Philippine Heart Association
43rd Annual Convention &
Scientific Meeting Landmark
Trials Session
Role of Cilostazol in
Stroke Prevention
DANTE D. MORALES, MD,FPCP, FPCC
May 24, 2012
Crowne Plaza Manila Galleria
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 2.1 -3.6 and antiplatelet Aspirin
Source: Cochrane Review, In:The Cochrane Library, Issue 1 2002
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 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 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
CSPS 2 Study
n = 1337
2557 patients with non
cardioembolic stroke
Cilostazol 100 mg BID
R
Aspirin 81 mg OD
n = 1335
• 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
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
Patient Selection Criteria:
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
Baseline Characteristics (1)
Cilostazol
group
(N=1337)
Aspirin
group
(N=1335)
P value
959 (71.7)
957 (71.7)
0.98
Age (years)
63.59.2
63.49.0
0.76
BMI (kg/m2)
24.03.1
23.93.1
0.54
435 (32.5)
420 (31.5)
869 (65.0)
874 (65.6)
33 (2.5)
41 (3.1)
~28
414 (31.0)
419 (31.4)
29~56
354 (26.5)
338 (25.3)
Male [number of cases (%)]
Stroke subtypes (No.(%))
Atherothrombotic
Lacunar
Undetermined
Days after onset (%)
0.57
0.35
57~112
343 (25.7)
320 (24.0)
113~
226 (16.9)
258 (19.3)
Baseline Characteristics (2)
mRS (No.(%))
Cilostazol
group
(N=1337)
Aspirin
group
(N=1335)
Grade 0
207 (15.5)
186 (13.9)
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)
385 (28.8)
403(30.2)
0.43
640 (47.9)
624 (46.7)
0.56
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
Smoking (No.(%))
Alcohol intake (No.(%))
Complications (No.(%))
P value
0.55
Occurrence of Primary Endpoint
(Stroke)
Treatment
group
Number
of
patients
Incidence
Cilostazol
group
1337
82
Aspirin
group
1335
119
Total
duration of
observation
2965.9
3203.6
Occurrence
rate per
person-year
HR
Estimate (95%
CI)
Estimate
(95% CI)
0.0276
(0.0223~0.0343)
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
0.743
(0.564~0.981)
Logrank
test
p-value
0.0357*
Incidence of Primary and Secondary endpoints
Kaplan-Meier Plots for Occurrence of Stroke
Kaplan-Meier Plots for Safety endpoints
(Hemorrhagic Events)
Conclusions of CSPS
Clinical Meaning of CSPS
• 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
Conclusions
 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
.
MATCH BLEEDING EVENTS
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
MATCH
Life-threatening
bleeding
Major
Bleeding
Minor
Bleeding
Clopidogrel + ASA
N = 3,579
Clopidogrel + placebo
N = 3,781
96 (3%)
73 (2%)
120 (3%)
49 (1%)
22 (1%)
39 (1%)
p<0.0001 for all
BENEFIT
ARR=0.5%
NNT=200
BLEEDING (all)
ARI=4.8%
NNH=21
Diener et al. Lancet 2004; 364: 331–337.
CHARISMA
• Clopidogrel and Aspirin versus Aspirin Alone for
the Prevention of Atherothrombotic Events
CHARISMA TRIAL DESIGN
Patients age ≥45 years
at high risk for
atherothrombotic
events
R
(n=15 603)
Clopidogrel
75 mg/day
(n=7802)
Low-dose ASA 75-162 mg/day
Double-blind treatment up to 1040 primary
efficacy events*
Low-dose ASA 75-162 mg/day
Placebo
1 tablet/day
(n=7801)
1-month
visit
3-month
visit
Visits every 6 months
* MI (fatal or non-fatal), stroke (fatal or non-fatal), or cardiovascular death;
event-driven trial
Bhatt DL et al. Am Heart J 2004; 148: 263–268.
Final visit
(fixed study
end date)
Overall population: Primary and secondary efficacy results
(MI/stroke/CV death/hospitalization)†
Clopidogrel
Placebo
Endpoint* - n (%)
+ ASA
+ ASA
(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)
0.90
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
1301 (16.7)
1395 (17.9)
0.92 (0.86, 0.995)
0.04
866 (11.1)
957 (12.3)
0.90 (0.82, 0.98)
0.02
Principal secondary endpoint†
Hospitalization‡
†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.