1. ASENT 13 th Annual Meeting Mega Clinical Studies - Lessons from CSPS2 - Norio Tanahashi Saitama Medical University International Medical Center ， Japan #28-Tanahashi

2. Background The efficacy of aspirin and other antiplatelets in secondary prevention of cerebral infarction has been demonstrated in various studies and meta- analyses, mostly conducted in the US and EU. A significant reduction in risk of recurrence of cerebral infarction for cilostazol compared with placebo was demonstrated in the Cilostazol Stroke Prevention Study （ CSPS ） Cilostazol Stroke Prevention Study Ⅱ （ CSPS Ⅱ） is the first, long-term, large-scale, phase4 clinical trial in Japan. #28-Tanahashi

4. AntiplateletImprovement of endothelial functionVasodilation Anti-atherosclerosis CilostazolCilostazol Antiplatelet Improvement of endothelial function Vasodilation Anti-atherosclerosis Treatment strategy for atherothrombotic cerebral infarction #28-Tanahashi

5. Cilostazol is Superior to Aspirin for Secondary Stroke Prevention ： Results of CSPS Ⅱ Multi-center, randomized, prospective, double-blind, active-controlled, parallel-group comparative study in Japan #28-Tanahashi

6. Outline of study plan Objective ： This study was designed to investigate whether cilostazol is superior to aspirin in secondary prevention of cerebral infarction in stroke patients in Japan. Number of participants ： 1300 in each group, for a total of 2600 Number of study institutions ： 294 Study period ： 5 years, （ December 2003 to December 2008 ） #28-Tanahashi

7. Aspirin 81mg Cilostazol 200mg R Multi-center, randomized, double-blind, active-controlled, parallel-group, comparative study 1300 Duration of treatment: 1–5 years Primary endpoint ： Occurrence of stroke (cerebral infarction, cerebral hemorrhage, or subarachnoid hemorrhage) Study period ： December 2003-December 2008 Study design #28-Tanahashi

8. Main inclusion and exclusion criteria Main inclusion criteria Patients in stable condition within 182 days （ 26 weeks ） of occurrence of cerebral infarction Patients with infarct-related foci detected by x-ray CT scan or MRI Patients aged 20-80 years （ inclusive ） at time of consent Patients having no cardiac diseases possibly associated with cardiogenic cerebral embolism Main exclusion criteria Patients with hemorrhage or bleeding tendency Patients with ischemic heart failure Patients with peptic ulcer Patients with severe blood disorders Patients with severe hepatic or renal disorders Patients with malignant neoplasm or who have received any therapy for malignant neoplasm within 5 years prior to study enrollment #28-Tanahashi

9. Criteria for Evaluation Primary endpoint Occurrence of stroke （ cerebral infarction, cerebral hemorrhage, or subarachnoid hemorrhage ） during the treatment period Secondary endpoints Recurrence of cerebral infarction during the treatment period Occurrence of ischemic cerebrovascular diseases （ cerebral infarction or TIA ） during the treatment period Occurrence of all-cause death during the treatment period Occurrence of cerebral stroke, TIA, angina pectoris, myocardial infarction, cardiac failure, or hemorrhage requiring hospitalization during the treatment period #28-Tanahashi

10. Cilostazol （ｎ =1337 ） Aspirin （ｎ =1335 ） P value Male sex - n （％） 959 （ 71.7 ） 957 （ 71.7 ） 0.98 Age * （ Yr ） 63.5±9.263.4±9.00.76 BMI * （ kg/m 2 ） 24.0±3.123.9±3.10.54 Stroke subtypes - n （％） Atherothrombotic Lacunar Undetermined 435 （ 32.5 ） 869 （ 65.0 ） 33 （ 2.5 ） 420 （ 31.5 ） 874 （ 65.5 ） 41 （ 3.1 ） 0.57 Days after onset - n （％） - 28 days 29-56 days 57-112 days 113 -< days 414 （ 31.0 ） 354 （ 26.5 ） 343 （ 25.7 ） 226 （ 16.9 ） 419 （ 31.4 ） 338 （ 25.3 ） 320 （ 24.0 ） 258 （ 19.3 ） 0.35 ＊ Mean±SD Patients characteristics1 #28-Tanahashi

11. Cilostazol （ n=1337 ） Aspirin （ n=1335 ） P value Severity at baseline （ Classification by Modified Rankin Scale ） n （％） 0.55 Grade 0 Grade 1 Grade 2 Grade 3 Grade 4 Grade 5 207 （ 15.5 ） 612 （ 45.8 ） 406 （ 30.4 ） 73 （ 5.5 ） 39 （ 2.9 ） 0 （ 0.0 ） 186 （ 13.9 ） 613 （ 45.9 ） 432 （ 32.4 ） 69 （ 5.2 ） 35 （ 2.6 ） 0 （ 0.0 ） Smoking - n （％） 385 （ 28.8 ） 403 （ 30.2 ） 0.43 Alcohol intake - n （％） 640 （ 47.9 ） 624 （ 46.7 ） 0.56 Complications - n （％） Hypertension Ischemic heart disease Diabetes mellitus Dyslipidemia 976 （ 73.0 ） 11 （ 0.8 ） 382 （ 28.6 ） 560 （ 41.9 ） 991 （ 74.2 ） 18 （ 1.3 ） 393 （ 29.4 ） 599 （ 44.9 ） 0.10 0.47 0.19 0.62 0.12 ＊ Mean±SD Patients characteristics 2 #28-Tanahashi

12. Cilostazol （ｎ =1337 ） Aspirin （ n=1335 ） Antihypertensive agents ARB Ca antagonists ACE inhibitors 900 （ 67.3 ） 617 （ 46.1 ） 627 （ 46.9 ） 111 （ 8.3 ） 999 （ 74.8 ） 723 （ 54.2 ） 753 （ 56.4 ） 121 （ 9.1 ） Lipid-lowering agents Statins 401 （ 30.0 ） 362 （ 27.1 ） 452 （ 33.9 ） 402 （ 30.1 ） Antidiabetic agents 271 （ 20.3 ） 278 （ 20.8 ） Digestive agents 863 （ 64.5 ） 908 （ 68.0 ） n （％） Concomitant medications #28-Tanahashi

13. Primary and secondary endpoint Cilostazol （ n ＝ 1337 ） Aspirin （ n ＝ 1335 ） Hazard ratio （ 95% confidence interval ） Hazard ratio Log-rank test P value No of patients （％） 【 Efficacy end point 】 Primary endpoint Stroke （ Cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage ） 82 （ 2.76 ） 119 （ 3.71 ） 0.74 （ 0.56- 0.98 ） 0.04 Secondary end point Cerebral infarction 72 （ 2.43 ） 88 （ 2.75 ） 0.88 （ 0.65- 1.20 ） 0.42 Ischemic cerebrovascular disorder （ Cerebral infarction, TIA ） 86 （ 2.90 ） 103 （ 3.21 ） 0.90 （ 0.68- 1.19 ） 0.46 Death from any cause 13 （ 0.42 ） 13 （ 0.39 ） 1.07 （ 0.50- 2.31 ） 0.86 Composite secondary end point * 138 （ 4.66 ） 186 （ 5.81 ） 0.80 （ 0.64- 0.99 ） 0.04 【 Safety end point 】 Bleeding events （ cerebral hemorrhage, subarachnoid hemorrhage, bleeding requiring hospitalization ） 23 （ 0.77 ） 57 （ 1.78 ） 0.46 （ 0.30- 0.71 ） ＜ 0.001 00.511.52.02.5 Cilostazol better Aspirin better *Cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage, TIA, angina pectoris, myocardial infarction, cardiac failure or hemorrhage requiring hospitalization, death #28-Tanahashi

14. 133711371063103198994189686478868657045033122713568298 13351227114810891046100596792683775062850937725515275337 0 017001600150014001300120011001000900800700600500400300200100 15 （％） 5 10 Aspirin Cilostazol P=0.0357 Log-rank test RRR=25.7 ％ Aspirin Cilostazol Primary end point ： Occurrence of stroke （ cerebral infarction, cerebral hemorrhage, or subarachnoid hemorrhage ） n No of occurrence Estimate Incidence /year Cilostazol1337822.76% Aspirin13351193.71% No. at Risk Cumulative incidence Days after randomization #28-Tanahashi

15. 0 25 017001600150014001300120011001000900800700600500400300200100 11361062103198794189686378768656944933122713568298 1226114510871045100596692383675062850837625515275337 5 15 10 20 P=0.0437 Log-rank test RRR=20.1 ％ Occurrence of cerebral stroke, TIA, angina pectoris, myocardial infarction, cardiac failure, or hemorrhage requiring hospitalization （％） n No of occurrence s Estimate Incidence /year Cilostazol13371384.66% Aspirin13351865.81% 1337 1335 Aspirin Cilostazol Aspirin No. at Risk Cumulative incidence Days after randomization Cilostazol #28-Tanahashi

16. 0 10 017001600150014001300120011001000900800700600500400300200100 11371063103299094289686478868657045133122713568298 1227114910901047100696792783675162850937725515275337 Occurrence of bleeding events （ cerebral hemorrhage, subarachnoid hemorrhage, bleeding requiring hospitalization ） 5 P=0.0004 Log-rank 検定 RRR=54.2 ％ （％） n No of occurrence s Estimate Incidence /year Cilostazol1337230.77% Aspirin1335571.78% 1337 1335 Aspirin Cilostazol Aspirin No. at Risk Cumulative incidence Days after randomization Cilostazol #28-Tanahashi

17. * ： Fisher の正確検定 Summary of adverse events Cilostazol （ｎ =1337 ） Aspirin （ｎ =1335 ） P value * n （％） Headache 313 （ 23.4 ） 217 （ 16.3 ）＜ 0.001 Diarrhea 164 （ 12.3 ） 85 （ 6.4 ）＜ 0.001 Palpitations 156 （ 11.7 ） 71 （ 5.3 ）＜ 0.001 Dizziness 129 （ 9.6 ） 97 （ 7.3 ） 0.03 Tachycardia 89 （ 6.7 ） 21 （ 1.6 ）＜ 0.001 Hypertension 120 （ 9.0 ） 185 （ 13.9 ）＜ 0.001 Constipation 110 （ 8.2 ） 155 （ 11.6 ） 0.003 #28-Tanahashi

18. Results Cilostazol significantly reduced occurrence of stroke （ cerebral infarction, cerebral hemorrhage, or subarachnoid hemorrhage ） compared with aspirin. （ P=0.0357,RRR=25.7 ％ ）。 Cilostazol significantly reduced occurrence of cerebral stroke, TIA, angina pectoris, myocardial infarction, cardiac failure, or hemorrhage requiring hospitalization compared with aspirin. （ P=0.0437 、 RRR=20.1 ％ ） Cilostazol significantly reduced occurrence of bleeding events （ cerebral hemorrhage, subarachnoid hemorrhage, bleeding requiring hospitalization ） （ P=0.0004 、 RRR=54.2 ％） #28-Tanahashi

19. Conclusions Cilostazol demonstrated efficacy in preventing recurrent stroke in patients with cerebral infarction, with less bleeding compared to aspirin for the first time. Cilostazol is a suitable first option for the prevention of recurrent stroke. #28-Tanahashi

20. Occurrence of Stroke Occurrence of Stroke -CSPS2 Sub analysis- -CSPS2 Sub analysis- （ n=869 ） （ n=874 ） （ n=435 ） （ n=420 ） 2.08 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 4.0 4.5 3.03 3.06 4.07 RRR 32% RRR 25% （％ /person ・ year ） Cilostazol Aspirin Atherothrombotic Lacunar #28-Tanahashi

21. Occurrence of Cerebral Infarction -CSPS2 Sub analysis- -CSPS2 Sub analysis- （ n=869 ） （ n=874 ） （ n=435 ） （ n=420 ） 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0 1.77 2.45 2.69 2.88 RRR 28% RRR 7% Atherothrombotic Lacunar （％ /person ・ year ） Cilostazol Aspirin #28-Tanahashi

22. Incidence of Hemorrhagic Stroke among Ischemic Stroke Subtypes CSPS2 sub-analysis （ n=869 ）（ n=874 ）（ n=435 ）（ n=420 ） 1.4 0 p=0.003 0 AtherothromboticLacunar （％ /person ・ year ） Cilostazol Aspirin 1.2 1.0 0.8 0.6 0.4 0.2 0.31 0.59 0.36 1.20 #28-Tanahashi

23. Occurrence of Intracranial Hemorrhage Stroke subtype 0100200300400500600700800900100011001200130014001500160017001800 Lacunar 86974169467464860857855850844337329821515193421530 Atherothrombotic4353673413313173102962862622251821411057141251340 No. at risk 0 2 4 6 0 2 4 6 01002003004005006007008009001000110012001300140015001600170018000100200300400500600700800900100011001200130014001500160017001800 Stroke subtype 0100200300400500600700800900100011001200130014001500160017001800 Lacunar 87480475371068965863261054548841032624216292461940 Atherothrombotic4203893653483283183062902652391971661258756271330 No. at risk Days after randomization Atherothrombotic infarction Lacunar infarction Atherothrombotic infarction Lacunar infarction P=0.829, log-rank test P=0.114, log-rank test Cilostazol group Aspirin group (%) (%) Cumulative incidence #28-Tanahashi

24. n=1507 1.59 years – mean follow up Aspirin 81mg / day (n=757) Sarpogrelate 100mgTID (n=750) Design of S-ACCESS R ● Subject : Ischemic stroke patients -Primary Endpoint: Cerebral infarction -Secondary Endpoint: Clusters of serious vascular events (stroke, acute coronary syndrome, or vascular event-related death) ● Multi-center, double-blind, randomized study conducted in Japan Shinohara Y, et al. Stroke 2008; 39: 1827-1833. #28-Tanahashi

25. Results of S-ACCESS Incidence (%/person-year) 6.1 4.9 0.6 1.0 Intracranial hemorrhage Cerebral infarction P=0.19 #28-Tanahashi

26. n=19185 1.91 years – mean follow up Aspirin 325mg/day (n=9586) Clopidogrel 75mg/day 3 (n=9599) Design of CAPRIE R ● Subject : Patients with ischemic stroke, MI, or symptomatic PAD -Primary Endpoint: Composite of ischemic stroke, MI, or vascular death -Secondary Endpoint: Amputation, vascular death ● Multi-center, double-blind, randomized study CAPRIE Steering Committee. Lancet 1996; 348: 1329-1339. #28-Tanahashi

27. Results of CAPRIE Incidence (%/person-year) 5.3 5.8 0.2 0.3 Intracranial hemorrhage Ischemic stroke, MI, or vascular death P=0.043 #28-Tanahashi

28. Design of CHARISMA n=15603 28 months - median follow up Aspirin 75 - 162mg/day (n=7801) Clopidogrel 75mg/day + Aspirin 75 - 162mg/day (n=7802) R ● Subject : Patients with clinically evident vascular disease or multiple risk factors -Primary Endpoint: Composite of MI, stroke or deaths from cordiovascular causes -Secondary Endpoint: Composite of MI, stroke, death from cardiovascular causes, or hospitalization for unstable angina, TIA, or a revascularization procedure ● Multi-center, double-blind, randomized study Bhatt DL, et al. N Engl J Med 2006; 354: 1706-1717. #28-Tanahashi

29. Results of CHARISMA Incidence 2.9 3.1 0.1 (%/person-year) MI, stroke or deaths from cordiovascular causes Intracranial hemorrhage #28-Tanahashi

30. Design of ESPRIT n=2739 3.5 years – mean follow up Aspirin 30-325mg/day (n=1376) Aspirin 30-325mg/day + Dipyridamole 200mg BID (n=1363) R ● Subject : TIA or minor stroke -Primary Endpoint: Composite of death from all vascular causes, non-fatal stroke, non-fatal MI, or major bleeding complication -Secondary Endpoint: Death from all causes, death from all vascular Causes, death from all vascular causes and non-fatal stroke, all major ischemic events, all vascular events ● Multi-center, double-blind, randomized study The ESPRIT Study Group. Lancet 2006; 367: 1665-1673. #28-Tanahashi

31. Results of ESPRIT 3.6 4.5 0.3 0.4 (%/person-year) Incidence Intracranial hemorrhage Death from all vascular causes, non-fatal stroke, non-fatal MI, or major bleeding complication #28-Tanahashi

32. Incidence of Intracranial Hemorrhage ― Western vs. Japan trials － Incidence (%/person-year) 0.2 0.3 0.1 0.3 0.4 0.6 1.0 0.3 0.9 Trials in Western PopulationTrials in Japanese Population #28-Tanahashi

33. Modified from Toyoda K.: Drugs, 69, 633-647, 2009 Hisayamacho, Japan Male Hisayamacho, Japan Female Shibata, Japan Changsha, China Beijing, China Shanghai, China New Mexico, USA Giessen, Germany Framingham, USA Rochester, USA East Asian Hispanic Caucasian 020406080100120140 Annual incidence of cerebral hemorrhage (/100,000 person) Annual incidence of cerebral hemorrhage in general population Anti Thrombotic Therapy – 2010 Recurrent stroke prevention considering risk/benefit Kazunori Toyoda ： Nikkei Medical on-line http://medical.nikkeibp.co.jp/inc/mem/pub/special/att/hcp/rensai/201008/516371.html （ as of October 2010) #28-Tanahashi

35. Mechanism of Cilostazol on less bleeding Protective Effects of Cilostazol on Barrier Function of Vasculature ● Inhibition of MMP-9 expression which degrade peri-vascular matrix ● Improvement of Endothelial Barrier function PLoS ONE 1 December 2010, Volume 5 e15178 Pharmacological Research 55 (2007) 104–110 #28-Tanahashi

36. Intracranial hemorrhage was more frequent in S-ACCESS and CSPS2 compared with the trials conducted in western in the aspirin group Cilostazol decrease Incidence of intracranial hemorrhage Compared with Aspirin In CSPS2, more intracranial hemorrhage was observed in patients with lacunar infarction compared with those with atherothrombotic infarction. High bleeding tendency in Japanese population might be attributable to high rate of lacunar patients ( ＞ 60%) enrolled in these trials. Summary #28-Tanahashi

37. Conclusion Japanese population are considered to have higher bleeding tendency That ‘s reason why Lacuna infarcton is higher rate in japanese population Thus results of western trials may not be applicable to Japanese population. #28-Tanahashi