Hypothesis: baseline risk status of the patients and proximity to a recent cardiovascular event influence the response to dual anti-platelet therapy. Patients with symptomatic CAD, CVD or PAD and all those with a history of CV events were included in this analysis (n=13,434).

How do we interpret the data? Patients with documented vascular events, irrespective of inclusion group Does baseline risk influence the treatment effect?

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

Death/MI/stroke % Quartile 1 Quartile 2 Quartile 3 Quartile 4 Clopidogrel +Aspirin Placebo+Aspirin Hazard Ratio p value Cardiovascular outcomes according to quartiles of baseline CV risk. Q4: severe bleeds: 3.1% C vs 3.2% P and ICH 1.0%C vs 1.0%P moderate bleeds 4.2%C vs 2.6% P, (p=0.02).

How do we interpret the data? Patients with documented vascular events, irrespective of inclusion group Does baseline risk influence the treatment effect? The impact of proximity to a CV event

Documented CV Disease Patients: Primary Outcome (MI/Stroke/CV Death) Cerebrovascular (n=4320) Placebo +ASA (9.6%) RRR: 16.0% p=0.088 Clopidogrel + ASA (8.1%) Months since randomization Cardiovascular (n=5835) Clopidogrel + ASA (6.5%) Placebo + ASA (7.4%) Primary outcome event rate (%) Months since randomization RRR: 13.9% p= PAD (n=2838) Placebo + ASA (8.7%) Clopidogrel + ASA (7.6%) RRR: 13.1% p= Months since randomization Bhatt DL, Fox KA, Hacke W, et al. N Engl J Med. 2006: 354; 1-12 Median time from qualifying event to randomization: 23.3 months3.5 months23 months

Enrolled within 6/12 of event Death/MI/StrokeDeath (all)CV deathMIStroke percent Placebo Clopidogrel p= p= 0.06

Proximity to a recent CV event (MI/stroke) was associated with significant benefit with clopidogrel. For those randomized within 6 months of MI or stroke, the frequency further MI/stroke or death was 8.2% C vs 10.8% P (HR 0.76, 95%CI , p=0.034). In those patients who had a documented prior vascular event or with confirmed PAD (n=9478) the risk of death/MI/stroke was 7.3%C vs 8.8%P (HR 0.83, 95% CI , p=0.01).

How do we interpret the data? Primary outcome by categories of included patients Patients with included with documented MI or ischemic stroke

Event rate over time for primary outcome in CAD patients with inclusion MI vs coronary inclusion criteria other than MI RRR [95%CI]: 22.6 % [2.2, 38.7] p = RRR [95%CI]: % [-58.0, 23.0] p = CAD patients with qualifying MI (N=3846) CAD patients without qualifying MI (N=1989)

Event rate over time for primary outcome in CVD patients with qualifying IS vs qualifying TIA RRR [95%CI]: 22.0 % [2.4, 37.6] p = RRR [95%CI]: % [-74.4, 24.6] p = CVD patients with qualifying IS (N=3245) CVD patients with qualifying TIA (N=1233)

Balance between efficacy and safety outcomes in MI / IS / PAD patients Efficacy OutcomeNo. (%) with event Absolute number of efficacy events prevented by clopidogrel Clopidogrel (N=4735) Placebo (N=4743) MI / Stroke / CV death347 (7.33) 416 (8.77) 69 Safety OutcomeNo. (%) with event Absolute number of bleeding events induced by clopidogrel Clopidogrel (N= 4735) Placebo (N= 4743) Severe / moderate GUSTO bleeding 172 (3.63) 126 (2.66) 46 All events prevented 107 ( includes TIA, UA, revascularization)

Conclusions: For the overall population the trend for benefit (7% RR) was non-significant Commencing therapy with clopidogrel within 6 months of a stroke or MI suggests evidence of benefit on rates of future death/MI/stroke. Higher risk groups, including those with clear evidence of vascular disease and recent vascular events, suggests the potential for greater benefit