Rol actual de los nuevos antiplaquetarios en el Sindrome Coronario Agudo Dr. 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 ASA=Acetylsalicylic Acid; ACS=Acute Coronary Syndrome; PCI=Percutaneous Coronary Intervention 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 5Wiviott SD

W et al. Circulation 2005;111:2560-2564

et al. Rev Cardiovasc Med 2006;7:214-225

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

2Gurbel

P et al. Semin Thromb Hemost 2005;31(2):174-183 PA, Tantry US. Nat Clin Pract Cardiovasc Med 2006;3(7):387-395

Variabilidad en Respuesta a Clopidogrel Absorción Intestinal

Mala adherencia Administración Inadecuada Absorción Variable Interacciones Drogas

Metabolismo Hepático Vía Citocromo P450

Polimorfismos Genéticos enzimas CYP Interacciones Drogas (3A4/5; 2C19)

Metabolito activo Receptor P2Y12 (inhibición irreversible) Expresión de receptor GP IIb/IIIa

Polimorfismos Genéticos receptor P2Y12 Vías Alternativas de activación plaquetaria Liberación de ADP circulante Reactividad plaquetaria basal elevada Polimorfismos Genéticos

CYP = cytochrome P450 O’Donoghue M, Wiviott SD. Circulation. 2006;114:e600-e606.

The First Clopidogrel Resistance Study (300 mg): A “Fingerprint” of Clopidogrel Response Variability

2 Hours Resistance

Resistance = 63%

Resistance

20

Patients (%)

Patients (%)

24

24 Hours

12

10

≤ -30 (-20,-10] (0,10] (20,30] (40,50] >60 (-30,-20] (-10,0] (10,20] (30,40] (50,60]

≤ -30 (-20,-10] (0,10] (20,30] (40,50] (-30,-20] (-10,0] (10,20] (30,40] (50,60]

 Aggregation (%)

28

Patients (%)

Patients (%)

30 Days Resistance = 31%

Resistance

11

≤ -10

(-10,0]

(0,10]

>60

 Aggregation (%)

5 Days 22

Resistance = 31%

(10,20] (20,30] (30,40] (40,50] (50,60]

 Aggregation (%)

>60

Resistance = 15%

14 Resistance

≤ -30

(-20,-10] (-30,-20]

(-10,0]

(0,10]

(20,30] (10,20]

(40,50] (30,40]

>60 (50,60]

 Aggregation (%)

Gurbel PA et al. Circulation. 2003;107:2908-2913.

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):3171-3175 P et al. Catheter Cardiovasc Interv 2003;59(3):295-302 3Cuisset T et al. J Thromb Haemost 2006; 4(3):542-549 2Barragan

Clopidogrel Response Variability and Increased Risk of Ischemic Events Primary PCI for STEMI (N = 60)

5 µM ADP-induced Platelet Aggregation Clop resist

100

Q1

80

Q2

60 Q3

40

40 P = 0.007

Percent

Baseline (%)

120

Death/ACS/CVA by 6 mo

30 20

40 Q4 Quartiles of response

20 0

10 0

1

2

3

4 Days

5

6

6.7

Q1

Q2

0

0

Q3

Q4

Matetzky S et al. Circulation. 2004;109:3171-3175. Wiviott SD, Antman EM. Circulation. 2004;109:3064-3067.

Patients (%)

Variabilidad de Respuesta a Clopidogrel: Aumento de la Dosis (300 mg vs. 600 mg)

33 30 27 24 21 18 15 12 9 6 3 0

300 mg Clopidogrel

600 mg Clopidogrel Resistance = 28% (300 mg) Resistance = 8% (600 mg)

≤-30

(-20,-10] (-30,-20] (-10,0]

(0,10]

(10,20]

(20,30]

(30,40]

(40,50]

(50,60]

(60,70]

> 70

D Aggregation (5 µM ADP-induced Aggregation) at 24 Hr

Gurbel PA et al. J Am Coll Cardiol. 2005;45:1392-1396.

Platelet P2 Receptors/Inhibitors Ticlopidine Clopidogrel Prasugrel Cangrelor Ticagrelor

ADP

Receptor subtype

X

P2Y12

P2Y1 P2X1

Molecular structure

Secondary Messenger system

Functional response

Intrinsic ion channel

[Na+/Ca2+]i

Shape Change Aggregation

Adapted From Bhatt and Topol, Nature Reviews Drug Disc 2:15-28, 2003

G protein

G protein

GPCR Gq

GPCR Gj

PLC/IP3 [Ca2+]j

AC [cAMP]

Shape change Transient aggregation

Sustained aggregation Secretion

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

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

5-8 días

5-10 días

24 hrs

CURE

TRITON

PLATO

Clase

Duración

Trials

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

Inhibition of Platelet Aggregation (%)

Comparing Response of Clopidogrel (300 mg) and Prasugrel (60 mg) by IPA at 24 Hours 100.0

(20 µM ADP) 80.0

60.0

40.0

20.0

Background Variability

0.0

-20.0

Response to Clopidogrel

Response to Prasugrel Brandt J et al. Am Heart J. 2007;153:66.e9-66.e16

TRITON TIMI-38 Study Design ACS (STEMI or UA/NSTEMI) and Planned PCI ASA

N=13,600

Double-blind CLOPIDOGREL 300 mg LD/ 75 mg MD

PRASUGREL 60 mg LD/ 10 mg MD

Median duration of therapy: 12 months

First-degree end point: Second-degree end points:

CV death, MI, stroke CV death, MI, stroke, rehospitalization, recurrent ischemia, UTVR

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 Wiviott SD, et al. Am Heart J. 2006;152:627-635.

TRITON TIMI-38: Balance of Efficacy and Safety 15

End Point (%)

CV Death/MI/Stroke

138 events

Clopidogrel

12.1 9.9

10 Prasugrel

TIMI Major Non-CABG Bleeds

5

Prasugrel

Clopidogrel

0

0 30 60 90

180

270

360

2.4 1.8

450

HR 0.81 (0.73-0.90) P = .0004 NNT = 46

35 events HR 1.32 (1.03-1.68) P = .03 NNH = 167

Days HR = hazard ratio; NNT = number needed to treat; NNH = number needed to harm Wiviott SD, et al. N Engl J Med. 2007;357:2001-2015.

TRITON TIMI-38: Stent Thrombosis (ARC Definite + Probable) 3

Any Stent at Index PCI N = 12,844

End Point (%)

Clopidogrel

2.4 (142)

2

74 events 1.1 (68)

1

Prasugrel HR 0.48 P < .0001 NNT = 77

0

0 30 60 90

180

270

360

450

Days

ARC = Academic Research Consortium; PCI = percutaneous coronary intervention Wiviott SD, et al. N Engl J Med. 2007;357:2001-2015.

Diabetic Subgroup N=3146 18

Clopidogrel

Endpoint (%)

16

17.0

CV Death / MI / Stroke

14

12.2 12

Prasugrel

10

HR 0.70 P