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Anti platelet therapy

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  • Percutaneous coronary intervention is inherently thrombogenic. Deep vessel wall injury induced by balloon dilatation and stent implantation triggers thrombosis resulting in thrombin generation, platelet activation and a profound, systemically detectable inflammatory response. These responses, namely thrombin generation, platelet activation and vascular inflammation lead to vessel thrombus formation, which in turn leads to vessel occlusion and downstream passage of clot, myocardial ischemia and infarction. In order to combat this response, several pharmacological agents have been developed to suppress these effect.
  • This slide places our findings in the context of prior studies of antiplatelet therapy in ACS. The introduction of single antiplatelet therapy with aspirin, as summarized in the APTC report, was associated with a 22% reduction in ischemic events. Moving to dual antiplatelet therapy with clopidogrel + aspirin in CURE produced a further 20% reduction in ischemic events. The higher IPA achieved with the combination of prasugrel and aspirin produced yet a further 19% reduction in ischemic events. Each of these advances in antiplatelet therapy was associated with a progressive increase in major bleeds as depicted in the red bars along the bottom. In each case, as with TRITON-TIMI 38, the absolute reduction in ischemic events was greater than the increase in major bleeds, resulting in net clinical benefit with increasingly potent oral antiplatelet regimens.
  • To answer this question, we are currently recruiting up to 850 sites for participation in a global phase 3 trial of prasugrel vs. clopidogrel in patients with acute coronary syndromes with planned PCI, called TRITON-TIMI 38. This trial will enroll 13,000 patients across the ACS spectrum. Patients will be randomized to either prasugrel or standard doses of clopidogrel. Patients will be followed on maintenance therapy for a median of 12 months. The primary endpoint will be the composite of cardiovascular death, MI and stroke. Important secondary endpoints include bleeding, recurrent ischemia and urgent target vessel revascularization. Thank you for your attention.
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    • 1. Platelet Activation in ACS
    • 2. Platelet Activation in Angina Pectoris1 800 700 600 500 400 300 200 100 0 30 25 20 15 10 5 0 750 700 650 600 550 500 450 400 350 300 250 Fibrinogen (mg/dl) CD62 (+) Platelets GP IIb/IIIa (MFI) Unstable Angina Stable Angina 1 Chakhtoura, Watson, et al. Am J Cardiol. 2000;86:835-839. p=0.028 p=0.026 p=0.04
    • 3. Mean Platelet Volume in Stable and Unstable Angina 8 9 10 11 12 Syndrome: Noncardiac Stable Unstable Unstable Angina Angina Angina + PTCA Pizzulli L et al. Eur Heart J. 1998;19:80-84.
    • 4. Thrombosis RIsk Progression (TRIP) Study Relation Between Platelet Physiology and Inflammation and Disease ActivityRelation Between Platelet Physiology and Inflammation and Disease Activity InflammationInflammation CRP(ug/mL) p=.006 p=0.2 0 5 10 15 20 25 AS SA UA Interleukin-8(pg/mL) 0 4 8 12 16 AS SA UA P<.001 p=.11 Platelet-Fibrin 60 63 66 69 72 AS SA UA Clot-Strength(mm) P=.002P=.002 P=.053P=.053 AS SA UA 0 1.5 3 4.5 6 Fibrinogen(mg/mL) P=.15P=.15 P=.22P=.22 Prothrombotic StateProthrombotic StateReactive PlateletsReactive Platelets 0 14 28 42 56 AS SA UA GPIIb/IIIa- Unstimulated(MFI) p=.051 P<.001 0 60 120 180 240 300 AS SA UA GPIIb/IIIa- ADP-Stimulated(MFI) P=.14 P=.002 AS = Asymptomatic Patients, SA=AS = Asymptomatic Patients, SA= Stable Angina, UA=Stable Angina, UA= Unstable AnginaUnstable Angina A distinct pathophysiological state of heightened platelet reactivity to ADP, platelet activation, hypercoagulability, and inflammation marks the development of symptomatic cardiovascular disease from chronic stable disease InflammationInflammation ?? ?? Prothrombotic StateProthrombotic State (Hypercoagulability)(Hypercoagulability) Unstable CoronaryUnstable Coronary Artery DiseaseArtery Disease ReactiveReactive PlateletsPlatelets Gurbel PA et al. J Am Coll Cardiol. 2007;49:196A.
    • 5. Platelet Hyper-Reactivity in Acute Coronary Syndromes 50 40 30 20 10 0 0.5 ADP 1.0 ADP 1.5 ADP 2.0 ADP ACS Patients* Controls Agonist Concentration (uM) *Despite ASA Treatment Williams et al. Circulation. 2003;108:IV-378. %Aggregation
    • 6. 0 10 20 30 40 50 Spontaneous Platelet Activation in Acute Coronary Syndromes: TIMI 12 Results Normals Patients Baseline Day 7 Day 28 %PlateletsCD62 Controls TIMI 12 ACS Ault KA et al. J Am Coll Cardiol. 1999;33:634-639.
    • 7. Conclusion • ACS is a “Platelet-Centric Disease” Shear Stress, PCIShear Stress, PCI Plaque RupturePlaque Rupture Platelet Platelet ADPADP TxATxA 22 Granule Secretion MembraneMembrane PL’sPL’s PlateletPlatelet AggregationAggregation Microaggregates Myocardial Infarction GPIIb/IIIaGPIIb/IIIa ActivationActivation XX XX XX Initial Activation Sustained Activation P-selectinP-selectin CD-40LCD-40L PLT-WBCPLT-WBC Aggregation/Aggregation/ MicroparticlesMicroparticles Inflammation CytokineCytokine ReleaseRelease GrowthGrowth FactorFactor ReleaseRelease Restenosis Stent Thrombosis ProcoagulantProcoagulant StateState Hypercoagulability ThrombinThrombin TFTF AspirinAspirin ClopidogrelClopidogrel GP IIb/IIIa InhibitorGP IIb/IIIa Inhibitor TFTF
    • 8. Primary Therapeutic Goal for ACS: •Attenuate platelet activation and aggregation •Prevent the development of occlusive thrombus •Arrest procoagulant activity and inflammation •Promote platelet disaggregation •Facilitate perfusion Treat the Platelet!Treat the Platelet! Prevent Ischemic Events • MPA=Maximum Platelet Aggregation • “Resistance” = < 10% platelet aggregation Adapted from: von BeckerathN, et al. Circulation 2005;112(19):2946-2950
    • 9. Clinical Practice Guideline Recommendations for Antiplatelet Therapy in ACS
    • 10. 2007 ACC/AHA ACS Guidelines2007 ACC/AHA ACS Guidelines Oral Antiplatelet TherapyOral Antiplatelet Therapy Adapted from: King et al. Circulation. 2008;117:261-295. PRIOR TO OR DURING A PCI, IT IS RECOMMENDED • Patients ALREADY TAKING daily long-term aspirin therapy should take 75 mg to 325 mg of aspirin • Patients NOT ALREADY TAKING daily long-term aspirin therapy should be given 300 mg to 325 mg of aspirin at least 2 hours, and preferably 24 hours, prior to the procedure • A loading dose of clopidogrel*, generally 600 mg, should be administered before or when PCI is performed • In patients undergoing a PCI within 12 to 24 hours of receiving fibrinolytic therapy, clopidogrel 300 mg oral loading dose may be considered * Higher oral loading doses of clopidogrel more rapidly inhibit platelet aggregation and achieve a higher absolute level of inhibition of platelet aggregation, but the additive clinical efficacy and safety of these higher oral loading doses have not been rigorously established
    • 11. 2007 ACC/AHA ACS Guidelines2007 ACC/AHA ACS Guidelines Oral Antiplatelet TherapyOral Antiplatelet Therapy Adapted from: King et al. Circulation. 2008;117:261-295. AT THE TIME OF THE PCI, IT IS REASONABLE TO GIVE • In patients for where there is concern about risk of bleeding, a lower dose of 75 mg to 162 mg of aspirin during the initial period after stent implantation • If clopidogrel is given, supplementation with GP IIb/IIIa receptor antagonists can be beneficial • For patients with an absolute contraindication to aspirin, a 300 mg to 600 mg loading dose of clopidogrel (administered at least 6 hours prior PCI) and/or a GP IIb/IIIa antagonist
    • 12. 2007 ACC/AHA ACS Guidelines2007 ACC/AHA ACS Guidelines Oral Antiplatelet TherapyOral Antiplatelet Therapy Adapted from: King et al. Circulation. 2008;117:261-295. THE FOLLOWING MIGHT BE CONSIDERED • Continue clopidogrel therapy beyond 1 year following DES placement REMEMBER TO CONSIDER CLOPIDOGREL RESISTANCE • ? ticlopidine • Think of replacing clopidogrel therapy with prasugrel
    • 13. Recommended Dosing of Antiplatelet AgentsRecommended Dosing of Antiplatelet Agents Drug Recommended Dose Dosing Adjustments GP IIb/IIIa Inhibitors Abciximab Bolus: 0.25 mg/kg (10-60 minutes before the start of PCI) and infusion 0.125 µg/kg/min (to a maximum of 10 µg/min) for 12 hours Eptifibatide Bolus: 180 µg/kg and infusion 2 µg/kg per min ↓ infusion by 50% to 1 µg/kg per min if CrCl < 50 mL per min or serum creatinine = 2 mg–4 mg/dL Tirofiban Bolus: 0.4 µg/kg and infusion 0.1 µg/kg per min ↓ bolus and infusion by 50% to 0.05 µg/kg per min if CrCl < 30 mL/min Aspirin Initial dose: 162-325 mg Maintenance: 75 mg-162 mg/day Clopidogrel Loading dose: 300mg/600mg; Maintenance: 75mg per day Ticlopidine 250 mg bid with food in combination with aspirin (75- 162 mg/day) for up to 30 days of therapy following stent implantation Adapted from: Alexander KP et al. JAMA. 2005;294:3108-3116.
    • 14. Clopidogrel Response Variability
    • 15. Clopidogrel Mechanism of Action Papathanasiou et al. Hellenic J Cardiol. 2007;48:352. • AC-adenyl cyclase; • PKA-protein kinase A • PLC - phospholipase C; • VASP - vasodilator stimulated phosphoprotein A
    • 16. Variable Response to Clopidogrel • Platelet aggregation before and after Clopidogrel (%) – “Resistance” = < 10% platelet aggregation Adapted from: Gurbel PA et al. Circulation 2003; 107: 2908-2913
    • 17. Clopidogrel Response Variability GP IIb/IIIa receptorGP IIb/IIIa receptor expressionexpression Hepatic MetabolismHepatic Metabolism Cytochrome P450 pathwayCytochrome P450 pathway Poor compliance Inadequate administration Variable absorption Drug-drug interactions Genetic polymorphisms CYP enzymes (CYP3A4/5, CYP2C19, CYP1A2) Drug-drug interactions Genetic polymorphisms P2Y12 receptor Alternate pathways of platelet activation - Release of circulating ADP Higher baseline platelet reactivity Genetic polymorphisms O’Donoghue M, Wiviott SD. Circulation. 2006;114:e600-e606. Intestinal AbsorptionIntestinal Absorption P2YP2Y1212 ReceptorReceptor (irreversible inhibition)(irreversible inhibition) Active MetaboliteActive Metabolite
    • 18. ~30% 75mg/day for 30days Post-PCI ~30%-40% 75mg/day for 5-7days volunteers ~30%-40% 300 mg load Post-PCI ~30%-50% 600 mg load Post-PCI ~1.4x 150mg/d vs. 75mg/d for 30days Post-PCI3 Inhibition of Platelet Aggregation (Wide Response Variability)1 Mechanism of Clopidogrel Response VariabilityMechanism of Clopidogrel Response Variability Clopidogrel Bisulfate Intestinal Absorption Inactive Carboxylic Acid Metabolite CYP3A4 CYP3A5 CYP2C19 Active Thiol Metabolite P2Y12 Receptor Limited absorption capacity with ceiling effect at 600mg loading doseLimited absorption capacity with ceiling effect at 600mg loading dose Hepatic P450 Cytochromes lipophilic statins Genetic polymorphisms Genetic polymorphisms Multistep Conversion 15% Esterases 85% 1. Gurbel PA et al. Thromb Res. 2007;120:311-21. 2. Taubert et al. Clin Pharmacol. 2006;80:486-501. 3. von Beckerth et al. Eur Heart J.2007;28:1814-9. P-glycoprotein (MDR1 3435T genotype)2 ? Smoking, proton pump inhibitorsCYP1A2 CYP2B6, 2C19
    • 19. What is the Antiplatelet Effect of Clopidogrel? (i) Delayed onset and unpredictability of pharmacodynamic response (ii) A modest degree of mean platelet inhibition (30-50%) (iii) Wide response variability with non-responsiveness or resistance that is associated with ischemic events including stent thrombosis Mechanism of Clopidogrel Response Variability and Nonresponsiveness (i) CYP isoenzymes variable activity - genetic polymorphisms or drug-drug interactions - lipophilic statins, proton pump inhibitors, smoking (ii) Variable intestinal absorption - ? genetic polymorphisms Gurbel PA et al. J Am Coll Cadriol. 2008;51:261-263
    • 20. The First Clopidogrel Resistance Study (300 mg) A “Fingerprint” of Clopidogrel Response Variability Gurbel PA et al. Circulation. 2003;107:2908-2913 2 Hours 24 Hours 5 Days 30 Days Resistance = 31% 10 20 ≤ -30 (-30,-20] (-20,-10] (-10,0] (0,10] (10,20] (20,30] (30,40] (40,50] (50,60] >60 Resistance Resistance ∆ Aggregation (%) 14 28 ≤ -30 (-30,-20] (-20,-10] (-10,0] (0,10] (10,20] (20,30] (30,40] (40,50] (50,60] >60 Resistance = 31% ∆ Aggregation (%) Resistance Patients(%) 11 22 ≤ -10 (-10,0] (0,10] (10,20] (20,30] (30,40] (40,50] (50,60] >60 Resistance = 63%Resistance Patients(%) 12 24 ≤ -30 (-30,-20] (-20,-10] (-10,0] (0,10] (10,20] (20,30] (30,40] (40,50] (50,60] >60
    • 21. P2Y12 – A Pivotal Platelet Receptor Gurbel PA et al. Rev Cardiovasc Med. 2006;7:S20-S28 ShearShear GPIIb/IIIa Activation Platelet Aggregation Inflammation ADPADP TxATxA22 MembraneMembrane PhospholipidsPhospholipids Granule Secretion Sustained Activation CollagenCollagen ThrombinThrombin P2Y12 Receptor Activation ADPADP Procoagulant Surface Coagulation P-selectin CD-40L Expression Clopidogrel Prasugrel Tricagrelor Cangrelor PRT128 X TxATxA22 Amplification Amplification
    • 22. Residual Platelet Aggregation Stratified by CYP2C19*2 Genotype 0 20 40 60 Baseline Before PCI Pre-discharge CYP2C19 *1/*1 CYP2C19 *1/*2 CYP2C19 *2/*2 Trenk D et al. J Am Coll Cardiol. 2008:51:1925-1934
    • 23. Clopidogrel Non-Responsiveness Correlation With CYP3A4 Enzyme Activity 0 20 40 60 80 100 Aggregation(%) 80  980  9 37  2037  20 5.0 4.0 3.0 2.0 1.0 0 1.9  0.71.9  0.7 2.7  1.02.7  1.0 Platelet aggregation CYP3A4** 4 hours post clopidogrel* activity *450 mg PO (P=0.0002); **P=0.15 Nonresponders (25%)Nonresponders (25%) 14 CO2exhaled/h(%) Lau WC et al. J Am Coll Cardiol. 2003;41:225A Responders (75%)Responders (75%)
    • 24. Clopidogrel Metabolism and Effect P2Y12 GPIIb/IIIa ActivationGPIIb/IIIa Activation Platelet AggregationPlatelet Aggregation X PLC cAMP VASP-P Ca++ Mobilization ADP Adenylyl Cyclase Granule Secretion ADP Gq G12 Shape Change P2Y1 PI3-K Rap-1b Akt Rho Kinase Gi ADP Release Clopidogrel Prasugrel Intestinal Absorption CYP P450 Conversion Active Thiol Metabolite Irreversible Binding Gurbel PA et al.Gurbel PA et al. Nat Clin Pract Cardiovasc Med. 2006;3:387-395
    • 25. DES Thrombosis and Residual Platelet ReactivityPercentofpatientsfreefrom definiteorprobableST(%) Responders Nonresponders* *Residual platelet aggregation (10 µM ADP) ≥70% Buonamici P et al. J Am Coll Cardiol. 2007;49:2312-2317 Time (Days) 98 198 1 91  391  3 Log rank P<0.001
    • 26. Overcoming Limitations of Clopidogrel Therapy
    • 27. The New Drugs Strategies to Overcome the Limitations of Clopidogrel Therapy P2Y12 Inhibitors Cangrelor ATP Analogue Parenteral Direct, Reversible Phase 3 Prasugrel Thienopyridine Oral Prodrug, Irreversible Phase 3 AZD 6140 Cyclopentyltriazolo- Oral Direct, Reversible Phase 3 pyrimidine (CPTP) PRT060128 ? Parenteral/ Direct, Reversible Phase 2 Oral PAR-1 Inhibitors SCH530348 Himbacine Oral Direct Phase 2 Derivative Soluble GP VI, P2Y1 Inhibitors, GPIb Inhibitors
    • 28. Inhibition of ADP-Induced Aggregation The Old and the New Drugs MaintenanceDoses Clopidogrel Prasugrel AZD6140 LoadingDoses 16% 29% 0 7 14 21 28 35 300 mg 600 mg AbsoluteInhibition(%) 20uMADP Gurbel et al. J Am Coll Cardiol. 2005;45:1392 Jakubowski et al. J Cardiovasc Pharmacol. 2007;49:167 36% 60% 0 15 30 45 60 75 300 mg Clopidogrel 60 mg Prasugrel RelativeInhibition 20uMADP(%) 17% 52% 0 15 30 45 60 300 mg Clopidogrel 180 mg AZD6140 RelativeInhibition 20uMADP(%) Storey et al. J Am Coll Cardiol. 2006;47:204A Von Beckerath et al. Eur Heart J. 2007 Jakubowski et al. J Cardiovasc Pharmacol. 2007;49:167 Storey et al. J Am Coll Cardiol. 2006;47:204A 45% 65% 0 15 30 45 60 75 75 mg 150 mg Post-TreatmentAggregation 5uMADP(%) 38% 65% 0 15 30 45 60 75 75 mg Clopidogrel 15 mg Prasugrel RelativeInhibition 20uMADP(%) 25% 52% 0 15 30 45 60 75 mg Clopidogrel 180 mg bid AZD6140 RelativeInhibition 20uMADP(%)
    • 29. Emerging Treatment Options Prasugrel
    • 30. Evolution of Antiplatelet Therapy in ACS 0 1 08 Placebo APTC CURE TRITON-TIMI 38 Single Antiplatelet Rx Dual Antiplatelet Rx Higher IPA ASA ASA + Clopidogrel ASA + Prasugrel- 22% - 20% - 19% + 60% + 38% + 32% Reduction in Ischemic Events Increase in Major Bleeds
    • 31. Prasugrel More Effective Platelet Inhibition Prasugrel vs Clopidogrel1 • More potent • More rapid in onset • More consistent inhibition of platelet aggregation (IPA) • Less frequent poor IPA response • More efficient generation of its active metabolite 1. Wiviott SD et al. Am Heart J. 2006;152:627-635. 2. Payne CD et al. Am J Cardiol. 2006;98:S8. Time Post-dose (Day/Hour) IPA in healthy subjects2 -1 0 0 1 0 2 0 3 0 4 0 5 0 6 0 7 0 8 0 9 0 1 0 0 1/.25 1/.5 1/1 1/2 1/4 1/6 2/0 3/0 4/0 5/0 6/0 7/0 8/0 9/0 Pras 60/10 Clop 600/75 Clop 300/75 InhibitionofPlateletAggregation(%)
    • 32. ****** *** *** *** Comparative Platelet-Inhibition by Prasugrel and Clopidogrel in Aspirin-Treated Patients with Coronary Artery Disease 0 20 40 60 80 100 Wallentin L et al. Eur Heart J. 2008;29:21-30. MPA*(%) h 0 0.5 1 2 4 24 + 4 Predose Day Day 14+3 29+3*20 µM ADP max platelet agg ***p<0.001 Day 1 Loading dose Maintenance doses / / Clopidogrel Prasugrel *** ***
    • 33. Prasugrel Is Effective for Clopidogrel Non-Responders * Responder 25% IPA at 4 and 24 hours -20-20 00 2020 4040 6060 8080 100100 IPAat24hours(%)IPAat24hours(%) Response toResponse to Prasugrel 60 mg Response toResponse to Clopidogrel 300 mg Clopidogrel ResponderClopidogrel Responder Clopidogrel Non-responderClopidogrel Non-responder InterpatientInterpatient VariabilityVariability InterpatientInterpatient VariabilityVariability Brandt JT. Am Heart J. 2007;153: 66e9.
    • 34. “Resistance” to Clopidogrel is a Pharmacokinetic Problem Husted S et al. Eur Heart J. 2006;27:1038. Brandt et al. J Am Coll Cardiol. 2005;45:87A.Brandt et al. J Am Coll Cardiol. 2005;45:87A. Disperse StudyDisperse Study (n=39 stable ASCVD)(n=39 stable ASCVD) Healthy Volunteer Crossover StudyHealthy Volunteer Crossover Study 60 mg60 mg300 mg Uniform response: “Polygenetic and environmental influence” ???
    • 35. PRASUGRELPRASUGREL 60 mg LD/ 10 mg MD60 mg LD/ 10 mg MD CLOPIDOGRELCLOPIDOGREL 300 mg LD/ 75 mg MD300 mg LD/ 75 mg MD TRITON-TIMI 38 Study Design Double-blind ACS (STEMI or UA/NSTEMI) & Planned PCI ASA 11oo endpoint:endpoint: CV death, MI, strokeCV death, MI, stroke 22oo endpoints:endpoints: CV death, MI, stroke, rehosp-rec ischCV death, MI, stroke, rehosp-rec isch CV death, MI, UTVRCV death, MI, UTVR Median duration of therapy - 12 monthsMedian duration of therapy - 12 months N=13,600 Wiviott SD et al. Am Heart J. 2006;152:627-635. UTVR: urgent target vessel revascularization; NSTEMI: non-ST segment elevation MI
    • 36. TRITON TIMI-38 Balance of Efficacy and Safety Days 35 events HR 0.81 (0.73-0.90) P = .0004 HR 1.32 (1.03-1.68) P = .03 138 events NNT = 46 NNH = 167 Wiviott SD et al. N Engl J Med. 2007;357:2001-2015. EndPoint(%) 12.1 9.9 1.8 2.4 0 5 10 15 0 30 60 90 180 270 360 450 CV Death/MI/Stroke TIMI Major Non-CABG Bleeds Clopidogrel Prasugrel Prasugrel Clopidogrel HR = hazard ratio; NNT = number needed to treat; NNH = number needed to harm
    • 37. TRITON-TIMI-38 Primary Endpoint- CV Death, MI, StrokePrimary Endpoint- CV Death, MI, StrokePrimaryEndpoint(%) 0 5 10 15 0 30 60 90 180 270 360 450 HR 0.81 p=0.0004 Prasugrel Clopidogrel HR 0.80 P=0.0003 HR 0.77 P=0.0001 Days 12.1 % 9.9 % ~ 10% Recurrent Ischemic Events - What is the Reason for Treatment Failure? - Ceiling effect of P2Y12 blocker? - Selected patients with high platelet reactivity? - Other unblocked pathways? e.g. Thrombin - PAR-1? Wiviott SD et al. N Engl J Med. 2007;357:2001-2015. Bleeding Events = Prasugrel (1.4%) vs. Clopidogrel (0.9%), p=0.01
    • 38. TRITON TIMI-38 Bleeding Events* Wiviott SD et al. N Engl J Med. 2007;357:2001-2015. ARD 0.5% HR 1.52 P = .01 PercentageofEvents ARD 0.6% HR 1.32 P = .03 NNH = 167 Clopidogrel Prasugrel ARD 0.2% P = .23 ARD 0% P = .74 ARD 0.3% P = .002 1.8 0.9 0.9 0.1 0.3 2.4 1.4 1.1 0.4 0.3 0 2 4 TIMI Major Bleeds Life-threatening Nonfatal Fatal ICH ICH in Patients with Prior Stroke/TIA (N = 518) Clop 0 (0)%Clop 0 (0)% Pras 6 (2.3)% (P = .02) *N = 13,457 TIA = transient ischemic attack; ICH = intracranial hemorrhage; ARD = absolute risk difference
    • 39. TRITON TIMI-38 Net Clinical Benefit Bleeding Risk Subgroups Overall ≥60 kg <60 kg <75 No Yes 0.5 1 2 Prior Stroke / TIA Age Weight Risk (%) + 37 -16 -1 -16 +3 -14 -13 Prasugrel Better Clopidogrel BetterHR Pint = 0.006 Pint = 0.18 Pint = 0.36 Post-hoc analysis Wiviott SD et al. N Engl J Med. 2007;357:2001-2015. ≥75
    • 40. TRITON TIMI-38: Stent Thrombosis (ARC Definite + Probable) Days 0 1 2 3 0 30 60 90 180 270 360 450 HR 0.48 P < .0001 Prasugrel Clopidogrel 2.4 (142) 74 events NNT = 77 1.1 (68) EndPoint(%) Any Stent at Index PCI N = 12,844 ARC = Academic Research Consortium; PCI = percutaneous coronary intervention Wiviott SD et al. N Engl J Med. 2007;357:2001-2015.
    • 41. 0.0 0.5 1.0 1.5 2.0 2.5 Stent Thrombosis* in Triton TIMI-38 DES Number at risk Days Prasugrel 2865 2782 2762 2746 2524 2474 2205 2123 1846 1334 Clopidogrel 2878 2760 2737 2726 2508 2472 2225 2140 1887 1367 Wiviott SD et al. Lancet. 2008;371:1353-1363. Clopidogrel 0.84 vs. 2.31% HR 0.36 (0.22-0.58), p<0.0001 Prasugrel 1 year 0.74 vs. 2.05% HR 0.35 (0.21 – 0.58), p<0.0001 %ofparticipants 0 50 100 150 200 250 300 350 400 450 * ARC definite or probable
    • 42. 0.0 0.5 1.0 1.5 2.0 2.5 Stent Thrombosis* in Triton TIMI-38 BMS Number at risk Days Prasugrel 3237 3123 3086 3065 2757 2692 2419 2338 2008 1614 Clopidogrel 3224 3065 3035 3014 2722 2675 2368 2294 1997 1600 Clopidogrel 1.27 vs. 2.41% HR 0.52 (0.35-0.77), p=0.0009 Prasugrel 1 year 1.22 vs. 2.27% HR 0.53 (0.36 – 0.79), p=0.0014 %ofparticipants 0 50 100 150 200 250 300 350 400 450 Wiviott SD et al. Lancet. 2008;371:1353-1363.
    • 43. PRINCIPLE-TIMI 44 Prasugrel versus High Dose Clopidogrel Adapted from Wiviott et al. Circulation. 2007;116:2923. 60 Prasugrel 10 Prasugrel / Day 600 Clopidogrel 50 Clopidogrel / Day %IPA(20MADP) p<0.0001 p<0.0001 0 10 20 30 40 50 60 70 80 90 100 6 Hours Post Load 14 Days Chronic Rx Prasugrel Clopidogrel 74.8 ± 13.0 31.8 ± 21.1 61.3 ± 17.8 46.1 ± 21.3
    • 44. Summary • Stent Thrombosis – rare complication of PCI with high mortality. • Study data indicate that prasugrel is a drug with more rapid, consistent, and greater inhibition of platelet aggregation – superior to standard dose clopidogrel to prevent ischaemic events – major reductions (~50%) in ST across a broad array of clinical procedural characteristics • Intensive antiplatelet therapy with PRASUGREL in stented patients as compared to CLOPIDOGREL: – Brings Substantial reduction in ST, regardless of stent type or ST definition - Early and Late • Effective in a broad range of clinical / procedural characteristics – Fewer ischemic events, more major bleeding