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The Cleveland Clinic Foundation

C lopidogrel for H igh A therothrombotic R isk and I schemic S tabilization, M anagement and A voidance ( CHARISMA ). The Cleveland Clinic Foundation.

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The Cleveland Clinic Foundation

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  1. Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management and Avoidance(CHARISMA) The Cleveland Clinic Foundation 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

  2. CHARISMA: Rationale

  3. 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.

  4. CAPRIE: Clopidogrel Superior to ASA in Sub-Population with Prior CABG1, 2 RRR 36.3% p=0.004 10 RRR 8.7% 9.1% p=0.043 ASA 8 Clopidogrel 5.8% 6 5.8% 5.3% Event rate/year* (%) 4 2 0 All CAPRIE (n=19,185)1 Prior CABG (n=1480)2 *MI, ischemic stroke, vascular death 1. CAPRIE Steering Committee. Lancet 1996; 348: 1329–1339. 2. Bhatt DL et al. Circulation 2001; 103: 363368.

  5. 38† 21† p=0.106 9† p=0.042 25 21.5% ASA p=0.096 20 17.7% 17.7% Clopidogrel 15.6% 12.7% 15 11.8% Event rate*/year (%) 10 5 0 Patients without diabetes (n=15,233) Patients with diabetes (n=3866) Patients treated with insulin (n=1134) CAPRIE: Clopidogrel Provided Amplified Benefit in Patients with Diabetes1 *MI, stroke, vascular death or rehospitalization for ischemic events/bleeding †Number of events prevented per 1000 patients per year compared with ASA 1. Bhatt DL et al. Am J Cardiol 2002; 90: 625628.

  6. CAPRIE: Clopidogrel Provides Amplified Benefit in Patients with High Vascular Risk1 RRR 14.9% p=0.045 12 10.2% RRR 8.7% 8.8% 10 ASA p=0.043 Clopidogrel 8 5.8% Event rate/year* (%) 5.3% 6 4 2 0 All CAPRIE patients (n=19,099) Prior history of major acute event (MI or ischemic stroke) (n=4496) *MI, ischemic stroke or vascular death;mean duration of treatment was 1.6 years 1. Ringleb PA et al. Stroke 2004; 35: 528–532.

  7. CURE: Early and Long-Term Benefits of Clopidogrel in ACS Patients1 Placebo†(n=6303) 0.14 20% RRR p <0.001 0.12 0.10 Clopidogrel† (n=6259) 0.08 Cumulative hazard rate* 0.06 0.04 0.02 0 0 3 6 9 12 Months of follow-up *MI, stroke or cardiovascular death †On a background of standard therapy (including ASA) 1. The CURE Investigators.N Engl J Med 2001; 345: 494–502.

  8. CURE: Relationship Between Major Bleeding and ASA Dose in ACS Patients1 4.9% 5.0 3.7% 4.0 3.4% 3.0% 2.8% 3.0 Placebo* Incidence of major bleeding (%) Clopidogrel* 1.9% 2.0 1.0 0 ≤100 mg (n=5320) ≥200 mg (n=4110) 101–199 mg (n=3109) ASA dose (range 75–325 mg) *On a background of standard therapy (including ASA) 1. Peters RJG et al. Circulation 2003; 108: 16821687.

  9. CREDO: Long-Term (1 Year) Benefits of Clopidogrel in PCI Patients MI, stroke, or death – ITT population 15 Placebo* Clopidogrel* 11.5% 27% RRR P=0.02 10 8.5% Combined endpoint occurrence (%) 5 0 0 3 6 9 12 Months from randomization * Plus ASA and other standard therapies. Steinhubl S, Berger P, Tift Mann III J et al. JAMA. 2002;Vol 288,No 19:2411-2420.

  10. CHARISMA: Design

  11. Study Objectives1 Primary objective: • To assess whether clopidogrel 75 mg daily is superior to placebo in preventing the occurrence of major ischemic complications (stroke, MI, cardiovascular death) in high-risk patients aged ≥45 years, receiving a background of standard therapy including low-dose ASA Secondary objective: • To evaluate the safety of clopidogrel, in terms of the incidence of fatal or severe bleeding (GUSTO definition*) *The Global Use of Strategies To Open occluded coronary Arteries (GUSTO) definition for severe bleeding includes intracerebral bleeding or bleeding complications resulting in substantial hemodynamic compromise requiring treatment2 1. Bhatt DL et al. Am Heart J 2004; 148: 263–268. 2. GUSTO Investigators. N Engl J Med 1993; 329: 673–682.

  12. 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, Topol EJ, et al. Am Heart J 2004; 148: 263–268.

  13. Inclusion Criteria • Patients aged ≥45 years • with • at least one of the following: • 1) Documented coronary disease • and/or • 2) Documented cerebrovascular disease • and/or • 3) Documented symptomatic PAD • and/or • 4) Two majororone major and two minoror three minor risk factors • With written informed consent • Without exclusion criteria Bhatt DL, Topol EJ, et al. Am Heart J 2004; 148: 263–268.

  14. 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, Topol EJ, et al. Am Heart J 2004; 148: 263–268.

  15. Inclusion Criteria: Patients with Multiple Risk Factors Only • For the risk factor only population, two majororone major andtwo minororthree minor atherothrombotic risk factors must be present ABI= Ankle Brachial Index Bhatt DL, Topol EJ, et al. Am Heart J 2004; 148: 263–268.

  16. 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, Topol EJ, et al. Am Heart J 2004; 148: 263–268.

  17. 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, Topol EJ, et al. Am Heart J 2004; 148: 263–268. 1GUSTO Investigators. N Engl J Med 1993; 329: 673–682.

  18. 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, Topol EJ, et al. Am Heart J 2004; 148: 263–268. 1GUSTO Investigators. N Engl J Med 1993; 329: 673–682.

  19. 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.

  20. Time Since Qualifying Event1 1. Bhatt DL, Fox K, Hacke W, et al. Am Heart J 2005; 150: 401.

  21. CHARISMA: Results

  22. 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 10.0 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. 2006, in press.

  23. Overall Population: Prior Medical History Clopidogrel + ASA (%) Placebo + ASA (%) Characteristic (n=7802) (n=7801) Hypertension 73.3 73.9 Hypercholesterolemia 73.7 74.2 Congestive heart failure 6.0 5.9 Prior MI 34.2 34.9 Atrial fibrillation 3.8 3.7 Prior stroke 24.9 24.3 TIA 12.0 11.9 Diabetes 42.3 41.7 PAD 22.6 22.7 PCI 22.4 23.1 CABG 19.5 19.9 Carotid endarterectomy 5.4 5.2 Peripheral angioplasty or bypass 11.3 11.0 Diabetic nephropathy 12.9 12.9 Bhatt DL, Fox KA, Hacke W, et al. 2006, in press.

  24. 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. 2006, in press.

  25. 8 6 4 2 0 Overall Population: Primary Efficacy Outcome (MI, Stroke, or CV Death)† Placebo + ASA* 7.3% Clopidogrel + ASA* 6.8% Cumulative event rate (%) RRR: 7.1% [95% CI: -4.5%, 17.5%] P=0.22 0 6 12 18 24 30 Months since randomization§ † 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. 2006, in press.

  26. 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 *All patients received ASA 75-162mg/day †First Occurrence of MI, Stroke, CV Death, or Hospitalization for UA, TIA, or Revascularization §The number of patients followed beyond 30 months decreases rapidly to zero and there are only 38 primary efficacy events that occurred beyond this time (23 clopidogrel and 15 placebo) Bhatt DL, Fox KA, Hacke W, et al. 2006, in press.

  27. Overall Population: Secondary Efficacy Results Clopidogrel Placebo + ASA + ASA Endpoint* - N (%) (n=7802) (n=7801)RR (95% CI)pvalue Principle Secondary Endpoint† 1301 (16.7) 1395 (17.9) 0.92 (0.86, 0.995) 0.04 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 147 (1.9) 159 (2.0) 0.92 (0.74, 1.16) 0.48 Ischemic Stroke 132 (1.7) 160 (2.1) 0.82 (0.66, 1.04) 0.10 Stroke 149 (1.9) 185 (2.4) 0.80 (0.65, 0.997) 0.05 Hospitalization‡ 866 (11.1) 957 (12.3) 0.90 (0.82, 0.98) 0.02 *Intention to treat analysis †First occurrence of MI (fatal or not), stroke (fatal or not), cardiovascular death (including hemorrhagic death), or hospitalization for UA, TIA, or a revascularization procedure ‡For UA, TIA, or revascularization Bhatt DL, Fox KA, Hacke W, et al. 2006, in press.

  28. 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) 1.44 (0.79, 2.63) 0.23 Primary ICH 26 (0.3) 27 (0.4) 0.93 (0.54, 1.58) 0.78 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. 2006, in press.

  29. 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 Better Placebo Better * A statistical test for interaction showed marginally significant heterogeneity (p=0.045) in treatment response for these pre-specified subgroups of patients Adapted from Bhatt DL, Fox KA, Hacke W, et al. 2006, in press.

  30. Primary Efficacy Outcome (MI/Stroke/CV Death)by Category of Inclusion Qualifying CAD, CVD or PAD (N=12,153) Multiple Risk Factor (N=3,284) 10 RRR: -20% [95% CI: -58.8%, 9.3%] p=0.20 RRR: 12.5% [95% CI: 0.2%, 23.2%] p=0.046 10 Clopidogrel + ASA* 6.6% 8 8 Placebo + ASA* 7.9% 6 6 Primary outcome event rate (%) Primary outcome event rate (%) Clopidogrel +ASA* 6.9% 4 4 Placebo + ASA* 5.5% 2 2 0 0 0 6 12 18 24 30 0 6 12 18 24 30 Months since randomization Months since randomization *All patients received ASA 75-162 mg/day Bhatt DL. Presented at ACC 2006.

  31. Documented CV Disease Population: 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) 0.87 (0.47, 1.60) 0.65 GUSTO Moderate Bleeding 128 (2.1) 79 (1.3) 1.63 (1.23, 2.15) <0.001 *Adjudicated outcomes by intention to treat analysis Adapted from Bhatt DL, Fox KA, Hacke W, et al. 2006, in press.

  32. 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 Bhatt DL. Presented at ACC 2006.

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

  34. Conclusions • In patients with multiple risk factors only, without clearly established CV disease, dual antiplatelet 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

  35. 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 by patient type: • NOT Recommended for Primary Prevention • Benefit in Secondary Prevention (CAD, CVD, or PAD) • CV death/MI/stroke - 10 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

  36. THANK YOU!!!

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