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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 200 mg/day + aspirin 100 mg/day did not significantly reduce intracranial artery stenosis (IAS) progression vs aspirin alone (9.6% vs 5.6%; P=0.53) over 2 years. IAS progression was far lower than expected in both arms (~6–10% vs predicted 35–60%), likely due to aggressive risk-factor control. Exploratory logistic regression showed significant reduction in composite vascular events + silent infarcts (OR 0.37, 95% CI 0.14–0.97; P=0.04). 165 randomized (CA n=83, A n=82); 163 ITT (CA n=83, A n=80); 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%) — attributed to aggressive risk-factor control in both arms.
Vascular events numerically lower: annual rate 3.1% vs 7.4%; adjusted HR 0.39 (95% CI 0.12–1.13); P=0.09, NS.
Exploratory logistic regression composites significant: all vascular events + silent infarcts OR 0.37 (95% CI 0.14–0.97), P=0.04; stroke + silent infarcts OR 0.34 (95% CI 0.12–0.96), P=0.04; all vascular events + worsening mRS + silent infarcts OR 0.41 (95% CI 0.18–0.92), P=0.03.
No deaths in either group. Serious hemorrhage 4/83 (CA) vs 3/80 (A); subtypes: CA — GI 2, vitreous 1, hematuria 1; A — SAH 1, cerebral hemorrhage 1, GI 1.
Underpowered: 163 ITT (planned 200). Event rates far below projected.
Baseline imbalances favoring risk in CA arm: males 77.1% vs 53.8% (p<0.01), hypertension 83.1% vs 68.8% (p=0.04), diabetes 48.2% vs 25.0% (p<0.01) — biases against CA.
SBP reduced from 137.4 to 131.1 mm Hg and total cholesterol from 195.4 to 182.9 mg/dL in all patients over 2 years (both p<0.01).
163 ITT patients across 60 Japanese centers, open-label, 2-year follow-up.
Supports rationale for 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 (mean 762 days)

Centers: 60

Countries: Japan

Sample Size: 165

Sample Size (ITT): 163

Analysis: Intention-to-treat

Stratification: Age (≥70 vs <70) and stenosis location (supraclinoid ICA/M1 MCA vs basilar artery)

Inclusion Criteria

Noncardioembolic ischemic stroke 2 weeks to 6 months prior to entry
Responsible lesion identified on magnetic resonance imaging (MRI)
Intracranial artery stenosis >50% on MRA in the supraclinoid internal carotid artery, the M1 portion of the middle cerebral artery, or the basilar artery
Age 45–85 years
Able to visit an outpatient clinic

Exclusion Criteria

Potential cardiac sources of embolism
History of symptomatic intracranial hemorrhage
Other hemorrhagic diseases (active peptic ulcer, hemophilia, or coagulation abnormalities)
Hypersensitivity to cilostazol or aspirin
Congestive heart failure or uncontrollable angina pectoris
Thrombocytopenia (<100,000/mm³)
Liver dysfunction (AST or ALT >100 IU/L)
Renal dysfunction (creatinine >2.0 mg/dL)
Inability to be followed up during the study period
Current use of cilostazol or warfarin
Inability to undergo MRI
Scheduled percutaneous transluminal coronary angioplasty or bypass surgery
Enrollment in other clinical trials

Baseline Characteristics

Characteristic	Median Age	Female %	BMI (median)	mRS distribution %	Infarct size %	Stenosis severity %	Stenosis location %
CA	68.3	22.9	23.7
A	68.3	46.2	23.9
Note	Table 1 values are medians with ranges (CA 45–84; A 50–82)
P-value				0.31	0.24	1.00	0.82

Arms

Field	CA Group: Cilostazol + Aspirin	Control
N Randomized	83	82
N ITT	83	80
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 (annual incidence)	Secondary	7.4%	3.1%	0.39	0.09
Stroke (annual recurrence)	Secondary	5.2%	2.5%	0.44	0.19
Ischemic stroke (annual recurrence)	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 Hemorrhage	Adverse	3/80 — subarachnoid hemorrhage 1, cerebral hemorrhage 1, GI bleeding 1	4/83 — GI bleeding 2, vitreous hemorrhage 1, hematuria 1
Death	Adverse	0	0

Criticisms

Small sample size — underpowered to detect differences in the primary endpoint and adjudicated event outcomes.
Open-label design; potential for ascertainment bias.
Primary endpoint (IAS progression) not statistically different.
Composite benefits derive from post-hoc exploratory logistic regression without control for multiple testing.
Lack of central adjudication for stroke subtype.
Baseline imbalances (males, HTN, DM higher in CA arm) required covariate adjustment.
2-year follow-up may be short for a chronic stenotic vascular disease.
Japanese-only population may limit generalizability.

Funding

Operational and technical support provided by the Translational Research Informatics Center / Foundation for Biomedical Research and Innovation (FBRI), Kobe, Japan. FBRI is a public interest corporation receiving financial resources from the Japanese government and pharmaceutical companies including Otsuka Pharmaceutical Co., Ltd. (manufacturer of cilostazol). Otsuka had no role in data collection, data analysis, data interpretation, or writing of the report.

Based on: CATHARSIS (Cerebrovascular Diseases Extra, 2015)

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

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

Content summarized and formatted by NeuroTrials.ai.

CATHARSIS

(2015)

Objective

Cilostazol plus aspirin versus aspirin alone in preventing progression of intracranial artery stenosis (IAS) and recurrent vascular events.

Study Summary

• Cilostazol plus aspirin did not significantly reduce IAS progression compared to aspirin alone, but exploratory analyses suggested a lower risk of composite vascular and silent infarct outcomes in the combination group. 165 randomized; 163 in ITT (CA n=83, A n=80).

Intervention

Cilostazol 200 mg/day + aspirin 100 mg/day vs. aspirin 100 mg/day alone. Patients were treated and followed for 2 years.

Study Design

Arms: Array

Outcome

• Primary: IAS progression on MRA — 9.6% (CA) vs. 5.6% (A); p=0.53
• New silent brain infarcts — 4.8% (CA) vs. 10.0% (A); p=0.24
• Worsening mRS — 10.1% vs. 18.9%; p=0.17
• All vascular events — 3.1% (CA) vs. 7.4% (A); adjusted HR 0.39 (95% CI 0.12–1.13); p=0.09
• Stroke — 2.5% vs. 5.2%; adjusted HR 0.44 (95% CI 0.11–1.50); p=0.19
• Ischemic stroke — 2.5% vs. 4.5%; adjusted HR 0.47 (95% CI 0.13–1.73); p=0.26
• Serious hemorrhage — 4/83 (CA: GI 2, vitreous 1, hematuria 1) vs. 3/80 (A: SAH 1, cerebral hemorrhage 1, GI 1)
• No deaths in either group

Bottom Line

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%) — attributed to aggressive risk-factor control in both arms.
Vascular events numerically lower: annual rate 3.1% vs 7.4%; adjusted HR 0.39 (95% CI 0.12–1.13); P=0.09, NS.
Exploratory logistic regression composites significant: all vascular events + silent infarcts OR 0.37 (95% CI 0.14–0.97), P=0.04; stroke + silent infarcts OR 0.34 (95% CI 0.12–0.96), P=0.04; all vascular events + worsening mRS + silent infarcts OR 0.41 (95% CI 0.18–0.92), P=0.03.
No deaths in either group. Serious hemorrhage 4/83 (CA) vs 3/80 (A); subtypes: CA — GI 2, vitreous 1, hematuria 1; A — SAH 1, cerebral hemorrhage 1, GI 1.
Underpowered: 163 ITT (planned 200). Event rates far below projected.
Baseline imbalances favoring risk in CA arm: males 77.1% vs 53.8% (p<0.01), hypertension 83.1% vs 68.8% (p=0.04), diabetes 48.2% vs 25.0% (p<0.01) — biases against CA.
SBP reduced from 137.4 to 131.1 mm Hg and total cholesterol from 195.4 to 182.9 mg/dL in all patients over 2 years (both p<0.01).
163 ITT patients across 60 Japanese centers, open-label, 2-year follow-up.
Supports rationale for larger CSPS.com trial (n≈4,000) for definitive evidence on cilostazol in IAS.

Study Design

Study Type: Multicenter, open-label, randomized controlled trial
Randomization: Yes
Blinding: Open-label
Sample Size: 165
Follow-up: 2 years (mean 762 days)
Centers: 60
Countries: Japan

Primary Outcome

Definition: Progression of intracranial artery stenosis at 2 years (on MRA)

Control	Intervention	HR/OR	P-value
5.6%	9.6%	-	0.53

Limitations & Criticisms

Small sample size — underpowered to detect differences in the primary endpoint and adjudicated event outcomes.
Open-label design; potential for ascertainment bias.
Primary endpoint (IAS progression) not statistically different.
Composite benefits derive from post-hoc exploratory logistic regression without control for multiple testing.
Lack of central adjudication for stroke subtype.
Baseline imbalances (males, HTN, DM higher in CA arm) required covariate adjustment.
2-year follow-up may be short for a chronic stenotic vascular disease.
Japanese-only population may limit generalizability.

Citation

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

View Original Publication →

CATHARSIS

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

Clinical Question

Bottom Line

Major Points

Design

Inclusion Criteria

Exclusion Criteria

Baseline Characteristics

Arms

Outcomes

Criticisms

Funding

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