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