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Rol actual de los nuevos antiplaquetarios en el
Sindrome Coronario AgudoDr. Ramón Corbalán H.
Facultad de Medicina
Pontificia Universidad Católica de Chile
Meadows TA, Bhatt DL. Circ Res. 2007;100:1261-1275.
Terapia Antiplaquetaria Dual
La inhibición de las plaquetas es una estrategia clave para tratar y
prevenir recurrencia de eventos isquémicos en pacientes
• Con sindromes coronarios agudos1,2
• Sometidos a PCI3
Las metas de este tratamiento son la inhibición rápida, consistente y
efectiva de la activación y agregación plaquetaria3-5
La terapia antiplaquetaria dual con AAS y una tienopiridina
(Clopidogrel) ha constituído el goal standard de tratamiento en
pacientes con SCA1
1Anderson JL et al. Circulation 2007;116:e148-304
2Antman EM et al. Circulation 2008;117:296-329
3King SB et al. Circulation 2008;117:261-295
4Hochholzer W et al. Circulation 2005;111:2560-2564
5Wiviott SD et al. Rev Cardiovasc Med 2006;7:214-225
ASA=Acetylsalicylic Acid; ACS=Acute Coronary Syndrome; PCI=Percutaneous Coronary Intervention
Limitaciones de Clopidogrel
Puede demorar entre 5 y 7 días en alcanzar niveles
plasmáticos efectivos cuando se inicia como dosis de
mantención.1
Importante variación interindividual en niveles de
inhibición plasmática2:
• 20% a 30% de pacientes pueden tener niveles mínimos de
inhibición plaquetaria con las dosis de carga de 300mg y de
mantención de 300mg
• Este fenómeno se ha denominado “ resistencia a clopidogrel ”
1Savi P et al. Semin Thromb Hemost 2005;31(2):174-1832Gurbel PA, Tantry US. Nat Clin Pract Cardiovasc Med 2006;3(7):387-395
Expresión de receptor GP IIb/IIIa
Metabolismo HepáticoVía Citocromo P450
Mala adherencia
Administración Inadecuada
Absorción Variable
Interacciones Drogas
Polimorfismos Genéticos enzimas CYP
Interacciones Drogas (3A4/5; 2C19)
Polimorfismos Genéticos receptor P2Y12
Vías Alternativas de activación plaquetaria
Liberación de ADP circulante
Reactividad plaquetaria basal elevada
Polimorfismos Genéticos
Absorción Intestinal
Receptor P2Y12
(inhibición irreversible)
Metabolito activo
CYP = cytochrome P450
O’Donoghue M, Wiviott SD. Circulation. 2006;114:e600-e606.
Variabilidad en Respuesta a Clopidogrel
The First Clopidogrel Resistance Study (300 mg):
A “Fingerprint” of Clopidogrel Response
Gurbel PA et al. Circulation. 2003;107:2908-2913.
2 Hours
5 Days
Aggregation (%)
Resistance = 63% Resistance = 31%Resistance
Resistance = 31%
Resistance
Resistance = 15%
Aggregation (%) Aggregation (%)
Resistance
Pa
tie
nts
(%
)
12
24
≤ -30
(-30,-20]
(-20,-10]
(-10,0]
(0,10]
(10,20]
(20,30]
(30,40]
(40,50]
(50,60]
>60
Pa
tie
nts
(%
)
11
22
≤ -10 (-10,0] (0,10] (10,20] (20,30] (30,40] (40,50] (50,60] >60
14
28
≤ -30
(-30,-20]
(-20,-10]
(-10,0]
(0,10]
(10,20]
(20,30]
(30,40]
(40,50]
(50,60]
>60
10
20
≤ -30
(-30,-20]
(-20,-10]
(-10,0]
(0,10]
(10,20]
(20,30]
(30,40]
(40,50]
(50,60]
>60
Aggregation (%)
Resistance
Pa
tie
nts
(%
)P
ati
en
ts (
%)
24 Hours
30 Days
Variability
Relevancia Clínica
Estudios recientes sugieren que la menor inhibición
plaquetaria post Clopidogrel puede ser relevante1-3
Los niveles bajos de inhibición plaquetaria se han
asociado con mayor riesgo de:
• Aumento de eventos cardiovasculares1
• Trombosis subaguda de stents2
• Eventos Isquémicosevents 3
1Matetzky S et al. Circulation 2004;109(25):3171-31752Barragan P et al. Catheter Cardiovasc Interv 2003;59(3):295-3023Cuisset T et al. J Thromb Haemost 2006; 4(3):542-549
0
20
40
60
80
100
120
0
10
20
30
40
5 µM ADP-induced Platelet Aggregation Death/ACS/CVA by 6 mo
Days
1 2 3 4 5 6
Base
lin
e (
%)
Quartiles of response
Q1
Q2
Q3
Q4
Clop resist 40
6.7
0 0
Perc
en
t
P = 0.007
Q1 Q2 Q3 Q4
Matetzky S et al. Circulation. 2004;109:3171-3175. Wiviott SD, Antman EM. Circulation. 2004;109:3064-3067.
Clopidogrel Response Variability andIncreased Risk of Ischemic Events Primary PCI for STEMI (N = 60)
Variabilidad de Respuesta a Clopidogrel: Aumento de la Dosis (300 mg vs. 600 mg)
Gurbel PA et al. J Am Coll Cardiol. 2005;45:1392-1396.
0
3
6
9
12
15
18
21
24
27
30
33
≤-30(-30,-20]
(-20,-10](-10,0]
(0,10](10,20]
(20,30](30,40]
(40,50](50,60]
(60,70]> 70
300 mg Clopidogrel
600 mg Clopidogrel
D Aggregation (5 µM ADP-induced Aggregation) at 24 Hr
Pati
en
ts (
%)
Resistance = 28% (300 mg)
Resistance = 8% (600 mg)
Platelet P2 Receptors/Inhibitors
G protein
Molecular structure Intrinsic ion
channel
G protein
Receptor subtype
P2X1
P2Y1 P2Y12
GPCRGj
GPCRGq
PLC/IP3[Ca2+]j
AC[cAMP]
Shape changeTransient
aggregation
Sustainedaggregation
Secretion
SecondaryMessenger system
Functional response
[Na+/Ca2+]i
Shape Change
Aggregation
ADP
X
Adapted From Bhatt and Topol, Nature Reviews Drug Disc 2:15-28, 2003
TiclopidineClopidogrelPrasugrelCangrelorTicagrelor
Inhibidores Receptor P2Y12
Indirectos
(Tienopiridinas)
• Ticlopidina
• Clopidogrel
• Prasugrel
Directos (No
Tienopiridinas)
• Cangrelor
• Ticagrelor
• Elinogrel
Necesidad de nuevos agentes
antiplaquetarios:
1. Prodroga
2. Variabilidad Interindividual
3. Bloqueador Irreversible
4. Resistencia
5. Interacción medicamentos
Inhibidores Receptor P2Y12
Clopidogrel Prasugrel Ticagrelor
Clase Tienopiridina Tienopiridina Análogo ATP
Reversibilidad irreversible irreversible reversible
Administración oral oral oral
Efecto peak 2-3 hrs 1 hr 1,5 hrs
Eliminación 3 hrs 3,7 hrs 12 hrs
Duración 5-8 días 5-10 días 24 hrs
Trials CURE TRITON PLATO
Inhibidores Receptor P2Y12 Prasugrel
• Inhibición plaquetaria más rápida y consistente
• Conversión a metabolito menos dependiente de CYP
• Concentración plasmática máxima en 30 minutos
• Menor variabilidad interindividual
• Aprobado por FDA
-20.0
0.0
20.0
40.0
60.0
80.0
100.0
Inh
ibit
ion
of
Pla
tele
t A
gg
reg
ati
on
(%
)
Response to Prasugrel
Response to Clopidogrel
Comparing Response of Clopidogrel (300 mg) and
Prasugrel (60 mg) by IPA at 24 Hours
Brandt J et al. Am Heart J. 2007;153:66.e9-66.e16
(20 µM ADP)
Background
Variability
TRITON TIMI-38 Study Design
Double-blind
ACS (STEMI or UA/NSTEMI) and Planned PCI
ASA
PRASUGREL
60 mg LD/ 10 mg MD
CLOPIDOGREL
300 mg LD/ 75 mg MD
First-degree end point: CV death, MI, stroke
Second-degree end points: CV death, MI, stroke, rehospitalization,
recurrent ischemia, UTVR
Median duration of therapy: 12 months
N=13,600
Wiviott SD, et al. Am Heart J. 2006;152:627-635.
UTVR = urgent target vessel revascularization; TRITON TIMI = TRial to assess Improvement in Therapeutic
Outcomes by optimizing platelet inhibitioN with prasugrel Thrombolysis In Myocardial Infarction
FDA-approved dosage for clopidogrel: 75 mg daily; 300 mg loading dose
Prasugrel is not yet approved for use
Days
35
events
TRITON TIMI-38: Balance of Efficacy and Safety
HR 0.81
(0.73-0.90)
P = .0004
HR 1.32
(1.03-1.68)
P = .03
138
events
NNT = 46
NNH = 167
Wiviott SD, et al. N Engl J Med. 2007;357:2001-2015.
En
d P
oin
t (%
)
12.1
9.9
1.8
2.4
0
5
10
15
0 30 60 90 180 270 360 450
CV Death/MI/Stroke
TIMI Major
Non-CABG Bleeds
Clopidogrel
Prasugrel
Prasugrel
Clopidogrel
HR = hazard ratio; NNT = number needed to treat; NNH = number needed to harm
TRITON TIMI-38: Stent Thrombosis (ARC Definite + Probable)
Days
0
1
2
3
0 30 60 90 180 270 360 450
HR 0.48
P < .0001
Prasugrel
Clopidogrel 2.4
(142)
74 events
NNT = 77
1.1
(68)
En
d P
oin
t (%
)
Any Stent at Index PCI
N = 12,844
ARC = Academic Research Consortium; PCI = percutaneous coronary interventionWiviott SD, et al. N Engl J Med. 2007;357:2001-2015.
Diabetic Subgroup
0
2
4
6
8
10
12
14
16
18
0 30 60 90 180 270 360 450
HR 0.70
P<0.001
Days
En
dp
oin
t (%
)
CV Death / MI / Stroke
TIMI Major
NonCABG Bleeds
NNT = 21
N=3146
17.0
12.2
Prasugrel
Clopidogrel
Prasugrel
Clopidogrel 2.6
2.5
TRITON TIMI-38 Net Clinical Benefit: Bleeding Risk Subgroups
Overall
≥60 kg
<60 kg
<75
No
Yes
0.5 1 2
Prior
Stroke / TIA
Age
Weight
Risk (%)
+ 37
-16
-1
-16
+3
-14
-13
Prasugrel Better Clopidogrel BetterHR
Pint = 0.006
Pint = 0.18
Pint = 0.36
Post-hoc analysisWiviott SD, et al. N Engl J Med. 2007;357:2001-2015.
≥75
Subgrupos de Riesgo de Hemorragias
Consideraciones terapeuticas
Significant
Net Clinical Benefit
with Prasugrel
80%
MD
10 mg
16%
4%
Terapia Antiplaquetaria en SCA
Single
Antiplatelet Rx
Dual
Antiplatelet Rx
Higher
IPA
ASAASA +
Clopidogrel ASA +
Prasugrel
- 22%
- 20%
- 19%
+ 60% + 38% + 32%
Reduction
in
Ischemic
Events
Increase
in
Major
Bleeds
Resumen
El estudio TRITON-TIMI 38 demostró superioridad de
Prasugrel tanto en sus dosis de carga como de
mantención para reducisr eventos isquémicos en
pacientes con Sindromes Coronarios Agudos
Sin embargo, se observó un mayor riesgo de
hemorragias en los pacientes tratados con Prasugrel
Comparado con Clopidogrel la administración de
Prasugrel resultó en.
Efecto más rápido
Inhibición plaquetaria mayor y consistente
Adams RJ. et al. Stroke. 2008;39;1647-1652
AHA/ASA Secondary Prevention Guidelines
Class III Recommendation
The addition of aspirin to clopidogrel increases the risk of hemorrhage.
Combination therapy of aspirin and clopidogrel is not routinely
recommended for ischemic stroke or TIA patients unless they have a
specific indication for this therapy (ie, coronary stent of acute coronary
syndrome) (Class III, Level of Evidence A).
OH
OH
O
OH
N
F
S
NH
NN
NN
F
Inhibidores Receptor P2Y12Ticagrelor
• Primer inhibidor directo, reversible, vo
• No es pro-droga, no requiere activación metabólica
• Mayor inhibición plaquetaria que clopidogrel
• “onset” y “offset” más rápido que clopidogrel
• Recuperación funcional de las plaquetas
PLATO study design
6–12 months treatment
PCI = percutaneous coronary interventionCV = cardiovascular
NSTEMI ACS (moderate-to-high risk) STEMI (if primary PCI) (N=18,624)
Clopidogrel-treated or -naive; randomized <24 hours of index event
After randomization, 1,261 patients underwent CABG and were on
study drug treatment for ≤7 days prior to surgery
Primary endpoint: CV death + MI + Stroke
Primary safety endpoint: Total major bleeding
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)
Recommendations for patients undergoing CABG:
Study drugs withheld prior to surgery – 5 days for clopidogrel and
24–72 hours for ticagrelor. Study drug be restarted as soon as
possible after surgery and prior to discharge
PLATO main endpoints*
No. at risk
Clopidogrel
Ticagrelor
9,291
9,333
8,521
8,628
8,362
8,460
8,124
Months from randomization
6,743
6,743
5,096
5,161
4,047
4,1478,219
0 2 4 6 8 10 12
12
11
10
9
8
7
6
5
4
3
2
1
0
13
K-M
esti
mate
d r
ate
(%
)
9.8
11.7
HR 0.84 (95% CI 0.77–0.92), p=0.0003
Clopidogrel
Ticagrelor
K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval * Wallentin, L et al., New Eng J Med. 2009;361:1045–1057
0 2 4 6 8 10 12
10
5
0
15
Clopidogrel
Ticagrelor
11.20
11.58
HR 1.04 (95% CI 0.95–1.13), p=0.434
K-M
esti
mate
d r
ate
(%
)
Months from randomization
Primary safety endpointPrimary efficacy endpoint
9,186
9,235
7,305
7,246
6,930
6,826
6,670 5,209
5,129
3,841
3,783
3,479
3,4336,545
PLATOTicagrelor: Perfil de Seguridad
0
2
4
6
8
10
12
Hgia Mayor PLATO TIMI Mayor Txf GR Hgia Riesgo vital/fatal Hgia Fatal
KM
estim
ad
o (
% p
or
añ
o)
Ticagrelor Clopidogrel
Sin aumento de hemorragias
Cannon et al. Lancet 2010;375:283-293.
PLATOTicagrelor: Impacto en Mortalidad Cardiovascular
0 60 120 180 240 300 360
6
4
3
2
1
0
Clopidogrel
Ticagrelor
4.0
5.1
HR 0.79 (95% CI 0.69–0.91), p=0.001
7
5
9,291
9,333
8,865
8,294
8,780
8,822
8,589
Days after randomisation
7079
7119
5,441
5,482
4,364
4,4198,626
Cum
ula
tive in
cid
ence (
%)
Disminución de mortalidad
cardiovascular
Cannon et al. Lancet 2010;375:283-293.
PLATOTicagrelor: Trombosis del Stent
Trombosis
Stent (%)
Ticagrelor
(n=6.732)
Clopidogrel
(n=6.676)HR (95% IC) p
Definitiva 1,0 1,60,62
(0,45-0,85)0,003
Probable o
Definitiva1,7 2,3
0,72
(0,56-0,93)0,01
Posible,
Probable o
Definitiva2,2 3,1
0,72
(0,58-0,90)0,003
Cannon et al. Lancet 2010;375:283-293.
PLATO: Dosis de AAS y eficacia:
Circulation 2011; DOI: 10.1161/CIR.0b013e318226950d
CURE: Relation Between Safety
and ASA Dosage1
1. Clopidogrel Prescribing Information, US, February 2002.
0.0%
1.0%
2.0%
3.0%
4.0%
5.0%
6.0%
Ble
ed
ing
rate
(%
)
2.0%
2.6%2.3%
3.5%
4.0%
4.9%
ASA dose 75–325 mg
100–200 mg > 200 mg< 100 mg
Placebo*
Clopidogrel*
*On top of standard therapy (including ASA)
La dosis más segura de AAS asociada a tienopiridinas es
de ≤ 100 mg
TROMBOSIS TARDIA DE STENTS
Recomendación de ASA + Clopidogrel por un año
Long-term Thienopyridine therapy and autcomes in patients with ACS treated
with Coronary stenting: The primary results of The TIMI-38 Coronary Stent
Registry.
N=2.110 pts (1679pts › 12 meses TAD)
Conclusion: In ACS pts receiving stents, prolonged thienopyridine was not associated
with lower trombotic events: however, there was a tendency toward lower rates in
those with DES.M. Bonaca et al ACC 2011
Death, MI, or Stent Thrombosis at 2
years
TIMI Major or Minor Bleeding at 2 years
% %
La terapia antiplaquetaria dual post PCI+ stents recubiertos debiera
mantenerse por 12 meses
Platelet Receptors
Platelet
Thrombin
ADP
Epinephrine
Collagen Anionic
phospholipid
surfaces
GP
IIb/IIIa
Platelet
Fibrinogen
GP Ia
P2Y1
GP VI
PAR-4
TBX A2 TBXA2-R
Serotonin 5HT2A
P2Y12
PAR-1
GP
IIb/IIIa
EPI-R
SCH 530348 is an oral, potent, selective thrombin receptor antagonist (TRA)
being developed for the prevention and treatment of atherothrombosis.
Preclinical and early clinical studies have demonstrated SCH 530348 to have
antithrombotic properties, with no increase in bleeding time or clotting times
(aPTT, PT, ACT).
TRA Background
Galbulimima baccata
Himbacine derivative
Bark of the Australian Magnolia
Found in the tropical zones of eastern
Malaysia, New Guinea, northern
Australia and the Solomon Islands.
~25%
Development Strategy for Thrombin Receptor Antagonist
Reduction
of Clinical
Events
ASA Clopidogrel TRANo Tx
↑38%
No Add’l D Major
Bleeding
6-20%
SCA se caracterizan por formación aumentada de trombina
que persiste incluso luego del evento agudo
Trombina es el principal activador de la plaqueta
Actúa a través de receptor PAR-1
El bloqueo de los receptores PAR-1 tendría ventajas
potenciales en el corto y largo plazo
Estudios iniciales en pacientes sometidos a PCI electiva han
mostrado resultados alentadores: TRA-PCI
Actualmente en evaluación en SCA: TRACER
Antagonista de los receptores de Trombina (TRA)
TRACERSCH 530348 (Vorapaxar) en SCA
• Muerte cardiovascular a 1 año, IAM, Stroke, Isquemia recurrente con Rehosp, Revascularización Coronaria Urgente •
SCA SIN SDST
N = 10,000
SCH 530348
40 mg carga, 2.5 mg/día
n=5000
Placebo
(y terapia usual)
n=5000
Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome
PARE !!!!
TRILOGY ACS: TaRgeted platelet Inhibition to cLarify the Optimal strateGy to medicallY
manage Acute Coronary Syndromes
TRILOGY ACS – Objetivo Primario
• Probar la hipótesis de que la combinación de
AAS+Prasugrel es superior a la de AAS+Clopidogrel
administrados a pacientes con SCA SEST dentro de los
primeros 7 días y en los que se decide manejo médico.
• Objetivo primario compuesto: Muerte CV, IAM o ACV
Necesidad Médica Insatisfecha:Los pacientes con manejo médico solo de
su SCA
Existe un grupo variable de pacientes en los
que no se efectúa intervención precoz post
SCA
Es una población diferente: Edad avanzada,
alta incidencia de insuficiencia renal, más co-
morbilidades
Poco estudiados en ensayos clínicos
randomizados
Conclusiones
Actualmente importante “armamentario” de
antiagregantes plaquetarios para el manejo de los
SCA y uso rutinario en PCI.
Preocupación por Clopidogrel y efecto de
Polimorfismos: necesidad de investigarlos ???
Bloqueo plaquetario triple: atractiva posibilidad,
pero... esperar resultados de TRACER y TRA 2P
Mejores perspectivas considerando todo lo anterior:
• Prasugrel
• Ticagrelor
• Vorapaxar