1. Clinical Trial Efficacy Senior Biostatistician Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, Connecticut James Street, PhD

2. ESPS-2 The Second European Stroke Prevention Study Tested the safety and efficacy of ER-DP and ASA, alone and in combination, to prevent stroke and death in patients with prior TIA or ischemic stroke Tested the safety and efficacy of ER-DP and ASA, alone and in combination, to prevent stroke and death in patients with prior TIA or ischemic stroke Addressed four primary clinical questions Addressed four primary clinical questions –Does low-dose ASA prevent stroke or death? –Does ER-DP prevent stroke or death? –Are the effects of ER-DP and ASA additive when combined in AGGRENOX™? –Is AGGRENOX™ well tolerated?

3. ESPS-2 Study Design Multicenter, randomized, double-blind, placebo-controlled Multicenter, randomized, double-blind, placebo-controlled 2 x 2 factorial design 2 x 2 factorial design 6602 patients from 59 centers, centrally randomized within 3 months of qualifying event (TIA or stroke) 6602 patients from 59 centers, centrally randomized within 3 months of qualifying event (TIA or stroke) Treatment and follow-up time: 2 years (visits at 1 and 3 months, then at 3-month intervals) Treatment and follow-up time: 2 years (visits at 1 and 3 months, then at 3-month intervals)

4. 1 2 4 15 8 4 9 2 2 2 4 3 3 13 countries 13 countries 59 centers 59 centers 6602 patients ESPS-2 Geographical Distribution of Participating Centers

5. ESPS-2 Study Design Multicenter, randomized, double-blind, placebo-controlled Multicenter, randomized, double-blind, placebo-controlled 2 x 2 factorial design 2 x 2 factorial design 6602 patients from 59 centers, centrally randomized within 3 months of qualifying event (TIA or stroke) 6602 patients from 59 centers, centrally randomized within 3 months of qualifying event (TIA or stroke) Treatment and follow-up time: 2 years (visits at 1 and 3 months, then at 3-month intervals) Treatment and follow-up time: 2 years (visits at 1 and 3 months, then at 3-month intervals)

6. ESPS-2 Treatment Arms N = 6602 Placebo (n = 1649) ASA 25 mg bid (n = 1649) ER-DP 200 mg bid (n = 1654) AGGRENOX™ 25 mg ASA/ 200 mg ER-DP bid (n = 1650)

7. TIAStroke AGGRENOX™ AGGRENOX™24.4%75.5% DP DP 23.5%76.5% ASA ASA23.8%76.2% Placebo Placebo23.0%77.0% Overall23.7%76.3% Qualifying Events

8. Entry Criteria Men and women >18 years of age Men and women >18 years of age Ischemic stroke or TIA within three months prior to randomization Ischemic stroke or TIA within three months prior to randomization Neurological and general clinical condition stabilized before entry Neurological and general clinical condition stabilized before entry Exclusion criteria Exclusion criteria –No history of gastric bleeding or other bleeding disturbances –Active peptic ulcer –Known hypersensitivity to study medications –Any life-threatening condition

9. Sample Size and Interim Analysis Protocol-planned sample size = 5000 patients Protocol-planned sample size = 5000 patients One interim analysis planned in protocol One interim analysis planned in protocol –Consider early termination for efficacy –Re-estimate sample size –Blind to treatment Steering and Ethics Committees agreed to increase sample size to 7000 patients Steering and Ethics Committees agreed to increase sample size to 7000 patients

10. Primary Efficacy Endpoints MMAG*-confirmed endpoint stroke (fatal or non-fatal) MMAG*-confirmed endpoint stroke (fatal or non-fatal) Death (any cause) Death (any cause) MMAG blind to treatment * MMAG = Morbidity and Mortality Assessment Group.

11. Secondary Efficacy Endpoints Four secondary endpoints identified in protocol Four secondary endpoints identified in protocol –Transient Ischemic Attacks –Myocardial Infarction –Other Vascular Events (PE, DVT, PAO, RVA) –Ischemic Events (stroke, MI, sudden death) MMAG-reviewed secondary endpoints other than TIA MMAG-reviewed secondary endpoints other than TIA

12. Supportive Analyses of Primary Endpoints Numerous robustness tests Numerous robustness tests Exploratory subgroup analyses, including: Exploratory subgroup analyses, including: –Gender –Age –Type of qualifying event –History of TIA or stroke prior to qualifying event –History of MI –Hypertension –Atrial fibrillation –Geographic location...

13. Analysis Plans Primary analyses conducted per protocol Primary analyses conducted per protocol –Two-year follow-up –Intent-to-treat –Gehan-Wilcoxon survival analysis –Factorial analysis Secondary and robustness analysis plans confirmed at pre-NDA meeting Secondary and robustness analysis plans confirmed at pre-NDA meeting

14. Factorial Design Can detect drug effects with fewer patients Can detect drug effects with fewer patients Main effects of ER-DP and ASA Main effects of ER-DP and ASA –ER-DP groups vs No ER-DP groups –ASA groups vs No ASA groups Interaction of ER-DP with ASA Interaction of ER-DP with ASA –Compare ER-DP effects with/without ASA Design allows pairwise comparisons of any two treatment arms Design allows pairwise comparisons of any two treatment arms

15. Primary endpoint: Stroke Primary endpoint: Stroke –Primary analysis –Robustness analyses Secondary endpoints Secondary endpoints –TIA –OVE –Ischemic events –MI Primary endpoint: Death Primary endpoint: Death Composite endpoint: Non-Fatal Stroke or Death Composite endpoint: Non-Fatal Stroke or Death ESPS-2 Results

16. Treatment Cessation Total No.16501654164916496602 of Patients Completed62.261.968.266.064.6 Study Treated until57.355.862.059.458.6 month-24 Treated until5.06.0 6.26.5 5.9 death Ceased37.838.131.834.035.4 Treatment AGGRENOX TM ER-DPASAPlaceboOverall %%%

17. Stroke 0.75 0.8 0.85 0.9 0.9516121824 Kaplan-Meier Estimate of Survival Months of Follow-Up Aggrenox TM ER-DPASAPlacebo

18. STROKE Primary Factorial Analysis Relative RiskGehan-Wilcoxon Factorial EffectReduction %P-Value ER-DP18.9.001 ASA21.2<.001 Interaction–.850

19. STROKE Supportive Pairwise Comparison Relative RiskGehan-Wilcoxon ComparisonReduction %P-Value AGGRENOX TM vs ASA 22.1.008 AGGRENOX TM vs ER-DP 24.4.002 AGGRENOX TM vs Placebo 36.8<.001 ER-DP vs Placebo16.5.036 ASA vs Placebo18.9.009

20. STROKE Robustness Analyses AnalysisER-DPASAER-DPASAPlacebo Primary.001<.001.002.008<.001 Cox-Adjusted.001<.001.003.007<.001 Logrank.001<.001.003.010<.001 Stratified by Center.001<.001.002.006<.001 Investigator-diagnosed.001<.001.003.007<.001 First 5002.001<.001.002.001<.001 Worst-case.001<.001.003.013<.001 Main EffectsAggrenox TM versus

21. CONCLUSION Stroke Endpoint Low-dose (50 mg/d) ASA prevents stroke Low-dose (50 mg/d) ASA prevents stroke ER-DP prevents stroke to a comparable degree ER-DP prevents stroke to a comparable degree AGGRENOX™ exhibits additive benefits AGGRENOX™ exhibits additive benefits Results highly statistically significant and robust Results highly statistically significant and robust

22. SECONDARY ENDPOINTS Summary ER-DP vsASA vsAGGRENOX TM EndpointNo ER-DPNo ASAvs Placebo Odds Reduction % Stroke*22%(.001)24%(<.001)41%(<.001) TIA20%(.001)25%(<.001)40%(<.001) OVE40%(.004)34% (.012)62%(<.001) Ischemic Event20%(.001)21%(<.001)38%(<.001) MI1%(.939)21% (.100)23% (.217) *Primary endpoint, included for reference.

23. SECONDARY ENDPOINTS Conclusion TIA, OVE and Ischemic Events confirm the efficacy of ER-DP and ASA both individually and additively in the combination AGGRENOX™ TIA, OVE and Ischemic Events confirm the efficacy of ER-DP and ASA both individually and additively in the combination AGGRENOX™ Acute MI showed a positive trend on AGGRENOX™ vs placebo, consistent with effect of ASA component Acute MI showed a positive trend on AGGRENOX™ vs placebo, consistent with effect of ASA component

24. Months of Follow-Up 0.80 0.85 0.90 1.00 6121824 Kaplan-Meier Estimate of Survival 0 Patient Survival 0.75 0.95 Aggrenox TM ER-DPASAPlacebo

25. ER-DP3.1.725 ASA6.5.239 Interaction–.420 DEATH Primary Factorial Analysis Relative RiskGehan-Wilcoxon Factorial Effect Reduction %P-Value

26. DEATH Supportive Pairwise Comparison Pairwise Relative RiskGehan-Wilcoxon Comparison Reduction %P-Value AGGRENOX TM vs ASA -2.0.744 AGGRENOX TM vs ER-DP 1.6.791 AGGRENOX TM vs Placebo 9.2.285 ER-DP vs Placebo7.7.421 ASA vs Placebo11.0.162

27. No statistically significant risk reduction found No statistically significant risk reduction found ~10% risk reduction in death on AGGRENOX™, comparable to that on ASA alone ~10% risk reduction in death on AGGRENOX™, comparable to that on ASA alone Risk reductions comparable to those seen in meta-analyses of placebo-controlled studies of ASA in stroke and TIA patients Risk reductions comparable to those seen in meta-analyses of placebo-controlled studies of ASA in stroke and TIA patients CONCLUSION Death Endpoint

28. Nonfatal Stroke or Death Months of Follow-Up 0.75 0.8 0.85 0.9 0.95 1 6121824 Kaplan-Meier Estimate of Survival DP + ASA ASADPPlacebo

29. NONFATAL STROKE OR DEATH Primary Factorial Analysis ER-DP14.0.003 ASA12.2.002 Interaction–.504 Relative RiskGehan-Wilcoxon Factorial Effect Reduction %P-Value

30. NONFATAL STROKE OR DEATH Supportive Pairwise Comparison Pairwise Relative RiskGehan-Wilcoxon Comparison Reduction %P-Value AGGRENOX TM vs ASA 12.1.084 AGGRENOX TM vs ER-DP 10.3.079 AGGRENOX TM vs Placebo 24.4<.001 ER-DP vs Placebo15.7.012 ASA vs Placebo13.9.009

31. Factorial analysis shows Factorial analysis shows –Highly significant efficacy of both components –Additive efficacy in AGGRENOX™ Pairwise comparisons show Pairwise comparisons show –24.4% risk reduction on AGGRENOX™ vs placebo (P =.00002) –Favorable trends on AGGRENOX™ vs components NONFATAL STROKE OR DEATH Conclusion

32. Efficacy Conclusion AGGRENOX TM is significantly more effective than aspirin alone and dipyridamole alone in reducing the risk of stroke in TIA and stroke patients AGGRENOX TM is significantly more effective than aspirin alone and dipyridamole alone in reducing the risk of stroke in TIA and stroke patients This conclusion is based on reliable, well-controlled, generalizable evidence This conclusion is based on reliable, well-controlled, generalizable evidence –Large, multicenter trial –Factorial design demonstrating effectiveness of monotherapies and additive effectiveness of the combination –Statistically very persuasive findings –Consistency across subgroups –Significant benefit on distinct, prespecified endpoints

34. Efficacy Conclusion AGGRENOX  is significantly more effective than aspirin alone in reducing the risk of stroke in TIA and stroke patients AGGRENOX  is significantly more effective than aspirin alone in reducing the risk of stroke in TIA and stroke patients This conclusion is based on reliable, well-controlled, generalizable, robust and highly significant evidence This conclusion is based on reliable, well-controlled, generalizable, robust and highly significant evidence

35. Summary Patient Disposition Intent-to-Treat1649(100.0)1650(100.0)1654(100.0)1649(100.0)6602(100.0) Population Completed1088(66.0)1027(62.2)1023(61.9)1125(68.2)4263(64.6) Study Treated until980(59.4)945(57.3)923(55.8)1023(62.0)3871(58.6) month-24 Treated until108(6.5)82(5.0)100(6.0)102(6.2)392(5.9) death Ceased561(34.0)623(37.8)631(38.1)524(31.8)2339(35.4) Treatment Placebo AGGRENOX TM ER-DPASAOverall Placebo AGGRENOX TM ER-DPASAOverall n (%)n (%)n (%)n (%)n (%) Total No.16491650165416496602 of Patients Randomized Treatment Group

36. Aggrenox ®  Safety Director, General Medicine Boehringer Ingelheim Pharmaceuticals, Inc. Ridgefield, Connecticut Alan Ranhosky, MD

37. ESPS-2 The Second European Stroke Prevention Study Tested efficacy of ASA/ER-DP for secondary stroke prevention Tested efficacy of ASA/ER-DP for secondary stroke prevention Addressed clinical questions Addressed clinical questions –Does low-dose ASA prevent stroke? –Does ER-DP prevent stroke? –Is ASA/ER-DP superior to ASA alone? To ER-DP alone? –Is ASA/ER-DP well tolerated?

38. Multicenter, randomized, double-blind, placebo-controlled trial Multicenter, randomized, double-blind, placebo-controlled trial 2 x 2 factorial design 2 x 2 factorial design 6602 patients from 59 centers centrally randomized within 3 months of qualifying event (TIA or stroke) 6602 patients from 59 centers centrally randomized within 3 months of qualifying event (TIA or stroke) Treatment and follow-up time: 2 years (visits at 1 and 3 months, then at 3-month intervals) Treatment and follow-up time: 2 years (visits at 1 and 3 months, then at 3-month intervals) ESPS-2 Study Design

39. 1 2 4 15 8 4 9 2 2 2 4 3 3 13 countries 13 countries 59 centers 59 centers 6602 patients ESPS-2 Geographical Distribution of Participating Centers

40. ESPS-2 Treatment Arms N = 6602 Placebo (n = 1649) ASA 25 mg BID (n = 1649) ER-DP 200 mg BID (n = 1654) ASA/ER-DP 25 mg ASA/ 200 mg ER-DP BID (n = 1650)

41. ASA/ER-DPER-DP PlaceboASA ESPS-2 2 x 2 Factorial Design Allows statistical detection of drug effects with fewer patients Comparing ASA vs no ASA, ER-DP vs no ER-DP Comparing ASA vs no ASA, ER-DP vs no ER-DP Allows direct comparison between any two treatment arms

42. ESPS-2 Primary Efficacy Endpoints MMAG-confirmed first stroke (fatal or non-fatal) MMAG-confirmed first stroke (fatal or non-fatal) Death (any cause) Death (any cause)

43. ESPS-2 Protocol-Defined Secondary Efficacy Endpoints Transient ischemic attacks Transient ischemic attacks Other vascular events Other vascular events Myocardial infarction Myocardial infarction Ischemic events (stroke, MI, or sudden death) Ischemic events (stroke, MI, or sudden death)

44. ESPS-2 Other Secondary Efficacy Endpoints Fatal stroke Fatal stroke Non-fatal stroke Non-fatal stroke Non-fatal stroke or death Non-fatal stroke or death Vascular death Vascular death

45. Use of Placebo Comparison Placebo comparison included because of conflicting data from previous stroke trials Placebo comparison included because of conflicting data from previous stroke trials Placebo comparison needed to assess potential benefits of low-dose ASA Placebo comparison needed to assess potential benefits of low-dose ASA At the beginning of the trial (1988/89), all 60 independent ethical review committees (one at each study site) agreed that the use of placebo was appropriate At the beginning of the trial (1988/89), all 60 independent ethical review committees (one at each study site) agreed that the use of placebo was appropriate

46. GCP Compliance Use of several oversight committees Use of several oversight committees Informed consent from every patient Informed consent from every patient Ethics Committee approvals both locally and centrally Ethics Committee approvals both locally and centrally On-site monitoring On-site monitoring Careful QA of case report forms Careful QA of case report forms

47. Patient Survival Months of Follow-Up 0.85 0.90 0.95 1.00 6121824 Kaplan-Meier Estimate of Survival 0 Fatal Non-Fatal DP + ASA ASADPPlacebo

48. Fatal and Non-fatal Stroke Estimates of Survival Months of Follow-Up Kaplan-Meier Estimate of Survival