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ESPS-2: European Stroke Prevention Study

Multicentre, randomized, double-blind, placebo-controlled trial 6,602 patients randomized within 3 months of qualifying event (TIA or stroke) Treatment and follow-up time: 2 years Visits at 1 month and 3 months, then at 3-month intervals. ESPS-2: European Stroke Prevention Study .

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ESPS-2: European Stroke Prevention Study

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

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

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

  4. Mechanisms of Actionof Aggrenox® Dipyridamole ASA Increases plasma adenosine Inhibits platelet phosphodiesterase Irreversibly inhibits cyclooxygenase and thromboxane A2 Inhibition of platelet activation and aggregation

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

  6. 100 95 ASA 90 85 80 6 12 18 24 ESPS-2 Results:Stroke-Free Survival ER DP ASA/ER DP Patients without stroke (%) Placebo Time (months) Kaplan-Meier stroke-free survival curves

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

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

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

  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) Intervention NNT 34 143 70 101 2 years 1.91 years 5 years 5 years ER DP = Extended release dipyridamole ASA = Acetylsalicylic acid

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

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

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

  15. ESPS-2: Conclusions • 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) • Combined treatment with ER DP + ASA reduces the risk of stroke by 37% vs. placebo (p<0.001) • Combined treatment with ER DP + ASA is significantly superior to ASA alone (RRR 23.1%, p<0.006) • ER DP and ASA have an additive effect in secondary prevention of stroke • The addition of ER DP to ASA does not increase the risk of bleeding Diener et al. J Neurol Sci 1997;151:S1-S77 Diener et al. J Neurol Sci 1996;143:1-13

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

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