1. Rol actual de los nuevosantiplaquetarios en elSindrome Coronario AgudoDr. Ramn Corbaln H.Facultad de MedicinaPontificia Universidad Catlica de Chile

2. Meadows TA, Bhatt DL. Circ Res. 2007;100:1261-1275. 3. Terapia Antiplaquetaria Dual La inhibicin de las plaquetas es una estrategia clave para tratar yprevenir recurrencia de eventos isqumicos en pacientes Con sindromes coronarios agudos1,2 Sometidos a PCI3 Las metas de este tratamiento son la inhibicin rpida, consistente yefectiva de la activacin y agregacin plaquetaria3-5 La terapia antiplaquetaria dual con AAS y una tienopiridina(Clopidogrel) ha constitudo el goal standard de tratamiento enpacientes con SCA11Anderson JL et al. Circulation 2007;116:e148-3042Antman EM et al. Circulation 2008;117:296-3293King SB et al. Circulation 2008;117:261-2954Hochholzer W et al. Circulation 2005;111:2560-25645Wiviott SD et al. Rev Cardiovasc Med 2006;7:214-225ASA=Acetylsalicylic Acid; ACS=Acute Coronary Syndrome; PCI=Percutaneous CoronaryIntervention 4. Limitaciones de ClopidogrelPuede demorar entre 5 y 7 das en alcanzar nivelesplasmticos efectivos cuando se inicia como dosis demantencin.1Importante variacin interindividual en niveles deinhibicin plasmtica2: 20% a 30% de pacientes pueden tener niveles mnimos deinhibicin plaquetaria con las dosis de carga de 300mg y demantencin de 300mg Este fenmeno 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 5. Expresin de receptorGP IIb/IIIaMetabolismo HepticoVa Citocromo P450Mala adherenciaAdministracin InadecuadaAbsorcin VariableInteracciones DrogasPolimorfismos Genticos enzimas CYPInteracciones Drogas (3A4/5; 2C19)Polimorfismos Genticos receptor P2Y12Vas Alternativas de activacin plaquetariaLiberacin de ADP circulanteReactividad plaquetaria basal elevadaPolimorfismos GenticosAbsorcin IntestinalReceptor P2Y12(inhibicin irreversible)Metabolito activoCYP = cytochrome P450ODonoghue M, Wiviott SD. Circulation. 2006;114:e600-e606.Variabilidad en Respuesta a Clopidogrel 6. The First Clopidogrel Resistance Study (300 mg):A Fingerprint of Clopidogrel ResponseGurbel PA et al. Circulation. 2003;107:2908-2913.2 Hours5 Days Aggregation (%)Resistance = 63% Resistance = 31%ResistanceResistance = 31%ResistanceResistance = 15% Aggregation (%) Aggregation (%)ResistancePatients(%)1224 -30(-30,-20](-20,-10](-10,0](0,10](10,20](20,30](30,40](40,50](50,60]>60Patients(%)1122 -10 (-10,0] (0,10] (10,20] (20,30] (30,40] (40,50] (50,60] >601428 -30(-30,-20](-20,-10](-10,0](0,10](10,20](20,30](30,40](40,50](50,60]>601020 -30(-30,-20](-20,-10](-10,0](0,10](10,20](20,30](30,40](40,50](50,60]>60 Aggregation (%)ResistancePatients(%)Patients(%)24 Hours30 DaysVariability 7. Relevancia ClnicaEstudios recientes sugieren que la menor inhibicinplaquetaria post Clopidogrel puede ser relevante1-3Los niveles bajos de inhibicin plaquetaria se hanasociado con mayor riesgo de: Aumento de eventos cardiovasculares1 Trombosis subaguda de stents2 Eventos Isqumicosevents 31Matetzky 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 8. 0204060801001200102030405 M ADP-induced Platelet Aggregation Death/ACS/CVA by 6 moDays1 2 3 4 5 6Baseline(%)Quartiles of responseQ1Q2Q3Q4Clop resist 406.70 0PercentP = 0.007Q1 Q2 Q3 Q4Matetzky 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) 9. Variabilidad de Respuesta a Clopidogrel:Aumento de la Dosis (300 mg vs. 600 mg)Gurbel PA et al. J Am Coll Cardiol. 2005;45:1392-1396.03691215182124273033-30(-30,-20](-20,-10](-10,0](0,10](10,20](20,30](30,40](40,50](50,60](60,70]> 70300 mg Clopidogrel600 mg ClopidogrelD Aggregation (5 M ADP-induced Aggregation) at 24 HrPatients(%)Resistance = 28% (300 mg)Resistance = 8% (600 mg) 10. Platelet P2 Receptors/InhibitorsG proteinMolecular structure Intrinsic ionchannelG proteinReceptor subtypeP2X1P2Y1 P2Y12GPCRGjGPCRGqPLC/IP3[Ca2+]jAC[cAMP]Shape changeTransientaggregationSustainedaggregationSecretionSecondaryMessenger systemFunctional response[Na+/Ca2+]iShape ChangeAggregationADPXAdapted From Bhatt and Topol, Nature Reviews Drug Disc 2:15-28, 2003TiclopidineClopidogrelPrasugrelCangrelorTicagrelor 11. Inhibidores Receptor P2Y12 Indirectos(Tienopiridinas) Ticlopidina Clopidogrel Prasugrel Directos (NoTienopiridinas) Cangrelor Ticagrelor ElinogrelNecesidad de nuevos agentesantiplaquetarios:1. Prodroga2. Variabilidad Interindividual3. Bloqueador Irreversible4. Resistencia5. Interaccin medicamentos 12. Inhibidores Receptor P2Y12Clopidogrel Prasugrel TicagrelorClase Tienopiridina Tienopiridina Anlogo ATPReversibilidad irreversible irreversible reversibleAdministracin oral oral oralEfecto peak 2-3 hrs 1 hr 1,5 hrsEliminacin 3 hrs 3,7 hrs 12 hrsDuracin 5-8 das 5-10 das 24 hrsTrials CURE TRITON PLATO 13. 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 14. -20.00.020.040.060.080.0100.0InhibitionofPlateletAggregation(%)Response toPrasugrelResponse toClopidogrelComparing Response of Clopidogrel (300 mg) andPrasugrel (60 mg) by IPA at 24 HoursBrandt J et al. Am Heart J. 2007;153:66.e9-66.e16(20 M ADP)BackgroundVariability 15. TRITON TIMI-38 Study DesignDouble-blindACS (STEMI or UA/NSTEMI) and Planned PCIASAPRASUGREL60 mg LD/ 10 mg MDCLOPIDOGREL300 mg LD/ 75 mg MDFirst-degree end point: CV death, MI, strokeSecond-degree end points: CV death, MI, stroke, rehospitalization,recurrent ischemia, UTVRMedian duration of therapy: 12 monthsN=13,600Wiviott SD, et al. Am Heart J. 2006;152:627-635.UTVR = urgent target vessel revascularization; TRITON TIMI = TRial to assess Improvement in TherapeuticOutcomes by optimizing platelet inhibitioN with prasugrel Thrombolysis In Myocardial InfarctionFDA-approved dosage for clopidogrel: 75 mg daily; 300 mg loading dosePrasugrel is not yet approved for use 16. Days35eventsTRITON TIMI-38: Balance of Efficacyand SafetyHR 0.81(0.73-0.90)P = .0004HR 1.32(1.03-1.68)P = .03138eventsNNT = 46NNH = 167Wiviott SD, et al. N Engl J Med. 2007;357:2001-2015.EndPoint(%)12.19.91.82.40510150 30 60 90 180 270 360 450CV Death/MI/StrokeTIMI MajorNon-CABG BleedsClopidogrelPrasugrelPrasugrelClopidogrelHR = hazard ratio; NNT = number needed to treat; NNH = number needed to harm 17. TRITON TIMI-38: Stent Thrombosis(ARC Definite + Probable)Days01230 30 60 90 180 270 360 450HR 0.48P < .0001PrasugrelClopidogrel 2.4(142)74 eventsNNT = 771.1(68)EndPoint(%)Any Stent at Index PCIN = 12,844ARC = Academic Research Consortium; PCI = percutaneous coronary interventionWiviott SD, et al. N Engl J Med. 2007;357:2001-2015. 18. Diabetic Subgroup0246810121416180 30 60 90 180 270 360 450HR 0.70P