TOSS-2
Efficacy and Safety of Combination Antiplatelet Therapies in Patients With Symptomatic Intracranial Atherosclerotic Stenosis
Year of Publication: 2011
Authors: Sun U. Kwon, MD; Keun-Sik Hong, MD; Dong-Wha Kang, ..., MD; Jong S. Kim
Journal: Stroke
Citation: Stroke. 2011;42:2883-2890.
Link: https://doi.org/10.1161/STROKEAHA.110.609370
PDF: https://www.ahajournals.org/doi/reader/1...EAHA.110.609370
PDF: Clinical Question
In patients with acute symptomatic intracranial atherosclerotic stenosis (ICAS), what is the efficacy of aspirin plus cilostazol versus aspirin plus clopidogrel on the progression of ICAS?
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).
Design
Study Type: Investigator-initiated, randomized, double-blind, multicenter clinical trial
Randomization: 1
Blinding: Double-blind (patients and investigators assessing MRI/MRA data)
Enrollment Period: August 2005 and May 2008
Follow-up Duration: 7 months (for imaging endpoints)
Centers: 20
Countries: East Asian countries
Sample Size: 457
Analysis: Intention-to-treat basis for clinical events and safety; full analysis set for primary and MRI-based endpoints. Adjusted relative risk and CI using Mantel-Haenszel method. Kaplan-Meier curve with log rank test for time to clinical events. Post hoc χ² trend test for stenosis changes. Subgroup analysis without adjustment for multiple comparisons. P<0.05 for statistical significance.
Inclusion Criteria
- Acute ischemic stroke patients aged 35 years or older
- Symptomatic intracranial atherosclerotic stenosis (ICAS) within 2 weeks of symptom onset
- Symptomatic ICAS defined as a significant focal stenosis in the M1 segment of the middle cerebral artery or basilar artery on MRA, relevant to acute lesions of the index stroke identified by diffusion-weighted imaging.
Exclusion Criteria
- Nonatherosclerotic vasculopathy (e.g., arterial dissection or moyamoya disease)
- Thrombolytic therapy for the index stroke
- Embolic heart disease
- Significant stenosis of arteries proximal to the symptomatic stenosis
- Scheduling for revascularization for the stenosis
Baseline Characteristics
| Characteristic | Control | Active |
|---|---|---|
| Age (y) | 64.58±11.11 | 66.42±11.33 |
| Male, n (%) | 112 (49.8) | 122 (52.6) |
| Hypertension, n (%) | 154 (68.4) | 177 (76.3) |
| Diabetes, n (%) | 89 (39.6) | 105 (45.3) |
| Smoking, n (%) | 94 (41.8) | 97 (41.8) |
| Family history of stroke, n (%) | 47 (20.9) | 70 (30.2) |
| Hyperlipidemia, n (%) | 105 (46.7) | 112 (48.3) |
| National Institutes of Health Stroke Scale score | 3.4±3.0 | 3.1±3.1 |
| Location of symptomatic stenosis - Middle cerebral artery, n (%) | 185 (82.2) | 188 (81.0) |
| Location of symptomatic stenosis - Basilar artery, n (%) | 40 (17.8) | 44 (19.0) |
| Severity of symptomatic stenosis - No. of stenoses, n (%) | 1 (0.4) | 1 (0.4) |
| Severity of symptomatic stenosis - Mild, n (%) | 74 (32.9) | 69 (29.7) |
| Severity of symptomatic stenosis - Moderate, n (%) | 72 (32.0) | 86 (37.1) |
| Severity of symptomatic stenosis - Severe, n (%) | 77 (34.2) | 72 (31.0) |
| Severity of symptomatic stenosis - Occlusion, n (%) | 1 (0.4) | 4 (1.7) |
| Time from qualifying event to randomization (d) | 7.82±3.15 | 8.03±3.34 |
| Time from qualifying event to magnetic resonance angiogram (d) | 3.92±2.64 | 4.06±2.36 |
| Concomitant medications - Angiotensin receptor blocker, n (%) | 71 (34.3) | 86 (42.5) |
| Concomitant medications - Angiotensin-converting enzyme inhibitor n (%) | 33 (15.9) | 39 (19.3) |
| Concomitant medications - Calcium channel blocker n (%) | 94 (45.4) | 94 (46.5) |
| Concomitant medications - Other antihypertensive agent n (%) | 95 (45.8) | 93 (46.0) |
| Concomitant medications - Statin n (%) | 147 (71.0) | 138 (68.3) |
Arms
| Field | Cilostazol Group | Control |
|---|---|---|
| Intervention | 100 mg cilostazol twice daily, with aspirin (75-150 mg once daily). Statin therapy and aggressive control of atherosclerosis risk factors were strongly recommended. | 75 mg clopidogrel once daily, with aspirin (75-150 mg once daily). Statin therapy and aggressive control of atherosclerosis risk factors were strongly recommended. |
| Duration | 7 months | 7 months |
Outcomes
| Outcome | Type | Control | Intervention | HR / OR / RR | P-value |
|---|---|---|---|---|---|
| Progression of symptomatic intracranial atherosclerotic stenosis (ICAS) on MRA, defined as worsening in the degree of stenosis by 1 grade or more. | Primary | 32 of 207 (15.5%) | 20 of 202 (9.3%) | 0.61 | 0.092 |
| Regression of symptomatic ICAS | Secondary | 49 of 207 (23.7%) | 61 of 202 (30.2%) | 0.139 | |
| Progression of asymptomatic ICAS | Secondary | 13 of 414 (3.1%) | 8 of 404 (2.0%) | 0.306 | |
| Regression of asymptomatic ICAS | Secondary | 15 of 414 (3.6%) | 26 of 404 (6.4%) | 0.068 | |
| New ischemic lesions on follow-up MRI | Secondary | 23 of 191 (12.0%) | 34 of 182 (18.7%) | 0.078 | |
| New ischemic lesions in the territory of ICAS | Secondary | 17 of 191 (8.9%) | 22 of 182 (12.0%) | 0.321 | |
| Total cardiovascular events (nonfatal stroke, nonfatal MI, and vascular death) | Secondary | 10 (4.4%) of 225 patients | 15 (6.4%) of 232 patients | 0.312 | |
| Nonfatal stroke | Secondary | 6 (2.6%) | 11 (4.7%) | 0.324 | |
| Nonfatal myocardial infarction | Secondary | 2 (0.8%) | 3 (1.3%) | 0.624 | |
| Vascular death | Secondary | 2 (0.8%) | 1 (0.4%) | 0.607 | |
| Major hemorrhagic complications | Adverse | 6 (2.6%) | 2 (0.9%) | 0.163 | |
| Life threatening hemorrhage | Adverse | 2 (0.8%) | 1 (0.4%) | ||
| Other major hemorrhage | Adverse | 4 (1.7%) | 1 (0.4%) | ||
| Headache | Adverse | 35 (15.1%) | 62 (26.7%) |
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.
Subgroup Analysis
No significant interaction was seen with the therapeutic effect of either cilostazol or clopidogrel, except for smoking (P=0.013 for the interaction).
Funding
Korea Otsuka Pharmaceutical (KOP) Company, Korea Otsuka International Asia, and Arab Co Ltd.
Based on: TOSS-2 (Stroke, 2011)
Authors: Sun U. Kwon, MD; Keun-Sik Hong, MD; Dong-Wha Kang, ..., MD; Jong S. Kim
Citation: Stroke. 2011;42:2883-2890.
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