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

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

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

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

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

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

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 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

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

Cilostazol （ｎ =1337 ） Aspirin （ｎ =1335 ） P value Male sex - n （％） 959 （ 71.7 ） 957 （ 71.7 ） 0.98 Age * （ Yr ） 63.5± ± BMI * （ kg/m 2 ） 24.0± ± 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 days 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

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 （ 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 ） ＊ Mean±SD Patients characteristics 2 #28-Tanahashi

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

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 （ ） 0.04 Secondary end point Cerebral infarction 72 （ 2.43 ） 88 （ 2.75 ） 0.88 （ ） 0.42 Ischemic cerebrovascular disorder （ Cerebral infarction, TIA ） 86 （ 2.90 ） 103 （ 3.21 ） 0.90 （ ） 0.46 Death from any cause 13 （ 0.42 ） 13 （ 0.39 ） 1.07 （ ） 0.86 Composite secondary end point * 138 （ 4.66 ） 186 （ 5.81 ） 0.80 （ ） 0.04 【 Safety end point 】 Bleeding events （ cerebral hemorrhage, subarachnoid hemorrhage, bleeding requiring hospitalization ） 23 （ 0.77 ） 57 （ 1.78 ） 0.46 （ ） ＜ Cilostazol better Aspirin better *Cerebral infarction, cerebral hemorrhage, subarachnoid hemorrhage, TIA, angina pectoris, myocardial infarction, cardiac failure or hemorrhage requiring hospitalization, death #28-Tanahashi

（％） 5 10 Aspirin Cilostazol P= 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 Cilostazol % Aspirin % No. at Risk Cumulative incidence Days after randomization #28-Tanahashi

P= 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 Cilostazol % Aspirin % Aspirin Cilostazol Aspirin No. at Risk Cumulative incidence Days after randomization Cilostazol #28-Tanahashi

Occurrence of bleeding events （ cerebral hemorrhage, subarachnoid hemorrhage, bleeding requiring hospitalization ） 5 P= Log-rank 検定 RRR=54.2 ％ （％） n No of occurrence s Estimate Incidence /year Cilostazol % Aspirin % Aspirin Cilostazol Aspirin No. at Risk Cumulative incidence Days after randomization Cilostazol #28-Tanahashi

* ： 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 ）＜ Diarrhea 164 （ 12.3 ） 85 （ 6.4 ）＜ Palpitations 156 （ 11.7 ） 71 （ 5.3 ）＜ Dizziness 129 （ 9.6 ） 97 （ 7.3 ） 0.03 Tachycardia 89 （ 6.7 ） 21 （ 1.6 ）＜ Hypertension 120 （ 9.0 ） 185 （ 13.9 ）＜ Constipation 110 （ 8.2 ） 155 （ 11.6 ） #28-Tanahashi

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= 、 RRR=20.1 ％ ） Cilostazol significantly reduced occurrence of bleeding events （ cerebral hemorrhage, subarachnoid hemorrhage, bleeding requiring hospitalization ） （ P= 、 RRR=54.2 ％） #28-Tanahashi

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

Occurrence of Stroke Occurrence of Stroke -CSPS2 Sub analysis- -CSPS2 Sub analysis- （ n=869 ） （ n=874 ） （ n=435 ） （ n=420 ） RRR 32% RRR 25% （％ /person ・ year ） Cilostazol Aspirin Atherothrombotic Lacunar #28-Tanahashi

Occurrence of Cerebral Infarction -CSPS2 Sub analysis- -CSPS2 Sub analysis- （ n=869 ） （ n=874 ） （ n=435 ） （ n=420 ） RRR 28% RRR 7% Atherothrombotic Lacunar （％ /person ・ year ） Cilostazol Aspirin #28-Tanahashi

Incidence of Hemorrhagic Stroke among Ischemic Stroke Subtypes CSPS2 sub-analysis （ n=869 ）（ n=874 ）（ n=435 ）（ n=420 ） p= AtherothromboticLacunar （％ /person ・ year ） Cilostazol Aspirin #28-Tanahashi

Occurrence of Intracranial Hemorrhage Stroke subtype Lacunar Atherothrombotic No. at risk Stroke subtype Lacunar Atherothrombotic 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

n= 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: #28-Tanahashi

Results of S-ACCESS Incidence (%/person-year) Intracranial hemorrhage Cerebral infarction P=0.19 #28-Tanahashi

n= 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: #28-Tanahashi

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

Design of CHARISMA n= months - median follow up Aspirin mg/day (n=7801) Clopidogrel 75mg/day + Aspirin mg/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: #28-Tanahashi

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

Design of ESPRIT n= years – mean follow up Aspirin mg/day (n=1376) Aspirin mg/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: #28-Tanahashi

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

Incidence of Intracranial Hemorrhage ― Western vs. Japan trials － Incidence (%/person-year) Trials in Western PopulationTrials in Japanese Population #28-Tanahashi

Modified from Toyoda K.: Drugs, 69, , 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 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 （ as of October 2010) #28-Tanahashi

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

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

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