1. The Landscape of Oral Antiplatelet Agents 2009 George D. Dangas, MD, PhD, FSCAI, FACC Associate Professor of Medicine Columbia University Medical Center

2. Disclosures Advisory Board: Accumetrics, Astra- Zeneca Advisory Board: Accumetrics, Astra- Zeneca Consultant: Lilly, Daichi-Sankyo Consultant: Lilly, Daichi-Sankyo Speaker honoraria: Sanofi-Aventis, BMS Speaker honoraria: Sanofi-Aventis, BMS

3. EPISTENT: IV vs po Anti-Platelet Rx IV placebo/abciximab & po ticlopidine preRx/no-preRx Steinhubl SR, Circulation 1998;98:I-573 % MACE (Death, MI, Urgent Revasc) Placebo/ No PreRx N=343 Abciximab/ N=328Abciximab/ PreRx PreRxN=466Placebo/ PreRx N=466 13.4 8.9 5.5 5.2 33%  P=0.033 38%  P=0.028 Currently Ticlopidine is reserved for clopidogrel allergy. Requires frequent CBC

4. Proportion Event-Free Benefit of Clopidogrel Therapy at Early and Late Time Intervals Months 0.90 0.92 0.94 0.96 0.98 1.00 14681012 Weeks Proportion Event-Free 0.90 0.92 0.94 0.96 0.98 1.00 01234 RRR 21% P=0.003 95% CI 0.67– 0.92 P=0.003 Clopidogrel + ASA Placebo + ASA MI, stroke, CV Death: 0–30 days Yusuf S et al for the CURE Trial Investigators. Circulation. 2003;107:966-972. MI, stroke, CV Death: 31 d - 1 y RRR 18% P=0.009 95% CI 0.70– 0.95 P=0.009 Clopidogrel + ASA Placebo + ASA CURE ACS pts

5. CLARITY trial of APT in STEMI: Occluded Artery (or D/MI thru Angio/HD) PlaceboClopidogrel P=0.00000036P=0.00000036 Odds Ratio 0.64 (95% CI 0.53-0.76) 1.00.40.60.81.21.6 Clopidogrelbetter Placebobetter n=1752n=1739 36% Odds Reduction 36% Odds Reduction

6. Safety of Long-Term Clopidogrel 3 Placebo Controlled Trials P=0.001 NEJM 2006;354:1706-17 N=15,603 2.5 year FU GUSTO major + moderate bleed N=12,563 1 year FU CURE major bleed NEJM 2001;345;494-502 N=2,116 1 year FU TIMI major bleed JAMA 2002;288:2411-20 P=0.07 P<0.001

7. Placebo + ASA* Clopidogrel + ASA* Major Bleeding by ASA Dose <100 mg 2.6%2.0% 100–200 mg 3.5% 2.3% >200 mg 4.9% 4.0% ASA Dose CURE

8. Mean ±SDControlVASP-guidedp VASP after first LD, %68 ±1169 ±100.4 VASP after adjustment, %  38 ±14**<0.001 Bonello et al. J Am Coll Cardiol 2008 MACE: CV death, MI, revascularization Log rank p =0.007 Step-wise reloading increased % Inhibition and % responders After a 600mg clopidogrel LD, poor responders (PRI ≥ 50%) received additional 600mg bolus (max 2400 mg) until reaching therapeutic target.

9. Study Design, Flow and Compliance 25,087 ACS Patients (UA/NSTEMI 70.8%, STEMI 29.2%) Planned Early (<24 h) Invasive Management with intended PCI Ischemic ECG Δ (80.8%) or ↑cardiac biomarker (42%) 25,087 ACS Patients (UA/NSTEMI 70.8%, STEMI 29.2%) Planned Early (<24 h) Invasive Management with intended PCI Ischemic ECG Δ (80.8%) or ↑cardiac biomarker (42%) PCI 17,232 (70%) Angio 24,769 (99%) Angio 24,769 (99%) No PCI 7,855 (30%) No Sig. CAD 3,616CABG 1,809CAD 2,430 Randomized to receive (2 X 2 factorial): CLOPIDOGREL: Double-dose (600 mg then150 mg/d x 7d then 75 mg/d) vs Standard dose (300 mg then 75 mg/d) ASA: High Dose (300-325 mg/d) vs Low dose (75-100 mg/d) Efficacy Outcomes:CV Death, MI or stroke at day 30 Stent Thrombosis at day 30 Safety Outcomes:Bleeding (CURRENT defined Major/Severe and TIMI Major) Key Subgroup: PCI v No PCI Clop in 1st 7d (median) 7d 7 d 2 d 7d Complete Followup 99.8% Compliance:

10. Days Cumulative Hazard 0.0 0.01 0.02 0.03 0.04 036912151821242730 Clopidogrel: Double vs Standard Dose Primary Outcome: PCI Patients Clopidogrel Standard Clopidogrel Double HR 0.85 95% CI 0.74-0.99 P=0.036 15% RRR CV Death, MI or Stroke

11. Clopidogrel Double vs Standard Dose Bleeding PCI Population Clopidogrel Standar d N= 8684 Double N=8548 Hazard Ratio 95% CIP TIMI Major 1 0.5 1.060.70-1.610.79 CURRENT Major 2 1.11.61.441.11-1.860.006 CURRENT Severe 3 0.81.11.391.02-1.900.034 Fatal0.150.070.470.18-1.230.125 ICH0.0350.0461.350.30-6.040.69 RBC transfusion ≥ 2U 0.911.351.491.11-1.980.007 CABG-related Major0.1 1.690.61-4.70.31 1 ICH, Hb drop ≥ 5 g/dL (each unit of RBC transfusion counts as 1 g/dL drop) or fatal 2 Severe bleed + disabling or intraocular or requiring transfusion of 2-3 units 3 Fatal or ↓Hb ≥ 5 g/dL, sig hypotension + inotropes/surgery, ICH or txn of ≥ 4 units

12. Definite Stent Thrombosis in 4 Groups (Angiographically Proven) Days Cumulative Hazard 0.0 0.004 0.008 0.012 036912151821242730 C Standard, A Low C Standard, A High C Double, A Low C Double, A High Standar d Clop Double Clop HRP P Int n High ASA1.20.60.490.003 Low ASA1.20.80.60.0580.35

13. PRINCIPLE-TIMI 44: Comparison of Prasugrel with Higher Dose Clopidogrel P<0.0001 for each IPA (%; 20  M ADP) Hours 14 Days IPA (%; 20  M ADP) P<0.0001 Prasugrel 10 mg Clopidogrel 150 mg Wiviott et al Circ 2007 N=201 Prasugrel 60 mg Clopidogrel 600 mg

14. Balance of Efficacy and Safety 0 5 10 0306090180270360450 P=0.0004 HR 0.81 (0.73-0.90) P=0.0004 Prasugrel Clopidogrel Days Endpoint (%) 12.1 9.9 P=0.03 HR 1.32 (1.03-1.68) P=0.03 Prasugrel Clopidogrel 1.8 2.4 138 events 35 events CV Death / MI / Stroke TIMI Major NonCABG Bleeds NNT = 46 NNH = 167 15

15. TIMI-38 STENT ANALYSIS Definite/Probable ST: DES Only (N=5743) % of Subjects HR 0.29 [0.15-0.56]P=0.0001 HR 0.46 [0.22-0.97]P=0.04 DAYS EARLY STLATE ST 1.44% 0.42% 71% 0.91% 0.42% 54% CLOPIDOGREL PRASUGREL Wiviott et al, SCAI-ACCi2 2008

16. TIMI-38 STENT ANALYSIS Definite/Probable ST: BMS Only (N=6461) % of Subjects HR 0.45 [0.28-0.73]P=0.0009 HR 0.68 [0.35-1.31]P=0.24 DAYS EARLY STLATE ST 1.66% 0.75% 55% 0.78% 0.53% 32% CLOPIDOGREL PRASUGREL Wiviott et al, SCAI-ACCi2 2008

17. AZD6140: Inhibition of Platelet aggregation Compared With Clopidogrel in NSTEMI ACS Patients (DISPERSE-2) Inhibition of platelet aggregation after initial doses Storey, RF et al. J Am Coll Cardiol.2007;50:1852-6 *P<0.05 Mean % inhibition of platelet aggregation derived from maximum aggregation response after addition of ADP 20 mol/l (optical aggregometry).

18. PLATO study design 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

19. K-M estimate of time to first primary efficacy event (composite of CV death, MI or stroke) 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 4,147 060120180240300360 12 11 10 9 8 7 6 5 4 3 2 1 0 13 Cumulative incidence (%) 9.8 11.7 8,219 HR 0.84 (95% CI 0.77–0.92), p=0.0003 Clopidogrel Ticagrelor K-M = Kaplan-Meier; HR = hazard ratio; CI = confidence interval

20. No. at risk Clopidogrel Ticagrelor 9,291 9,333 8,560 8,678 8,405 8,520 8,177 Days after randomisation 6,703 6,796 5,136 5,210 4,109 4,191 060120180240300360 6 5 4 3 2 1 0 7 Cumulative incidence (%) Clopidogrel Ticagrelor 5.8 6.9 8,279 HR 0.84 (95% CI 0.75–0.95), p=0.005 060120180240300360 6 4 3 2 1 0 Clopidogrel Ticagrelor 4.0 5.1 HR 0.79 (95% CI 0.69–0.91), p=0.001 7 5 9,291 9,333 8,865 8,294 8,780 8,822 8,589 Days after randomisation 7079 7119 5,441 5,482 4,364 4,4198,626 Myocardial infarction Cardiovascular death Cumulative incidence (%) Secondary efficacy endpoints over time

21. Non-CABG and CABG-related major bleeding p=0.026 p=0.025 NS 9 K-M estimated rate (% per year) Non-CABG PLATO major bleeding 8 7 6 5 4 3 2 1 0 Non-CABG TIMI major bleeding CABG PLATO major bleeding CABG TIMI major bleeding 4.5 3.8 2.8 2.2 7.4 7.9 5.3 5.8 Ticagrelor Clopidogrel

22. Safety of New DAPT Regimens 3 Active Controlled Trials (vs Standard Clop) P=0.001N=25,087 1-month FU CURRENT major bleed NEJM 2009 P<0.001 P=0.32N=13,608 15-month FU TIMI major+minor bleed NEJM 2007 N=18,864 12-month FU PLATO Major bleed NEJM 2009 TIMI major+minor bleed NEJM 2007 PLATO Major bleed NEJM 2009 P=0.03 P=0.002 Non-CABG related bleeding

23. Efficacy of New DAPT Rx in ACS 3 Active Controlled Trials (vs Standard Clop) P=0.37N=25,087 1-month FU D/MI/CVA ESC 2009 P=0.02N=13,608 15-month FU D/MI/CVA NEJM 2007 Def/Prob ESC 2009 Def/Prob NEJM 2007 Def/Prob NEJM 2009 P=0.0003 P=0.002 P<0.001 P<0.001N=18,864 1- Year FU D/MI/CVA NEJM 2009

24. Efficacy of New DAPT Rx: ACS+PCI 3 Active Controlled Trials (vs Standard Clop) P=0.04N=17,232 1-month FU D/MI/CVA ESC 2009 P<0.001 P=0.02N=13,608 15-month FU D/MI/CVA NEJM 2007 Def/Prob ESC 2009 Def/Prob NEJM 2007 Def/Prob NEJM 2009 P=0.0 P=0.002 P<0.001N=11,289 1-year FU D/MI/CVA TCT 2009

25. ACC/AHA/SCAI Guideline Update for PCI Oral Antiplatelet Adjunctive Therapies In patients in whom subacute thrombosis may be catastrophic or lethal (unprotected left main, bifurcating left main, or last patent coronary vessel), platelet aggregation studies may be considered and the dose of clopidogrel increased to 150 mg per day if less than 50% inhibition of platelet aggregation is demonstrated. IIIaIIbIII C

26. Antiplatelet Therapy Summary Major recent advances in clinical research have established the value of early + sustained therapy with combination oral antiplatelet agents for CAD Major recent advances in clinical research have established the value of early + sustained therapy with combination oral antiplatelet agents for CAD More complex combination regimens are under investigations that address the different clinical situations More complex combination regimens are under investigations that address the different clinical situations Prasugrel: newest addition as an FDA approved agent. Improved efficacy. Drawback bleeding. Need for risk stratification Prasugrel: newest addition as an FDA approved agent. Improved efficacy. Drawback bleeding. Need for risk stratification Ticagrelor: newest clinical results with improved efficacy. Reversibility likely related to less CABG bleeding. Ticagrelor: newest clinical results with improved efficacy. Reversibility likely related to less CABG bleeding. Cilostazol Cilostazol  3ple combination therapy investigational