Disclosure

1. Disclosure Dr. Bhatt has received honoraria from: Astra Zeneca, Bristol-Myers Squibb, Eli Lilly, Millennium, Schering Plough, sanofi aventis, The Medicines Company. This presentation discusses off-label uses of clopidogrel. This study was funded by sanofi aventis and Bristol-Myers Squibb.

2. Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance(CHARISMA) Deepak L. Bhatt M.D., Keith A. A. Fox M.B.Ch.B., Werner Hacke M.D., Peter B. Berger M.D., Henry R. Black M.D., William E. Boden M.D., Patrice Cacoub M.D., Eric A. Cohen M.D., Mark A. Creager M.D., J. Donald Easton M.D., Marcus D. Flather M.D., Steven M. Haffner M.D., Christian W. Hamm M.D., Graeme J. Hankey M.D., S. Claiborne Johnston M.D., Koon-Hou Mak M.D., Jean-Louis Mas M.D., Gilles Montalescot M.D., Ph.D., Thomas A. Pearson M.D., P. Gabriel Steg M.D., Steven R. Steinhubl M.D., Michael A. Weber M.D., Danielle M. Brennan M.S., Liz Fabry-Ribaudo M.S.N., R.N., Joan Booth R.N., Eric J. Topol M.D., on behalf of the CHARISMA Investigators

3. Study Organization Investigators National Coordinators Data Safety Monitoring Board Sponsors C5 Clinical Event Adjudication Committee Operations Committee Executive Committee C5=The Cleveland Clinic Cardiovascular Coordinating Center Bhatt DL et al. Am Heart J 2004; 148: 263–268.

4. Executive Committee Chairman • Eric J Topol Co-Chairmen/Investigators • Keith AA Fox • Werner Hacke Member/International Principal Investigator • Deepak L Bhatt Members/Investigators • Peter B Berger • William E Boden • Eric Cohen • Marcus Flather • Christian W Hamm • S Claiborne Johnston • Jean-Louis Mas • Thomas A Pearson • Steven R Steinhubl • Henry R Black • Patrice Cacoub • J Donald Easton • Steven M Haffner • Graeme J Hankey • Koon-Hou Mak • Gilles Montalescot • P Gabriel Steg • Michael Weber Bhatt DL et al. Am Heart J 2004; 148: 263–268.

5. National Coordinators Germany and Austria • Ulrich Hoffmann • Franz-Josef Neumann Greece • Alexios P Dimas Hungary • Tamàs Forster Italy • Diego Ardissino Mexico • Ricardo Alvarado The Netherlands • Harry Roger Büller Norway • Bent Indredavik Poland • Zbigniew A Gaciong Portugal • Joao Morais Russia • Viacheslav Mareev Spain • Amadeo Betriu • Luis M Ruilope South Africa • Anthony J Dalby Sweden • Jan B Östergren Switzerland • Thomas F Luscher Turkey • Hakan Kultursay United Kingdom • Marcus D Flather • Keith AA Fox United States • William E Boden • J Donald Easton • Steven M Haffner • Thomas A Pearson • Steven R Steinhubl Argentina • Sebastian F Ameriso • Fernando A Cura Australia • Phillip Aylward • Graeme J Hankey Belgium • Benoît J Boland Brazil • Angelo Amato • Vicenzo De Paola Canada • Eric A Cohen • André Roussin • Phillip Teal Czech Republic • Edvard Ehler Denmark • Henrik Sillesen Finland • Markku Nieminen France • P Gabriel Steg Bhatt DL, Fox K, Hacke W, et al. Am Heart J 2005; 150: 401.

6. Trial Committees Clinical Events Committee • A Michael Lincoff (Chairman) • Sorin J Brener (cardiology) • Cathy A Sila (neurology) Data Safety Monitoring Board • Robert L Frye (Chairman) • Pierre Amarenco • Lawrence M Brass: A Great Doctor, A Great Investigator, A Great Friend • Marc Buyse • Lawrence S Cohen • David L DeMets • Valentin Fuster • Robert G Hart • John R Marler • Charles McCarthy • Albert Schömig Bhatt DL, Fox K, Hacke W, et al. Am Heart J 2005; 150: 401.

7. CAPRIE: Superior Efficacy of Clopidogrel versus ASA Patients with recent ischemic stroke, recent MI or symptomatic PAD 20 8.7%† RRR (p=0.043) ASA 16 Clopidogrel 12 Cumulative event rate* (%) 8 4 0 0 3 6 9 12 15 18 21 24 27 30 33 36 Months of follow-up *MI, ischemic stroke or vascular death †Intent-to-treat analysis (n=19,185) CAPRIE Steering Committee. Lancet 1996; 348: 1329–1339.

8. ASA 9.1%† RRR (p=0.018) 20 Clopidogrel 15 10 Cumulative event rate* (%) 5 0 10 35 30 5 15 20 25 Months of follow-up CAPRIE: Clopidogrel Reduced the Rate of Rehospitalization Patients with recent ischemic stroke, recent MI or symptomatic PAD *Rehospitalization for ischemia (angina pectoris,TIA, limb ischemia) or bleeding (gastrointestinal, intracranial or other) †On-treatment analysis (n=19,099) Bhatt DL et al. Am Heart J 2000; 140: 6773.

9. CHARISMA Trial Design Clopidogrel 75 mg/day (n=7802) Patients age ≥ 45 years at high risk of atherothrombotic events Low dose ASA 75162 mg/day R Double-blind treatment up to 1040 primary efficacy events* (n=15603) Low dose ASA 75162 mg/day Placebo 1 tablet/day (n=7801) Final visit (Fixed study end date) Visits every 6 months 1-month visit 3-month visit * MI (fatal or non-fatal), stroke (fatal or non-fatal), or cardiovascular death; event-driven trial Bhatt DL et al. Am Heart J 2004; 148: 263–268.

10. Inclusion Criteria • Patients aged ≥45 years • with • at least one of the following: • 1A) Documented coronary disease • and/or • 1B) Documented cerebrovascular disease • and/or • 1C) Documented symptomatic PAD • and/or • 2) Two majororone major and two minoror three minor risk factors • With written informed consent • Without exclusion criteria Bhatt DL et al. Am Heart J 2004; 148: 263–268.

11. Exclusion Criteria • Requirement for clopidogrel such as: • recent acute coronary syndrome without ST-segment elevation • investigator’s assessment clopidogrel required long-term • Need for chronic therapy with high dose (> 162 mg/day) ASA or non-steroidal anti-inflammatory drug (except COX-2 inhibitors) • Current use of other oral anti-thrombotic medications with intention for long term treatment (e.g. OAC) • Planned revascularization procedure (OK after the procedure if no open-label clopidogrel is needed) Bhatt DL et al. Am Heart J 2004; 148: 263–268.

12. Primary Study Endpoints Primary efficacy endpoint: • The first occurrence of any component of the following cluster: – MI (Fatal or Non-fatal) – Stroke (Fatal or Non-fatal stroke from any cause) – Cardiovascular death (including hemorrhagic death)  Primary safety endpoint: • Severe bleeding (GUSTO definition1), including fatal bleeding or intracranial hemorrhage (ICH) Bhatt DL et al. Am Heart J 2004; 148: 263–268. 1GUSTO Investigators. N Engl J Med 1993; 329: 673–682.

13. Other Study Endpoints Principal Secondary Efficacy Endpoint: • First occurrence of MI (fatal or non-fatal), stroke (fatal or non-fatal), cardiovascular death, or hospitalization for UA, TIA or revascularization Other Efficacy Endpoints: • Individual components of the primary and secondary endpoints Other Safety Endpoints: • Fatal bleeding • Primary intracranial hemorrhage • Moderate bleeding (GUSTO definition) 1 Bhatt DL et al. Am Heart J 2004; 148: 263–268. 1GUSTO Investigators. N Engl J Med 1993; 329: 673–682.

14. Overall Population: Baseline Characteristics Clopidogrel + ASA Placebo + ASA Characteristic (n=7802) (n=7801) Age Median (range)* 64.0 (39-95) 64.0 (4593) Female 29.7 29.8 Ethnicity Caucasian 80.4 79.9 Hispanic 9.9 10.7 Asian 5.0 5.0 Black 3.2 3.0 Other 1.5 1.4 Inclusion group Documented cardiovascular disease 77.7 78.1 Multiple risk factors 21.3 20.8 Neither criterion 1.0 1.1 Smoking Status Current 20.1 20.3 Former 48.8 48.7 *Data for age are in years, all other data expressed as percent Bhatt DL, Fox KA, Hacke W, et al. NEJM 2006.

15. Overall Population: Concomitant Medications* Clopidogrel + ASA (%) Placebo + ASA (%) Medication (n=7802) (n=7801) ASA 99.7 99.7 Open-label clopidogrel 9.9 10.4 Diuretics 48.2 47.1 Nitrates 23.2 24.1 Calcium antagonists 36.7 36.9 Beta blockers 55.0 55.7 Angiotensin II receptor blockers 25.5 25.9 ACE inhibitors 60.1 60.7 Other antihypertensives 12.4 12.4 Statins 76.8 76.9 Antidiabetic medications 41.8 41.5 *Maximal frequency of usage of each agent at any time during the trial (assessed after baseline and at every follow-up visit) Bhatt DL, Fox KA, Hacke W, et al. NEJM 2006.

16. Placebo + ASA* 7.3% 8 Clopidogrel + ASA* 6.8% 6 Cumulative event rate (%) 4 RRR: 7.1% [95% CI: -4.5%, 17.5%] p=0.22 2 0 0 6 12 18 24 30 Months since randomization Overall Population: Primary Efficacy Outcome (MI, Stroke, or CV Death)† † First Occurrence of MI (fatal or non-fatal), stroke (fatal or non-fatal), or cardiovascular death *All patients received ASA 75-162 mg/day §The number of patients followed beyond 30 months decreases rapidly to zero and there are only 21 primary efficacy events that occurred beyond this time (13 clopidogrel and 8 placebo) Bhatt DL, Fox KA, Hacke W, et al. NEJM 2006.

17. 20 15 Cumulative event rate (%) 10 5 0 0 6 12 18 24 30 Months since randomization§ Overall Population: Principal Secondary Efficacy Outcome (MI/Stroke/CV Death/Hospitalization)† Placebo + ASA* 17.9% Clopidogrel + ASA* 16.7% RRR: 7.7% [95% CI: 0.5%, 14.4%] p = 0.04 †First Occurrence of MI, Stroke, CV Death, or Hospitalization for UA, TIA, or Revascularization *All patients received ASA 75-162 mg/day §The number of patients followed beyond 30 months decreases rapidly to zero and there are only 38 secondary efficacy events that occurred beyond this time (23 clopidogrel and 15 placebo) Bhatt DL, Fox KA, Hacke W, et al. NEJM 2006.

18. Overall Population: Primary and Secondary Efficacy Results (MI/Stroke/CV Death/ Hospitalization)† Clopidogrel Placebo + ASA + ASA Endpoint* - N (%) (n=7802) (n=7801)RR (95% CI)pvalue Primary Efficacy Endpoint 534 (6.8) 573 (7.3) 0.93 (0.83,1.05) 0.22 All Cause Mortality 371 (4.8) 374 (4.8) 0.99 (0.86, 1.14) 0.90 Cardiovascular Mortality∆ 238 (3.1) 229 (2.9) 1.04 (0.87, 1.25) 0.68 Myocardial Infarction (nonfatal)∆ 146 (1.9) 155 (2.0) 0.94 (0.75, 1.18) 0.59 Ischemic Stroke (nonfatal) 132 (1.7) 163 (2.1) 0.81 (0.64, 1.02) 0.07 Stroke (nonfatal)∆ 150 (1.9) 189 (2.4) 0.79 (0.64, 0.98) 0.03 Principal Secondary Endpoint† 1301 (16.7) 1395 (17.9) 0.92 (0.86, 0.995) 0.04 Hospitalization‡ 866 (11.1) 957 (12.3) 0.90 (0.82, 0.98) 0.02 †First occurrence of MI (fatal or not), stroke (fatal or not), cardiovascular death (including hemorrhagic death), or hospitalization for UA, TIA, or revascularization *Intention to treat analysis ∆Components of the primary efficacy endpoint. Patients that did not die from CV causes, are counted for the first non-fatal event of MI or stroke. ‡For UA, TIA, or revascularization Bhatt DL, Fox KA, Hacke W, et al. NEJM 2006.

19. Overall Population: Safety Results Clopidogrel Placebo + ASA + ASA Safety Outcome* - N (%) (n=7802) (n=7801) RR (95% CI) p value GUSTO Severe Bleeding 130 (1.7) 104 (1.3) 1.25 (0.97, 1.61) 0.09 Fatal Bleeding 26 (0.3) 17 (0.2) 1.53 (0.83, 2.82) 0.17 Primary ICH 26 (0.3) 27 (0.3) 0.96 (0.56, 1.65) 0.89 GUSTO Moderate Bleeding 164 (2.1) 101 (1.3) 1.62 (1.27, 2.08) <0.001 *Adjudicated outcomes by intention to treat analysis ICH= Intracranial Hemorrhage Bhatt DL, Fox KA, Hacke W, et al. NEJM 2006.

20. Primary Efficacy Results (MI/Stroke/CV Death) by Pre-Specified Entry Category Population RR (95% CI) p value Qualifying CAD, CVD or PAD * 0.88 (0.77, 0.998) 0.046 (n=12,153) Multiple Risk Factors * 1.20 (0.91, 1.59) 0.20 (n=3,284) Overall Population† 0.93 (0.83, 1.05) 0.22 (n=15,603) 1.2 1.4 1.6 0.4 0.6 0.8 Clopidogrel + ASA Better Placebo + ASA Better * A statistical test for interaction showed marginally significant heterogeneity (p=0.045) in treatment response for these pre-specified subgroups of patients † 166 patients did not meet any of the main inclusion criteria but were followed (intent-to-treat analysis) Bhatt DL, Fox KA, Hacke W, et al. NEJM 2006

21. 1.2 1.4 1.6 0.4 0.6 0.8 Clopidogrel + ASA Better Placebo + ASA Better Primary Efficacy Results (MI/Stroke/CV Death) by Category of Inclusion Criteria Population N RR (95% CI) p value Qualifying CV Disease 12,153 0.88 (0.77, 0.998) 0.046 Coronary 5,835 0.86 (0.71, 1.05) 0.13 Cerebrovascular 4,320 0.84 (0.69, 1.03) 0.09 PAD 2,838 0.87 (0.67, 1.13) 0.29 Multiple Risk Factors 3,284 1.20 (0.91, 1.59) 0.20 Overall Population 15,603 0.93 (0.83, 1.05) 0.22 Bhatt DL. Presented at ACC 2006.

22. Multiple Risk Factor Population: Primary and Secondary Efficacy Results(MI/Stroke/CV Death/ Hospitalization)† Clopidogrel Placebo + ASA + ASA Endpoint* – N (%) (n=1659) (n=1625)RR (95% CI)pvalue Primary Efficacy Endpoint 109 (6.6) 89 (5.5) 1.20 (0.91, 1.59) 0.20 All Cause Mortality 89 (5.4) 62 (3.8) 1.41 (1.02, 1.95) 0.04 Cardiovascular Mortality∆ 64 (3.9) 36 (2.2) 1.74 (1.16, 2.62) 0.01 Myocardial Infarction (nonfatal)∆ 25 (1.5) 26 (1.6) 0.95 (0.55, 1.64) 0.84 Ischemic Stroke (nonfatal) 16 (1.0) 23 (1.4) 0.68 (0.36, 1.29) 0.24 Stroke (nonfatal)∆ 20 (1.2) 27 (1.7) 0.73 (0.41, 1.29) 0.27 Principal Secondary Endpoint† 224 (13.5) 216 (13.3) 1.01 (0.84, 1.22) 0.88 Hospitalization‡ 140 (8.4) 147 (9.0) 0.93 (0.74, 1.18) 0.55 †First occurrence of MI (fatal or not), stroke (fatal or not), cardiovascular death (including hemorrhagic death), or hospitalization for UA, TIA, or revascularization *Intention to treat analysis ∆Components of the primary efficacy endpoint. Patients that did not die from CV causes, are counted for the first non-fatal event of MI or stroke. ‡For UA, TIA, or revascularization Bhatt DL, Fox KA, Hacke W, et al. NEJM 2006.

23. Multiple Risk Factor Population: Safety Results Clopidogrel Placebo + ASA + ASA Safety Outcome* - N (%) (n=1659) (n=1625) RR (95% CI) p value GUSTO Severe Bleeding 34 (2.0) 20 (1.2) 1.67 (0.96, 2.88) 0.07 Fatal 7 (0.4) 4 (0. 2)1.71 (0.50, 5.84) 0.38 Primary ICH 7 (0.4) 6(0.4) 1.14 (0.38, 3.39) 0.81 GUSTO Moderate Bleeding 36 (2.2) 22 (1.4) 1.60 (0.95, 2.71) 0.08 *Adjudicated outcomes by Intention to treat analysis Bhatt DL, Fox KA, Hacke W, et al. NEJM 2006.

24. Patients with Qualifying CV Disease (CAD, CVD, PAD): Safety Results Clopidogrel Placebo + ASA + ASA Safety Outcome* - N (%) (n=6062) (n=6091) RR (95% CI) p value GUSTO Severe Bleeding 95 (1.6) 84 (1.4) 1.14 (0.85, 1.52) 0.39 Fatal 19 (0.3) 13 (0.2) 1.47 (0.73, 2.97) 0.28 Primary ICH 19 (0.3) 21 (0.3) 0.91 (0.49, 1.69) 0.76 GUSTO Moderate Bleeding 128 (2.1) 79 (1.3) 1.63 (1.23, 2.15) <0.001 *Adjudicated outcomes by intention to treat analysis Bhatt DL, Fox KA, Hacke W, et al. NEJM 2006.

25. Conclusions • 7.1% RRR for the primary endpoint (first occurrence of MI/Stroke/CV Death) in the overall population did not reach statistical significance • 7.7% RRR for the secondary endpoint which included hospitalizations was statistically significant • The overall outcome was influenced by divergent findings in the two main sub-groups enrolled in the trial

26. Conclusions • In patients with multiple risk factors, without clearly documented CV disease, dual antiplatelet therapy was not beneficial - excess in CV mortality as well as an increase in bleeding • In patients with documented CV disease (CAD, CVD, or PAD) long-term clopidogrel plus ASA resulted in a significant 12.5% RRR in MI/Stroke/CV Death with no significant increase in severe bleeding compared to ASA alone

27. THANK YOU!!!To all the CHARISMA Investigators and CHARISMA Patients

28. Backup Slides

29. Clinical Implications • In acute setting, prior studies have shown the benefit of dual antiplatelet therapy for 1 year post ACS or PCI • For stable patients, CHARISMA suggests differential long-term effects of dual antiplatelet therapy by patient type: • NOT Recommended for Primary Prevention • Benefit in Secondary Prevention (CAD, CVD, or PAD) • CV death/MI/stroke - 9 events prevented per 1000 patients treated • Balanced by 2 severe GUSTO bleeds per 1000 patients treated • These data and future trials will help physicians decide which non-acute/stable patients should receive long-term dual antiplatelet therapy

30. 10 Placebo + ASA 8.8% Clopidogrel + ASA 7.3% 8 6 Primary outcome event rate (%) 4 RRR: 17.1 % [95% CI: 4.4%, 28.1%] p=0.01 2 0 0 6 12 18 24 30 Months since randomization Primary Endpoint (MI/Stroke/CV Death) in Patients with Previous MI, IS, or PAD*“CAPRIE-like Cohort” N=9,478 * Post hoc analysis Bhatt DL. Presented at ACC 2006.