Nuevos antiagregantes

Novedades en la Práctica Clínica en el 2010 Nuevos Antiagregantes A. Cequier Área Malalties del Cor (AMC) IDIBELL. Hospital Universitario de Bellvitge Universidad de Barcelona.

Barcelona

Angel Cequier • En relación a esta presentación tengo los siguientes conflictos de interés: Participación en Consejos Consultivos (“Advisory Boards”) de: - The Medicines Company - Iroko - Ferrer - Schering-Plough / MSD - Lilly Daiichi-Sankyo - Sanofi-Aventis

ST - Elevation Acute Myocardial Infarction

Plaque rupture and thrombus in AMI

Non ST - Elevation Acute Coronary Syndrome

Embolization and microvascular occlusion in non-ST ACS

Ruptura Placa Aterosclerótica y Activación Plaquetaria

La activación de las plaquetas y coagulación son procesos inseparables que recíprocamente se autopotencian

Integrating Treatment in ACS

Non ST-Elevation ACS Invasive Strategy Pre-PCI: ASA + 600 mg Clopidogrel + UFH/Enoxa

Intermediate risk

High – risk

Angiography 24 – 48 hrs

Early upstream IIb/IIIa + UFH/Enoxa or Bivalirudin (in high-risk for bleeding)

+ Angiography < 24 hrs Per-PCI: Increased anatomic risk: Abciximab

r o l e r g Can el r g u s Pra r o l e r g Tica rel g o d i lop C D H

Integrating Treatment in ACS

Primary PCI in STEMI Pre-PPCI:

ASA + 600 mg Clopidogrel + UFH / LMWH

Per-PPCI:

High-Risk Patient High Bleeding Risk

Acute stent thrombosis Large thrombus burden No reflow

Bivalirudin

IIb/IIIa Inhibitors Catheter aspiration

b a m i x i c ic. Ab grel Prasu lor re g a c i T l e r g o d pi o l C HD Low-Risk Patient

Nuevos Antiagregantes en el 2010 1.- Antiagregantes parenterales a) Inhibidores IIb/IIIa b) Cangrelor

2.- Antiagregantes Orales a) Prasugrel b) Ticagrelor c) Dosis altas de Clopidogrel d) Nuevos antiplaquetarios

Intracoronary vs Intravenous bolus Abciximab during Primary Angioplasty in STEMI

The Leipzig Trial 154 ptes with STEMI and Primary Angioplasty Randomized to Abciximab: - Intracoronary (after IRA recanalization with wire) - Intravenous (before PCI)

Individual values for MR infart size vs enzymatic infart size (AUC) Thiele et al. Circulation 2008; 118: 49-57

Platelet Inhibition with CANGRELOR during PCI. CHAMPION Trials Cangrelor: iv. P2Y12 inhibitor Plasme half-life: 3-6 m.

Recovery platelet function: 60 m.

CHAMPION PCI Cangrelor administered iv 30 m. before and 2 hours after PCI was not superior to loading dose of 600 mg of clopidogrel P< 0.001

Primary Efficacy and Safety (2 studies) 48-hour incidence of the primary end point (death, MI or revascularization) and bleeding

CHAMPION PLATAFORM Periprocedural Cangrelor during PCI was not superior to placebo.

Harrington RA, et al. NEJM 2009; 361: 2318.

Bhatt DP, et al. NEJM 2009; 361: 2330.

Nuevos Antiagregantes en el 2010 1.- Antiagregantes parenterales a) Inhibidores IIb/IIIa b) Cangrelor

2.- Antiagregantes Orales a) Prasugrel b) Ticagrelor c) Dosis altas de Clopidogrel d) Nuevos antiplaquetarios

Modo de Acción del Clopidogrel, Prasugrel y Ticagrelor Clopidogrel y Prasugrel son pro-fármacos. Sus metabolitos activos se unen a P2Y12. Tras su absorción intestinal deben ser oxidados para generar metabolitos activos. Su actividad esta afectada por polimorfismos genéticos. El ticagrelor es absorbido en el intestino y no requiere ninguna biotransformación para su activación.

Prasugrel

Schoming A. NEJM 2009; 361: 1108

Prasugrel vs Clopidogrel in Pts with Acute Coronary Syndromes TRITON-TIMI 38 13608 pts, with moderate-to-high-risk ACS scheduled PCI 10074 pts with NSTsACS; 3534 pts with STeACS; GP IIb/IIIa inhibitors: 55%

Prasugrel (60 mg + 10 mg/d) vs Clopidogrel (300 mg + 75 mg/d)

Death, MI, CVA

Major bleeding

TRITON-TIMI 38. NEJM 2007; 357: 2001

TRITON TIMI-38 STEMI cohort

TRITON-TIMI 38

PCI for STEMI

Prasugrel vs Clopidogrel CV death, MI, stroke at 15 months

Clopidogrel Prasugrel

15

Proportion of patients (%)

12.4

10

9.5 6.5

10.0 p=0.002 RRR=32%

5 HR=0.79 (0.65–0.97) NNT=42 Age-adjusted HR=0.81 (0.66-0.99)

0 0

50

100

Montalescot et al. Lancet 2009; 373: 723

150

200

250

Time (Days)

300

350

400

450

p=0.02 RRR=21%

Prasugrel vs Clopidogrel in Stent Thrombosis

TRITON-TIMI 38 (Lancet 2008; 371: 1353)

Definite/Probable Stent Thrombosis BMS Only HR 0.52 [0.35-0.77] P=0.0009

2.5

Definite/Probable Stent Thrombosis DES Only 2.41%

CLOPIDOGREL

HR 0.36 [0.22-0.58] P<0.0001

2.31%

2.5

CLOPIDOGREL 2

2

48% 64%

1.5

1.5

PRASUGREL 1.27%

1

1

PRASUGREL 0.84%

0.5

0.5

1 year: 0.74% vs 2.05% HR 0.35 [0.21-0.58], P<0.0001

1 year: 1.22 vs 2.27% HR 0.53 [0.36-0.79], P=0.0014

0

0 0

50

100

150

200

DAYS

250

300

350

400

450

0

50

100

150

200

250

DAYS

300

350

400

450

Primary End Point

Greater Clinical Benefit With Prasugrel in Patients with Diabetes Mellitus TRITON-TIMI 38 Stent Thrombosis

Wiviott SD, et al. Circulation 2008; 118: 1626

Patients with DM tended to have a greater reduction in ischemic events without an increase in TIMI major bleeding with Prasugrel compared to Clopidogrel

Prasugrel vs Clopidogrel in Pts with Acute Coronary Syndromes TRITON-TIMI 38

Net Clinical Benefit: Post-hoc Analysis

TRITON-TIMI 38. NEJM 2007; 357: 2001

Indicaciones de Prasugrel en Angioplastia Primaria

• Todos los pacientes con IAM con elevación persistente del segmento ST que no presenten contraindicación para su administración.

• Dosis de carga de 60 mg.

Indicaciones de Prasugrel en SCAseST (Sin contraindicaciones Prasugrel)

Riesgo

Alto

Intermedio

Bajo

Diabetes

AAS 250 mg Prasugrel 60 mg Inh. IIb/IIIa Heparina

Si

No

AAS 250 mg Prasugrel 60 mg Heparina

AAS 250 mg Clopidogrel 600 mg Heparina

AAS 250 mg Clopidogrel 300mg

Last Clop 75mg MD

Clopidogrel 600 mg LD

Clop 600mg LD

Pras 60 mg or 10mg

Last Pras Pras 10 mg Mean ±10 SDmg MD MD 20 µM ADP

Pras Last Clop10mg Prasugrel Last 10mg MD LD 75 mg MDMD 60 mg

Patients received aspirin 81 mg daily

SWITCH

LD, loading dose MD, maintenance dose

* 100

Last Clop 75mg MD

Clop 600mg LD

‡ 80

† †§

‡** †§

60 40 20

†

† †§ †§ †§

Pras 60 mg or 10mg

Pras 10mg MD

Last 10mg MD

Mean ± SD 20 µM ADP

SWITCH

§

§ §

Baseline Clopidogrel 600 mg LD Clopidogrel 75 mg MD Prasugrel 10 mg MD Prasugrel 60 mg LD/ § § mg§ MD Prasugrel 10 §

Maximal Platelet Aggregation (MPA, %)

Maximal Platelet Aggregation (MPA, %)

Maximal Platelet Aggregation (%)

Maximal Platelet Aggregation to 20 µM Adenosine Diphosphate (ADP) with Switching

100 80 60

Baseline Clopidogrel 600 mg LD Clopidogrel 75 mg MD Prasugrel 10 mg MD Prasugrel 60 mg LD/ Prasugrel 10 mg MD

40 20 0 Hour

0

0 0.5 1

Day

-7

1

2

4 24 0

2

4 24 0.5 1

11

2 12

4 24 0

0

0

15 16 17

0 2

4 24

22

0 Hour

0 0 0.5 1 2 4 24 0 2 4 24 0.5 1 2 4 24 0 0 0 0 2 4 24

Day

-7

1

11

12

15 16 17

22

*p<0.001 post-aspirin vs. drug-free baseline †p<0.001, ‡p<0.05 vs. zero time point of respective dose, the last measurement with clopidogrel §p<0.001, **p≤0.01 vs. clopidogrel 75 mg MD on day 11 Payne CD et al. Platelets 2008;19: 275

Prasugrel en pacientes ya tratados con Clopidogrel

con s e t n Pacie levado de e s riesgo is de stent os tromb

Relación con el tiempo desde la dosis de carga de Clopidogrel Clopidogrel

Prasugrel

– Si < 6 h de la dosis de carga

No dosis de carga.

– Si 6 - 48 h de la dosis de carga*

30/60 mg Prasugrel.

– Si > 48 h de la dosis de carga

60 mg Prasugrel.

*Si dosis de carga de Clopidogrel 600 mg: 30 mg Prasugrel.

Si dosis de carga de Clopidogrel 300 mg: 60 mg Prasugrel.

Nuevos Antiagregantes en el 2010 1.- Antiagregantes parenterales a) Inhibidores IIb/IIIa b) Cangrelor

2.- Antiagregantes Orales a) Prasugrel b) Ticagrelor c) Dosis altas de Clopidogrel d) Nuevos antiplaquetarios

Ticagrelor vs Clopidogrel in Patients with ACS n= 18624 pts, ACS, with or without ST-segment elevation

PLATO Study

Ticagrelor: 180 mg loading dose, 90 mg twice daily Clopidogrel: 300-600 mg loading dose, 75 mg daily 11.7%

9.8 %

Composite end-point: CV death, MI or stroke Wallentin et al. NEJM 2009; August 30; on line

Time to the First Major Bleeding end-point

New Oral P2Y12 Antagonists in ACS With Renal Dysfunction Hazard ratio for efficacy evaluated as the composite end point of CV death, MI or stroke in the CURE, CREDO, TRITON and PLATO trials according to renal function

Montalescot G, Silvain J. Circulation 2010; 122: 1049

Nuevos Antiagregantes en el 2010 1.- Antiagregantes parenterales a) Inhibidores IIb/IIIa b) Cangrelor

2.- Antiagregantes Orales a) Prasugrel b) Ticagrelor c) Dosis altas de Clopidogrel d) Nuevos antiplaquetarios

Doble dosis de Clopidogrel (600 mg + 150/d) en Ptes con SCA sometidos a una Estrategia Invasiva

Pacientes sometidos a ICP

CURRENT OASIS 7 Población total

End-point primario 30 d. p= ns

End-point primario (muerte, IM o ACV) 30 días

Sangrado mayor 2,5% vs 2%; p= 0.01 Current OASIS 7 Investigadores NEJM 2010; 363: 930 / Lancet 2010; 376: 1233

Trombosis (definitiva) de stents

Trombosis de Stent y Nuevos Fármacos Antiplaquetarios

Reducción en la tasa de Trombosis de Stent con fármacos antiplaquetarios mas potentes Dixon SR, et al. JACC 2010; 55: 2272

Nuevos Antiagregantes en el 2010 1.- Antiagregantes parenterales a) Inhibidores IIb/IIIa b) Cangrelor

2.- Antiagregantes Orales a) Prasugrel b) Ticagrelor c) Dosis altas de Clopidogrel d) Nuevos antiplaquetarios

LANCELOT-ACS

Oral Anti-Platelet Therapies P2Y12 Inhibition: Clopidogrel Ticlodipine Prasugrel Ticagrelor Elinogrel

ADP

ADP P2Y12 ADP

Thrombin

PAR-1 Inhibition: Atopaxar Vorapaxar

cAMP

PAR-1

GP IIb/IIIa (Fibrinogen receptor)

Adapted from Schafer. Am J Med. 1996;101:199-209.

PLATELET COX TXA2 Aspirin

Activation

Collagen TXA2

TRA•CER Study Design Patients with high-risk Non-ST-Segment Elevation Acute Coronary Syndrome . Admission < 24h of symptoms

Double-blind

N=12,636

Standard Medical Therapy AAS + Clopidogrel + Heparin +/- GPIIb/IIa

VORAPAXAR

TRA 40 mg + 2.5 mg/d

1:1

Placebo

AR X A ptor P e c O e r T A -1

PAR with ACS a i v n ibitio ility in pts h n i t le teMonths; rab e a e Follow-Up Day 30; 4, 8, 12 l l c e o P r t a and ent gonist reveEvery yyear m sible. 6 months t a r t t . e a n ) f a e o a after 1st r c o i S ial ft ón r r o vo y Únic c T i t i s y t h S e o t p agud com -A C mon o T s 3 u O ( l L a CE v. y or N I i 10 A C a í P L v r E ss 20 T e Po r A g V n Co NO

EL R G O ELIN Y12 ptor P2

C INDuration: >1 year follow-up; >2334e M1° . ESEP u h g Dono ´events O and >1457 key 2° EP 0 1 ress 20

Estudio

C Cong S E .

S Rao

Benefit vs Risk: Fragil Balance

Guidelines on Myocardial Revascularization ESC/EACTS

Antithrombotic treatment options in STEMI Patients

Wijns W, Kolh P et al. ESC Congress. Stockholm, August 2010

Guidelines on Myocardial Revascularization ESC/EACTS

Antithrombotic treatment options in NSTE-ACS

Wijns W, Kolh P et al. ESC Congress. Stockholm, August 2010

Feasibility of Maintaining Long-Term Double Antiplatelet Therapy (DAT) after Drug-Eluting Stent Implantation Hospital Universitario de Bellvitge

n= 1737 ptes, indication of coronary angiography with probable PCI

DAT with possible recommendation or without contraindications

78,7 %

DAT not recommended or contraindicated

21,3 %

Ferreiro JL, Cequier A, et al. EHJ 2008; 29 (Abst Suppl): 842

8%

Pending non-cardiac surgery

7,3 %

Oral anticoagulation

4,1 %

Neoplasia, liver disease

4,1 %

Recent bleeding

2,5 %

Allergy / ASA or Clopidogrel intolerance

1%

Other causes

Doble dosis de Clopidogrel en Ptes con SCA sometidos a una Estrategia Invasiva CURRENT OASIS 7 25.087 ptes, SCAseST 70.8 %, IMEST 29,2 % Estrategia invasiva precoz (< 24h) con intención de ICP ECG isquémico (81%) o biomarcadores cardiacos +(42%)

Aleatorizado a recibir (2 X 2 factorial): CLOPIDOGREL: Doble-dosis (600 mg carga , 150 mg/d x 7d , 75 mg/d) Dosis estándar (300 mg carga, 75 mg/d) AAS: Dosis alta (300-325 mg/d) vs Dosis baja (75-100 mg/d)

Variables Eficacia:

Muerte CV, IM o ictus a 30 días Trombosis del stent a 30 días Variables Seguridad: Hemorragia (CURRENT y TIMI)

Current OASIS 7 Investigators. NEJM 2010; 363: 930.

Ticagrelor in Patients with a Planned Invasive Strategy for ACS PLATO Study

1 year stent thrombosis

P= 0.025

p= ns

Cumulative first primary efficacy end-point Cannon CP et al. Lancet 2010; 375: 283

Time to total major bleeding

A Novel Thrombin Receptor Antagonist in PCI (TRA - PCI):

Major Efficacy Endpoint Results Primary (PCI) Cohort

VORAPAXAR

Risk Ratio & 95% CI

Placebo

D/MI All TRA

TRA

7.3%

4.5% 5.4% 4.2% 4.0%

7.3%

4.3% 5.4% 4.2% 3.5%

10 mg 20 mg 40 mg

MI All TRA 10 mg 20 mg 40 mg 0.1

0.5

TRA Better Lancet 2009; 373:919-28

1

1.5

Placebo Better

2

ELINOGREL

ATOPAXAR

Único antagonista receptor P2Y12 competitivo y reversible.

Acción directa: sin metabolito activo Por vía iv. y oral (uso agudo y crónico).

LANCELOT-ACS Trial

Estudio INNOVATE PCI

- Platelet inhibition via PAR-1 receptor - Safety and tolerability in pts with ACS - 3 months of treatment

Farmacocinética vs Clopidogrel

Rao S. ESC Congress 2010

O´Donoghue M. ESC Congress 2010