Nuevos Antiplaquetarios en Síndromes Coronarios Agudos 2012
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Nuevos Antiplaquetarios en Síndromes Coronarios Agudos 2012
- 1. State of art: Antigregantes plaquetarios en Síndromes Coronarios Agudos Dr Ignacio Cabrera Samith Becado de las Medicina, 2 º año Universidad de Santiago de Chile 27 Junio 2012
- 2. Aterotrombosis y microcirculación Plaque Embolization Microvascular rupture obstruction Adapted from: Topol EJ, Yadav JS. Circulation 2000; 101: 570–80, and Falk E et al. Circulation 1995; 92: 657–71.
- 3. Cascada de la coagulación
- 4. Meadows TA, Bhatt DL. Circ Res. 2007;100:1261-1275.
- 5. Terapia Antiplaquetaria Dual • La inhibición de las plaquetas es una estrategia clave para prevenir recurrencia de eventos isquémicos en pacientes – Con sindromes coronarios agudos1,2 – Sometidos a PCI3 • Las metas de este tratamiento son la inhibición rápida, consistente y efectiva de la activación y agregación plaquetaria3-5 • La terapia antiplaquetaria dual con AAS y una tienopiridina constituyen el goal standard de tratamiento en pacientes con SCA desde que se inicia y progresa la terapia intervencional • Las preguntas pendientes: ¿Duración del tratamiento? ¿ Efecto en prevención secundaria en pacientes con aterotrombosis? ¿Eficacia en tratamiento médico? ¿Riesgo de hemorragias? ¿Alternativas diferentes? ASA=Acetylsalicylic Acid; ACS=Acute Coronary Syndrome; PCI=Percutaneous Coronary Intervention 1 Anderson JL et al. Circulation 2007;116:e148-304 4 Hochholzer W et al. Circulation 2005;111:2560-2564 2 Antman EM et al. Circulation 2008;117:296-329 5 Wiviott SD et al. Rev Cardiovasc Med 2006;7:214-225 3 King SB et al. Circulation 2008;117:261-295
- 6. Los Estudios que avalan Terapia Antiplaquetarias Dual: CURE CREDO CREDO-PCI CLARITY COMIT
- 7. Limitaciones de Clopidogrel Latencia de su efecto Variantes genéticas Resistencia a la droga ¿Alternativas? ¿Alternativas en la Farmacia del Dr. Simi?
- 8. Inhibidores Receptor P2Y12 Riesgo de eventos CV en portadores de gen CYP2C19*2 LOF tratados con clopidogrel Meta-análisis de 10 estudios (11,959 pacientes) Portador de gen Eventos LOF (%) No portador (%) OR (95% IC) p 1,29 MACE 9,7 7,8 <0,001 (1,12-1,49) Trombosis 3,45 2,9 0,9 <0,001 Intrastent (2,14-5,57) 1,79 Muerte 1,8 1,0 0,019 (1,10-2,91) Hulot JS et al. JACC 2010; 56:134-143.
- 9. Primer Estudio de resistencia al Clopidogrel (300 mg): A “Fingerprint” of Clopidogrel Response Variability 2 Hours 24 Hours 24 Resistance Resistance = 31% Resistance Resistance = 63% 20 Patients (%) Patients (%) 12 10 ≤ -30 (-20,-10] (0,10] (20,30] (40,50] >60 ≤ -30 (-20,-10] (0,10] (20,30] (40,50] >60 (-30,-20] (-10,0] (10,20] (30,40] (50,60] (-30,-20] (-10,0] (10,20] (30,40] (50,60] ∆ Aggregation (%) ∆ Aggregation (%) 5 Days 30 Days 22 28 Resistance Resistance = 31% 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] (0,10] (20,30] (40,50] >60 (-30,-20] (-10,0] (10,20] (30,40] (50,60] ∆ Aggregation (%) ∆ Aggregation (%) Gurbel PA et al. Circulation. 2003;107:2908-2913.
- 10. Clopidogrel Response Variability and Increased Risk of Ischemic Events Primary PCI for STEMI (N = 60) 5 µM ADP-induced Platelet Aggregation Death/ACS/CVA by 6 mo 120 Clop resist 40 40 100 Q1 P = 0.007 Baseline (%) 80 30 Q2 Percent 60 20 Q3 40 Q4 10 6.7 20 Quartiles of response 0 0 0 0 1 2 3 4 5 6 Q1 Q2 Q3 Q4 Days Matetzky S et al. Circulation. 2004;109:3171-3175. Wiviott SD, Antman EM. Circulation. 2004;109:3064-3067.
- 11. Variabilidad de Respuesta a Clopidogrel: Aumento de la Dosis (300 mg vs. 600 mg) 33 300 mg Clopidogrel 30 600 mg Clopidogrel 27 24 Resistance = 28% (300 mg) Resistance = 8% (600 mg) Patients (%) 21 18 15 12 9 6 3 0 ≤-30 (-20,-10] (0,10] (20,30] (40,50] (60,70] (-30,-20] (-10,0] (10,20] (30,40] (50,60] > 70 D Aggregation (5 µM ADP-induced Aggregation) at 24 Hr Gurbel PA et al. J Am Coll Cardiol. 2005;45:1392-1396.
- 12. CURRENT-OASIS 7: Muerte CV, IM, AVE a 30 Días Mehta SR, et al, ESC; September 2009; Barcelona, Spain.
- 13. CURRENT-OASIS 7: Conclusiones Autores Test a doble dosis de clopidogrel redujo significativamente la trombosis de stents y eventos CV mayores. En pacientes no sometidos a PCI la doble dosis de clopidogrel no tuvo diferencia con la dosis estándar. Un exceso modesto de hemorragias mayores por criterios CURRENT, pero no hubo diferencias en HIC, hemorragias fatales. Mehta SR, et al, ESC; September 2009; Barcelona, Spain.
- 14. Novedades en Antiplaquetarios... “Armamentario Terapeútico” más allá del Clopidogrel: ¿qué tenemos? Bloqueo plaquetario Triple: ¿realidad o ficción? Cuales son los antiplaquetarios con mejores perspectivas futuras?
- 15. Platelet P2 Receptors/Inhibitors Ticlopidine Clopidogrel Prasugrel ADP Cangrelor Ticagrelor X Receptor subtype P2Y1 P2Y12 P2X1 G protein G protein Molecular structure Intrinsic ion GPCR GPCR channel Gq Gj Secondary Messenger system [Na+/Ca2+]i PLC/IP3 AC [cAMP] [Ca2+]j Shape change Sustained Functional response Shape Change Transient aggregation Aggregation aggregation Secretion Adapted From Bhatt and Topol, Nature Reviews Drug Disc 2:15-28, 2003
- 16. Inhibidores Receptor P2Y12 • Indirectos (Tienopiridinas) - Ticlopidina - Clopidogrel - Prasugrel • Directos (No Tienopiridinas) - Cangrelor - Ticagrelor - Elinogrel
- 17. Inhibidores Receptor P2Y12 Clopidogrel Prasugrel Ticagrelor Clase Tienopiridina Tienopiridina Análogo ATP Reversibilidad irreversible irreversible reversible Administración oral oral oral Efecto peak 2-3 hrs 1 hr 1,5 hrs Eliminación 3 hrs 3,7 hrs 12 hrs Duración 5-8 días 5-10 días 24 hrs Trials CURE TRITON PLATO
- 18. Comparing Response of Clopidogrel (300 mg) and Prasugrel (60 mg) by IPA at 24 Hours 100.0 (20 µM ADP) Inhibition of Platelet Aggregation (%) 80.0 60.0 40.0 20.0 Background 0.0 Variability -20.0 Response to Clopidogrel Response to Prasugrel Brandt J et al. Am Heart J. 2007;153:66.e9-66.e16
- 19. TRITON TIMI-38 Study Design ACS (STEMI or UA/NSTEMI) and Planned PCI ASA N=13,600 Double-blind CLOPIDOGREL PRASUGREL 300 mg LD/ 75 mg MD 60 mg LD/ 10 mg MD Median duration of therapy: 12 months First-degree end point: CV death, MI, stroke Second-degree end points: 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.
- 20. TRITON TIMI-38: Balance of Efficacy and Safety 15 138 Clopidogrel eventos CV Death/MI/Stroke 12.1 HR 0.81 (0.73-0.90) End Point (%) 10 9.9 P = .0004 Prasugrel NNT = 46 5 TIMI Major 35 Non-CABG Bleeds Prasugrel eventos 2.4 HR 1.32 1.8 (1.03-1.68) Clopidogrel P = .03 0 0 30 60 90 180 270 360 450 NNH = 167 Days 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.
- 21. Subgrupos de Riesgo de Hemorragias Consideraciones terapeuticas Re Gu duc i e Ag ded d M b D Wt e > 7 y P <6 5o K 0k r g 16% Pras r Av o CVA Prio id ugre / TI A 4% l Significant MD Net Clinical Benefit with 10 mg Prasugrel 80%
- 22. Terapia Antiplaquetaria en SCA ASA ASA + Clopidogrel ASA + Prasugrel - 22% Reduction in - 20% Ischemic Events - 19% Increase in + 60% + 38% + 32% Major Bleeds Placebo APTC CURE TRITON-TIMI 38 Single Dual Higher Antiplatelet Rx Antiplatelet Rx IPA
- 23. Ticagrelor (AZD 6140): Antagonista oral reversible del P2Y12 HO N N N HO H N F O N N F S OH • Direct acting – Not a pro-drug; does not require metabolic activation – Rapid onset of inhibitory effect on the P2Y12 receptor – Greater inhibition of platelet aggregation than clopidogrel • Reversibly bound – Degree of inhibition reflects plasma concentration – Faster offset of effect than clopidogrel – Functional recovery of circulating platelets within ~48 hours
- 24. 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 Ticagrelor If pre-treated, no additional loading dose; 180 mg loading dose, then if naive, standard 300 mg loading dose, 90 mg bid maintenance; then 75 mg qd maintenance; (additional 90 mg pre-PCI) (additional 300 mg allowed pre-PCI) 6–12 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 24–72 hours for ticagrelor. Study drug be restarted as soon as possible after surgery and prior to PCI = percutaneous coronary intervention discharge CV = cardiovascular
- 25. PLATO main endpoints* Primary efficacy endpoint Primary safety endpoint 13 15 12 Clopidogrel 11.7 11 Ticagrelor 10 9.8 11.58 9 11.20 K-M estimated rate (%) 10 K-M estimated rate (%) Ticagrelor Clopidogrel 8 7 6 5 5 4 3 2 1 HR 0.84 (95% CI 0.77–0.92), p=0.0003 HR 1.04 (95% CI 0.95–1.13), p=0.434 0 0 0 2 4 6 8 10 12 0 2 4 6 8 10 12 Months from randomization Months from randomization No. at risk Ticagrelor 9,333 8,628 8,460 8,219 6,743 5,161 4,147 9,235 7,246 6,826 6,545 5,129 3,783 3,433 Clopidogrel 9,291 8,521 8,362 8,124 6,743 5,096 4,047 9,186 7,305 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;361:1045–1057
- 26. PLATO Ticagrelor: Impacto en Mortalidad Cardiovascular 7 Disminución de mortalidad cardiovascular Disminución de mortalidad cardiovascular 6 5 Clopidogrel 5.1 Cumulative incidence (%) 4 4.0 3 Ticagrelor 2 1 0 HR 0.79 (95% CI 0.69–0.91), p=0.001 0 60 120 180 240 300 360 Days after randomisation 9,333 8,294 8,822 8,626 7119 5,482 4,419 9,291 8,865 8,780 8,589 7079 5,441 4,364 Cannon et al. Lancet 2010;375:283-293.
- 27. PLATO Ticagrelor: Trombosis del Stent Trombosis Ticagrelor Clopidogrel HR (95% IC) p Stent (%) (n=6.732) (n=6.676) 0,62 Definitiva 1,0 1,6 0,003 (0,45-0,85) Probable o 0,72 1,7 2,3 0,01 Definitiva (0,56-0,93) Posible, 0,72 Probable o 2,2 3,1 0,003 Definitiva (0,58-0,90) Cannon et al. Lancet 2010;375:283-293.
- 28. PLATO: Dosis de AAS y eficacia:
- 29. Receptores Plaquetarios Platelet Platelet PAR-1 Thrombin PAR-4 Fibrinogen GP P2Y1 ADP IIb/IIIa P2Y12 GP TBX A2 TBXA2-R IIb/IIIa Epinephrine EPI-R Serotonin 5HT2A GP VI Collagen Anionic GP Ia phospholipid surfaces
- 30. Antagonista de los receptores de Trombina (TRA) SCA se caracterizan por formación aumentada de trombina que persiste incluso luego del evento agudo. Trombina es el principal activador de la plaqueta. Actúa a través de receptor PAR-1 . El bloqueo de los receptores PAR-1 tendría ventajas potenciales en el corto y largo plazo. Estudios iniciales en pacientes sometidos a PCI electiva han mostrado resultados alentadores: TRA-PCI Estudios Terminados: TRACER y TRA 2P
- 31. Morrow et al. ACC 2012, Chicago, March 24, 2012
- 32. 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 Placebo 40 mg carga, 2.5 mg/día (y terapia usual) n=5000 n=5000 • Muerte cardiovascular a 1 año, IAM, Stroke, Isquemia recurrente con Rehosp, Revascularización Coronaria Urgente • STOP !!!! STOP !!!!
- 33. Morrow et al. ACC 2012, Chicago, March 24, 2012
- 34. Morrow et al. ACC 2012, Chicago, March 24, 2012
- 35. Morrow et al. ACC 2012, Chicago, March 24, 2012
- 36. Morrow et al. ACC 2012, Chicago, March 24, 2012
- 37. ¿Cuánto debe prolongarse la terapia AP Dual? Valgimigli et al. Circ 2012 Gwon et al. Circ 2012
- 38. 2 años de stent trombosis, definitiva y probable, de acuerdo a interrupcion de DAPT 0,07 0,06 6,2% p = 0.05 0,05 0,04 0,03 0,02 2,3% 2,3% 1,5% 0,01 1,1% 0,8% 0 0,5% 0,5% p = 0.75 n n tio io on m m uat ua ati 24 ati PT 6 m in 12 tin 4m u at -2 tin 1- ont 6- con inu DA on 12 scon sc s co No di di di PT PT PT nt DA DA Kedhi et al, ACC 2012 DA dis SE2936415 Rev. A
- 39. Data on Abbott vascular file
- 40. TIEMPO DE PRIMERA INTERRUPCION DE DAPT Y STENT TROMBOSIS A 1 A ÑO
- 41. LIMITES ANALISIS POST HOC TAMAÑO DE MUESTRA INTERRUPCION DAPT PEQUEÑO PARA ANALISIS DE RIESGO DAPT COMPLIANCE BASADA EN AUTO REPORTE Y NO CONTEO
- 42. Conclusiones ► Los pacientes con bajo peso o signos de insuficiencia renal tienen mayor riesgo de sangrado con terapia dual. ► En esos casos las dosis de AAS deben ser bajas y las tienopiridinas y bloqueadores ADP deben reducirse a la mitad de la dosis. ► La terapia dual está contraindicada en pacientes con antecedentes de AVE previo por mayor riesgo de HIC.
- 43. Conclusiones ► Actualmente importante “armamentario” de antiagregantes plaquetarios para el manejo de los SCA y uso rutinario en PCI. ► Bloqueo plaquetario triple: atractiva posibilidad pero riesgo de más hemorragias ► Mejores perspectivas para TAD: ● Prasugrel ● Ticagrelor ● Vorapaxar (??)
- 44. FIN GRACIAS POR SU ATENCIÓN Dr Ignacio Cabrera Samith Becado de las Medicina, 2 º año Universidad de Santiago de Chile 27 Junio 2012
Editor's Notes
- References: 1. Topol EJ, Yadav JS. Circulation 2000; 101: 570–80. 2. Drouet L. Cerebrovasc Dis 2002; 13(suppl 1): 1–6. Through the development of new imaging modalities and specific therapeutics that serve as probes, microvascular obstruction, owing to embolization, has become increasingly recognized as an important sequelae of atherosclerotic and atherothrombotic vascular disease. 1 Thrombus formation on an atherosclerotic plaque is a dynamic process in which platelets aggregate but also spontaneously disaggregate, leading to embolization of platelet aggregates from an evolving thrombus, which can lead to inflammation or microvascular obstruction. 2 Additionally, particulate matter may also shed from the ruptured atherosclerotic lesion. 2 Altogether, the release of microemboli, which occurs while a plaque is active and can last for hours, days or weeks, leads to microvascular obstruction in the myocardium, brain or peripheral tissues, resulting for example in cardiac insufficiency or vascular dementia. 2
- Background on antiplatelet therapy Pharmacological inhibition of platelets with a combination of aspirin (ASA) and a thienopyridine is a currently recommended approach to prevent recurrent ischemic events in acute coronary syndrome (ACS) patients undergoing percutaneous coronary intervention (PCI). 1-3 The goals of antiplatelet therapy are to provide rapid and consistent high levels of inhibition of platelet activation and aggregation. Important clinical benefits have been demonstrated with current antiplatelet treatments in large, multinational trials over the last decade resulting in clinical guidelines for antiplatelet therapy. 1 Anderson JL et al. Circulation 2007;116:e148-304 2 Antman EM et al. Circulation 2008;117:296-329 3 King SB et al. Circulation 2008;117:261-295 4 Hochholzer W et al. Circulation 2005;111:2560-2564 5 Wiviott SD et al. Rev Caridovasc Med 2006;7:214-225
- TRITON-TIMI 38 was a phase 3, randomized, double-blind, parallel-group, multinational, clinical trial. Approximately 13000 patients with moderate to high-risk ACS undergoing PCI (9500 unstable angina/non–ST-segment elevation myocardial infarction [MI], 3500 ST-segment elevation MI) were randomized to prasugrel 60 mg loading dose followed by 10 mg daily or clopidogrel 300 mg loading dose followed by 75 mg daily for up to 15 months. The primary end point was the time of the first event of cardiovascular death, MI, or stroke. Analyses were performed first in the unstable angina/non–ST-segment elevation MI cohort and, conditionally, on the whole ACS population. Major safety end points included TIMI major and minor bleeding unrelated to coronary artery bypass graft surgery.
- To compare prasugrel, a new thienopyridine, with clopidogrel, the authors randomly assigned 13,608 patients with moderate-to-high-risk acute coronary syndromes with scheduled percutaneous coronary intervention to receive prasugrel (a 60-mg loading dose and a 10-mg daily maintenance dose) or clopidogrel (a 300-mg loading dose and a 75-mg daily maintenance dose), for 6 to 15 months. The primary efficacy end point was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The key safety end point was major bleeding. Results: The primary efficacy end point occurred in 12.1% of patients receiving clopidogrel and 9.9% of patients receiving prasugrel (hazard ratio for prasugrel vs. clopidogrel, 0.81; 95% confidence interval [CI], 0.73 to 0.90; P<0.001). The authors also found significant reductions in the prasugrel group in the rates of myocardial infarction (9.7% for clopidogrel vs. 7.4% for prasugrel; P<0.001), urgent target-vessel revascularization (3.7% vs. 2.5%; P<0.001), and stent thrombosis (2.4% vs. 1.1%; P<0.001). Major bleeding was observed in 2.4% of patients receiving prasugrel and in 1.8% of patients receiving clopidogrel (hazard ratio, 1.32; 95% CI, 1.03 to 1.68; P = 0.03). Also greater in the prasugrel group was the rate of life-threatening bleeding (1.4% vs. 0.9%; P = 0.01), including nonfatal bleeding (1.1% vs. 0.9%; hazard ratio, 1.25; P = 0.23) and fatal bleeding (0.4% vs. 0.1%; P = 0.002). Figure: Cumulative Kaplan–Meier estimates of the rates of key study end points during the follow-up period showing data for the primary efficacy end point (death from cardiovascular causes, nonfatal myocardial infarction [MI], or nonfatal stroke). In the overall cohort, a total of 781 patients (12.1%) in the clopidogrel group had the primary end point, as compared with 643 patients (9.9%) in the prasugrel group (hazard ratio, 0.81; 95% CI, 0.73 to 0.90; P<0.001), supporting the primary hypothesis of superior efficacy. Conclusions: In patients with acute coronary syndromes with scheduled percutaneous coronary intervention, prasugrel therapy was associated with significantly reduced rates of ischemic events, including stent thrombosis, but with an increased risk of major bleeding, including fatal bleeding. Overall mortality did not differ significantly between treatment groups.
- To compare prasugrel, a new thienopyridine, with clopidogrel, the authors randomly assigned 13,608 patients with moderate-to-high-risk acute coronary syndromes with scheduled percutaneous coronary intervention to receive prasugrel (a 60-mg loading dose and a 10-mg daily maintenance dose) or clopidogrel (a 300-mg loading dose and a 75-mg daily maintenance dose), for 6 to 15 months. The primary efficacy end point was death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. The key safety end point was major bleeding. Results: The primary efficacy end point occurred in 12.1% of patients receiving clopidogrel and 9.9% of patients receiving prasugrel (hazard ratio for prasugrel vs. clopidogrel, 0.81; 95% confidence interval [CI], 0.73 to 0.90; P<0.001). The authors also found significant reductions in the prasugrel group in the rates of myocardial infarction (9.7% for clopidogrel vs. 7.4% for prasugrel; P<0.001), urgent target-vessel revascularization (3.7% vs. 2.5%; P<0.001), and stent thrombosis (2.4% vs. 1.1%; P<0.001). Major bleeding was observed in 2.4% of patients receiving prasugrel and in 1.8% of patients receiving clopidogrel (hazard ratio, 1.32; 95% CI, 1.03 to 1.68; P = 0.03). Also greater in the prasugrel group was the rate of life-threatening bleeding (1.4% vs. 0.9%; P = 0.01), including nonfatal bleeding (1.1% vs. 0.9%; hazard ratio, 1.25; P = 0.23) and fatal bleeding (0.4% vs. 0.1%; P = 0.002). Figure: The rate of definite or probable stent thrombosis, as defined by the Academic Research Consortium, was significantly reduced in the prasugrel group as compared with the clopidogrel group, with 68 patients (1.1%) and 142 patients (2.4%), respectively, having at least one occurrence (hazard ratio, 0.48; 95% CI, 0.36 to 0.64; P<0.001). Conclusions: In patients with acute coronary syndromes with scheduled percutaneous coronary intervention, prasugrel therapy was associated with significantly reduced rates of ischemic events, including stent thrombosis, but with an increased risk of major bleeding, including fatal bleeding. Overall mortality did not differ significantly between treatment groups.