Antiagregantes Plaquetarios en Pacientes con SCA

1. Antiagregantes Plaquetarios en Pacientes con SCA Dr Ramón Corbalán Departamento Enfermedades Cardiovaculares Pontificia Universidad Cátolica de Chile

2. Terapia Antiplaquetaria Dual La inhibición de las plaquetas es una estrategia clave en el tratmiento de 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 SCAdesde que se inicia y progresa en la terapia intervencional Las preguntas pendientes: ¿Duración del tratamiento? ¿ Efectos en pacientes tratados solo médicamente? ¿Riesgo de hemorragias? ¿Alternativas diferentes? ASA=Acetylsalicylic Acid; ACS=Acute Coronary Syndrome; PCI=Percutaneous Coronary Intervention 4Hochholzer W et al. Circulation 2005;111:2560-2564 5Wiviott SD et al. Rev Cardiovasc Med 2006;7:214-225 1Anderson JL et al. Circulation 2007;116:e148-304 2Antman EM et al. Circulation 2008;117:296-329 3King SB et al. Circulation 2008;117:261-295

3. Los Estudios que avalan Terapia Antiplaquetarias Dual: • CURE • CREDO • CREDO-PCI • CLARITY • COMIT

4. Limitaciones de Clopidogrel • Latencia de su efecto • Variantes genéticas • Resistencia a la droga • ¿Alternativas?

5. Inhibidores Receptor P2Y12Riesgo de eventos CV en portadores de gen CYP2C19*2 LOF tratados con clopidogrel Meta-análisis de 10 estudios (11,959 pacientes) Hulot JS et al. JACC 2010; 56:134-143.

6. Clopidogrel Response Variability andIncreased Risk of Ischemic Events Primary PCI for STEMI (N = 60) 5 µM ADP-induced Platelet Aggregation Death/ACS/CVA by 6 mo Clop resist 40 120 40 100 Q1 P = 0.007 30 80 Q2 Baseline (%) Percent 60 20 Q3 40 Q4 6.7 10 20 Quartiles of response 0 0 0 0 Q1 Q2 Q3 Q4 1 2 3 4 5 6 Days Matetzky S et al. Circulation. 2004;109:3171-3175. Wiviott SD, Antman EM. Circulation. 2004;109:3064-3067.

7. Variabilidad de Respuesta a Clopidogrel: Aumento de la Dosis (300 mg vs. 600 mg) 33 300 mg Clopidogrel 30 600 mg Clopidogrel 27 Resistance = 28% (300 mg) 24 Resistance = 8% (600 mg) 21 18 Patients (%) 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.

8. CURRENT-OASIS 7: Eventos Primarios y Dosis de Clopidogrel /AAS a 30 Días Mehta SR, et al, ESC; September 2009; Barcelona, Spain.

9. CURRENT-OASIS 7: Muerte CV, IM, AVE a 30 Días Mehta SR, et al, ESC; September 2009; Barcelona, Spain.

10. 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 o post CRVM

11. Novedades en Antiplaquetarios... • “ArmamentarioTerapeútico” másallá del Clopidogrel: ¿quétenemos? • Bloqueoplaquetario Triple: ¿realidad o ficción? • Cuales son los antiplaquetarios con mejoresperspectivasfuturas?

12. Platelet P2 Receptors/Inhibitors G protein G protein Ticlopidine Clopidogrel Prasugrel Cangrelor Ticagrelor ADP X Receptor subtype P2Y12 P2Y1 P2X1 Intrinsic ion channel GPCR Gj GPCR Gq Molecular structure Secondary Messenger system PLC/IP3 [Ca2+]j [Na+/Ca2+]i AC [cAMP] Shape change Transient aggregation Sustained aggregation Secretion Shape Change Aggregation Functional response Adapted From Bhatt and Topol, Nature Reviews Drug Disc 2:15-28, 2003

13. Necesidad de nuevosagentesantiplaquetarios: • Prodroga • VariabilidadInterindividual • Bloqueador Irreversible • Resistencia • Interacciónmedicamentos Inhibidores Receptor P2Y12 • Indirectos (Tienopiridinas) • Ticlopidina • Clopidogrel • Prasugrel • Directos (No Tienopiridinas) • Cangrelor • Ticagrelor • Elinogrel

14. Comparing Response of Clopidogrel (300 mg) and Prasugrel (60 mg) by IPA at 24 Hours 100.0 (20 µM ADP) 80.0 60.0 40.0 Inhibition of Platelet Aggregation (%) 20.0 Background Variability 0.0 -20.0 Response to Clopidogrel Response to Prasugrel Brandt J et al. Am Heart J. 2007;153:66.e9-66.e16

15. TRITON TIMI-38 Study Design ACS (STEMI or UA/NSTEMI) and Planned PCI ASA N=13,600 Double-blind CLOPIDOGREL 300 mg LD/ 75 mg MD PRASUGREL 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 InfarctionFDA-approved dosage for clopidogrel: 75 mg daily; 300 mg loading dosePrasugrel is not yet approved for use Wiviott SD, et al. Am Heart J. 2006;152:627-635.

16. 138 events 15 Clopidogrel CV Death/MI/Stroke 12.1 HR 0.81(0.73-0.90)P = .0004 9.9 10 NNT = 46 Prasugrel End Point (%) TIMI Major Non-CABG Bleeds 5 Prasugrel 2.4 HR 1.32(1.03-1.68)P = .03 1.8 Clopidogrel 0 NNH = 167 0 30 60 90 180 270 360 450 TRITON TIMI-38: Balance of Efficacy and Safety 35 events 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.

17. TRITON TIMI-38 Net Clinical Benefit: Bleeding Risk Subgroups Risk (%) + 37 Yes Prior Stroke / TIA -16 Pint = 0.006 No -1 ≥75 Age -16 Pint = 0.18 <75 +3 <60 kg Weight -14 Pint = 0.36 ≥60 kg -13 Overall 0.5 1 2 Prasugrel Better Clopidogrel Better HR Post-hoc analysisWiviott SD, et al. N Engl J Med. 2007;357:2001-2015.

18. Subgrupos de Riesgo de Hemorragias Consideraciones terapeuticas Reduced MDGuided by PKAge > 75 or Wt < 60 kg Avoid PrasugrelPrior CVA/TIA 16% 4% Significant Net Clinical Benefit with Prasugrel80% MD 10 mg

19. Terapia Antiplaquetaria en SCA ASA ASA + Clopidogrel ASA + Prasugrel Reduction inIschemicEvents - 22% - 20% - 19% Increase in Major Bleeds + 32% + 38% + 60% Single Antiplatelet Rx Dual Antiplatelet Rx Higher IPA

20. Ticagrelor (AZD 6140): an oral reversible P2Y12 antagonist Ticagrelor is a cyclo-pentyl-triazolo-pyrimidine (CPTP) • 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

21. 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 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) Ticagrelor 180 mg loading dose, then 90 mg bid maintenance; (additional 90 mg 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 discharge PCI = percutaneous coronary interventionCV = cardiovascular

22. PLATO main endpoints* Primary safety endpoint Primary efficacy endpoint 13 15 12 11.7 Clopidogrel 11 Ticagrelor 10 11.58 9.8 11.20 9 10 Clopidogrel Ticagrelor 8 7 K-M estimated rate (%) K-M estimated rate (%) 6 5 5 4 3 2 HR 0.84 (95% CI 0.77–0.92), p=0.0003 1 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 9,235 7,246 6,826 6,545 5,129 3,783 3,433 Ticagrelor 9,333 8,460 4,147 8,628 8,219 6,743 5,161 9,186 7,305 6,930 6,670 5,209 3,841 3,479 Clopidogrel 9,291 8,362 4,047 8,521 8,124 6,743 5,096 K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval * Wallentin, L et al., New Eng J Med. 2009;361:1045–1057

23. PLATOTicagrelor: Impacto en Mortalidad Cardiovascular 7 • Disminución de mortalidad cardiovascular 6 Clopidogrel 5.1 5 4.0 4 Ticagrelor Cumulative incidence (%) 3 2 1 HR 0.79 (95% CI 0.69–0.91), p=0.001 0 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.

24. PLATO: Dosis de AAS y eficacia:

25. 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 • Los nuevos antiagregantes son más potentes, pero a expensas de un mayor riesgo de sangrado

26. PAR-1 PAR-4 P2Y1 P2Y12 TBX A2 TBXA2-R Serotonin 5HT2A GP VI Platelet Receptors Platelet Platelet Thrombin Fibrinogen GP IIb/IIIa ADP GP IIb/IIIa EPI-R Epinephrine Collagen Anionic phospholipid surfaces GP Ia

27. Antagonista de los receptores de Trombina (TRA) y Triple Inhibición Plaquetaria • SCA se caracterizanporformaciónaumentada de trombinaquepersisteinclusoluego del eventoagudo • Trombinaes el principal activador de la plaqueta • Actúa a través de receptor PAR-1 • El bloqueo de los receptores PAR-1 tendríaventajaspotenciales en el corto y largo plazo • Estudiosiniciales en pacientessometidos a PCI electivahanmostradoresultadosalentadores: TRA-PCI • EstudiosTerminados: TRACER y TRA 2P

28. Morrow et al. ACC 2012, Chicago, March 24, 2012

29. TRACERSCH 530348 (Vorapaxar) en SCA Thrombin Receptor Antagonist for Clinical Event Reduction in Acute Coronary Syndrome SCA SIN SDST N = 10,000 SCH 530348 40 mg carga, 2.5 mg/día n=5000 Placebo (y terapia usual) n=5000 STOP !!!! • Muerte cardiovascular a 1 año, IAM, Stroke, Isquemia recurrente con Rehosp, Revascularización Coronaria Urgente •

30. Morrow et al. ACC 2012, Chicago, March 24, 2012

31. Morrow et al. ACC 2012, Chicago, March 24, 2012

32. Morrow et al. ACC 2012, Chicago, March 24, 2012

33. Morrow et al. ACC 2012, Chicago, March 24, 2012

34. Morrow et al. ACC 2012, Chicago, March 24, 2012

38. Conclusiones • Actualmente importante “armamentario” de antiagregantesplaquetarios 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 (??)

39. Conclusiones • Los nuevos antiagregantes (Prasugrel, Ticagrelor) son más potentes que Clopidogrel, pero se asocian a mayor riesgo de sangrado. • La inhibición antiplaquetaria triple (AAS+Clop+Vorapaxar) no está indicada en SCA y sería efectiva en prevención secundaria solo en pacientes con IAM previo. • La prevención secundaria con TAD o TAT tendría efectos benéficos en pacientes con IAM previo: CHARISMA, TRA 2P ¿PEGASUS?

40. Trial Schema Stable pts with history of MI 1-3 yrs prior + 1 additional atherothrombosis risk factor* N ~ 21,000 * Age >65 yrs, diabetes, 2nd prior MI, multivessel CAD, or chronic non-end stage renal dysfunction RANDOMIZE DOUBLE BLIND Planned treatment with ASA 75 – 150 mg & Standard background care Ticagrelor90 mg bid Ticagrelor60 mg bid Placebo Follow-up Visits Q4 mos for 1st yr, then Q6 mos Min 12 mos and median 26 mos follow-up Event-driven trial Primary Efficacy Endpoint: CV Death, MI, or Stroke Primary Safety Endpoint: TIMI Major Bleeding

41. TRILOGY ACS:TaRgeted platelet Inhibition to cLarify the Optimal strateGy to medicallY manage Acute Coronary Syndromes Protocol Synopsis Presented byHelene Petitjean, MD Daiichi-Sankyo

42. An Unmet Medical Need:Medically-Managed UA/NSTEMI Patients Substantial sub-group of ACS population despite trend towards invasive/interventional treatment Different from PCI population: older, high incidence of renal insufficiency, more co-morbidities Less commonly studied in randomized clinical trials

43. Study Design 9326 patients in 8 regions, 52 countries(Primary: 7243 patients < 75 years old) Medically Managed UA/NSTEMI Patients Randomization Stratified by: Age, Country, Prior Clopidogrel Treatment (Primary analysis cohort — Age < 75 years) Median Timeto Enrollment = 4.5 Days Medical Management Decision ≤ 72 hrs (No prior clopidogrel given) — 4% of total Medical Management Decision ≤ 10 days (Clopidogrel started ≤ 72 hrs in-hospital OR on chronic clopidogrel) — 96% of total Clopidogrel1300 mg LD + 75 mg MD Prasugrel130 mg LD + 5or 10 mg MD Clopidogrel1 75 mg MD Prasugrel15or 10 mg MD Minimum Rx Duration: 6 months; Maximum Rx Duration: 30 months Primary Efficacy Endpoint: CV Death, MI, Stroke All patients were on aspirin, and low-dose aspirin (< 100 mg) was strongly recommended. For patients < 60 kg or ≥ 75 years, 5 mg MD of prasugrel was given. Adapted from Chin CT et al. Am Heart J 2010;160:16-22.e1. Roe Mt et al NEJM 2012

44. Primary Efficacy Endpoint and TIMI Major Bleeding Through 30 Months(Age < 75 years; 7243) HR (95% CI): 0.91 (0.79, 1.05) P = 0.21 Endpoint (%) HR (95% CI): 1.31 (0.81, 2.11) P = 0.27 Roe MT et al NEJM 2012

45. Incidence of Outcomes by Angiography Status(Age < 75 years) P < 0.001 P < 0.001 P = 0.09

46. Primary Efficacy Endpoint to 30 Months(Age < 75 years) Angio N=3085 No Angio N=4158 10.7% vs 14.9%P = 0.031 HR (95% CI):0.77 (0.61, 0.98) 16.3% vs 16.7%P = 0.954 HR (95% CI):1.01 (0.84, 1.20) P interaction = 0.08

47. Myocardial Infarction Angio No Angio 7.2% vs 10.3%P = 0.042 HR (95% CI):0.74 (0.55, 1.00) 9.2% vs 10.6%P = 0.989 HR (95% CI):1.00 (0.79, 1.26) P interaction = 0.12

48. Stroke Angio No Angio 0.6% vs 2.4%P = 0.004 HR (95% CI):0.30 (0.13,0.71) 2.2% vs 2.0%P = 0.933 HR (95% CI):1.03 (0.58,1.83) P interaction = 0.02

49. Conclusions Overall, in the TRILOGY ACS Trial prasugrel did not reduce cardiovascular events among patients managed medically for ACS. When treated with prasugrel compared to clopidogrel, patients triaged to medical therapy following angiography tended to have: Lower rates of the combined endpoint of CVD/MI/CVA Lower rates of MI, CVA alone, and recurrent ischemic events A trend to higher rates of TIMI major bleeding. Though hypothesis generating, these results are consistent with previous trials and suggest that when angiography is performed and coronary disease is confirmed, the benefits and risks of intensive antiplatelet therapy exist whether medical therapy or PCI is elected.