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Selección lógica de antiplaquetarios en SCA-ICP Dr. José Luis Ferreiro Hospital Universitario de Bellvitge: Área de Enfermedades del Corazón Unidad de.

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Presentation on theme: "Selección lógica de antiplaquetarios en SCA-ICP Dr. José Luis Ferreiro Hospital Universitario de Bellvitge: Área de Enfermedades del Corazón Unidad de."— Presentation transcript:

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

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

3 G COX-1 AA TxA 2 G ADP G Thrombin TxA 2 INHIBITORS P2Y 12 INHIBITORS COX-1 Inhibitors Aspirin TxA 2 Ticlopidine Clopidogrel Prasugrel Ticagrelor GP IIB/IIIA INHIBITORS Abciximab Tirofiban Eptifibatide G 5HT2A fibrinogen G ADP G PGE PI3K Intracellular signaling GP IIb/IIIa GP VI GP Ib/IX/V AVAILABLE ANTIPLATELET DRUGS Ferreiro JL et al. Circ Cardiovasc Interv 2012;5:

4 G COX-1 AA TxA 2 G ADP G Thrombin TxA 2 INHIBITORS P2Y 12 INHIBITORS PAR-1 INHIBITORS TP inhibitors Picotamide Ridogrel Ramatroban Terutroban EV-077 TxA 2 Cangrelor Elinogrel Vorapaxar Atopaxar G 5HT2A fibrinogen G ADP G PGE PI3K Intracellular signaling GP IIb/IIIa GP VI GP Ib/IX/V GP VI antagonists Kistomin Revacept GP Ib antagonists 6B4-Fab 5HT2A antagonists APD791 EP antagonists DG-041 P2Y 1 inhibitors MRS2179 MRS2500 PIP3K inhibitors TGX-221 AGENTS ON DEVELOPMENT Ferreiro JL et al. Circ Cardiovasc Interv 2012;5:

5 Does one size fit all??

6 INDEX  Clopidogrel variability in response  Novel P2Y 12 inhibitors  Prasugrel  Ticagrelor  Subgroup analyses  Balancing efficacy and safety

7 C LOPIDOGREL : V ARIABILITY IN R ESPONSE

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

9 % Platelet aggregation (LTA-ADP 20  M) Patients (n) Angiolillo DJ et al. Am J Cardiol 2006;97: ↑ Ischemic risk CLOPIDOGREL: VARIABILITY IN RESPONSE ↑ Bleeding risk

10 Patients with UA/NSTEMI or STEMI planned for early invasive strategy i.e. intent for PCI as early as possible within 72 hours Randomize Clopidogrel Standard Dose Group 300 mg Day 1; 75 mg Days 2-30 Clopidogrel High Dose Group 600 mg Day 1; 150 mg Days 2-7; 75 mg Days 8-30 Randomize ASA low dose At least 300 mg Day 1; mg Days 2-30 ASA high dose At least 300 mg Day 1; mg Days 2-30 ASA low dose At least 300 mg Day 1; mg Days 2-30 ASA high dose At least 300 mg Day 1; mg Days 2-30 Primary Efficacy Outcome Composite of CV Death, MI, or stroke up to day 30 Primary Safety Outcome Major Bleeding up to day 30 n=25,087 Double Blind Open Label CURRENT/OASIS 7: STUDY DESIGN Mehta SR et al. NEJM 2010;363:

11 Measure Standard Dosing Double Dosing CV death, MI, and stroke, overall cohort (n=25,087) ● PCI cohort (n=17,232) ● No PCI cohort (n=7,855) MI, overall cohort ● PCI cohort ● No PCI cohort CURRENT OASIS-7 T RIAL C OMPARISON OF C LOPIDOGREL D OSING : P RIMARY O UTCOME AND C OMPONENTS Odds Ratio P=0.016 P=0.025 Double Better Standard Better Mehta SR et al. NEJM 2010;363:

12 N OVEL P2Y 12 I NHIBITORS

13 ClopidogrelPrasugrelTicagrelorCangrelor Elinogrel Group Thienopyridine CPTPATP analogQuinazolinedione Administration oral IVIV and oral Receptor blockade irreversible reversible Onset of action 2-8 h30 min-4 h30 min – 2 hseconds Offset of action 7-10 days 3-5 days60-90 minutes 50 min (IV) 12 h (oral) CYP drug interactions yesnoyesno P2Y 12 INHIBITORS Modified from Angiolillo DJ and Ferreiro JL. Rev Esp Cardiol 2010;63:60-76

14 Angiolillo DJ et al. JACC Interv 2011 NOVEL ORAL P2Y 12 INHIBITORS More potent and less variability!!

15 TRITON TIMI-38: STUDY DESIGN Wiviott SD et al. NEJM 2007;357:

16 Primary endpoint: CV death + MI + Stroke Primary safety endpint: Total major bleeding 6–12-month exposure 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) NSTE-ACS (moderate-to-high risk) STEMI (if primary PCI) Clopidogrel-treated or -naive; randomised within 24 hours of index event (N=18,624) PCI = percutaneous coronary intervention; ASA = acetylsalicylic acid; CV = cardiovascular; TIA = transient ischaemic attack PLATO: STUDY DESIGN Wallentin L et al. NEJM 2009;361:

17 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: mg  Study length (median)  TRITON: 14.5 months  PLATO: 9 months TRITON VERSUS PLATO

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

19 ClopidogrelPrasugrelTicagrelor 2011 ACCF/AHA UA/NSTEMI Class I; LOE AClass I; LOE B Not FDA approved or marketed at the time of writing of Guidelines 2011 ACCF/AHA/SCAI PCI Class I; LOE B* 2011 ESC NSTEACSClass I; LOE AClass I; LOE B 2010 ESC/EACTS/EAPCI Myocardial Revascularization Elective PCI: Class I; LOE A NSTE-ACS: Class I; LOE B STEMI: Class I; LOE C NSTE-ACS: Class IIa; LOE B STEMI: Class I; LOE B NSTE-ACS: Class I; LOE B STEMI: Class I; LOE B GUIDELINES OK, but… what do we do?

20 CLOPIDOGREL: STEMI 89,2% patients with poor response to clopidogrel 24,3% patients with poor response to ASA Patients with suboptimal response (%) ASAClopidogrel VerifyNow24.3%89.2% LTA (AA/ADP)38.9%84.2% MEA95% Ferreiro JL et al. Reunión de la Sección de Hemodinámica, Santander 2012.

21 Montalescot G et al. Lancet 2009;373: PRASUGREL: STEMI Pretreatment allowed

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

23 HR 0.70 P<0.001 Days Endpoint (%) CV Death/MI/Stroke TIMI Major Non-CABG Bleeds NNT=21 (n=3146) Prasugrel Clopidogrel Prasugrel Clopidogrel Wiviott SD et al. Circulation 2008;118:1626–36. PRASUGREL: DM PATIENTS

24 Ferreiro JL et al. Circulation : NEW STRATEGIES IN ACS: DM PATIENTS TRITON-TIMI (0.58 – 0.85) PLATO (0.76 – 1.03) CURRENT OASIS (0.66 – 1.15) (PCI Cohort) Study% of EventsHazard Ratio (95% confidence interval) Standard New Drug/Approach New Drug/Approach Better Standard Clopidogrel Better

25 Hazard Ratio [95% confidence interval] Study 0.48 [ ] 0.73 [ ,94] 0.68 [ ,85] TRITON-TIMI 38 PLATO CURRENT-OASIS 7 % of events StandardNew Drug / Approach 3, New Drug / Approach Better Standard Clopidogrel Better NEW STRATEGIES IN ACS/PCI: STENT THROMBOSIS Ferreiro JL et al. Circ Cardiovasc Interv 2012;5:

26 TICAGRELOR James SK et al. BMJ Useful in non-invasive strategy

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

28 James S et al. Circulation. 2010;122:1056–1067. TICAGRELOR: CKD CKD Normal renal function CV death, MI or stroke (%) Days after randomization p for interaction = 0,13 Renal function analytic control 1 month after initiating therapy

29 OVERALL >=60 kg < 60 kg < 75 >=75 No Yes Prior Stroke / TIA Age Wgt Risk (%) Prasugrel BetterClopidogrel Better HR P int = P int = 0.18 P int = 0.36 PRASUGREL: VULNERABLE SUBGROUPS Wiviott SD et al. NEJM 2007;357:

30 AGE & DM With DiabetesWithout Diabetes CV Death, Nonfatal MI, or Nonfatal Stroke (%) <75 years≥75 years<75 years≥75 years P=0.034 P=0.002 P= n= n= n= n= n= n= n= n=652 *Composite of CV death, nonfatal MI, or nonfatal stroke. P=NS HR=0.64 (95% CI, 0.4–1.0) HR=1.1 (95% CI, 0.8–1.4) HR=0.72 (95% CI, 0.6–0.9) HR=0.82 (95% CI, 0.7–0.9) ClopidogrelPrasugrel

31 B ALANCING I SCHEMIC AND B LEEDING R ISK

32 BALANCING ISCHEMIA / BLEEDING Inhibition of platelet aggregation High risk of ischemic events High risk of bleeding events “Sweet spot” Ischemic riskBleeding risk Ischemic risk Bleeding risk Ferreiro JL et al. Thromb Haemost 2010;103:

33 T HERAPEUTIC W INDOW Sibbing et al. JACC 2010;56:317-8 OR 0.40, 95% CI Elective PCI

34 T HERAPEUTIC W INDOW Campo G et al. J Am Coll Cardiol. 2011;57: Elective PCI

35  Clopidogrel: Great variability in response  Novel P2Y 12 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 CONCLUSIONS

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 CLOPIDOGRELTICAGRELORPRASUGREL NO riesgo alto de sangrado 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 ictus previo y >60Kg y ≤75 años (Individualizar en DM >75 años) Ictus previo o ≤60Kg o >75 años *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 SCASEST Riesgo alto* alteraciones segmento ST; elevación troponina >10 veces el límite inferior; angor refractario; insuficiencia cardiaca Riesgo bajo / intermedio CLOPIDOGREL**TICAGRELORPRASUGREL NO riesgo alto de sangrado 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 ictus previo y >60Kg (Individualizar en >75 años) Ictus previo o ≤60Kg *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 DMNo DM **Valorar ticagrelor en pacientes con IRC (Pacientes en que se indica estrategia invasiva) Hospital Universitario de Bellvitge: Indicaciones de Antiagregación Oral en SCA

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 Heart Diseases Institute. Director: Dr. Ángel Cequier Interesados en fellowship:

40 G RACIAS POR SU A TENCIÓN Interesados en fellowship:

41

42 B ACKUP SLIDES

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

44 HR 0.81 ( ) P= Prasugrel Clopidogrel DAYS Endpoint (%) HR 1.32 ( ) P=0.03 Prasugrel Clopidogrel events 35 events CV Death / MI / Stroke TIMI Major NonCABG Bleeds NNT = 46 NNH = 167 TRITON TIMI-38: EFFICACY AND SAFETY Wiviott SD et al. NEJM 2007;357:

45 PLATO: EFFICACY No. at risk Clopidogrel Ticagrelor 9,291 9,333 8,521 8,628 8,362 8,460 8,124 Days after randomisation 6,743 5,096 5,161 4,047 4, Cumulative incidence (%) ,219 HR 0.84 (95% CI 0.77–0.92), p= Clopidogrel Ticagrelor K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval Wallentin L et al. NEJM 2009;361:

46 K-M estimated rate (% per year) Non-CABG PLATO major bleeding Non-CABG TIMI major bleeding CABG PLATO major bleeding CABG TIMI major bleeding p=0.026 p=0.03 NS Ticagrelor Clopidogrel PLATO: SAFETY Wallentin L et al. NEJM 2009;361:

47 Efficacy A reduction in: Prasugrel Ticagrelor CV Death/MI/Stroke 19% 16% Stent thrombosis52% 25% MI24%16% CV death11%21% Early benefit18%12% (3 days) (30 days) Late benefit20%20% (~14.5 mo)(~9 mo) PRASUGREL VERSUS TICAGRELOR

48 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: “SWITCHING”: FROM CLOPIDOGREL TO PRASUGREL

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

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

51 Arm A ARM B Arm C Placebo < 24hr pre-PCI Prasugrel 60mg during PCI Prasugrel 10mg MD Clopidogrel 600mg < 24hr pre-PCI Prasugrel 60mg during PCI Prasugrel 10mg MD Clopidogrel 600mg < 24hr pre-PCI Prasugrel 30mg during PCI Prasugrel 10mg MD PRASUGREL AFTER CLOPIDOGREL LOADING

52 Patients on aspirin (81 mg/day) and prasugrel (10 mg/day) ≥ 14 days post-PCI 10 mg prasugrel (N=22) 30 mg prasugrel (N=21) 60 mg prasugrel (N=21) Pharmacodynamic testing: 1 hour Pharmacodynamic testing: Baseline Pharmacodynamic testing: 4 hour PRASUGREL RELOAD Angiolillo DJ et al. J Am Coll Cardiol 2012 [in press]

53 * † ** †† P2Y12 Reactivity Index (%) Angiolillo DJ et al. J Am Coll Cardiol 2012 [in press] PRASUGREL RELOAD

54 PRASUGREL: CABG Wiviott SD et al. NEJM 2007;357:


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