1. ESPS-2: European Stroke Prevention Study s Multicentre, randomized, double-blind, placebo-controlled trial s 6,602 patients randomized within 3 months of qualifying event (TIA or stroke) s Treatment and follow-up time: 2 years –Visits at 1 month and 3 months, then at 3-month intervals Diener et al. J Neurol Sci 1997;151:S1-S77 Diener et al. J Neurol Sci 1996;143:1-13

2. Placebo(n=1,649) ESPS-2: Treatment Arms n=6,602 ER DP 200 mg bid (n=1,654) ASA 25 mg bid (n=1,649) ASA/ER DP 25 mg ASA/ 200 mg ER DP bid(n=1,650)

3. Aggrenox ® Capsule ASA Dipyridamole HP cellulose protective coating: water soluble polymers Tartaric acid: dipyridamole solubiliser Dipyridamole Extended Release Pellets Sustained release coating: water insoluble polymers

4. Mechanisms of Action of Aggrenox ® Inhibition of platelet activation and aggregation Dipyridamole IncreasesplasmaadenosineInhibitsplateletphosphodiesterase ASA Irreversibly inhibits cyclooxygenase and thromboxane A 2

5. ESPS-2 Results: Stroke Rates at 24 Months PlaceboASAER DPASA/ER DP 0 4 8 12 16 15.2% 12.5%* 12.8%* 9.5%* Incidence (%) *p<0.001 vs. placebo

6. ER DP ASA/ER DP ASA Placebo Patients without stroke (%) Time (months) 80 85 90 95 100 6121824 ESPS-2 Results: Stroke-Free Survival Kaplan-Meier stroke-free survival curves

7. Number of events % ESPS-2: Secondary Endpoint Vascular Events* (MI, Stroke, Vascular Death After Two Years) ER DP = Extended release dipyridamole ASA = Acetylsalicylic acid * Antiplatelet Trialists’ Collaboration (APT) definition ER DP + ASA ER DP ASA Placebo 246 / 1650 324 / 1654 314 / 1649 361 / 1649 14.9 19.6 19.0 21.9 vascular events / N Diener et al. J Neurol Sci 1997;151:S1-S77

8. ASA/ER DP vs. ASA 0 RRR (%) ASA/ ER DP vs. Placebo 37.0%* ER DP vs. Placebo 16.3% † ASA vs. Placebo 18.1% † 23.1%** ESPS-2: Effects on Stroke – RRR (Pairwise Comparisons) ER DP = Extended release dipyridamole ASA = Acetylsalicylic acid RRR = Relative Risk Reduction * p<0.001, **p<0.006, † p<0.05 10 20 30 40 Diener et al. J Neurol Sci 1997;151:S1-S77 Diener et al. J Neurol Sci 1996;143:1-13

9. ESPS-2: Effects on Stroke – Events Prevented (Pairwise Comparisons) ER DP = Extended release dipyridamole ASA = Acetylsalicylic acid NNT = Number Needed to Treat ER DP + ASA vs. Placebo ER DP vs. Placebo ASA vs. Placebo ER DP + ASA vs. ASA 58‰ 26‰ 29‰ 30‰ 18 39 35 34 Events prevented NNT Diener et al. J Neurol Sci 1997;151:S1-S77

10. Antiplatelet Agents vs. ASA: Prevention of Combined Endpoint* (Indirect Comparison Across Studies) † Statistically significant CI = confidence interval * TASS, CAPRIE & ESPS-2: stroke, MI, vascular death RRR (%) p=0.20 p=0.26 p=0.003 † CAPRIE -6–19 TASS -12–30 ESPS-2 7–36 0 5 10 15 20 25 7.3% 9% 22% Adapted from Albers et al. Chest 1998;114:683S-698S Albers, personal communication Clopidogrel CAPRIE: n=6,431 Ticlopidine TASS: n=3,069 ASA/ER DP ESPS-2: n=3,299 95% CI:

11. Number Needed to Treat (NNT) To prevent one stroke in Antiplatelet therapy a. ESPS-2 (ER DP + ASA vs. ASA) b. CAPRIE (Clopidogrel vs. ASA) (patients with inclusion criterion stroke) Antihypertensive therapy vs. placebo in the elderly (MRC) Lipid-lowering therapy Simvastatin vs. placebo (4S) 2 years 1.91 years 5 years NNT 34 143 70 101 ER DP = Extended release dipyridamole ASA = Acetylsalicylic acid Intervention

12. ESPS-2: Adverse Events * Significantly associated with treatment according to factorial analysis HeadacheGI EventsDizzinessBleeding events 0 20 40 60 80 100 Placebo ASA ER DP ASA/ER DP Patients reporting (%) * * * * * *

13. ESPS-2: Safety Severe or Fatal Bleeding ASA 20 (1.2%) ER DP 6 (0.4%) ER DP + ASA 27 (1.6%) Placebo 7 (0.4%) no significant difference ER DP = Extended release dipyridamole ASA = Acetylsalicylic acid Diener et al. J Neurol Sci 1997;151:S1-S77

14. s Use caution in patients with severe coronary artery disease (e.g. unstable angina or recently sustained myocardial infarction) as DP may aggravate chest pain s The dose of ASA in Aggrenox ® has not been proven to provide adequate treatment for recurrent MI or angina pectoris s Avoid use in children or teenagers with viral infections s Avoid use in patients with severe renal failure and in patients with severe hepatic insufficiency s Use caution in patients with inherited or acquired bleeding disorders s Patients should be alerted to signs and symptoms of GI side effects due to ASA component Aggrenox ® Precautions

15. s Treatment with low-dose ASA or ER DP alone is effective in preventing secondary stroke (factorial analysis RRR 18.1% (p=0.013) and 16.3% (p=0.039), respectively; statistically significant) s Combined treatment with ER DP + ASA reduces the risk of stroke by 37% vs. placebo (p<0.001) s Combined treatment with ER DP + ASA is significantly superior to ASA alone (RRR 23.1%, p<0.006) s ER DP and ASA have an additive effect in secondary prevention of stroke s The addition of ER DP to ASA does not increase the risk of bleeding ESPS-2: Conclusions Diener et al. J Neurol Sci 1997;151:S1-S77 Diener et al. J Neurol Sci 1996;143:1-13

16. If you take 1000 patients and follow them for 2 years... with ASA, you prevent 29 strokes with clopidogrel, you prevent 39 strokes with Aggrenox you prevent 58 strokes