PDF: TOSS-2
(2011)Objective
Aspirin plus cilostazol versus aspirin plus clopidogrel in patients with symptomatic intracranial atherosclerotic stenosis (ICAS).
Study Summary
Intervention
Randomized, double-blind, multicenter trial across 20 centers in East Asia. N=457 patients with acute ischemic stroke due to ICAS in MCA (M1) or basilar artery. Patients were randomized to: - Cilostazol 100 mg BID + aspirin 75–150 mg daily - Clopidogrel 75 mg daily + aspirin 75–150 mg daily Duration: 7 months. Follow-up MRA and MRI performed to assess ICAS progression and new ischemic lesions.
Study Design
Arms: Array
Outcome
• New ischemic lesions on MRI: 18.7% (cilostazol) vs. 12.0% (clopidogrel); p=0.078
• Total cardiovascular events: 6.4% vs. 4.4%; p=0.312
• Major hemorrhagic complications: 0.9% vs. 2.6%; p=0.163
• Cilostazol improved HDL and reduced ApoB and ApoB/ApoA1 ratio significantly more than clopidogrel
• Headache was more common with cilostazol
Bottom Line
This trial failed to show a significant difference between aspirin plus cilostazol and aspirin plus clopidogrel in preventing the progression of symptomatic ICAS and new ischemic lesions. Although cilostazol showed favorable changes in serum lipoproteins and trends towards less progression of symptomatic ICAS, further large trials are needed to determine long-term benefits.
Major Points
- 457 patients with acute symptomatic stenosis in the M1 segment of the middle cerebral artery or the basilar artery were randomized.
- The primary endpoint, progression of symptomatic ICAS, occurred in 20 of 202 (9.3%) patients in the cilostazol group and 32 of 207 (15.5%) in the clopidogrel group (P=0.092).
- Cardiovascular events occurred in 15 of 232 patients (6.4%) in the cilostazol group and 10 of 225 (4.4%) in the clopidogrel group (P=0.312).
- There were no significant differences in new ischemic lesions (18.7% vs 12.0%; P=0.078) and major hemorrhagic complications (0.9% vs 2.6%; P=0.163) between the groups.
- The cilostazol group showed significantly favorable changes in serum lipoproteins (lower total cholesterol, Apo B, Apo B/Apo A1 ratio, higher HDL) compared to baseline and some changes compared to clopidogrel.
- Overall change in symptomatic stenosis was significantly favorable (less progression and more regression) in the cilostazol group (P=0.049 by χ² trend test, post hoc analysis).
- Overall change in asymptomatic stenosis was also favorable in the cilostazol group (P=0.039 by χ² trend test, post hoc analysis).
Study Design
- Study Type
- Investigator-initiated, randomized, double-blind, multicenter clinical trial
- Randomization
- Yes
- Blinding
- Double-blind (patients and investigators assessing MRI/MRA data)
- Sample Size
- 457
- Follow-up
- 7 months (for imaging endpoints)
- Centers
- 20
- Countries
- East Asian countries
Primary Outcome
Definition: Progression of symptomatic intracranial atherosclerotic stenosis (ICAS) on MRA, defined as worsening in the degree of stenosis by 1 grade or more.
| Control | Intervention | HR/OR | P-value |
|---|---|---|---|
| 32 of 207 (15.5%) | 20 of 202 (9.3%) | 0.61 | 0.092 |
Limitations & Criticisms
- The study used a radiological surrogate marker (ICAS progression on MRA) rather than clinical events as the major endpoint, which requires validation with a larger sample size and longer follow-up for clinical outcomes.
- The study was underpowered for the primary endpoint as the observed incidence of ICAS progression in the clopidogrel group (15.5%) was less than the assumed 20%, potentially leading to a false negative result.
- The study relied on MRI surrogate endpoints, limiting evaluation of subjects who did not undergo follow-up MRI scanning, which could introduce bias despite no observed differences in dropout characteristics.
- Most dropouts occurred at the beginning of the study, and withdrawals were mainly due to headache or exclusion criteria violation, which may be unrelated to the endpoints, but still contributes to missing data.
- The analysis of MRI and angiographic data, while performed by blinded investigators, was done just after locking of clinical data, raising a potential for implicit bias, though efforts were made to ensure blinding.
- The definition of progression/regression was based on a 5-grade system on MRA, whose complete establishment in monitoring atherosclerotic progression has not been fully validated, despite high concordance with transcranial Doppler.
Citation
Stroke. 2011;42:2883-2890.