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.

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

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

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.

National Coordinators 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 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 Bhatt DL, Fox K, Hacke W, et al. Am Heart J 2005; 150: 401.

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.

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– 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

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

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

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 major or one major and two minor or three minor risk factors With written informed consent Without exclusion criteria Inclusion Criteria Bhatt DL et al. Am Heart J 2004; 148: 263–268.

Inclusion Criteria: Patients with Documented CV Disease One or more of the following primary criteria must be satisfied: –Documented cerebrovascular disease:  Previous TIA within the past 5 years  Previous ischemic stroke within the past 5 years –Documented coronary disease:  Stable angina with documented multivessel coronary disease  History of multivessel percutaneous coronary intervention (PCI)  History of multivessel CABG  Previous MI  Documented symptomatic PAD  Current intermittent claudication with an ABI ≤0.85  A history of intermittent claudication together with a previous related intervention (amputation, peripheral bypass, angioplasty, etc.) Bhatt DL et al. Am Heart J 2004; 148: 263–268.

Inclusion Criteria: Patients with Multiple Risk Factors Minor risk factors SBP  150 mm Hg (despite therapy) Primary hypercholesterolemia Currently smoking (>15 cigarettes per day) Male aged  65 years or female aged  70 years Major risk factors Type 1 or 2 diabetes (treated with medications) Diabetic nephropathy ABI <0.9 Asymptomatic carotid stenosis  70% Presence of at least one carotid plaque Bhatt DL et al. Am Heart J 2004; 148: 263–268. For the risk factor only population, two major or one major and two minor or three minor atherothrombotic risk factors must be present ABI= Ankle Brachial Index

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.

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 definition 1 ), including fatal bleeding or intracranial hemorrhage (ICH) Bhatt DL et al. Am Heart J 2004; 148: 263– GUSTO Investigators. N Engl J Med 1993; 329: 673–682.

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– GUSTO Investigators. N Engl J Med 1993; 329: 673–682.

Bleeding Definitions: GUSTO Criteria Severe bleeding: Fatal bleeding Primary or post-traumatic intracranial hemorrhage Substantial hemodynamic compromise requiring treatment to sustain cardiac output Moderate: Bleeding that required transfusion, but did not result in hemodynamic compromise or meet definition for GUSTO severe bleeding Minor bleeding: Other bleeding, not requiring transfusion or causing hemodynamic compromise GUSTO Investigators. N Engl J Med 1993; 329: 673–682.

Overall Population: Baseline Characteristics Clopidogrel + ASAPlacebo + ASA Characteristic (n=7802)(n=7801) Age Median (range)* 64.0 (39-95) 64.0 (45  93) Female Ethnicity Caucasian Hispanic Asian Black Other Inclusion group Documented cardiovascular disease Multiple risk factors Neither criterion Smoking Status Current Former *Data for age are in years, all other data expressed as percent Bhatt DL, Fox KA, Hacke W, et al. NEJM 2006.

Overall Population: Concomitant Medications* Clopidogrel + ASA (%) Placebo + ASA (%) Medication(n=7802)(n=7801) ASA Open-label clopidogrel Diuretics Nitrates Calcium antagonists Beta blockers Angiotensin II receptor blockers ACE inhibitors Other antihypertensives Statins Antidiabetic medications *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.

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 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 Cumulative event rate (%) Months since randomization Placebo + ASA* 7.3% Clopidogrel + ASA* 6.8% RRR: 7.1% [95% CI: -4.5%, 17.5%] p=0.22

Overall Population: Principal Secondary Efficacy Outcome (MI/Stroke/CV Death/Hospitalization) † † First Occurrence of MI, Stroke, CV Death, or Hospitalization for UA, TIA, or Revascularization *All patients received ASA 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) Placebo + ASA * 17.9% Clopidogrel + ASA * 16.7% RRR: 7.7% [95% CI: 0.5%, 14.4%] p = 0.04 Cumulative event rate (%) Months since randomization § Bhatt DL, Fox KA, Hacke W, et al. NEJM 2006.

Overall Population: Primary and Secondary Efficacy Results (MI/Stroke/CV Death/ Hospitalization) † ClopidogrelPlacebo+ ASA Endpoint* - N (%) (n=7802) (n=7801) RR (95% CI) p value Primary Efficacy Endpoint534 (6.8)573 (7.3)0.93 (0.83,1.05)0.22 All Cause Mortality371 (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.

Overall Population: Safety Results Clopidogrel Placebo + ASA+ ASA Safety Outcome* - N (%) (n=7802) (n=7801) RR (95% CI)p value GUSTO Severe Bleeding130 (1.7)104 (1.3)1.25 (0.97, 1.61)0.09 Fatal Bleeding26 (0.3)17 (0.2)1.53 (0.83, 2.82)0.17 Primary ICH26 (0.3)27 (0.3)0.96 (0.56, 1.65)0.89 GUSTO Moderate Bleeding164 (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.

PopulationRR (95% CI) p value Qualifying CAD, CVD or PAD * 0.88 (0.77, 0.998) (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) Primary Efficacy Results (MI/Stroke/CV Death) by Pre-Specified Entry Category 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

PopulationNRR (95% CI)p value Qualifying CV Disease12, (0.77, 0.998)0.046 Coronary5, (0.71, 1.05)0.13 Cerebrovascular4, (0.69, 1.03)0.09 PAD2, (0.67, 1.13)0.29 Multiple Risk Factors3, (0.91, 1.59)0.20 Overall Population15, (0.83, 1.05)0.22 Primary Efficacy Results (MI/Stroke/CV Death) by Category of Inclusion Criteria Clopidogrel + ASA Better Placebo + ASA Better Bhatt DL. Presented at ACC 2006.

Patients with Qualifying CV Disease (CAD, CVD, PAD): Primary and Secondary Efficacy Results (MI/Stroke/CV Death/ Hospitalization) † ClopidogrelPlacebo+ ASA Endpoint* - N (%) (n=7802) (n=7801) RR (95% CI) p value Primary Efficacy Endpoint 420 (6.9)480 (7.9)0.88 (0.77, 0.998)0.046 All Cause Mortality 278 (4.6)306 (5.0)0.91 (0.78, 1.07)0.27 Cardiovascular Mortality ∆ 172 (2.8)191 (3.1)0.90 (0.74, 1.11)0.34 Myocardial Infarction (nonfatal) ∆ 120 (2.0)127 (2.1)0.95 (0.74, 1.22)0.67 Ischemic Stroke (nonfatal) 114 (1.9)140 (2.3)0.82 (0.64, 1.05)0.11 Stroke (nonfatal) ∆ 128 (2.1)162 (2.7)0.79 (0.63, 0.999)0.048 Principal Secondary Endpoint † 1066 (17.6)1169 (19.2)0.91 (0.83, 0.98)0.02 Hospitalization ‡ 720 (11.9)803 (13.2)0.89 (0.81, 0.99)0.03 †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.

Patients with Qualifying CV Disease (CAD, CVD or PAD): Primary Efficacy Outcome (MI/Stroke/CV Death) *All patients received ASA mg/day Clopidogrel +ASA* 6.9% Placebo + ASA* 7.9% RRR: 12.5% [95% CI: 0.2%, 23.2%] p=0.046 Bhatt DL. Presented at ACC N=12,153 Primary outcome event rate (%) Months since randomization

Patients with Qualifying CV Disease (CAD, CVD, PAD): Principal Secondary Efficacy Outcome Bhatt DL. Presented at ACC Months from Randomization Cumulative Event Rate, (%) Placebo + ASA * 19.2% Clopidogrel + ASA * 17.6% RRR: 9.5% [95% CI: 1.7%, 16.7%] P= *All patients received ASA mg/day N=12,153

Multiple Risk Factor Population: Primary and Secondary Efficacy Results (MI/Stroke/CV Death/ Hospitalization) † ClopidogrelPlacebo + ASA+ ASA Endpoint* – N (%) (n=1659) (n=1625) RR (95% CI) p value Primary Efficacy Endpoint109 (6.6)89 (5.5)1.20 (0.91, 1.59)0.20 All Cause Mortality89 (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.

Multiple Risk Factor Subgroup: Primary Efficacy Outcome (MI/Stroke/CV Death) Placebo + ASA* 5.5% Clopidogrel + ASA* 6.6% RRR: -20% [95% CI: -58.8%, 9.3%] p=0.20 *All patients received ASA mg/day Bhatt DL. Presented at ACC Primary outcome event rate (%) Months since randomization

Months from Randomization Multiple Risk Factor Population: Principal Secondary Efficacy Endpoint Cumulative Event Rate, (%) Placebo + ASA* 13.3% Clopidogrel + ASA* 13.5% RRR: -1.4% [95% CI: -22.2%, 15.9%] P=0.88 Bhatt DL. Presented at ACC N= *All patients received ASA mg/day

Multiple Risk Factor Population: Safety Results ClopidogrelPlacebo+ ASA Safety Outcome* - N (%)(n=1659) (n=1625) RR (95% CI) p value GUSTO Severe Bleeding34 (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.

Patients with Qualifying CV Disease (CAD, CVD, PAD): Safety Results ClopidogrelPlacebo+ ASA Safety Outcome* - N (%)(n=6062) (n=6091) RR (95% CI) p value GUSTO Severe Bleeding95 (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.

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

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

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

Backup Slides

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

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 (%) Months since randomization Clopidogrel + ASA 7.3% Placebo + ASA 8.8% N=9,478 Bhatt DL. Presented at ACC * Post hoc analysis