Pharmacodynamic Properties of P2Y 12 InhibitorsPharmacodynamic Properties of P2Y 12 InhibitorsClopidogrelPrasugrelTicagrelor*Cangrelor*Elinogrel*ClopidogrelPrasugrelTicagrelor*Cangrelor*Elinogrel*RouteOralOralOralIVOral/IVRouteOralOralOralIVOral/IVReceptor BindingIrreversibleIrreversibleReversibleReversibleReversibleReceptor BindingIrreversibleIrreversibleReversibleReversibleReversiblePro-drugMetabolismYesCYP 3A4/52B6, 2C9,2C19YesCYP 3A4,2B6, 2C9,2C19*Investigational Agent, ** Active metabolite half-lifeMetabolicPathwaysNoCYP 3A4NoPlasmaesteraseNoNot ReportedPro-drugMetabolismClearanceEnteral BioavailabilityTime to peak plateletinhibitionPlasma half lifeDuration of antiplateleteffectDrug Interactions orgenetic polymorphismsYesCYP 3A4/52B6,2C9,2C19Renal 50%Fecal 46%50%300mg LD:6hrs600mg LD:2hrs8 hours**7 - 10 daysYesRenal 68%Fecal 27%1 - 2 hours8 hours**7 - 10 days*Investigational Agent, ** Active metabolite half-lifeYesCYP 3A4,2B6,2C9,2C1980%NoNoCYP 3A4Renal 1%NotReported2 hours6 - 12 hours1 dayNoNoPlasmaesterase-IV only30 mins3 - 9 mins20 - 60 minsNotReportedNoNot ReportedRenal 52%Fecal 48%Not Reported20 mins (IV)12 hours1 dayNot ReportedK Anger et al Irwin and Rippes Crit Care Med.8th EditionIndividual Response Variability to Dual AntiplateletTherapy in the Steady State Phase of TreatmentBalance ofEfficacy and SafetyNumber of Patients2015105Bleeding riskIschemic riskEndpoint (%)1510CV Death / MI / StrokeClopidogrel12.1Prasugrel9.9138eventsHR 0.81(0.73-0.90)P=0.0004NNT = 460Adapted from Angiolillo DJ et al. Am J Cardiol.2006;97:38-43.2.512.522.532.542.552.562.572.582.592.57.517.527.537.547.557.567.577.587.597.5% Platelet Aggregation (LTA-ADP ADP 20µmol/L)5TIMI MajorNonCABG BleedsPrasugrelClopidogrel00 30 60 90 180 270 360 450Days2.41.835eventsHR 1.32(1.03-1.68)P=0.03NNH = 167PLATO 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)6–12-month exposurePrimary endpoint: CV death + MI + StrokePrimary safety endpoint: Total major bleedingPCI = percutaneous coronary intervention; ASA = acetylsalicylic acid;CV = cardiovascular; TIA = transient ischaemic attackTicagrelor180 mg loading dose, then90 mg bid maintenance;(additional 90 mg pre-PCI)Hierarchical testing major efficacy endpointsAll patients*Ticagrelor Clopidogrel(n=9,333) (n=9,291)HR for(95% CI) p value †Primary objective, n (%)CV death + MI + stroke 864 (9.8) 1,014 (11.7) 0.84 (0.77–0.92)
Total major bleedingK-M estimated rate (% per year)13121110987654321011.6NS11.2PLATO majorbleeding7.9NS7.7TIMI majorbleedingNS8.9 8.9Red celltransfusion *NS5.8 5.8PLATO lifethreatening/fatal bleedingTicagrelorClopidogrelNS0.3 0.3Fatal bleedingMajor bleeding and major or minor bleeding according to TIMI criteria refer to non-adjudicated events analysed with the useof a statistically programmed analysis in accordance with definition described in Wiviott SD et al. NEJM 2007;357:2001–15;* Proportion of patients (%); NS = not significantSubjectsSubjects who require PCI (with or without stent)1:1 randomization to main treatment groupsDouble blind, double dummyPlacebocapsules(to match)IndexProcedureEndpoints+Cangrelorbolus (30 µg/kg) &infusion (4 µg/kg/min)Clopidogrelcapsules(600 mg)Subjects who require PCIStudy drug infusion: for at least 2 hours or the durationof the procedure, whichever is longerClopidogrel capsules(600 mg)Placebo capsules(to match)Clopidogrel maintenance (at the discretion of the physician)+Placebobolus & infusion(to match)At 48 hours after randomization—• 1° efficacy endpoint: composite incidence of all-cause mortality, MI, and IDR• 2° efficacy endpoint: incidence of individual components, stroke & abrupt vessel closure• Safety endpoints: hemorrhage and transfusion• Safety: AEs/SAEsPrimary Endpoint:48-hour Death/MI/IDR (MITT)7.5%INNOVATE-PCI: Phase II TrialNon-Urgent PCI18-75 Years7.1%P = 0.59RRRClopidogrel 300or 600 mg Load,then 75 mg DailyElinogrel 80 mgIV then 50 mg,Oral Twice Daily60 DaysElinogrel 80 mgIV then 100 mg,Oral Twice DailyElinogrel 80 mgIV then 150 mg,Oral Twice DailyCangrelor: 3897 3623 3619 3619 3614 3606 3604 3603 3599Clopidogrel: 3871 3607 3606 3606 3602 3599 3598 3595 35881. Platelet activity2. Efficacy3.Safety4.TolerabilitySantilli F, Dabi G. Thromb Haemost 2009;101:220-221.