Selección lógica de antiplaquetarios en SCA-ICP

1. Selección lógica de antiplaquetarios en SCA-ICP SOLACI Simposium, México, 9-VIII-2012 Dr. José Luis Ferreiro Hospital Universitario de Bellvitge: Área de Enfermedades del Corazón Unidad de Cardiología Intervencionista – Laboratorio de Investigación Cardiovascular

2. CONFLICTS OF INTEREST • Honoraria for lectures: • Eli Lilly Co; Daiichi Sankyo, Inc.; AstraZeneca • Research grants: • Spanish Society of Cardiology

3. AVAILABLE ANTIPLATELET DRUGS P2Y12 INHIBITORS Ticlopidine Clopidogrel Prasugrel Ticagrelor TxA2 INHIBITORS COX-1 Inhibitors Aspirin G G G G G G ADP PGE TxA2 TxA2 ADP Thrombin 5HT2A Intracellular signaling PI3K AA COX-1 GP VI GP Ib/IX/V GP IIB/IIIA INHIBITORS Abciximab Tirofiban Eptifibatide fibrinogen GP IIb/IIIa Ferreiro JL et al. CircCardiovascInterv2012;5:433-45.

4. AGENTS ON DEVELOPMENT PAR-1 INHIBITORS P2Y12 INHIBITORS Vorapaxar Atopaxar TxA2 INHIBITORS Cangrelor Elinogrel TP inhibitors Picotamide Ridogrel Ramatroban Terutroban EV-077 G G G G G G ADP PGE TxA2 TxA2 Thrombin ADP 5HT2A Intracellular signaling PI3K AA COX-1 GP VI GP Ib/IX/V fibrinogen PIP3K inhibitors TGX-221 5HT2A antagonists APD791 P2Y1 inhibitors MRS2179 MRS2500 GP Ib antagonists 6B4-Fab GP IIb/IIIa EP antagonists DG-041 GP VI antagonists Kistomin Revacept Ferreiro JL et al. CircCardiovascInterv2012;5:433-45.

5. Does one size fit all??

6. INDEX • Clopidogrel variability in response • Novel P2Y12inhibitors • Prasugrel • Ticagrelor • Subgroup analyses • Balancing efficacy and safety

7. Clopidogrel: Variability in Response

8. CLOPIDOGREL: EFFICACY Primary Endpoint—MI / stroke/ CV Death 0.14 p=0.00009 N=12,562 20% RRR Placebo + ASA* 0.12 0.10 0.08 Clopidogrel + ASA* Cumulative Hazard Rate 0.06 Suboptimal response? 0.04 Primary outcome: 9.3% in clopidogrel + ASA group and 11.4% in placebo + ASA group. 0.02 0.00 9 0 6 12 3 Months of Follow-Up *Other standard therapies were used as appropriate. Yusuf S et al. N Engl J Med 2001;345:494-502.

9. CLOPIDOGREL: VARIABILITY IN RESPONSE ↑ Bleeding risk ↑ Ischemic risk 20 15 10 Patients (n) 5 0 2.5 12.5 22.5 32.5 42.5 52.5 62.5 72.5 82.5 92.5 7.5 17.5 27.5 37.5 47.5 57.5 67.5 77.5 87.5 97.5 % Platelet aggregation (LTA-ADP 20mM) Angiolillo DJ et al. Am J Cardiol 2006;97:38-43.

10. CURRENT/OASIS 7: STUDY DESIGN Patients with UA/NSTEMI or STEMI planned for early invasive strategy i.e. intent for PCI as early as possible within 72 hours n=25,087 Randomize Double Blind Clopidogrel Standard Dose Group300 mg Day 1; 75 mg Days 2-30 Clopidogrel High Dose Group600 mg Day 1; 150 mg Days 2-7; 75 mg Days 8-30 Randomize Randomize Open Label ASA high doseAt least 300 mg Day 1; 300-325 mg Days 2-30 ASA low doseAt least 300 mg Day 1; 75-100 mg Days 2-30 ASA low doseAt least 300 mg Day 1; 75-100 mg Days 2-30 ASA high doseAt least 300 mg Day 1; 300-325 mg Days 2-30 Primary Efficacy OutcomeComposite of CV Death, MI, or stroke up to day 30Primary Safety OutcomeMajor Bleeding up to day 30 Mehta SR et al. NEJM 2010;363:930-42.

11. CURRENT OASIS-7 TrialComparison of Clopidogrel Dosing: Primary Outcome and Components P=0.016 P=0.025 Mehta SR et al. NEJM 2010;363:930-42. Odds Ratio

12. Novel P2Y12Inhibitors

13. P2Y12 INHIBITORS Modified from Angiolillo DJ and Ferreiro JL. Rev Esp Cardiol 2010;63:60-76

14. Novel ORAL P2Y12 Inhibitors More potent and less variability!! Angiolillo DJ et al. JACC Interv 2011

15. TRITON TIMI-38: STUDY DESIGN WiviottSD et al. NEJM 2007;357:2001-15.

16. PLATO: STUDY DESIGN NSTE-ACS (moderate-to-high risk) STEMI (if primary PCI) Clopidogrel-treated or -naive; randomised within 24 hours of index event (N=18,624) 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-month exposure Primary endpoint: CV death + MI + Stroke Primary safety endpint: Total major bleeding PCI = percutaneous coronary intervention; ASA = acetylsalicylic acid; CV = cardiovascular; TIA = transient ischaemic attack Wallentin L et al. NEJM 2009;361:1045-57.

17. TRITON VERSUS PLATO Differences between studies • Population • TRITON: ACS undergoing PCI • PLATO: all ACS • Pretreatment (before PCI) • TRITON: Not allowed (except STEMI) • PLATO: Allowed • Loading dose of clopidogrel • TRITON: 300mg • PLATO: 300-600mg • Study length (median) • TRITON: 14.5 months • PLATO: 9 months

18. Non-CABG TIMI major bleeding TRITON PLATO Prasugrel vs Clopidogrel 2.4% vs 1.8% ARD 0.6%HR 1.32P=0.03NNH=167 TicagrelorvsClopidogrel 2.8% vs 2.2% ARD 0.6%HR 1.25P=0.03NNH=167 PRASUGREL VERSUS TICAGRELOR TRITON TIMI 38 (prasugrel vs clopidogrel) PLATO (ticagrelor vs clopidogrel)

19. GUIDELINES OK, but… what do we do?

20. CLOPIDOGREL: STEMI 24,3% patientswithpoor responseto ASA 89,2% patientswithpoor response toclopidogrel Ferreiro JL et al. Reunión de la Sección de Hemodinámica, Santander 2012.

21. PRASUGREL: STEMI Pretreatmentallowed Montalescot G et al. Lancet 2009;373:723-731.

22. K-M estimate of time to first primary efficacy event (composite of CV death, MI or stroke) TICAGRELOR: STEMI HR, 0.87; 95% CI, 0.75 to 1.01; P=0.07) K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval Steg PG et al. Circulation 2010;122:2131-2141

23. PRASUGREL: DM PATIENTS 18 17.0 (n=3146) Clopidogrel 16 CV Death/MI/Stroke 14 12.2 12 HR 0.70P<0.001 Prasugrel 10 Endpoint (%) 8 NNT=21 6 TIMI Major Non-CABG Bleeds 4 Clopidogrel 2.6 2.5 2 Prasugrel 0 0 30 60 90 180 270 360 450 Days Wiviott SD et al. Circulation 2008;118:1626–36.

24. NEW STRATEGIES IN ACS: DM PATIENTS Study % of Events Hazard Ratio (95% confidence interval) Standard New Drug/Approach TRITON-TIMI 38 17.0 12.2 0.70 (0.58 – 0.85) PLATO 16.2 14.1 0.88 (0.76 – 1.03) CURRENT OASIS 7 5.6 4.9 0.87 (0.66 – 1.15)(PCI Cohort) 0 0.5 1 1.5 Standard ClopidogrelBetter New Drug/ApproachBetter Ferreiro JL et al. Circulation 2011. 123:798-813.

25. Study % of events HazardRatio [95% confidenceinterval] Standard New Drug / Approach TRITON-TIMI 38 2.4 1.1 0.48 [0.36 - 0.64] PLATO 3,0 2.2 0.73 [0.57 - 0,94] CURRENT-OASIS 7 2.3 1.6 0.68 [0.55 - 0,85] New Drug / Approach Better Standard Clopidogrel Better NEW STRATEGIES IN ACS/PCI: STENT THROMBOSIS Ferreiro JL et al. CircCardiovascInterv2012;5:433-45.

26. TICAGRELOR Useful in non-invasivestrategy James SK et al. BMJ 2011.

27. PRASUGREL: MEDICAL TREATMENT Treatment Decision for Medical Management determined < 24 hrs Treatment Decision determined > 24 hrs OR chronic Clopidogrel Rx N = 7,800 < 75 yrs, N ~ 2,500  75 yrs Randomize < 24 h Start/Continue Clopidogrel < 24 h Randomize between 1-7 days Prasugrel 30 mg LD 10/5 mg MD* Clopidogrel 300 mg LD 75 mg MD Prasugrel 10/5 mg MD* Clopidogrel 75 mg MD * 5 mg MD of prasugrel for age  75 yrs or weight < 60 kg Median duration of treatment ~ 18 months

28. TICAGRELOR: CKD CKD Renal functionanalytic control 1 monthafterinitiatingtherapy CV death, MI orstroke (%) pforinteraction = 0,13 Normal renal function Daysafterrandomization James S et al. Circulation. 2010;122:1056–1067.

29. PRASUGREL: VULNERABLE SUBGROUPS Risk (%) + 54 Yes Prior Stroke / TIA -16 No Pint = 0.006 -1 >=75 Age -16 Pint = 0.18 < 75 +3 < 60 kg Wgt Pint = 0.36 -14 >=60 kg -13 OVERALL 0.5 1 2 Prasugrel Better Clopidogrel Better HR WiviottSD et al. NEJM 2007;357:2001-15.

30. AGE & DM Prasugrel Clopidogrel 30 HR=0.64(95% CI, 0.4–1.0) HR=0.72(95% CI, 0.6–0.9) HR=0.82(95% CI, 0.7–0.9) HR=1.1(95% CI, 0.8–1.4) 25 P=0.034 21.8 20 P=NS P=0.002 CV Death, Nonfatal MI, or Nonfatal Stroke (%) 16.4 15 15.3 14.9 14.8 P=0.004 10 10.8 9.5 7.8 5 n=1327 n=1336 n=249 n=234 n=4585 n=4551 n=652 n=674 0 <75 years ≥75 years <75 years ≥75 years With Diabetes Without Diabetes *Composite of CV death, nonfatal MI, or nonfatal stroke.

31. BalancingIschemic and BleedingRisk

32. BALANCING ISCHEMIA / BLEEDING High risk of ischemic events High riskof bleeding events “Sweet spot” Risk of any event Risk of any event Ischemic risk Ischemic risk Bleeding risk Bleeding risk Inhibition of platelet aggregation Ferreiro JL et al. Thromb Haemost 2010;103:1128-35.

33. TherapeuticWindow Elective PCI OR 0.40, 95% CI 0.22-0.75 Sibbing et al. JACC 2010;56:317-8

34. Therapeutic Window Elective PCI Campo G et al. J Am Coll Cardiol. 2011;57:2474-83.

35. CONCLUSIONS • Clopidogrel: Great variability in response • Novel P2Y12 inhibitors: Prasugrel and Ticagrelor • Proof of concept: More potent platelet inhibition is needed in ACS • Risk of bleeding, but favorable efficacy and safety profile • Subgroup analyses has limitations, but may help to define strategy • Prasugrel: only ACS undergoing PCI • Particular benefit in DM, STEMI, stent thrombosis • Contraindications: high risk of bleeding, prior stroke • Considerations: elderly, low-weight patients; CABG: 7 days • Ticagrelor: full spectrum of ACS • Particular benefit: CKD; reduction in CV mortality • Contraindications: high risk of bleeding, intracranial hemorrhage • Considerations: ASA dose, comorbidities (COPD), compliance; CABG: 5 days • Several agents: Which one is the best? Individualized therapy • Balance between ischemia and bleeding • Platelet function testing may play a role

36. Does one size fit all?? Individualized therapy

37. IAMCEST IAM extenso* ECG: Anterior (≥4 derivaciones) e Inferoposterior KT: Segmento proximal (arteria extensa) IAM no extenso Riesgo alto de sangrado Valorar: edad >80 años; ictus previo; HTA severa; antecedentes hemorrágicos; Hto<34%; ACO; vasculopatía periférica; acceso femoral; neoplasia activa; IRC severa; IQ reciente o ineludible NO riesgo alto de sangrado No ictus previo y >60Kg y ≤75 años (Individualizar en DM >75 años) Ictus previo o ≤60Kg o >75 años PRASUGREL TICAGRELOR CLOPIDOGREL *A valorar Inhibidores de la GP IIb/IIIa en pacientes con alto contenido trombótico Hospital Universitario de Bellvitge: Indicaciones de Antiagregación Oral en SCA

38. Hospital Universitario de Bellvitge: Indicaciones de Antiagregación Oral en SCA SCASEST (Pacientes en que se indica estrategia invasiva) Riesgo alto* alteraciones segmento ST; elevación troponina >10 veces el límite inferior; angor refractario; insuficiencia cardiaca Riesgo bajo / intermedio Riesgo alto de sangrado Valorar: edad >80 años; ictus previo; HTA severa; antecedentes hemorrágicos; Hto<34%; ACO; vasculopatía periférica; acceso femoral; neoplasia activa; IRC severa; IQ reciente o ineludible NO riesgo alto de sangrado DM No DM No ictus previo y >60Kg (Individualizar en >75 años) **Valorar ticagrelor en pacientes con IRC Ictus previo o ≤60Kg PRASUGREL TICAGRELOR CLOPIDOGREL** *A valorar uso upstream de Inhibidores de la GP IIb/IIIa en pacientes con: a) angor refractario pese a tratamiento completo o b) cambios ECG extensos con insuficiencia cardiaca

39. Unidad de Cardiología Intervencionista • Jefe de Sección: Dr. J.A. Gómez-Hospital • Dr. José Luis Ferreiro • Dr. Gerard Roura • Dr. Francesc Jara • Dr. Luis Teruel • Dr. Josep Gómez-Lara • Dra. Silvia Homs • Dr. Guillermo Sánchez-Elvira • Dr. Daniel Rivero Laboratorio de Investigación Cardiovascular • Director: Dr. José Luis Ferreiro • Sra. Gabriela Sosa • Sra. Paula Campreciós • Sra. Laia Rosenfeld • Sra. Olga Cañavate • Sra. Sonia Gómez • Dr. Kristian Rivera • Dra. Ana Marcano HeartDiseasesInstitute. Director: Dr. Ángel Cequier Interesados en fellowship: AMCInv@bellvitgehospital.cat AMCDir@bellvigehospital.cat

40. Gracias por su Atención Interesados en fellowship: AMCInv@bellvitgehospital.cat AMCDir@bellvigehospital.cat

42. Backupslides

43. CLOPIDOGREL IN ACS/PCI Acute STEMI UA/NSTEMI PCI COMMIT (CCS-2) 1 Year 1 Year 30 Days + Benefit + Benefit + Benefit NEJM 2005 JAMA 2002 NEJM 2001 Lancet 2005

44. TRITON TIMI-38: EFFICACY AND SAFETY 15 138 events Clopidogrel HR 0.81(0.73-0.90)P=0.0004 12.1 CV Death / MI / Stroke 9.9 10 NNT = 46 Prasugrel Endpoint (%) 5 35 events TIMI Major NonCABG Bleeds Prasugrel 2.4 HR 1.32(1.03-1.68)P=0.03 1.8 Clopidogrel 0 NNH = 167 0 30 60 90 180 270 360 450 DAYS Wiviott SD et al. NEJM 2007;357:2001-15.

45. PLATO: EFFICACY 13 12 11.7 Clopidogrel 11 10 9.8 9 Ticagrelor 8 7 Cumulative incidence (%) 6 5 4 3 2 HR 0.84 (95% CI 0.77–0.92), p=0.0003 1 0 0 60 120 180 240 300 360 Days after randomisation No. at risk Ticagrelor 9,333 8,628 8,460 8,219 6,743 5,161 4,147 Clopidogrel 9,291 8,521 8,362 8,124 6,743 5,096 4,047 K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval Wallentin L et al. NEJM 2009;361:1045-57.

46. PLATO: SAFETY 9 Ticagrelor Clopidogrel NS 7.9 8 7.4 7 NS 5.8 6 5.3 p=0.026 5 K-M estimated rate (% per year) 4.5 3.8 4 p=0.03 2.8 3 2.2 2 1 0 Non-CABGPLATO majorbleeding Non-CABGTIMI major bleeding CABGPLATO major bleeding CABG TIMI major bleeding Wallentin L et al. NEJM 2009;361:1045-57.

47. PRASUGREL VERSUS TICAGRELOR • Efficacy • A reduction in: PrasugrelTicagrelorCV Death/MI/Stroke19% 16% • Stent thrombosis 52%    25% • MI 24% 16% • CV death 11% 21% • Early benefit 18% 12% • (3 days) (30 days) • Late benefit 20% 20% • (~14.5 mo) (~9 mo)

48. “SWITCHING”: FROM CLOPIDOGREL TO PRASUGREL Similar findings obtained with MPA to 5 µM ADP, VASP PRI, and Verify Now® PRU Angiolillo DJ et al. J Am Coll Cardiol 2010; 56:1017-23.

49. TICAGRELOR: CABG Major Fatal/Life-Threatening Bleeding by Days from Last Dose of Treatment to CABG 100% Ticagrelor 80% Clopidogrel 60% % Patients with Bleeding post-CABG 40% 20% 0% 1 2 3 4 5 6 7 >8 Days Bleeding differences favor ticagrelor>5 days post discontinuation

50. ISSUE OF PRETREATMENT NSTEMI / Troponin +, n~4100+ (Event Driven) Clopidogrel Naive or Longterm 75mg Plan Angio/PCI >2h and <24h Diagnosis + Transfer to Cathlab >2h to <24h Randomize Pras 30 Inactive Angio Angio Cathlab Pras 30 Pras 60 PCI PCI Pras 10(5) for 30d PE: CV-D, MI, stroke, Urgent Revasc., GPI bailout @ 7d SEs: All TIMI Major Bleeding @ 7d; NetClinBenefit @ 7d 30d FU