Role of Cilostazol inStroke Prevention

Philippine Heart Association43rd 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 strokea. Anticoagulant and antiplateletsb. Thrombolytic

2. Secondary Preventiona. Antiplatelet agentsb. Anticoagulants

3. Risk factor management

Secondary Stroke Prevention1. Anticoagulants

a. WARRS Trial

2. Antiplateletsa. clopidogrel plus ASA (SPS3)b. cilostazol (CSPS 1&2)

Secondary Stroke Prevention1. Anticoagulants

a. WARRS Trial

2. Antiplateletsa. 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 2.1 -3.6 and antiplatelet Aspirin

Source: Cochrane Review, In:The Cochrane Library, Issue 1 2002

Secondary Stroke Prevention1. Anticoagulants

a. WARRS Trial

2. Antiplateletsa. 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 130-149mm 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 Prevention1. Anticoagulants

a. WARRS Trial

2. Antiplateletsa. clopidogrel plus ASA (SPS3)b. cilostazol (CSPS 1&2)

Secondary Stroke Prevention1. Anticoagulants

a. WARRS Trial

2. Antiplateletsa. 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 com-parative study

• Primary endpoints: Occurrence of stroke (cerebral infarction, cerebral hemorrhage, or subarachnoid hemorrhage)

• Secondary endpoints: Recurrence of cerebral infarction, Occurrence of ischemic cere-brovascular diseases (cerebral infarction or TIA), all-cause death angina pectoris, my-ocardial 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 criteriaPatients in a stable condition within 182 days (26

weeks) after occurrence of cerebral infarctionPatients with infarct-related foci detected by CT scan

or MRIPatients age 20 to 80 years (inclusive) at the time of

consentPatients having no cardiac diseases possibly

associated with cardiogenic cerebral embolism

Main exclusion criteriaPatients with hemorrhage or bleeding tendencyPatients with ischemic heart failurePatients with peptic ulcerPatients with severe blood disordersPatients with severe hepatic or renal disordersPatients 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) 63.59.2 63.49.0 0.76

BMI (kg/m2) 24.03.1 23.93.1 0.54

Stroke subtypes (No.(%))

Atherothrombotic435 (32.5) 420 (31.5)

0.57Lacunar 869 (65.0) 874 (65.6)

Undetermined 33 (2.5) 41 (3.1)

Days after onset (%) ~28 414 (31.0) 419 (31.4)

0.3529~56 354 (26.5) 338 (25.3)

57~112 343 (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 0 207 (15.5) 186 (13.9)

0.55

Grade 1 612 (45.8) 613 (45.9)Grade 2 406 (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) 0 (0.0)

Smoking (No.(%)) 385 (28.8) 403(30.2) 0.43Alcohol intake (No.(%)) 640 (47.9) 624 (46.7) 0.56

Complications (No.(%)) HT 976 (73.0) 991 (74.2) 0.47IHD 11 (0.8) 18 (1.3) 0.19DM 382 (28.6) 393 (29.4) 0.62DL 560 (41.9) 599 (44.9) 0.12

Occurrence of Primary Endpoint (Stroke)

Treatment group

Number of pa-tients

IncidenceTotal dura-tion of ob-servation

Occurrence rate per per-

son-yearHR

Log-rank

test p-valueEstimate (95%

CI)Estimate(95% CI)

Cilostazol group 1337 82 2965.9 0.0276

(0.0223~0.0343)0.743

(0.564~0.981) 0.0357*

Aspirin group 1335 119 3203.6 0.0371

(0.0310~0.0445)

Criteria of non-inferiority: Upper limit of 95%Cl *:P-value was lower than significance level 0.0471 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 com-pared 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 pa-tients)

• Remarkable relative risk reduction of stroke recurrence (25.3%)• Safer antiplatelet choice with low risk of cerebral hemorrhage

Clinical Meaning of CSPS

MATCH BLEEDING EVENTSAdding 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<0.0001 for all

BENEFITARR=0.5%NNT=200

BLEEDING (all)ARI=4.8%NNH=21

MATCH Life-threatening bleeding

Major Bleeding

Minor Bleeding

Clopidogrel + ASAN = 3,579

96 (3%) 73 (2%) 120 (3%)

Clopidogrel + placeboN = 3,781

49 (1%) 22 (1%) 39 (1%)

CHARISMA• 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 75-162 mg/day

Low-dose ASA 75-162 mg/day

(n=15 603)

Visits every 6 months3-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)†

Clopidogrel Placebo+ ASA + 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 mortality 371 (4.8) 374 (4.8) 0.99 (0.86, 1.14) 0.90CV 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) 0.59Ischemic stroke (nonfatal) 132 (1.7) 163 (2.1) 0.81 (0.64, 1.02) 0.07Stroke (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) 0.04Hospitalization‡ 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.