Rol actual de los nuevos antiplaquetarios en el Sindrome Coronario Agudo

Dr. Ramn Corbaln H. Facultad de Medicina

Pontificia Universidad Catlica de Chile

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

Terapia Antiplaquetaria Dual

La inhibicin de las plaquetas es una estrategia clave para tratar y prevenir recurrencia de eventos isqumicos en pacientes Con sindromes coronarios agudos1,2

Sometidos a PCI3
Las metas de este tratamiento son la inhibicin rpida, consistente y efectiva de la activacin y agregacin plaquetaria3-5 La terapia antiplaquetaria dual con AAS y una tienopiridina (Clopidogrel) ha constitudo el goal standard de tratamiento en pacientes con SCA1
ASA=Acetylsalicylic Acid; ACS=Acute Coronary Syndrome; PCI=Percutaneous Coronary Intervention
1Anderson 2Antman 3King 4Hochholzer 5Wiviott SD

JL et al. Circulation 2007;116:e148-304 EM et al. Circulation 2008;117:296-329 SB et al. Circulation 2008;117:261-295

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 das en alcanzar niveles plasmticos efectivos cuando se inicia como dosis de mantencin.1

Importante variacin interindividual en niveles de inhibicin plasmtica2:

20% a 30% de pacientes pueden tener niveles mnimos de inhibicin plaquetaria con las dosis de carga de 300mg y de mantencin de 300mg
Este fenmeno se ha denominado resistencia a clopidogrel

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

1Savi

Variabilidad en Respuesta a Clopidogrel

Absorcin Intestinal Mala adherencia Administracin Inadecuada Absorcin Variable Interacciones Drogas Metabolismo Heptico Va Citocromo P450 Metabolito activo Receptor P2Y12 (inhibicin irreversible) Expresin de receptor GP IIb/IIIa
CYP = cytochrome P450 ODonoghue M, Wiviott SD. Circulation. 2006;114:e600-e606.

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

Polimorfismos Genticos receptor P2Y12 Vas Alternativas de activacin plaquetaria Liberacin de ADP circulante Reactividad plaquetaria basal elevada
Polimorfismos Genticos

The First Clopidogrel Resistance Study (300 mg): A Fingerprint of Clopidogrel Response
2 Hours
24
Resistance
Resistance = 63%

Variability
20

24 Hours
Resistance

Resistance = 31%

Patients (%)

12

Patients (%)
-30 (-20,-10] (0,10] (20,30] (40,50] >60 (-30,-20] (-10,0] (10,20] (30,40] (50,60]

10

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

>60

Aggregation (%)

Aggregation (%)

5 Days
22
Resistance

30 Days
Resistance = 31% 28 Resistance = 15%

Patients (%)

11

Patients (%)

14 Resistance

-10

(-10,0]

(0,10]

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

>60

-30

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

(0,10] (10,20]

(20,30] (30,40]

(40,50] (50,60]

>60

Aggregation (%)

Aggregation (%)

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

Relevancia Clnica
Estudios recientes sugieren que la menor inhibicin plaquetaria post Clopidogrel puede ser relevante1-3 Los niveles bajos de inhibicin plaquetaria se han asociado con mayor riesgo de:
Aumento de eventos cardiovasculares1

Trombosis subaguda de stents2

Eventos Isqumicosevents 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 M ADP-induced Platelet Aggregation 120 100 Clop resist Q1

Death/ACS/CVA by 6 mo

40
30 20 10 0

40 P = 0.007

Baseline (%)

Q2
Q3

60

40
20 0 1 2 3 4 Days 5 6 Q4 Quartiles of response 6.7

Percent

80

0
Q1 Q2 Q3

0
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)

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)

Patients (%)

-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 M ADP-induced Aggregation) at 24 Hr

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

Platelet P2 Receptors/Inhibitors
ADP
Ticlopidine Clopidogrel Prasugrel Cangrelor Ticagrelor

Receptor subtype

P2Y1 P2X1

P2Y12

G protein Molecular structure Intrinsic ion channel GPCR Gq

G protein GPCR Gj

Secondary Messenger system

[Na+/Ca2+]i

PLC/IP3 [Ca2+]j Shape change Transient aggregation

AC [cAMP] Sustained aggregation Secretion

Functional response

Shape Change Aggregation

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

Inhibidores Receptor P2Y12

Indirectos (Tienopiridinas)
Ticlopidina

Clopidogrel
Prasugrel

Directos (No Tienopiridinas)

Cangrelor Ticagrelor

Necesidad de nuevos agentes antiplaquetarios: 1. Prodroga 2. Variabilidad Interindividual 3. Bloqueador Irreversible 4. Resistencia 5. Interaccin medicamentos

Elinogrel

Inhibidores Receptor P2Y12

Clopidogrel Prasugrel Ticagrelor

Clase Reversibilidad Administracin Efecto peak Eliminacin Duracin

Tienopiridina irreversible oral 2-3 hrs 3 hrs 5-8 das

Tienopiridina irreversible oral 1 hr 3,7 hrs 5-10 das

Anlogo ATP reversible oral 1,5 hrs 12 hrs 24 hrs

Trials

CURE

TRITON

PLATO

Inhibidores Receptor P2Y12 Prasugrel

Inhibicin plaquetaria ms rpida y consistente Conversin a metabolito menos dependiente de CYP Concentracin plasmtica mxima en 30 minutos Menor variabilidad interindividual Aprobado por FDA

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

(20 M ADP)
80.0

60.0

40.0

20.0

0.0

Background Variability

-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
Clopidogrel

138 events 12.1 9.9

CV Death/MI/Stroke
End Point (%) 10

Prasugrel

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

TIMI Major Non-CABG Bleeds

Prasugrel

2.4 1.8

Clopidogrel

0 30 60 90

180 Days

270

360

450

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

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

Clopidogrel
End Point (%) 2

2.4 (142)

74 events
1
1.1 (68)

Prasugrel
HR 0.48 P < .0001 NNT = 77

0 30 60 90

180

270

360

450

ARC = Academic Research Consortium; PCI = percutaneous coronary intervention

Wiviott SD, et al. N Engl J Med. 2007;357:2001-2015.

Days

Diabetic Subgroup
N=3146
18

Clopidogrel CV Death / MI / Stroke

17.0

16

Endpoint (%)

14

12.2 12
10 8 6 4

Prasugrel

HR 0.70 P<0.001 NNT = 21

TIMI Major NonCABG Bleeds

Clopidogrel Prasugrel

2.6

2
0

2.5

30 60 90

180

Days

270

360

450

TRITON TIMI-38 Net Clinical Benefit: Bleeding Risk Subgroups

Risk (%)

Prior
Stroke / TIA

Yes
No 75

+ 37
-16 Pint = 0.006 -1 -16 +3 -14
Pint = 0.36 Pint = 0.18

Age

<75
Weight <60 kg 60 kg

Overall
0.5 Prasugrel Better 1 HR
Clopidogrel Better

-13
2
Post-hoc analysis
Wiviott SD, et al. N Engl J Med. 2007;357:2001-2015.

Subgrupos de Riesgo de Hemorragias Consideraciones terapeuticas

16%
4%

MD 10 mg

Significant Net Clinical Benefit with Prasugrel 80%

Terapia Antiplaquetaria en SCA

ASA

ASA + Clopidogrel
- 22% - 20%

ASA + Prasugrel
Reduction in Ischemic Events
- 19%

+ 60%

+ 38%

+ 32%

Increase in Major Bleeds

Single Antiplatelet Rx

Dual Antiplatelet Rx

Higher IPA

Resumen
El estudio TRITON-TIMI 38 demostr superioridad de Prasugrel tanto en sus dosis de carga como de mantencin para reducisr eventos isqumicos en pacientes con Sindromes Coronarios Agudos Sin embargo, se observ un mayor riesgo de hemorragias en los pacientes tratados con Prasugrel Comparado con Clopidogrel la administracin de Prasugrel result en.

Efecto ms rpido

Inhibicin plaquetaria mayor y consistente

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).

Adams RJ. et al. Stroke. 2008;39;1647-1652

Inhibidores Receptor P2Y12 Ticagrelor

Primer inhibidor directo, reversible, vo No es pro-droga, no requiere activacin metablica Mayor inhibicin plaquetaria que clopidogrel onset y offset ms rpido que clopidogrel Recuperacin funcional de las plaquetas
HO N

N
HO O N

N H N N F

S OH

PLATO study design

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

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)

612 months treatment

Primary endpoint: CV death + MI + Stroke Primary safety endpoint: Total major bleeding
Recommendations for patients undergoing CABG: Study drugs withheld prior to surgery 5 days for clopidogrel and 2472 hours for ticagrelor. Study drug be restarted as soon as possible after surgery and prior to discharge

PCI = percutaneous coronary intervention CV = cardiovascular

PLATO main endpoints*

Primary efficacy endpoint
13 12 11 10 15 11.7 Ticagrelor 11.58 11.20

Primary safety endpoint

Clopidogrel

K-M estimated rate (%)

K-M estimated rate (%)

9.8 Ticagrelor

10

8
7 6 5 4 3 2

Clopidogrel

1
0 0 2

HR 0.84 (95% CI 0.770.92), p=0.0003

0 4 6 8 10 12 0 2

HR 1.04 (95% CI 0.951.13), p=0.434

10

12

No. at risk Ticagrelor Clopidogrel

Months from randomization

9,333 8,628 8,460 8,219 6,743 5,161 4,147 9,291 8,521 8,362 8,124 6,743 5,096 4,047 9,235 9,186

Months from randomization

7,246 7,305 6,826 6,545 5,129 3,783 3,433 6,930 6,670 5,209 3,841 3,479

K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval * Wallentin, L et al., New Eng J Med. 2009;361:10451057

PLATO Ticagrelor: Perfil de Seguridad

Ticagrelor
12

Clopidogrel

Sin aumento de hemorragias

10
KM estimado (% por ao)

0
Hgia Mayor PLATO TIMI Mayor Txf GR Hgia Riesgo vital/fatal Hgia Fatal

Cannon et al. Lancet 2010;375:283-293.

PLATO Ticagrelor: Impacto en Mortalidad Cardiovascular

7

Disminucin de mortalidad cardiovascular

Clopidogrel 5.1

Cumulative incidence (%)

4.0 Ticagrelor

1 HR 0.79 (95% CI 0.690.91), p=0.001 0

60

120

180

240

300

360

Days after randomisation

9,333 9,291

8,294 8,865

8,822 8,780

8,626 8,589

7119 7079

5,482 5,441

4,419 4,364

Cannon et al. Lancet 2010;375:283-293.

PLATO Ticagrelor: Trombosis del Stent

Trombosis Stent (%)

Ticagrelor (n=6.732)

Clopidogrel (n=6.676)

HR (95% IC)

Definitiva

1,0

1,6

0,62 (0,45-0,85)

0,003

Probable o Definitiva
Posible, Probable o Definitiva

1,7

2,3

0,72 (0,56-0,93)
0,72 (0,58-0,90)

0,01

2,2

3,1

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

6.0% 5.0% 4.9% 4.0%

Bleeding rate (%)

4.0%
3.0%

3.5% 2.6%
Placebo*

2.0%
2.0% 1.0% 0.0%

2.3%
Clopidogrel*

< 100 mg

100200 mg
ASA dose 75325 mg

> 200 mg

*On top of standard therapy (including ASA) 1. Clopidogrel Prescribing Information, US, February 2002.

La dosis ms segura de AAS asociada a tienopiridinas es de 100 mg

TROMBOSIS TARDIA DE STENTS

Recomendacin de ASA + Clopidogrel por un ao

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)

Death, MI, or Stent Thrombosis at 2 years

%

TIMI Major or Minor Bleeding at 2 years

%

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

La terapia antiplaquetaria dual post PCI+ stents recubiertos debiera mantenerse por 12 meses

Platelet Receptors
Platelet
PAR-1 PAR-4
Fibrinogen

Platelet

Thrombin

ADP
TBX A2 Epinephrine

P2Y1 P2Y12 TBXA2-R EPI-R

GP IIb/IIIa

GP IIb/IIIa

Serotonin
Collagen

5HT2A
GP VI

GP Ia

Anionic phospholipid surfaces

TRA Background
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).

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.

Development Strategy for Thrombin Receptor Antagonist

Reduction of Clinical Events

~25%
6-20%

38%

No Addl D Major Bleeding

No Tx

ASA

Clopidogrel

TRA

Antagonista de los receptores de Trombina (TRA)

SCA se caracterizan por formacin aumentada de trombina que persiste incluso luego del evento agudo Trombina es el principal activador de la plaqueta

Acta a travs de receptor PAR-1

El bloqueo de los receptores PAR-1 tendra ventajas potenciales en el corto y largo plazo Estudios iniciales en pacientes sometidos a PCI electiva han mostrado resultados alentadores: TRA-PCI

Actualmente en evaluacin en SCA:

TRACER

TRACER SCH 530348 (Vorapaxar) en SCA

Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome SCA SIN SDST N = 10,000

SCH 530348 40 mg carga, 2.5 mg/da n=5000

PARE !!!!

Placebo (y terapia usual) n=5000

Muerte cardiovascular a 1 ao, IAM, Stroke, Isquemia recurrente con Rehosp, Revascularizacin Coronaria Urgente

TRILOGY ACS: TaRgeted platelet Inhibition to cLarify the Optimal strateGy to medicallY manage Acute Coronary Syndromes

TRILOGY ACS Objetivo Primario

Probar la hiptesis de que la combinacin de AAS+Prasugrel es superior a la de AAS+Clopidogrel administrados a pacientes con SCA SEST dentro de los primeros 7 das y en los que se decide manejo mdico. Objetivo primario compuesto: Muerte CV, IAM o ACV

Necesidad Mdica Insatisfecha: Los pacientes con manejo mdico solo de su SCA

Existe un grupo variable de pacientes en los que no se efecta intervencin precoz post SCA Es una poblacin diferente: Edad avanzada, alta incidencia de insuficiencia renal, ms comorbilidades Poco estudiados en ensayos clnicos randomizados

Conclusiones
Actualmente importante armamentario de antiagregantes plaquetarios para el manejo de los SCA y uso rutinario en PCI. Preocupacin 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