1. Trial Vignettes Cameron G Densem TRITON-TIMI 38 ARMYDA 4 + 5 OPTIMA

2. NO CONFLICT OF INTEREST TO DECLARE

3. TR ial to Assess I mprovement in T herapeutic O utcomes by Optimizing Platelet Inhibitio N with Prasugrel-TIMI 38 Dual antiplatelet therapy Dual antiplatelet therapy Limitations of Clopidogrel Limitations of Clopidogrel Prasugrel, novel ADP inhibitor Prasugrel, novel ADP inhibitor More rapid, consistent and effective More rapid, consistent and effective JUMBO-TIMI 26 JUMBO-TIMI 26 MACEBleeding

4. 13 608 ACS Patients Scheduled PCI Known anatomy Clopidogrel 300mg Prasugrel 60mg PCI Clopidogrel 75mg Prasugrel 10mg Primary endpoint:CV Death Non-fatal MI Non-fatal CVA Secondary endpoints: Stent thrombosis (ARC) Bleeding Primary endpoint and TVR Loading Chronic 6-15 months Exclusions: Increased bleed risk Anaemia Low platelets Intracranial pathology Thienopyridine 5/7 Aspirin 75-162mg Aspirin 75-162mg

5. 99% had PCI 94% had at least 1 stent 47% at least 1 DES Median FU 14.5 mths 2.2% absolute reduction 19% relative reduction

6. PrasugrelClopidogrelHRP Cardiovascular Death2.1% 2.4% 0.89 0.31 Non fatal MI7.3% 9.5% 0.76 <0.001 1 0 Endpoint diabetics 12.2% 17.0% 0.70 <0.001 1 0 Endpoint non- diabetics 9.2% 10.6% 0.86 0.02 Urgent TVR 2.5% 3.7% 0.66 <0.001 Stent thrombosis 1.1% 2.4% 0.48 <0.001 (def/prob ARC) BMS 0.52 <0.001 DES 0.43 <0.001

7. PrasugrelClopidogrelHRP Non CABG TIMI Major2.4% 1.8% 1.32 0.03 Life threatening1.4% 0.9% 1.52 0.01 Fatal 0.4% 0.1% 4.19 0.002 Intracranial 0.3% 0.3% 1.12 0.74 Major/minor TIMI 5.0% 3.8% 1.31 0.002 Transfusion 4.0% 3.0% 1.34 <0.001 CABG TIMI major 13.4% 3.2% 4.73 <0.001 Bleeding

8. Post Hoc Analysis PrasugrelClopidogrelHRP Prev CVA/TIA23.0% 16.0% 1.54 0.04 Age >75% % 0.99 0.92 Weight <60Kg % % 1.03 0.89 End point: death any cause, non-fatal MI/CVA, non-CABG related nonfatal TIMI major bleed Age 60Kg10.2% 12.5% 0.80 <0.001 No CVA/TIA

9. Conclusions Reduction in ischaemic events Reduction in ischaemic events At a cost of increased bleeding At a cost of increased bleeding Subgroups Subgroups Diabetics Diabetics Age, CVA, body weight Age, CVA, body weight For every 100 patients treated: For every 100 patients treated: 23 MIs prevented 23 MIs prevented Excess of 6 non CABG TIMI major bleeds Excess of 6 non CABG TIMI major bleeds “…clinicians need to weigh the benefits and risks of intensive inhibition of platelet aggregation….”

10. Antiplatelet therapy for R eduction of MY ocardial D amage during A ngioplasty 4 and 5 Debate surrounding optimal dosage and timing of antiplatelet agents around time of PCI Debate surrounding optimal dosage and timing of antiplatelet agents around time of PCI Potential benefit of 600mg Clopiogrel loading Potential benefit of 600mg Clopiogrel loading ARMYDA-2 Death MI TVR

11. 350 patients Clopidogrel naive Angina or NSTEMI Unknown anatomy Clopidogrel 600mg Pretreatment n=174 Coronary Angiography 30 day Primary endpoint:CV Death Non-fatal MI TVR Secondary endpoints:Bleeding Biomarker release 4-8hrs Pre- PCI ARMYDA-5 Coronary Angiography PCI indicated Clopidogrel 600mg treatment n=176 Coronary Angioplasty

12. Composite primary endpoint: 30 day death, MI, TVR (all events MIs) 8% 11% p=0.56 Minor bleeding at 30 days 4% 5% p=ns

13. 464 patients on Clopidogrel>10 days Angina or NSTEMI Unknown anatomy Clopidogrel Reloading 600mg n=230 Placebo n=234 Coronary Angiography PCI n=180 30 day Primary endpoint:CV Death Non-fatal MI TVR Secondary endpoints: Biomarker release Bleeding 4-8hrs Pre- PCI CABG n=42 Exclusions: Primary PCI High bleed risk Low platelets Recent CABG ARMYDA-4 Medical n=62

14. Composite primary endpoint: 30 day death, MI, TVR 7% 8% p=0.96 % Individual events at 30 days % 7% 8% MI definition: post-procedural increase of CK-MB >3 times above UNL Post PCI peak levels of Troponin I (ng/ml) Placebo 0.52 +/- 2.2 0.39 +/- 1.1 Clopidogrel % 4% Bleeding

15. Conclusions 600mg Clopidogrel preloading confers no benefit relative to intra loading 600mg Clopidogrel preloading confers no benefit relative to intra loading 600mg Clopidogrel reloading confers no extra benefit if on chronic therapy 600mg Clopidogrel reloading confers no extra benefit if on chronic therapy Small sample sizes Small sample sizes

16. OPtimal TIMing of PCI in Unstable Angina Current guidelines recommend an early invasive strategy in high risk NSTE-ACS Current guidelines recommend an early invasive strategy in high risk NSTE-ACS The precise timing of early PCI is controversial. The precise timing of early PCI is controversial. Immediate PCI may prevent (spontaneous) cardiac events Immediate PCI may prevent (spontaneous) cardiac events Deferred PCI may lead to less peri-procedural complications Deferred PCI may lead to less peri-procedural complications

17. High Risk ACS Coronary Angiography N=251 Immediate PCI n=73 Abciximab Aspirin Clopidogrel 30 day Primary endpoint:CV Death Non-fatal MI TVR Exclusions n=109: No significant CAD 55 CABG 27 ISR 9 Clinically driven immediate PCI 8 Culprit lesion not amenable for PCI 6 CTO 4 OPTIMA Deferred PCI n=69

18. Deferment

19. Primary Endpoint 30 days: CV Death, Non-fatal MI, TVR No Mortality

20. CKMB (median): 9.8 (ng/L) 4.9 (ng/L) p<0.01 peak CKMB: Infarct Size %

21. Conclusions Immediate PCI increases rate of “peri- procedural” CK-MB release Immediate PCI increases rate of “peri- procedural” CK-MB release Small, select group of patients Small, select group of patients Preliminary data Preliminary data Underpowered, planned to recruit 600 Underpowered, planned to recruit 600 ?CK-MB best biomarker ?CK-MB best biomarker How long waiting for first cath How long waiting for first cath