Antiagregantes Plaquetarios en Pacientes con SCA

Dr Ramón Corbalán Departamento Enfermedades Cardiovaculares Pontificia Universidad Cátolica de Chile

Atherothrombosis and Microcirculation

Plaque rupture

Embolization

Microvascular obstruction

Adapted from: Topol EJ, Yadav JS. Circulation 2000; 101: 570–80, and Falk E et al. Circulation 1995; 92: 657–71.

Meadows TA, Bhatt DL. Circ Res. 2007;100:1261-1275.

Clotting Cascade

Terapia Antiplaquetaria Dual • La inhibición de las plaquetas es una estrategia clave en el tratmiento de 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 constituyen el goal standard de tratamiento en pacientes con SCA desde que se inicia y progresa en la terapia intervencional

• Las preguntas pendientes: ¿Duración del tratamiento? ¿ Efectos en pacientes tratados solo médicamente? ¿Riesgo de hemorragias? ¿Alternativas diferentes?

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 W 5Wiviott

et al. Circulation 2005;111:2560-2564 SD et al. Rev Cardiovasc Med 2006;7:214-225

Los Estudios que avalan Terapia Antiplaquetarias Dual:

CURE CREDO CREDO-PCI CLARITY COMIT

Limitaciones de Clopidogrel Latencia de su efecto Variantes genéticas Resistencia a la droga ¿Alternativas?

Inhibidores Receptor P2Y12 Riesgo de eventos CV en portadores de gen CYP2C19*2 LOF tratados con clopidogrel

Meta-análisis de 10 estudios (11,959 pacientes) Eventos

Portador de gen No portador (%) LOF (%)

OR (95% IC)

p

MACE

9,7

7,8

1,29 (1,12-1,49)

60

∆ Aggregation (%)

5 Days

11

(-10,0]

Resistance = 31%

10

∆ Aggregation (%)

≤ -10

Resistance

20

Patients (%)

Patients (%)

24

24 Hours

(0,10]

(10,20]

(20,30]

(30,40]

∆ Aggregation (%)

(40,50]

(50,60]

>60

Resistance = 15%

14 Resistance

≤ -30

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

(0,10] (-10,0]

(20,30] (10,20]

(40,50] (30,40]

>60 (50,60]

∆ Aggregation (%)

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

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

5 µM ADP-induced Platelet Aggregation 120

Clop resist

100

40

40

Q1

80

Q2

60 Q3

P = 0.007 Percent

Baseline (%)

Death/ACS/CVA by 6 mo

30 20

40 Q4

20

10

6.7

Quartiles of response

0 1

2

3

4 Days

5

6

0

Q1

Q2

0

0

Q3

Q4

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

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

Patients (%)

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

(-30,-20]

(-20,-10]

(-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.

ASA Dose Comparison Death/MI/Stroke at 30 days

0.03 0.01

0.02

HR 0.97 (0.86(0.86-1.09) P = 0.61

ASA 75-100 mg ASA 300-325 mg

0.0

Cumulative Hazard

0.04

25,087 ACS Patients with planned PCI

0

3

6

9

12

15 Days

18

21

24

27

30

CURRENT-OASIS 7. NEJM 2010;363:930

CURRENT-OASIS 7: Eventos Primarios y Dosis de Clopidogrel /AAS a 30 Días

Mehta SR, et al, ESC; September 2009; Barcelona, Spain.

CURRENT-OASIS 7: Muerte CV, IM, AVE a 30 Días

Mehta SR, et al, ESC; September 2009; Barcelona, Spain.

CURRENT-OASIS 7: Conclusiones Autores

Test a doble dosis de clopidogrel redujo significativamente la trombosis de stents y eventos CV mayores En pacientes no sometidos a PCI la doble dosis de clopidogrel no tuvo diferencia con la dosis estándar Un exceso modesto de hemorragias mayores por criterios CURRENT, pero no hubo diferencias en HIC, hemorragias fatales o post CRVM

Novedades en Antiplaquetarios...

“Armamentario Terapeútico” más allá del Clopidogrel: ¿qué tenemos? Bloqueo plaquetario Triple: ¿realidad o ficción? Cuales son los antiplaquetarios con mejores perspectivas futuras?

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

G protein

G protein

GPCR Gq

GPCR Gj

PLC/IP3 [Ca2+]j

AC [cAMP]

Shape change Transient aggregation

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

Sustained aggregation Secretion

Inhibidores Receptor P2Y12

•

•

Indirectos (Tienopiridinas)

-

Ticlopidina

-

Cangrelor

Necesidad de nuevos agentes antiplaquetarios: Clopidogrel 1. Prodroga 2. Variabilidad Interindividual Prasugrel 3. Bloqueador Irreversible 4. Resistencia Directos (No Tienopiridinas) 5. Interacción medicamentos

Ticagrelor Elinogrel

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

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

Inhibition of Platelet Aggregation (%)

(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: CV death, MI, stroke Second-degree end points: 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

2.4 1.8

Clopidogrel

0

0 30 60 90

180

270

360

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

17.0

16

CV Death / MI / Stroke

Endpoint (%)

14

12.2

12

Prasugrel

10

HR 0.70 P