Ibanez B, et al. Eur Heart J. 2006:8:G.3
Proporción variable de prodroga
metabolizada a droga activa a través
del citocromo P450
ADP
MECANISMO DE ACCION DE LAS
TIENOPIRIDINAS

6. CURE
CLOPIDOGREL

7. CURE
N Engl J Med, Vol. 345, No. 7 · August 16, 2001

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Primary End Point - MI/Stroke/CV Death
0,00
0,02
0,04
0,06
0,08
0,10
0,12
0,14
Cumulative
Hazard
Rate
Clopidogrel
+ ASA*
3 6 9
Placebo
+ ASA*
Months of Follow-Up
11.4%
9.3%
20% RRR
P < 0.001
N = 12,562
0 12
* In combination with standard therapy
The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.

9. CURE
CV death, MI,
stroke (Primary 11.4% 9.3% 20% < 0.001
end point)
MI 6.7% 5.2% 23%
Stroke 1.4% 1.2% 14%
CV death 5.5% 5.1% 7%
Relative
Risk
Reduction P value
Outcome
Placebo
+ ASA*
N = 6303
Clopidogrel
+ ASA*
N = 6259
* In combination with standard therapy
The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.
Main Efficacy Results - Primary Endpoint

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RRR P value
End Point
Placebo
+ ASA*
Clopidogrel
+ ASA*
Main Efficacy Results -
Second Primary End Point
Second Primary End Point 18.8% 16.5% 14% < 0.001
Refractory Ischemia 9.3% 8.7% 7% NS**
– Refractory Ischemia
in hospital 2.0% 1.4% 32% P < 0.001
– Refractory Ischemia
after discharge 7.6% 7.6% 1% NS**
Severe Ischemia 3.8% 2.8% 26% P = 0.003
Recurrent Ischemia 22.9% 20.9% 9% P = 0.01
Heart Failure† 4.4% 3.7% 18% P = 0.03
* In combination with standard therapy
** Not significant
† Heart failure was a secondary end point The CURE Trial Investigators. N Engl J Med. 2001;345:494-502.

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Alteraciones en la absorción
(polimorfismos proteína codificadora
glicoproteína-P (ABCB1*)
* Dosis adecuada/Adherencia al Tx
Alteraciones en la activación
(polimorfismos CYP450)
Alteraciones en la activación de
receptores P2Y12 (polimorfismos
P2RY12)
ABCB1: ATP-binding cassette sub-family B member 1 (gen codificador de la
glicoproteina-P)
Metabolito activo
15% dosis
ingerida
EL PROBLEMA DEL CLOPIDOGREL

12. CURE
PRASUGREL

13. CURE

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Double-blind
ACS (STEMI or UA/NSTEMI) & Planned PCI
ASA
PRASUGREL
60 mg LD/ 10 mg MD
CLOPIDOGREL
300 mg LD/ 75 mg MD
1o endpoint: CV death, MI, Stroke
2o endpoints: CV death, MI, Stroke, Rehosp-Rec Isch
CV death, MI, UTVR
Stent Thrombosis (ARC definite/prob.)
Safety endpoints: TIMI major bleeds, Life-threatening bleeds
Key Substudies: Pharmacokinetic, Genomic
Median duration of therapy - 12 months
N= 13,600
TRITON TIMI 38

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0
5
10
15
0 30 60 90 180 270 360 450
HR 0.81
(0.73-0.90)
P=0.0004
Prasugrel
Clopidogrel
HR 0.80
P=0.0003
HR 0.77
P=0.0001
Days
Primary
Endpoint
(%)
12.1
(781)
9.9
(643)
Primary Endpoint CV Death, MI, Stroke
NNT= 46
ITT= 13,608 LTFU = 14 (0.1%)

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Stent Thrombosis (ARC Definite + Probable)
0
1
2
3
0 30 60 90 180 270 360 450
HR 0.48
P <0.0001
Prasugrel
Clopidogrel
2.4
(142)
NNT= 77
1.1 (68)
Days
Endpoint
(%)
Any Stent at Index PCI
N= 12,844

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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
Endpoint
(%)
12.1
9.9
HR 1.32
(1.03-1.68)
P=0.03
Prasugrel
Clopidogrel 1.8
2.4
138
events
35
events
Balance of Efficacy and Safety
CV Death / MI / Stroke
TIMI Major
NonCABG Bleeds
NNT = 46
NNH = 167

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TICAGRELOR

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PLATO

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PLATO study design
Primary endpoint: CV death + MI + Stroke
Primary safety endpint: Total major bleeding
6–12-month exposure
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)
NSTE-ACS (moderate-to-high risk) STEMI (if primary PCI)
Clopidogrel-treated or -naive;
randomised within 24 hours of index event
(N=18,624)
PCI = percutaneous coronary intervention; ASA = acetylsalicylic acid;
CV = cardiovascular; TIA = transient ischaemic attack

21. CURE
8,688
8,763
0 10 20 30
8
6
4
2
0
Cumulative
incidence
(%)
Clopidogrel
Ticagrelor
4.77
5.43
HR 0.88 (95% CI 0.77–1.00), p=0.045
No. at risk
Clopidogrel
Ticagrelor
9,291
9,333
8,875
8,942
8,763
8,827
Days after randomisation
31 90 150 210 270 330
8
6
4
2
0
Clopidogrel
Ticagrelor
5.28
6.60
8,688
8,673
8,286
8,397
6,379
6,480
Days after randomisation*
HR 0.80 (95% CI 0.70–0.91), p<0.001
8,437
8,543
6,945
7,028
4,751
4,822
Cumulative
incidence
(%)
Primary efficacy endpoint over time (composite
of CV death, MI or stroke)
*Excludes patients with any primary event during the first 30 days

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Time to major bleeding – primary safety event
No. at risk
Clopidogrel
Ticagrelor
9,186
9,235
7,305
7,246
6,930
6,826
6,670
Days from first IP dose
5,209
5,129
3,841
3,783
3,479
3,433
0 60 120 180 240 300 360
10
5
0
15
Clopidogrel
Ticagrelor
11.20
11.58
6,545
HR 1.04 (95% CI 0.95–1.13), p=0.434
K-M
estimated
rate
(%
per
year)

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CUAL ES MEJOR..?

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CONCLUSIONES
• Individualizar el paciente, teniendo en cuenta
comorbilidades y aspecto sociocultural.
•Clopidogrel es una droga noble estudiada en múltiples
estudios ramdomizados que reunieron en total 42.000
pacientes, que ha demostrado beneficios.
• Prasugrel tiene un potente efecto antiagregante, y deberia
usarse en los subgrupos de pacientes en el que el beneficio
no exeda los perjuicios.
• Ticagrelor es una droga con la ventaja de ser reversible y
que ha demostrado amplio beneficio., en todos las
situaciones de SCA.

25. CURE