1. Aggrenox Is it as good as the ads?

2. 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

3. 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)

4. 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

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

6. 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

7. 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

8. 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

9. 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

10. 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

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. 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 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

14. 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

15. Conclusions Risk factor modification in asymptomatic patients (all of the usual culprits and sins) additionally, tailor treatment to the cause of symptomatic patients –endarterectomy –warfarin –antiplatelet drugs