1. What’s New in Acute Coronary Syndromes? Claudia Bucci BScPhm, PharmD Clinical Coordinator, Cardiovascular Diseases Sunnybrook Health Sciences Centre 13 th Annual Contemporary Therapeutic Issues in Cardiovascular Disease May 7, 2010

2. ObjectivesObjectives To review recent evidence of antiplatelet therapies in the management of ACS To review recent evidence of antiplatelet therapies in the management of ACS à Clopidogrel (CURRENT/OASIS-7) à Prasugrel (TRITON-TIMI 38) à Ticagrelor (PLATO) To provide an update on pharmacotherapeutic issues in the management of ACS. To provide an update on pharmacotherapeutic issues in the management of ACS.

3. Platelet Cascade Platelet 5HT PAF EPI ADP Thrombin Collagen TXA 2 Gp 2b/3a receptor Platelet Aggregation Clot Clopidogrel Prasugrel Ticagrelor ASA Platelet Abciximab Eptifibatide Tirofiban

4. Medication In Hospital Long-Term Aspirin 160mg to chew, followed by ECASA 81mg daily ECASA 81mg daily indefinitely Clopidogrel 300mg or 600mg X 1, followed by 75mg daily 75mg daily ≥ 1 year Minimum: 4 weeks (BMS) 3-6 months (DES) Use of Antiplatelets in ACS and PCI

5. Limitations of Current Antiplatelet Therapy Slow Onset Slow Onset Level of Platelet Inhibition Level of Platelet Inhibition Variability of Response Variability of Response à High on-treatment platelet reactivity leads to increased risk of ischemic events. increased risk of ischemic events. à Medication adherence à Patient factors à P2Y12 receptor affinity à Under-dosing

6. CURRENT/OASIS-7CURRENT/OASIS-7 R UA/NSTEMI or STEMI Clopidogrel Day 1 = 600 mg LD Day 2 – 7 = 150 mg daily Day 8-30 = 75 mg Clopidogrel Day 1 = 300 mg LD + placebo Day 2 – 7 = 75 mg daily + placebo Day 8-30 75 mg daily HIGH DOSE STANDARD DOSE All patients: ASA low dose (75-100mg) OR high dose (300-325mg) Up to 30 days www.clinicaltrialresults.org

7. 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 Efficacy Outcomes:CV Death, MI or stroke at day 30 Stent Thrombosis at day 30 Safety Outcomes:BleedingCURRENT/OASIS-7CURRENT/OASIS-7 www.clinicaltrialresults.org

8. Clopidogrel: Double vs Standard Dose StandardDoubleHR 95% CI PIntn CV Death/MI/Stroke PCI (2N=17,232) 4.53.90.850.74-0.990.036 0.016 No PCI (2N=7855) 4.24.91.170.95-1.440.14 Overall (2N=25,087) 4.44.20.950.84-1.070.370 MI PCI (2N=17,232) 2.62.00.780.64-0.950.012 0.025 No PCI (2N=7855) 1.41.71.250.87-1.790.23 Overall (2N=25,087) 2.21.90.860.73-1.030.097 CV Death PCI (2N=17,232) 1.91.90.960.77-1.190.68 1.0 No PCI (2N=7855) 2.82.70.960.74-1.260.77 Overall (2N=25,087) 2.22.10.960.81-1.140.628 Stroke PCI (2N=17,232) 0.40.40.880.55-1.410.59 0.50 No PCI (2N=7855) 0.80.91.110.68-1.820.67 Overall (2N=25,087) 0.50.50.990.70-1.390.950 www.clinicaltrialresults.org

9. 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 www.clinicaltrialresults.org

10. Stent Thrombosis 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 www.clinicaltrialresults.org

11. CURRENT-OASIS 7 Conclusions High Dose Clopidogrel High Dose Clopidogrel à stent thrombosis and major CV events in PCI patients. à ↑ CURRENT-defined major bleeds but not TIMI major, ICH or fatal. High Dose ASA High Dose ASA à No significant difference in efficacy or bleeding (with trends towards greater efficacy). www.clinicaltrialresults.org

12. Limitations of Current Antiplatelet Therapy Slow Onset Slow Onset Level of Platelet Inhibition Level of Platelet Inhibition Variability of Response Variability of Response à High on-treatment platelet reactivity leads to increased risk of ischemic events. à Medication adherence à Patient factors à P2Y12 receptor affinity à Under-dosing

13. Clopidogrel (Plavix®) Prasugrel (Effient®) Ticagrelor (Brilinta®) EvidenceCUREPCI-CURE TRITON-TIMI 38 PLATO Dose 300-600mg X 1 75 mg od (150mg X 7d) 60mg X 1, 10mg od 180mg X 1 90mg bid Approved Indications * MI, stroke, PAD (secondary prev’n) MI, stroke, PAD (secondary prev’n) ACS +/- PCI ACS +/- PCI NSTEMI/STEMI with PCI - Availability * Yes June 2010 - Cost$2.58/day?? Update: Antiplatelet Agents in ACS and PCI *as of May 2010

14. Clopidogrel (Plavix®) Prasugrel (Effient®) Ticagrelor (Brilinta®) MechanismIrreversibleIrreversibleReversible Inhibitory effect +++++ Onset 2 h < 30 min 1-2 h Peak response 2-5 h 2-4 h 1-3 h MetabolismProdrug (CYP 2C19, 3A, 2B6, 1A2) Prodrug (3A4, 2B6, 2C9, 2C19) Not a prodrug Duration 5-7 days 24 – 48 h Comparison of Antiplatelet Agents in ACS

15. N Engl J Med 2009; 361:1108

16. Inhibition of Platelet Aggregation (IPA) at 24 Hours (Healthy Volunteers) -20.0 0.0 20.0 40.0 60.0 80.0 100.0 Inhibition of Platelet Aggregation (%) Response to Prasugrel Response to Clopidogrel Clopidogrel Responder Clopidogrel Non-responder *Responder =  25% IPA at 4 and 24 h Interpatient Variability Brandt, Payne, Wiviott et al AHJ 2007

17. TRITON-TIMI 38 Double-blind ACS (STEMI or UA/NSTEMI) & Planned PCI ASA PRASUGREL 60 mg LD/ 10 mg MD CLOPIDOGREL 300 mg LD/ 75 mg MD 1 o endpoint: CV death, MI, Stroke 2 o endpoints:CV death, MI, Stroke, Rehosp-Rec Isch CV death, MI, UTVR Stent Thrombosis (ARC definite/prob.) Safety endpoints: TIMI major bleeds, Life-threatening bleeds Key Substudies: Pharmacokinetic, Genomic Median duration of therapy - 12 months N= 13,600 Wiviott SD et al. New Engl J Med 2007;357:2001-2015

18. 10 15 Days 0 5 0306090180270360450 Prasugrel Clopidogrel Intent To Treat: n=13,608; Lost to Follow-Up: n=14 (0.1%) HR 0.81 (0.73-0.90) P<0.001 ARR=2.2% NNT=46 12.1 (n=781) 9.9 (n=643) HR 0.77 (0.67-0.88) P<0.001 HR 0.80 (0.71-0.90) P<0.001 CV Death/MI/Stroke (%) TRITON-TIMI 38: CV Death, MI, Stroke Wiviott SD et al. New Engl J Med 2007;357:2001-2015

19. Prasugrel Clopidogrel TRITON-TIMI 38 5 10 15 0 0306090180270360450 Days After Randomization End Point (%) 120 1.8 (n=111) 2.4 (n=146) Non-CABG TIMI Major Bleeds CV Death, MI, Stroke P=0.03 P<0.001 ↓138 events ↑ 35 events 12.1 (n=781) 9.9 (n=643) Prasugrel Clopidogrel Wiviott SD et al. New Engl J Med 2007;357:2001-2015

20. TRITON-TIMI 38: Non-CABG TIMI Major Bleeds Patients (%) Non-CABG TIMI Major Through day 3 At study end After day 3 to study end (n=6,716) (n=6,741) Life Threatening Bleeds 1.8% 0.4% 0.3% 1.0% 0.6% n=111 2.4% n=146 0.9% n=56 1.4% n=85 P=0.03 P=0.26 P=0.03 P=0.01 Wiviott SD et al. New Engl J Med 2007;357:2001-2015

21. P=0.002 Odds Ratio 4.73 P<0.001 TIMI Major or Minor CABG-related TIMI Major Bleeding Requiring Transfusion P<0.001 At risk 6/189 At risk 24/179 (n=6,716) (n=6,741) Patients (%) 3.2% 13.4% n=244 n=182 n=231 n=303 3.8% 5.0% 3.0% 4.0% TRITON-TIMI 38: Other TIMI Bleeds Wiviott SD et al. New Engl J Med 2007;357:2001-2015

22. Prasugrel BetterClopidogrel Better HR P* value P** interaction 0.06- 0.080.22 0.10- 0.170.64 TRITON-TIMI 38: Non-CABG TIMI Major Bleed History of stroke or TIA Yes No Any of the following: Age >75 y, Body wt. <60 kg, History stroke/TIA Yes No *Tests HR=1.0 within subgroups; **Tests equality HR between subgroups Wiviott SD et al. New Engl J Med 2007;357:2001-2015

23. Ticagrelor versus Clopidogrel in ACS (PLATO) Primary endpoint: CV death + MI + Stroke Key secondary: CV death + MI + Stroke in patients intended for invasive management Total mortality + MI + Stroke CV death + MI + Stroke + recurrent ischaemia + TIA + arterial thrombotic events MI alone / CV death alone / Stroke alone / Total mortality Primary safety: 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) UA/NSTEMI (moderate-to-high risk) STEMI (if primary PCI) All receiving ASA; clopidogrel-treated or naive; randomised within 24 hours of index event (N=18,624) NEJM 2009;361:1045-57.

24. PLATO: CV Death, MI or Stroke Days after randomisation 060120180240300360 12 11 10 9 8 7 6 5 4 3 2 1 0 13 Cumulative incidence (%) 9.8 11.7 P<0.001 HR 0.84 (95% CI 0.77–0.92 ) RRR = 16%, ARR = 1.87%, NNT = 54 Clopidogrel Ticagrelor NEJM 2009;361:1045-57.

25. PLATO: Major Bleeding Days from first IP dose 060120180240300360 10 5 0 15 Clopidogrel Ticagrelor 11.2 11.6 HR 1.04 (95% CI 0.95–1.13), p=0.43 K-M estimated rate (% per year) NEJM 2009;361:1045-57.

26. PLATO Total Major Bleeding NS 0 K-M estimated rate (% per year) PLATO major bleeding 1 2 3 4 5 6 7 8 9 10 12 11 TIMI major bleeding Red cell transfusion * PLATO life- threatening/ fatal bleeding Fatal bleeding Ticagrelor Clopidogrel 11.6 11.2 7.9 7.7 8.9 5.8 0.3 NEJM 2009;361:1045-57.

27. PLATO Non-CABG and CABG-related Major Bleeding p=0.03 NS 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 Ticagrelor Clopidogrel 4.5 3.8 2.8 2.2 7.4 7.9 5.3 5.8 NEJM 2009;361:1045-57.

28. PLATO: Safety TicagrelorN=9333 Clopidogrel n=9291 p Dyspnea Dyspnea requiring discontinuation 13.8%0.9%7.8%0.1%<0.001<0.001 Ventricular Pauses ≥ 3 sec ≥ 5 sec 5.8%2.0%3.6%1.2%0.010.10 Increase in SrCr (%) 1month 12 month End of Tx 10±22 11±22 8±21 9±22 10±22 <0.001<0.0010.59 NEJM 2009;361:1045-57.

29. These slides have been provided, on request, by the AstraZeneca Medical Affairs  Last Maintenance Dose Loading Dose Onset Maintenance Offset 100 90 80 70 60 50 40 30 20 10 0 IPA % Ticagrelor (n=54) Clopidogrel (n=50) Placebo (n=12) 0.5 1 2 4 8 24 6 weeks 0 2 4 8 24 48 72 120 168 240 * * * * * * * * * ‡ † †  20 µM ADP- Final Extent Gurbel PA, et al Circulation. 2009 ;120:2577-2585.

30. Intensive Statin Therapy in PCI JACC 2009;54:2290-5.