1. CHARISMA: The “CAPRIE-like” Cohort Deepak L. Bhatt MD, FACC, FSCAI, FESC, FACP Associate Director, Cleveland Clinic Cardiovascular Coordinating Center Staff, Cardiac, Peripheral, and Carotid Intervention Associate Professor of Medicine

2. Disclosure Dr. Bhatt has served as a consultant to: Astra Zeneca, Bristol-Myers Squibb, Cardax, Cogentus, Daiichi Sankyo, Eli Lilly, Eisai, Glaxo Smith Kline, Johnson & Johnson, Medtronic, Millennium, Otsuka, Paringenix, PDL, sanofi aventis, Schering Plough, The Medicines Company, tns Healthcare, Vertex. Honoraria are donated to NPOs. Principal Investigator for CHARISMA, co-PI of CHAMPION, and co-chair of REACH, as well as other potentially related studies – no personal compensation, though the Cleveland Clinic does receive research funding. This presentation discusses off-label and/or investigational uses of aspirin, AZD6140, cangrelor, clopidogrel, prasugrel, drug-eluting stents.

3. Sponsors – C5 Abraxis Alexion Pharma AstraZeneca Atherogenics Aventis Biosense Webster Biosite Boehringer Ingelheim Boston Scientific Bristol-Myers Squibb (BMS) Cardionet Centocor Converge Medical Inc. Cordis Dr. Reddy’s Abraxis Alexion Pharma AstraZeneca Atherogenics Aventis Biosense Webster Biosite Boehringer Ingelheim Boston Scientific Bristol-Myers Squibb (BMS) Cardionet Centocor Converge Medical Inc. Cordis Dr. Reddy’s Edwards Lifesciences Esperion GE Medical Genentech Gilford GSK Guidant J&J Kensey-Nash Lilly Medtronic Merck Mytogen Novartis Edwards Lifesciences Esperion GE Medical Genentech Gilford GSK Guidant J&J Kensey-Nash Lilly Medtronic Merck Mytogen Novartis Novo Nordisk Orphan Therapeutics P&G Pharma Pfizer Roche Sankyo Sanofi-Aventis Schering-Plough Scios St. Jude Medical Takeda TMC VasoGenix Viacor Novo Nordisk Orphan Therapeutics P&G Pharma Pfizer Roche Sankyo Sanofi-Aventis Schering-Plough Scios St. Jude Medical Takeda TMC VasoGenix Viacor

4. CAPRIE: Superior Efficacy of Clopidogrel versus ASA *MI, ischemic stroke or vascular death † Intent-to-treat analysis (n=19,185) CAPRIE Steering Committee. Lancet 1996; 348: 1329–1339. 0 4 8 12 16 0369121518212427303336 Months of follow-up Cumulative event rate* (%) ASA Clopidogrel 8.7% † RRR (p=0.043) 20 Patients with recent ischemic stroke, recent MI or symptomatic PAD

5. CAPRIE: Clopidogrel Provides Amplified Benefit in Patients with High Vascular Risk Ringleb PA, Bhatt DL, Hirsch AT, et al. Stroke 2004; 35: 528–532. *MI, ischemic stroke or vascular death; mean duration of treatment was 1.6 years 5.8% 10.2% 5.3% 8.8% 0 2 4 6 8 10 All CAPRIE patients (n=19,099) Prior history of major acute event (MI or stroke; n=4496) Event rate/year* (%) ASA Clopidogrel 12 p=0.043 RRR 8.7% RRR 14.9% p=0.045

6. Months of Follow-up Yusuf S, et al. N Engl J Med. 2001;345:494-502. CURE Study: Primary End Point: MI/Stroke/CV Death Clopidogrel + Aspirin (n=6259) Placebo + Aspirin (n=6303) P <.001 N=12,562 369012 20% Relative Risk Reduction 0.12 0.14 0.10 0.06 0.08 0.00 0.04 0.02 Cumulative Hazard Rate

7. Mehta SR, et al. Lancet. 2001;358:527-533..00.05.10.15 010100300400200 Cumulative Hazard Rate Clopidogrel + Aspirin (n=1313) 31% Relative Risk Reduction Placebo + Aspirin (n=1345) Median time to PCI Days of Follow-up 12.6% 8.8% P=.002 PCI-CURE Study: CV Death or MI From Randomization

8. CLARITY: Incidence of CV Death, MI, RI  Urgent Revascularization Sabatine MS, Cannon CP, Gibson CM, et al. N Engl J Med. 2005;352:1179-89. Days End point (%) 0 5 10 15 051015202530 Placebo + ASA Clopidogrel + ASA Odds ratio 0.80 (95% CI, 0.65-0.97) P=0.026 20%

9. Days since randomization Event (%) 9% relative risk reduction (P=0.002) Placebo: 2310 events (10.1%) Clopidogrel: 2121 events (9.2%) COMMIT: Incidence of Death, Re-MI, or Stroke at 28 Days 0 7142821 1 2 3 4 5 6 7 9 8 0 COMMIT Collaborative Group. Lancet. 2005;366:1607.

10. Primary Endpoint (MI/Stroke/CV Death) in Patients With Previous MI, IS, or PAD* “CAPRIE-like Cohort” RRR: 17.1 % (95% CI: 4.4%, 28.1%) P=0.01 Primary Outcome Event Rate (%) 0 2 4 6 8 10 Months Since Randomization 0 612182430 Clopidogrel + ASA Placebo + ASA N=9,478 * Post hoc analysis. Bhatt DL, Flather MD, Hacke W, et al. J Am Coll Cardiol. 2007;49:1982-1988. 8.8% 7.3%

11. Primary Endpoint (MI/Stroke/CV Death) in Patients With Previous MI, IS, or PAD* “CAPRIE-like Cohort” *Post hoc analysis. Cardiovascular Death/MI/Stroke PlaceboClopidogrelHR (95% CI)P value Prior MI8.3%6.6%0.774 (0.613, 0.978)0.031 Prior IS10.7%8.4%0.780 (0.624, 0.976)0.029 Prior PAD8.7%7.6%0.869 (0.671, 1.125)0.085 Entire Cohort8.8%7.3%0.829 (0.719, 0.956)0.010 0.51 2 PlaceboClopidogrelP value Prior MI8.3%6.6%0.774 (0.613, 0.978)0.031 Prior IS10.7%8.4%0.780 (0.624, 0.976)0.029 Prior PAD8.7%7.6%0.869 (0.671, 1.125)0.085 Entire Cohort8.8%7.3%0.829 (0.719, 0.956)0.010 0.51 2 Bhatt DL, Flather MD, Hacke W, et al. J Am Coll Cardiol. 2007;49:1982-1988.

12. 10 8 6 4 2 0 CHARISMA―Prior MI 06121824 30 HR=0.774 (95% CI [0.613–0.978]) P=0.031 N=3,846 Primary Outcome Event Rate (%) Months Since Randomization 8.3% 6.6% Placebo + ASA Clopidogrel + ASA Bhatt DL, Flather MD, Hacke W, et al. J Am Coll Cardiol. 2007;49:1982-1988.

13. CHARISMA―CAD Without Prior MI 10 8 6 4 2 0 06121824 30 HR=1.103 (95% CI (0.770–1.580]) P=0.593 N=1,989 Primary Outcome Event Rate (%) Months Since Randomization 6.3% 5.7% Placebo + ASA Clopidogrel + ASA Bhatt DL, Flather MD, Hacke W, et al. J Am Coll Cardiol. 2007;49:1982-1988.

14. Timing of Severe or Moderate Bleeding Placebo + ASA Clopidogrel + ASA Days Since Randomization 1560 135270450630810 0.00008 0.00007 0.00006 0.00005 0.00004 0.00003 0.00002 0.00001 0 Hazard Function/d Bhatt DL, Flather MD, Hacke W, et al. J Am Coll Cardiol. 2007;49:1982-1988.

15. Median Time of Late Stent Thrombosis p = 0.04p = 0.0003p = 0.0052 Months Bavry, Kumbhani, Helton, Borek, Mood, Bhatt. AJM 2006. 0 4 8 12 16 20 DES/BMSSES/BMSPES/BMS

16. Clinical Presentation of Bare Metal In-stent Restenosis Chen MS, John JM, Chew DP, Lee DS, Ellis SG, Bhatt DL. Am Heart J. 2006;151:1260-1264.

17. Clopidogrel Use and Long-term Clinical Outcomes after DES - Duke Registry Endpoint (%) Adjusted outcomes were analyzed at 24 months Patients in the DES with clop. group had significantly lower rates of death or MI than did patients in the DES without clopidogrel group Among BMS patients, there were no differences in death or MI Adjusted rates of death or MI starting at 6 months Difference = -4.1 ± 3.5 P=.02 Difference = -0.5 ± 2.7 P=.70 Eisenstein EL, et al. JAMA. 2007;10;297(2):159-168.

18. Conclusions Dual antiplatelet therapy indicated for at least 1 year after ACS and/or PCI – CURE, PCI CURE, CREDO Potential benefit beyond 1 year in patients with prior ischemic events – CHARISMA subgroup Potential benefit beyond 1 year in patients with DES – registry data