Role of Cilostazol in Stroke Prevention Philippine Heart Association 43 rd Annual Convention & Scientific Meeting Landmark Trials Session May 24, 2012 Crowne Plaza Manila Galleria DANTE D. MORALES, MD,FPCP, FPCC

ESTABLISHED STROKE TREATMENT 1.Acute therapy for stroke a. Anticoagulant and antiplatelets b. Thrombolytic 2. Secondary Prevention a. Antiplatelet agents b. Anticoagulants 3. Risk factor management

Secondary Stroke Prevention 1.Anticoagulants a. WARRS Trial 2. Antiplatelets a. clopidogrel plus ASA (SPS3) b. cilostazol (CSPS 1&2)

Secondary Stroke Prevention 1.Anticoagulants a. WARRS Trial 2. Antiplatelets a. clopidogrel plus ASA (SPS3) b. cilostazol (CSPS 1&2)

Warfarin vs Aspirin WARRS trial - 4 RCTs of oral anticoagulants vs antiplatelet Rx in 1,870 patients with previous stroke Result: No difference in stroke recurrence nor major bleeding between Warfarin with INR and antiplatelet Aspirin Source: Cochrane Review, In:The Cochrane Library, Issue

Secondary Stroke Prevention 1.Anticoagulants a. WARRS Trial 2. Antiplatelets a. clopidogrel plus ASA (SPS3) b. cilostazol (CSPS 1&2)

2 X 2 Factorial design Group I Clopidogrel 75mg+ ASA 325mg Group II ASA 325mg + placebo Group III BP control <130mm Hg Group IV BP control mm Hg

SPS 3 status As of August 2011, due to excess in bleeding and mortality in the clopidogrel+ASA arm, this group was stopped. However the ASA+placebo and BP control arm proceeded as planned.

Secondary Stroke Prevention 1.Anticoagulants a. WARRS Trial 2. Antiplatelets a. clopidogrel plus ASA (SPS3) b. cilostazol (CSPS 1&2)

Secondary Stroke Prevention 1.Anticoagulants a. WARRS Trial 2. Antiplatelets a. clopidogrel plus ASA (SPS3) b. cilostazol (CSPS 1&2)

The Aim of CSPS2 To establish non-inferiority of Cilostazol compared with Aspirin in preventing recurrence of stroke To evaluate efficacy and safety-related events, in patients with non-cardioembolic cerebral infarction Non-inferiority: the case that the value of upper limit of the 95% Cl of the HR for recurrence of stroke between Cilostazol and Aspirin is not more than 1.33

2557 patients with non cardioembolic stroke Study design: A multi-center, double-blind, parallel-group, randomized, prospective comparative study Primary endpoints: Occurrence of stroke (cerebral infarction, cerebral hemorrhage, or subarachnoid hemorrhage) Secondary endpoints: Recurrence of cerebral infarction, Occurrence of ischemic cerebrovascular diseases (cerebral infarction or TIA), all-cause death angina pectoris, myocardial infarction, cardiac failure, or hemorrhage requiring hospitalization Recruitment Period: December 2003 to October 2006 Duration of treatment: Minimum of 1 year and maximum of 5 years Cilostazol 100 mg BID Aspirin 81 mg OD R n = 1337 n = 1335 CSPS 2 Study

Patient Selection Criteria: Main inclusion criteria Patients in a stable condition within 182 days (26 weeks) after occurrence of cerebral infarction Patients with infarct-related foci detected by CT scan or MRI Patients age 20 to 80 years (inclusive) at the 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 Patient Selection Criteria:

Baseline Characteristics (1) Cilostazol group (N=1337) Aspirin group (N=1335) P value Male [number of cases (%)] 959 (71.7)957 (71.7)0.98 Age (years) 63.5   BMI (kg/m 2 ) 24.0   Stroke subtypes (No.(%))Atherothrombotic 435 (32.5)420 (31.5) 0.57 Lacunar 869 (65.0)874 (65.6) Undetermined 33 (2.5)41 (3.1) Days after onset (%)~ (31.0)419 (31.4) ~ (26.5)338 (25.3) 57~ (25.7)320 (24.0) 113~ 226 (16.9)258 (19.3)

Baseline Characteristics (2) Cilostazol group (N=1337) Aspirin group (N=1335) P value mRS (No.(%))Grade (15.5)186 (13.9) 0.55 Grade (45.8)613 (45.9) Grade (30.4)432 (32.4) Grade 3 73 (5.5)69 (5.2) Grade 4 39 (2.9)35 (2.6) Grade 5 0 (0.0) Smoking (No.(%)) 385 (28.8)403(30.2)0.43 Alcohol intake (No.(%)) 640 (47.9)624 (46.7)0.56 Complications (No.(%))HT 976 (73.0)991 (74.2)0.47 IHD 11 (0.8)18 (1.3)0.19 DM 382 (28.6)393 (29.4)0.62 DL 560 (41.9)599 (44.9)0.12

Occurrence of Primary Endpoint (Stroke) Treatment group Number of patients Incidence Total duration of observation Occurrence rate per person-year HR Log- rank test p-value Estimate (95% CI) Estimate (95% CI) Cilostazol group (0.0223~0.0343) (0.564~0.981) * Aspirin group (0.0310~0.0445) Criteria of non-inferiority: Upper limit of 95%Cl *:P-value was lower than significance level for hazard ratio≤1.33

Incidence of Primary and Secondary endpoints

Kaplan-Meier Plots for Occurrence of Stroke

Kaplan-Meier Plots for Safety endpoints (Hemorrhagic Events)

Conclusions of CSPS  This study, CSPS II, clearly demonstrated non-inferiority of cilostazol compared with aspirin in preventing recurrence of stroke.  Cilostazol was significantly more effective than aspirin in preventing recurrent stroke, with fewer hemorrhagic events.  Therefore, cilostazol is recommended as an option for the prevention of stroke recurrence in non-cardioembolic stroke patients who can tolerate long term administration of this drug  Subgroup analysis and cost-effectiveness analysis are still on going. Conclusions High quality of evidence by large scale randomized study design (2557 patients) Remarkable relative risk reduction of stroke recurrence (25.3%) Safer antiplatelet choice with low risk of cerebral hemorrhage Clinical Meaning of CSPS

MATCH B LEEDING E VENTS Adding aspirin to clopidogrel resulted in significantly more bleeding complications than clopidogrel arm, doubling the number of events. Lancet 2004;364:331-37

MATCH: INCREASED BLEEDING COMPLICATIONS ON CLOPIDOGREL + ASA COMPARED TO CLOPIDOGREL MONOTHERAPY Diener et al. Lancet 2004; 364: 331–337. p< for all BENEFIT ARR=0.5% NNT=200 BLEEDING (all) ARI=4.8% NNH=21 MATCH Life-threatening bleeding Major Bleeding Minor Bleeding Clopidogrel + ASA N = 3, (3%) 73 (2%) 120 (3%) Clopidogrel + placebo N = 3, (1%) 22 (1%) 39 (1%)

CHARISMA Clopidogrel and Aspirin versus Aspirin Alone for the Prevention of Atherothrombotic Events Clopidogrel and Aspirin versus Aspirin Alone for the Prevention of Atherothrombotic Events

CHARISMA TRIAL DESIGN * MI (fatal or non-fatal), stroke (fatal or non-fatal), or cardiovascular death; event-driven trial Clopidogrel 75 mg/day (n=7802) Placebo 1 tablet/day (n=7801) 1-month visit Final visit (fixed study end date) Patients age ≥45 years at high risk for atherothrombotic events R Double-blind treatment up to 1040 primary efficacy events* Low-dose ASA mg/day (n=15 603) Visits every 6 months 3-month visit Bhatt DL et al. Am Heart J 2004; 148: 263–268.

Overall population: Primary and secondary efficacy results (MI/stroke/CV death/hospitalization) † ClopidogrelPlacebo+ ASA Endpoint* - n (%) (n=7802) (n=7801)RR (95% CI)pvalue Primary efficacy endpoint534 (6.8)573 (7.3)0.93 (0.83,1.05)0.22 All cause mortality371 (4.8)374 (4.8)0.99 (0.86, 1.14)0.90 CV mortality ∆ 238 (3.1)229 (2.9)1.04 (0.87, 1.25)0.68 Myocardial infarction (nonfatal) ∆ 146 (1.9)155 (2.0)0.94 (0.75, 1.18)0.59 Ischemic stroke (nonfatal) 132 (1.7)163 (2.1)0.81 (0.64, 1.02)0.07 Stroke (nonfatal) ∆ 150 (1.9)189 (2.4)0.79 (0.64, 0.98)0.03 Principal secondary endpoint † 1301 (16.7)1395 (17.9)0.92 (0.86, 0.995)0.04 Hospitalization ‡ 866 (11.1)957 (12.3)0.90 (0.82, 0.98)0.02 †First occurrence of MI (fatal or nonfatal), stroke (fatal or nonfatal), CV death (including hemorrhagic death), or hospitalization for UA, TIA, or revascularization *Intention-to-treat analysis ∆ Components of the primary efficacy endpoint. Patients that did not die from CV causes, are counted for the first nonfatal event of MI or stroke. ‡For UA, TIA, or revascularization Bhatt DL et al. NEJM 2006.