1. VBWG CHARISMA Clopidogrel for High Atherothrombotic Risk and Ischemic Stabilization, Management, and Avoidance trial

2. VBWG CHARISMA: Background and hypothesis The combination of clopidogrel plus aspirin has been demonstrated to be superior to aspirin in the treatment of patients with ACS and after coronary stenting. When added to the current standard of care, does long-term treatment with clopidogrel plus aspirin provide greater vascular protection than aspirin alone in a broad population of high-risk patients? Bhatt DL et al. Am Heart J. 2004;148:263-8. Bhatt DL et al. N Engl J Med. 2006;354:1706-17.

3. VBWG *n = 166 not in either category, but included in overall analysis † Coronary, cerebral, or peripheral CHARISMA: Study design Clopidogrel 75 mg ASA 75-162 mg n = 7802 Placebo ASA 75-162 mg n = 7801 Symptomatic patients with coronary, cerebrovascular, or peripheral arterial disease* n = 12,153 Follow-up until 1040 primary events Primary end point: First occurrence of MI, stroke (any cause), CV death (including hemorrhagic) Principal secondary end point: First occurrence of MI, stroke, CV death, hospitalization for UA, TIA, revascularization † Randomized Double-blind Bhatt DL et al. Am Heart J. 2004;148:263-8. Bhatt DL et al. N Engl J Med. 2006;354:1706-17. Asymptomatic patients with multiple atherothrombotic risk factors* n = 3284 N = 15,603

4. VBWG CHARISMA: Baseline characteristics Clopidogrel + ASA (n = 7802) Placebo + ASA (n = 7801) Age (years) Median Range 64.0 39.0–95.0 64.0 45.0–93.0 Female sex (%)29.729.8 Race/ethnicity (%) White Hispanic Asian Black Other 80.4 9.9 5.0 3.2 1.5 79.9 10.7 5.0 3.0 1.4 Smoking status (%) Current Former 20.1 48.9 20.3 48.7 Bhatt DL et al. N Engl J Med. 2006;354:1706-17.

5. VBWG CHARISMA: Baseline characteristics, cont’d Clopidogrel + ASA (n = 7802) (%) Placebo + ASA (n = 7801) (%) Hypertension73.373.9 Hypercholesterolemia73.774.2 Diabetes42.341.7 Prior MI34.234.9 Prior stroke24.924.3 PAD22.622.7 PCI22.423.1 CABG19.519.9 Bhatt DL et al. N Engl J Med. 2006;354:1706-17.Other comorbidities each occurred in <15%

6. VBWG CHARISMA: Concomitant medications Clopidogrel + ASA (n = 7802) (%) Placebo + ASA (n = 7801) (%) Statins76.876.9 Other lipid-lowering agents14.314.0 ACEIs64.064.6 ARBs25.525.9 β-blockers55.055.7 Diuretics48.247.1 Calcium antagonists36.736.9 Nitrates23.224.1 Antidiabetics41.841.5 Bhatt DL et al. N Engl J Med. 2006;354:1706-17.

7. VBWG CHARISMA: Treatment effect on primary end point Bhatt DL et al. N Engl J Med. 2006;354:1706-17. Cumulative incidence of MI, stroke, CV death; N = 15,603 7% RRR RR 0.93 (0.83–1.05) P = 0.22 Months 10 8 6 4 2 0 0612182430 Placebo Clopidogrel Events (%)

8. VBWG CHARISMA: Treatment effect on principal secondary end point Bhatt DL et al. N Engl J Med. 2006;354:1706-17. Cumulative incidence of MI, stroke, CV death, hospitalization for UA, TIA, revascularization ; * N = 15,603 *Coronary, cerebral, or peripheral 20 15 10 5 0 0612182430 Months Placebo Clopidogrel 8% RRR RR 0.92 (0.86-0.995) P = 0.04 Events (%)

9. VBWG CHARISMA: Safety end points Event rate number of patients (%) Clopidogrel + ASA Placebo + ASAP Severe bleeding Fatal bleeding Intracranial hemorrhage 130 (1.7) 26 (0.3) 104 (1.3) 17 (0.2) 27 (0.3) 0.09 0.17 0.89 Moderate bleeding164 (2.1)101 (1.3)<0.001 Bhatt DL et al. N Engl J Med. 2006;354:1706-17. GUSTO criteria; N = 15,603 GUSTO = Global Utilization of Streptokinase and t-PA for Occluded Coronary Arteries

10. VBWG n = 3284 n = 12,153 N = 15,603 CHARISMA: Treatment effect by inclusion criteria MI, stroke, CV death *Multiple atherothrombotic risk factors † Documented coronary, cerebrovascular, or peripheral arterial disease 0.51.01.5 Placebo better Clopidogrel better Asymptomatic* Symptomatic † All patients Hazard ratioRR (95% CI) 1.20 (0.91–1.59) 0.88 (0.77–0.998) 0.93 (0.83–1.05) Bhatt DL et al. N Engl J Med. 2006;354:1706-17. P = 0.20 P = 0.046 P = 0.22

11. VBWG CHARISMA: Safety end points by inclusion criteria Event rate (%) Clopidogrel + ASA Placebo + ASAP Symptomatic Severe bleeding Moderate bleeding 1.6 2.1 1.4 1.3 0.39 <0.001 Asymptomatic Severe bleeding Moderate bleeding 2.0 2.2 1.2 1.4 0.07 0.08 Bhatt DL et al. N Engl J Med. 2006;354:1706-17. GUSTO criteria

12. VBWG CHARISMA: Summary Primary efficacy end point 7% decrease in MI, stroke, CV death (nonsignificant) Principal secondary efficacy end point 8% decrease in MI, stroke, CV death, hospitalization for UA, TIA, revascularization (significant) Primary safety end point Severe bleeding was not significantly increased but a trend was noted Bhatt DL et al. N Engl J Med. 2006;354:1706-17.

13. VBWG CHARISMA: Summary, cont’d Symptomatic patients experienced a 12% reduction in the primary end point (significant) with no significant increase in severe bleeding Asymptomatic patients experienced a 20% increase in the primary end point (nonsignificant) with no significant increase in severe bleeding Overall, clopidogrel plus aspirin was not significantly more effective than aspirin alone in reducing the primary end point Bhatt DL et al. N Engl J Med. 2006;354:1706-17.