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CATHARSIS

Final Results of Cilostazol-Aspirin Therapy against Recurrent Stroke with Intracranial Artery Stenosis

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Year of Publication: 2015

Authors: Uchiyama S, Sakai N, Toi S, ..., for the CATHARSIS Study Group

Journal: Cerebrovascular Diseases Extra

Citation: Uchiyama S, et al. Cerebrovasc Dis Extra 2015;5:1–13.

Link: https://doi.org/10.1159/000369610

Clinical Question

Does cilostazol plus aspirin reduce progression of intracranial artery stenosis and vascular events more than aspirin alone in patients with symptomatic intracranial artery stenosis?

Bottom Line

Cilostazol 200mg/day + aspirin 100mg/day did not significantly reduce intracranial artery stenosis (IAS) progression vs aspirin alone (9.6% vs 5.6%; P=0.53) over 2 years. However, IAS progression was far lower than expected in both arms (~6-10% vs predicted 35-60%), likely due to aggressive risk factor control. Exploratory analyses showed significant reduction in composite vascular events + silent infarcts (OR 0.37; P=0.04). 163 patients, 60 Japanese centers.

        Major Points
        Primary endpoint NS: IAS progression 9.6% (CA) vs 5.6% (A) at 2 years (P=0.53).
IAS progression far lower than expected (9.6%/5.6% vs predicted 35-60%) — aggressive risk factor control in both arms.
Vascular events numerically lower: annual rate 3.1% vs 7.4% (HR 0.39; P=0.09, NS).
Exploratory composites significant: all events + silent infarcts OR 0.37 (P=0.04); + worsening mRS OR 0.41 (P=0.03).
No deaths in either group. Hemorrhage similar (4 CA vs 3 A).
Severely underpowered: 163 patients (planned 200+). Events far below projected.
Baseline imbalances: CA group had more males (77% vs 54%), hypertension (83% vs 69%), diabetes (48% vs 25%) — should bias against CA.
SBP reduced from 137 to 131 mmHg; total cholesterol from 195 to 183 mg/dL in both arms.
163 patients, 60 Japanese centers, open-label, 2-year follow-up.
Supports larger CSPS.com trial (n=4,000) for definitive evidence on cilostazol in IAS.

      

Design

Study Type: Multicenter, open-label, randomized controlled trial

Randomization: 1

Blinding: Open-label

Enrollment Period: June 2006 – March 2010

Follow-up Duration: 2 years

Centers: 60

Countries: Japan

Sample Size: 165

Analysis: Intention-to-treat

Inclusion Criteria

Noncardioembolic ischemic stroke 2 weeks to 6 months prior
Intracranial artery stenosis >50% on MRA
Ages 45–85
Able to attend outpatient follow-up

Exclusion Criteria

Cardiac sources of embolism
History of symptomatic intracranial hemorrhage
Active peptic ulcer or bleeding disorders
Hypersensitivity to cilostazol or aspirin
Severe heart failure or unstable angina
Platelet count <100,000/mm³
Severe liver or kidney dysfunction
Use of cilostazol or warfarin
Inability to undergo MRI
Scheduled for bypass/PTCA
Enrollment in other clinical trials

Arms

Field	CA Group: Cilostazol + Aspirin	Control
Intervention	Cilostazol 200 mg/day + Aspirin 100 mg/day	Aspirin 100 mg/day
Duration	2 years	2 years

Outcomes

Outcome	Type	Control	Intervention	HR / OR / RR	P-value
Progression of intracranial artery stenosis at 2 years (on MRA)	Primary	5.6%	9.6%		0.53
All vascular events	Secondary	7.4%	3.1%	0.39	0.09
Stroke	Secondary	5.2%	2.5%	0.44	0.19
Ischemic stroke	Secondary	4.5%	2.5%	0.47	0.26
New silent brain infarcts	Secondary	10.0%	4.8%		0.24
Worsening of mRS	Secondary	18.9%	10.1%		0.17
Major Bleeding	Adverse	3	4

Subgroup Analysis

Logistic regression suggested benefit in composite endpoints (vascular events + silent infarcts) for CA group

Criticisms

Small sample size reduced power to detect differences
Open-label design may introduce bias
Primary endpoint (IAS progression) showed no significant difference
Lack of event adjudication for stroke subtype
Shorter than optimal follow-up for chronic disease

Funding

Operational support from FBRI, Kobe, Japan. Cilostazol manufacturer (Otsuka) had no role in study design or analysis.

Based on: CATHARSIS (Cerebrovascular Diseases Extra, 2015)