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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
Limitaciones de Clopidogrel
Puede demorar entre 5 y 7 das en alcanzar niveles plasmticos efectivos cuando se inicia como dosis de mantencin.1
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
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]
>60
-30
(0,10] (10,20]
(20,30] (30,40]
(40,50] (50,60]
>60
Aggregation (%)
Aggregation (%)
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
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)
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.
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
(0,10]
(10,20]
(20,30]
(30,40]
(40,50]
(50,60]
(60,70]
> 70
Platelet P2 Receptors/Inhibitors
ADP
Ticlopidine Clopidogrel Prasugrel Cangrelor Ticagrelor
Receptor subtype
P2Y1 P2X1
P2Y12
G protein GPCR Gj
[Na+/Ca2+]i
Functional response
Adapted From Bhatt and Topol, Nature Reviews Drug Disc 2:15-28, 2003
Clopidogrel
Prasugrel
Necesidad de nuevos agentes antiplaquetarios: 1. Prodroga 2. Variabilidad Interindividual 3. Bloqueador Irreversible 4. Resistencia 5. Interaccin medicamentos
Elinogrel
Trials
CURE
TRITON
PLATO
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
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.
CV Death/MI/Stroke
End Point (%) 10
Prasugrel
Prasugrel
2.4 1.8
Clopidogrel
0 30 60 90
180 Days
270
360
450
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.
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
Days
Diabetic Subgroup
N=3146
18
17.0
16
Endpoint (%)
14
12.2 12
10 8 6 4
Prasugrel
Clopidogrel Prasugrel
2.6
2
0
2.5
30 60 90
180
Days
270
360
450
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.
16%
4%
MD 10 mg
ASA + Clopidogrel
- 22% - 20%
ASA + Prasugrel
Reduction in Ischemic Events
- 19%
+ 60%
+ 38%
+ 32%
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
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).
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
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)
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
Clopidogrel
9.8 Ticagrelor
10
8
7 6 5 4 3 2
Clopidogrel
1
0 0 2
10
12
K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval * Wallentin, L et al., New Eng J Med. 2009;361:10451057
Clopidogrel
10
KM estimado (% por ao)
0
Hgia Mayor PLATO TIMI Mayor Txf GR Hgia Riesgo vital/fatal Hgia Fatal
4.0 Ticagrelor
60
120
180
240
300
360
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
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
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.
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
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
GP IIb/IIIa
GP IIb/IIIa
Serotonin
Collagen
5HT2A
GP VI
GP Ia
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.
~25%
6-20%
38%
No Tx
ASA
Clopidogrel
TRA
TRACER
PARE !!!!
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
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
Vorapaxar