Presentation on theme: "Selección lógica de antiplaquetarios en SCA-ICP"— Presentation transcript:
1Selección lógica de antiplaquetarios en SCA-ICP SOLACI Simposium, México, 9-VIII-2012Dr. José Luis FerreiroHospital Universitario de Bellvitge: Área de Enfermedades del CorazónUnidad de Cardiología Intervencionista – Laboratorio de Investigación Cardiovascular1
2CONFLICTS OF INTEREST Honoraria for lectures: Research grants: Eli Lilly Co; Daiichi Sankyo, Inc.; AstraZenecaResearch grants:Spanish Society of Cardiology
8Primary Endpoint—MI / stroke/ CV Death CLOPIDOGREL: EFFICACYPrimary Endpoint—MI / stroke/ CV Death0.14p=N=12,56220% RRR0.12Placebo + ASA*0.100.08Clopidogrel + ASA*Cumulative Hazard Rate0.06Suboptimal response?0.04Slide 16 of Bates 10-1 Boston presentation0.02Primary outcome: 9.3% in clopidogrel + ASA group and 11.4% in placebo + ASA group.0.0036912Months of Follow-Up*Other standard therapies were used as appropriate.Yusuf S et al. N Engl J Med 2001;345:
9CLOPIDOGREL: VARIABILITY IN RESPONSE 2015↑ Bleeding risk↑ Ischemic risk10Patients (n)52.512.522.532.542.552.562.572.582.592.57.517.527.537.547.557.567.577.587.597.5% Platelet aggregation (LTA-ADP 20mM)Angiolillo DJ et al. Am J Cardiol 2006;97:38-43.
10CURRENT/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 hoursn=25,087RandomizeDouble BlindClopidogrel Standard Dose Group 300 mg Day 1; 75 mg Days 2-30Clopidogrel High Dose Group 600 mg Day 1; 150 mg Days 2-7; 75 mg Days 8-30RandomizeRandomizeOpen LabelASA low dose At least 300 mg Day 1; mg Days 2-30ASA high dose At least 300 mg Day 1; mg Days 2-30ASA low dose At least 300 mg Day 1; mg Days 2-30ASA high dose At least 300 mg Day 1; mg Days 2-30Acute ASA dosing (325/325 vs. 325/81) in ACSObjectiveTo evaluate the efficacy and safety of (1) a higher loading and initial maintenance dose of clopidogrel compared with the standard-dose regimen and (2) high-dose ASA compared with low-dose ASA in patients with ST or non–ST-segment-elevation ACS managed with an early invasive strategy.DesignMulticenter, international, randomized, 2×2 factorial design trial evaluating a clopidogrel high-dose regimen (600 mg loading dose on day 1 followed by 150 mg once daily on days 2 to 7, followed by 75 mg once daily on days 8-30) compared with the standard-dose regimen (300 mg loading dose on day 1, followed by 75 mg once daily on days 2-30) and high-dose ASA ( mg daily) versus low-dose ASA ( mg daily) in patients with ST or non–ST-segment-elevation ACS managed with an early invasive strategy. The clopidogrel dose comparison is double-blind and the ASA dose comparison is open-label. The primary outcome is the composite of death from cardiovascular causes, myocardial (re)infarction or stroke up to day 30. The primary safety outcome is major bleeding. The sample size is 18,000 to 20,000 patients.1. Mehta SR, Bassand JP, Chrolavicius S, Diaz R, Fox KA, Granger CB, Jolly S, Rupprecht HJ, Widimsky P, Yusuf S; CURRENT-OASIS 7 Steering Committee. Design and rationale of CURRENT-OASIS 7: a randomized, 2 x 2 factorial trial evaluating optimal dosing strategies for clopidogrel and aspirin in patients with ST and non-ST-elevation acute coronary syndromes managed with an early invasive strategy. Am Heart J. 2008;156:Primary Efficacy Outcome Composite of CV Death, MI, or stroke up to day 30 Primary Safety Outcome Major Bleeding up to day 30Mehta SR et al. NEJM 2010;363:
11CURRENT OASIS-7 Trial Comparison of Clopidogrel Dosing: Primary Outcome and Components MeasureStandard DosingDouble DosingCV death, MI, and stroke, overall cohort (n=25,087)4.44.2PCI cohort (n=17,232)4.53.9No PCI cohort (n=7,855)4.9MI, overall cohort2.21.9PCI cohort2.62.0No PCI cohort1.41.7Double BetterStandard BetterP=0.016There was no significant difference in the overall cohort of patients who received a higher loading and maintenance dose of clopidogrel, most likely because the patients who did not undergo PCI had no significant coronary disease by angiogram, or the drug was stopped when patients were scheduled for CABG surgery.In focusing on the 17 232 patients who underwent PCI, there was a significant 15% reduction in cardiovascular, death, MI, and stroke, and this reduction was driven by a significant 22% reduction in the risk of MI. In addition, there was a significant 42% reduction in the risk of definite stent thrombosis.clinical implications of this study are such that for every 1000 patients with ACS receiving PCI, doubling the loading and maintenance dose of clopidogrel will prevent an additional six MIs and seven stent thromboses with an excess three severe bleeds and no increase in fatal, CABG-related, or TIMI major bleeds. For those not undergoing PCI, they should continue using the standard dose of clopidogrel,P=0.025Mehta SR et al. NEJM 2010;363:Odds Ratio
13P2Y12 INHIBITORS Elinogrel Clopidogrel Prasugrel Ticagrelor Cangrelor GroupThienopyridineCPTPATP analogQuinazolinedioneAdministrationoralIVIV and oralReceptor blockadeirreversiblereversibleOnset of action2-8 h30 min-4 h30 min – 2 hsecondsOffset of action7-10 days7-10 days3-5 days60-90 minutes50 min (IV)12 h (oral)CYP drug interactionsyesnoModified from Angiolillo DJ and Ferreiro JL. Rev Esp Cardiol 2010;63:60-7613
14Novel ORAL P2Y12 Inhibitors More potent and less variability!!Angiolillo DJ et al. JACC Interv 2011
15TRITON TIMI-38: STUDY DESIGN Patients were candidates for the trial if they were moderate-high risk, had an acute coronary syndrome, and there was a plan to perform PCI.A sample size of 13, 600 was considered necessary to provide at least 90 % power to test the primary hypothesisAll patients were to receive ASA.Randomization was stratified by UA/NSTEMI vs STEMIDB study drug therapy consisted either of - standard dosing with clopidogrel with a LD of 300 mg and MD of 75 mg- OR prasugrel with a LD of 60 mg and MD of 10 mgDB study drug was to be given for a median of at least 12 months with a minimum of 6 mos and maximum of 15 monthsThe primary composite EP was CV death, MI, or Stroke through the end of the studyKey secondary EPs are listed here and among these was Stent thrombosis Key safety Eps included: TIMI major (non CABG) bleeds, and life-threatening bleedsTwo key substudies are evaluating pharmacokinetics and genomicsWiviott SD et al. NEJM 2007;357:15
16PLATO: STUDY DESIGNNSTE-ACS (moderate-to-high risk) STEMI (if primary PCI)Clopidogrel-treated or -naive;randomised within 24 hours of index event(N=18,624)ClopidogrelIf pre-treated, no additional loading dose;if naive, standard 300 mg loading dose,then 75 mg qd maintenance;(additional 300 mg allowed pre PCI)Ticagrelor180 mg loading dose, then90 mg bid maintenance;(additional 90 mg pre-PCI)6–12-month exposurePrimary endpoint: CV death + MI + StrokePrimary safety endpint: Total major bleedingPCI = percutaneous coronary intervention; ASA = acetylsalicylic acid; CV = cardiovascular; TIA = transient ischaemic attackWallentin L et al. NEJM 2009;361:
17Differences between studies TRITON VERSUS PLATODifferences between studiesPopulationTRITON: ACS undergoing PCIPLATO: all ACSPretreatment (before PCI)TRITON: Not allowed (except STEMI)PLATO: AllowedLoading dose of clopidogrelTRITON: 300mgPLATO: mgStudy length (median)TRITON: 14.5 monthsPLATO: 9 months
18PRASUGREL VERSUS TICAGRELOR TRITON TIMI 38(prasugrel vs clopidogrel)PLATO(ticagrelor vs clopidogrel)Prasugrel vs Clopidogrel2.4% vs 1.8%ARD 0.6% HR 1.32 P=0.03 NNH=167Ticagrelor vs Clopidogrel2.8% vs 2.2%ARD 0.6% HR 1.25 P=0.03 NNH=167Non-CABG TIMI major bleedingTRITONPLATO
19GUIDELINES OK, but… what do we do? Clopidogrel Prasugrel Ticagrelor ClopidogrelPrasugrelTicagrelor2011 ACCF/AHA UA/NSTEMIClass I; LOE AClass I; LOE BNot FDA approved or marketed at the time of writing of Guidelines2011 ACCF/AHA/SCAI PCIClass I; LOE B*2011 ESC NSTEACS2010 ESC/EACTS/EAPCIMyocardial RevascularizationElective PCI: Class I; LOE ANSTE-ACS: Class I; LOE BSTEMI: Class I; LOE CNSTE-ACS: Class IIa; LOE BSTEMI: Class I; LOE BOK, but… what do we do?
20CLOPIDOGREL: STEMI Patients with suboptimal response (%) ASA 89,2% patients with poor response to clopidogrel24,3% patients with poor response to ASAPatients with suboptimal response (%)ASAClopidogrelVerifyNow24.3%89.2%LTA (AA/ADP)38.9%84.2%MEA95%Ferreiro JL et al. Reunión de la Sección de Hemodinámica, Santander 2012.
21Pretreatment allowed PRASUGREL: STEMI Montalescot G et al. Lancet 2009;373:
22Steg PG et al. Circulation 2010;122:2131-2141 TICAGRELOR: STEMIK-M estimate of time to first primary efficacy event (composite of CV death, MI or stroke)HR, 0.87; 95% CI, 0.75 to 1.01; P=0.07)K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence intervalSteg PG et al. Circulation 2010;122:
23PRASUGREL: DM PATIENTS 24681012141618306090180270360450HR 0.70 P<0.001DaysEndpoint (%)CV Death/MI/StrokeTIMI Major Non-CABG BleedsNNT=21(n=3146)17.012.2PrasugrelClopidogrel2.62.5Wiviott SD et al. Circulation 2008;118:1626–36.
24NEW 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 Events Hazard Ratio (95% confidence interval)Standard New Drug/ApproachNew Drug/Approach BetterStandard Clopidogrel Better0.511.5CURRENT-OASIS= Clopidogrel Optimal Loading Dose Usage to Reduce Recurrent Events Optimal Antiplatelet Strategy for Interventions; PCI=percutaneous intervention; PLATO= A Study of Efficacy of New Drugs/Approaches in Reducing Adverse Outcomes in Diabetes Mellitus From Large-Scale Clinical Trials Platelet Inhibition and Patient Outcomes; TRITON-TIMI= Trial To Assess Improvement in Therapeutic Outcomes by Optimizing Platelet Inhibition With Prasugrel Thrombolysis in Myocardial Infarction.Ferreiro JL et al. Circulation :24
25NEW STRATEGIES IN ACS/PCI: STENT THROMBOSIS Hazard Ratio[95% confidence interval]Study0.48 [ ]0.73 [ ,94]0.68 [ ,85]TRITON-TIMI 38PLATOCURRENT-OASIS 7% of eventsStandardNew Drug / Approach3,02.22.31.62.41.1BetterStandard ClopidogrelFerreiro JL et al. Circ Cardiovasc Interv 2012;5:
26Useful in non-invasive strategy TICAGRELORUseful in non-invasive strategyJames SK et al. BMJ 2011.
27PRASUGREL: MEDICAL TREATMENT Treatment Decision for Medical Management determined < 24 hrsN = 7,800 < 75 yrs,N ~ 2,500 75 yrsTreatment Decision determined > 24 hrs OR chronic Clopidogrel RxRandomize < 24 hStart/Continue Clopidogrel < 24 hRandomize between 1-7 daysClopidogrel300 mg LD75 mg MDPrasugrel30 mg LD10/5 mg MD*Clopidogrel75 mg MDPrasugrel10/5 mg MD** 5 mg MD of prasugrel for age 75 yrs or weight < 60 kgMedian duration of treatment ~ 18 months
28TICAGRELOR: CKDCKDRenal function analytic control 1 month after initiating therapyCV death, MI or stroke (%)p for interaction = 0,13Normal renal functionDays after randomizationJames S et al. Circulation. 2010;122:1056–1067.
29PRASUGREL: VULNERABLE SUBGROUPS Risk (%)Yes+ 54Prior Stroke / TIA-16NoPint = 0.006-1>=75AgePint = 0.18-16< 75< 60 kg+3Wgt>=60 kgPint = 0.36-14As a result of the discordance between efficacy and safety with prasugrel –signficant reductions in events at the cost of a significant increase in bleeding we performed a series of post-hoc exploratory analyses to identify subgroups of patients that did not have a favorable net clinical benefit or who had net harm.The group with a prior cerebrovascular event (shown in red) had more primary endpoint events and increased bleeding with prasugrel, resulting in a significant net clinical benefit favoring clopidogrel. Patients without a prior cerebrovascular event, shown in green, had a net clinical benefit favoring prasugrel. The P value for interaction was significant atElderly patients and those with a low body weight (shown in yellow) tended to have better efficacy but more bleeding with prasugrel, resulting in a net clinical benefit near unity. The younger patients and those with higher body weights (shown in green) had siginificant net clinical benefit favoring prasugrel. The interaction P values for the elderly and low weight patients did not reach statistical significance.-13OVERALL0.512Prasugrel BetterClopidogrel BetterHRWiviott SD et al. NEJM 2007;357:29
30CV Death, Nonfatal MI, or Nonfatal Stroke (%) AGE & DM30ClopidogrelPrasugrelHR=0.72 (95% CI, 0.6–0.9)HR=0.64 (95% CI, 0.4–1.0)HR=0.82 (95% CI, 0.7–0.9)HR=1.1 (95% CI, 0.8–1.4)25P=0.03421.820P=NSP=0.002CV Death, Nonfatal MI, or Nonfatal Stroke (%)1516.415.314.814.9P=0.0041010.89.57.85PRESENTATION TIPSThis slide shows the data by patient’s age (≥75 years of age or <75 years of age) with and without diabetes.Indicate that this subgroup analysis was post hoc.KEY POINTSThis slide shows the efficacy results of prasugrel in patients <75 or ≥75 years of age ± diabetes, representing various subpopulations of the TRITON-TIMI 38 trial.Prasugrel reduced the primary endpoint in a specific high-risk patient subgroup: ≥75 years with diabetes.There is an increase in the hazard ratio (favoring clopidogrel) in patients ≥75 years without diabetes.The TRITON-TIMI 38 trial was not designed or powered to demonstrate independent efficacy or safety in patients with diabetes who were <75 years or ≥75 years.BACKGROUNDPatients ≥75 years of age who received prasugrel had an increased risk of fatal bleeding events (1.0%) compared with patients who received clopidogrel (0.1%). In patients ≥75 years of age, symptomatic intracranial hemorrhage occurred in 7 patients (0.8%) who received prasugrel and in 3 patients (0.3%) who received clopidogrel. Because of the risk of bleeding, and because effectiveness is uncertain in patients ≥75 years of age, use of prasugrel is generally not recommended in these patients, except in high-risk situations (diabetes and past history of MI) where its effect appears to be greater and its use may be considered.REFERENCEEffient® (prasugrel) prescribing information. Daiichi Sankyo, Inc. and Eli Lilly and Company.n=1327n=1336n=249n=234n=4585n=4551n=652n=674<75 years≥75 years<75 years≥75 yearsWith DiabetesWithout Diabetes*Composite of CV death, nonfatal MI, or nonfatal stroke.3030
32BALANCING ISCHEMIA / BLEEDING Inhibition of platelet aggregationHigh risk ofischemic eventsbleeding eventsRisk of any event“Sweet spot”Ischemic riskIschemic riskBleeding riskBleeding riskFerreiro JL et al. Thromb Haemost 2010;103:
33Therapeutic Window Elective PCI OR 0.40, 95% CI 0.22-0.75 Sibbing et al. JACC 2010;56:317-8
34Therapeutic Window Elective PCI Campo G et al. J Am Coll Cardiol. 2011;57:
35CONCLUSIONS Clopidogrel: Great variability in response Novel P2Y12 inhibitors: Prasugrel and TicagrelorProof of concept: More potent platelet inhibition is needed in ACSRisk of bleeding, but favorable efficacy and safety profileSubgroup analyses has limitations, but may help to define strategyPrasugrel: only ACS undergoing PCIParticular benefit in DM, STEMI, stent thrombosisContraindications: high risk of bleeding, prior strokeConsiderations: elderly, low-weight patients; CABG: 7 daysTicagrelor: full spectrum of ACSParticular benefit: CKD; reduction in CV mortalityContraindications: high risk of bleeding, intracranial hemorrhageConsiderations: ASA dose, comorbidities (COPD), compliance; CABG: 5 daysSeveral agents: Which one is the best? Individualized therapyBalance between ischemia and bleedingPlatelet function testing may play a role
36Individualized therapy Does one size fit all??Individualized therapy
37NO riesgo alto de sangrado Riesgo alto de sangrado Hospital Universitario de Bellvitge: Indicaciones de Antiagregación Oral en SCAIAMCESTIAM extenso*ECG: Anterior (≥4 derivaciones) e InferoposteriorKT: Segmento proximal (arteria extensa)IAM no extensoCLOPIDOGRELTICAGRELORPRASUGRELNO riesgo alto de sangradoRiesgo alto de sangradoValorar: edad >80 años; ictus previo; HTA severa; antecedentes hemorrágicos; Hto<34%; ACO; vasculopatía periférica; acceso femoral; neoplasia activa; IRC severa; IQ reciente o ineludibleNo 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
38SCASEST Riesgo alto* Riesgo bajo / intermedio CLOPIDOGREL** TICAGRELOR alteraciones segmento ST; elevación troponina >10 veces el límite inferior;angor refractario; insuficiencia cardiacaRiesgo bajo / intermedioCLOPIDOGREL**TICAGRELORPRASUGRELNO riesgo alto de sangradoRiesgo alto de sangradoValorar: edad >80 años; ictus previo; HTA severa; antecedentes hemorrágicos; Hto<34%; ACO; vasculopatía periférica; acceso femoral; neoplasia activa; IRC severa; IQ reciente o ineludibleNo 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 cardiacaDMNo DM**Valorar ticagrelor en pacientes con IRC(Pacientes en que se indica estrategia invasiva)Hospital Universitario de Bellvitge: Indicaciones de Antiagregación Oral en SCA
39Unidad de Cardiología Intervencionista Jefe de Sección: Dr. J.A. Gómez-HospitalDr. José Luis FerreiroDr. Gerard RouraDr. Francesc JaraDr. Luis TeruelDr. Josep Gómez-LaraDra. Silvia HomsDr. Guillermo Sánchez-ElviraDr. Daniel RiveroLaboratorio de Investigación CardiovascularDirector: Dr. José Luis FerreiroSra. Gabriela SosaSra. Paula CampreciósSra. Laia RosenfeldSra. Olga CañavateSra. Sonia GómezDr. Kristian RiveraDra. Ana MarcanoHeart Diseases Institute. Director: Dr. Ángel CequierInteresados en fellowship:
40Gracias por su Atención Interesados en fellowship:
43CLOPIDOGREL IN ACS/PCI UA/NSTEMIPCIAcute STEMICOMMIT(CCS-2)1 Year1 Year30 Days+ Benefit+ Benefit+ BenefitLooking across the full spectrum, there is now data on the use of clopidogrel in STEMI in addition to the data on the use of clopidogrel in NSTEMI, unstable angina, PCI and secondary prevention. The results of CHARISMA will be discussed later in the lecture.NEJM 2005NEJM 2001JAMA 2002Lancet 2005
44TRITON TIMI-38: EFFICACY AND SAFETY TIMI Major NonCABG Bleeds 15138 eventsClopidogrel12.1HR 0.81 ( ) P=0.0004CV Death / MI / Stroke9.910NNT = 46PrasugrelEndpoint (%)535 eventsTIMI Major NonCABG BleedsPrasugrelThis slide depicts the balance of efficacy and safety observed in the trial.At the top is shown the significant reduction in the primary endpoint as presented a few moments ago. The number needed to treat to prevent one event was 46At the bottom is the rate of TIMI major non CABG bleeds--a key safety endpoint-- which was 2.4% with prasugrel and 1.8% with clopidogrel—a 0.6% Absolute risk increase.The excess of 35 major bleeds with prasugrel corresponded to an HR of 1.32 and P value ofThe number of subjects who would need to be treated to result in one excess major bleed (NNH) was 167.2.4HR 1.32 ( ) P=0.031.8ClopidogrelNNH = 167306090180270360450DAYSWiviott SD et al. NEJM 2007;357:44
45Cumulative incidence (%) Days after randomisation PLATO: EFFICACY1312Clopidogrel11.711109.89Ticagrelor87Cumulative incidence (%)654321HR 0.84 (95% CI 0.77–0.92), p=0.000360120180240300360Days after randomisationNo. at riskTicagrelor9,3338,6288,4608,2196,7435,1614,147Clopidogrel9,2918,5218,3628,1246,7435,0964,047K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence intervalWallentin L et al. NEJM 2009;361:
46PLATO: SAFETY K-M estimated rate (% per year) Non-CABG PLATO major bleedingNon-CABG TIMI major bleedingCABG PLATO major bleedingCABG TIMI major bleedingp=0.026p=0.03NS9876543126.96.36.199.188.8.131.52.8TicagrelorClopidogrelWallentin L et al. NEJM 2009;361:
48FROM CLOPIDOGREL TO PRASUGREL “SWITCHING”:FROM CLOPIDOGREL TO PRASUGRELSimilar findings obtained with MPA to 5 µM ADP, VASP PRI, and Verify Now® PRUAngiolillo DJ et al. J Am Coll Cardiol 2010; 56:
49TICAGRELOR: CABGMajor Fatal/Life-Threatening Bleeding by Days from Last Dose of Treatment to CABG100%Ticagrelor80%Clopidogrel60%% Patients with Bleedingpost-CABG40%20%0%1234567>8DaysBleeding differences favor ticagrelor >5 days post discontinuation
50ISSUE OF PRETREATMENT NSTEMI / Troponin +, n~4100+ (Event Driven) Clopidogrel Naive or Longterm 75mgPlan Angio/PCI >2h and <24hDiagnosis+Transferto Cathlab>2h to <24hRandomizePras 30InactiveAngioAngioCathlabPras 30Pras 60PCIPCIPE: CV-D, MI, stroke, Urgent Revasc., GPI 7dSEs: All TIMI Major 7d; 7dPras 10(5)for 30d30d FU50
51PRASUGREL AFTER CLOPIDOGREL LOADING TRansferring from clopIdogrel loading Dose to Prasugrel Loading dose in ACS patiEnTs (TRIPLET)Phase 2 randomized, double blind, double dummy, 3-arm, parallel, active comparator, controlled studyArm APlacebo < 24hr pre-PCIPrasugrel 60mg during PCIPrasugrel 10mg MDARM BClopidogrel 600mg < 24hr pre-PCIArm CPrasugrel 30mg during PCI
52PRASUGREL RELOADPatients on aspirin (81 mg/day) and prasugrel (10 mg/day) ≥ 14 days post-PCI10 mg prasugrel(N=22)30 mg prasugrel(N=21)60 mg prasugrelPharmacodynamic testing: 1 hourPharmacodynamic testing: BaselinePharmacodynamic testing: 4 hourFigure 1Angiolillo DJ et al. J Am Coll Cardiol 2012 [in press]52
53P2Y12 Reactivity Index (%) PRASUGREL RELOAD*†**††P2Y12 Reactivity Index (%)Angiolillo DJ et al. J Am Coll Cardiol 2012 [in press]