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