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

Abstract

Purpose: To compare the effect of cilostazol plus aspirin versus aspirin alone on the progression of intracranial arterial stenosis (IAS), and to compare ischemic and hemorrhagic events in patients with symptomatic IAS, an investigator-driven, nationwide multicenter cooperative randomized controlled trial (CATHARSIS; ClinicalTrials.gov Identifier 00333164) was conducted. Methods: 165 noncardioembolic ischemic stroke patients with >50% stenosis in the responsible intracranial artery after 2 weeks to 6 months from the onset were randomly allocated to receive either cilostazol 200 mg/day plus aspirin 100 mg/day (n = 83, CA group) or aspirin 100 mg/day alone (n = 82, A group). The primary endpoint was the progression of IAS on magnetic resonance angiography at 2 years after randomization. Secondary endpoints were any vascular events, any cause of death, serious adverse events, new silent brain infarcts, and worsening of the modified Rankin Scale score. Results: Progression of IAS was observed in 9.6% of the CA group patients and in 5.6% of the A group patients, with no significant intergroup difference (p = 0.53). The incidence of the secondary endpoints tended to be lower in the CA group compared with the A group, although the differences were not significant. By using exploratory logistic regression analysis adjusted for patient background characteristics, it was shown that the risk for certain combinations of secondary endpoints was lower in the CA group than in the A group [all vascular events and silent brain infarcts: odds ratio (OR) = 0.37, p = 0.04; stroke and silent brain infarcts: OR = 0.34, p = 0.04; all vascular events, worsening of modified Rankin Scale scores and silent brain infracts: OR = 0.41, p = 0.03]. Major hemorrhage was observed in 4 patients of the CA group and in 3 of the A group. Conclusion: Progression ofIAS during the 2-year observation period appears to be less frequent than previously reported in stroke patients on antiplatelet agents after the acute phase, which could be due to the adequate control of risk factors, and because patients with stroke within 2 weeks after the onset were excluded. The results of the CATHARSIS trial suggest a potential utility of pharmacotherapies with cilostazol plus aspirin as well as of strict control of risk factors for the management of symptomatic IAS. Larger studies with higher statistical power are required to obtain conclusive results.

Cilostazol for Secondary Prevention of Stroke and Cognitive Decline

“…Of the 18 trials in patients with stroke, 2 only included patients with lacunar stroke (n=515), 11 , 12 3 only included patients with intracranial artery stenosis (n=755), 13 – 15 6 only included patients with noncardioembolic ischemic stroke (n=5264), 16 – 21 most trials excluded patients with cardioembolic stroke regardless of other inclusion criteria, and one trial included patients at high risk of intracerebral hemorrhage (n=1534). 22 In 9/18 trials, the stroke was lacunar in ≥40% of participants (n=6943); in the other 9 trials, <40% of patients had a lacunar ischemic stroke or the subtype proportion was not specified (n=3262).…”

“…The time to randomization after diagnosis was <2 weeks in 8 (n=1940), 12 , 14 , 15 , 19 – 21 , 23 , 24 between 2 weeks and 6 months in 5 (n=2123), 13 , 18 , 25 – 27 and 6 months or later in 6 trials (n=6406; including the one trial in cognitive decline/dementia) 10 , 11 , 16 , 17 , 22 , 28 and was not stated in the other trial in cognitive decline. 9 The duration of trial treatment was 4 weeks in 3 (n=344), 19 , 20 , 28 10 weeks in 1 (n=57), 11 4 months in 4 (n=1236), 12 , 20 , 22 , 23 6 to 8 months in 5 (n=753; including both trials in cognitive decline/dementia), 9 , 10 , 14 , 15 , 18 12 months in 1 (n=68), 27 and between 12 months and 5 years in 6 trials (n=8034).…”

“… 9 The duration of trial treatment was 4 weeks in 3 (n=344), 19 , 20 , 28 10 weeks in 1 (n=57), 11 4 months in 4 (n=1236), 12 , 20 , 22 , 23 6 to 8 months in 5 (n=753; including both trials in cognitive decline/dementia), 9 , 10 , 14 , 15 , 18 12 months in 1 (n=68), 27 and between 12 months and 5 years in 6 trials (n=8034). 13 , 16 , 17 , 22 , 25 , 26 …”

Comparison of long-term efficacy and safety between cilostazol and clopidogrel in chronic ischemic stroke: a nationwide cohort study

“…In cases with intracranial artery stenosis, cilostazol is reported to prevent the progression of symptomatic intracranial artery stenosis, either alone or in combination with aspirin, and to have better effect than aspirin. 31 – 33 Also, acute medication with cilostazol was found to be beneficial for the outcome of cerebral infarction due to small vessel disease, 34 and cilostazol could decrease cerebral arterial pulsatility in small vessel disease patients with mild white matter hyperintensity. 35 However, cilostazol plus aspirin had no significant difference compared with clopidogrel plus aspirin with respect to the reduced progression of artery stenosis, new ischemic lesions, and major hemorrhagic complications.…”

Assessment of Stroke and Concomitant Cerebrovascular Disease with Heart Disease Requires Invasive Treatment: Analysis of 249 Consecutive Patients with Heart Disease

“…Artery stenosis was classified into five grades based on the Cilostazol-Aspirin Therapy Against Recurrent Stroke with Intracranial Artery Stenosis Study as follows: normal, no evidence of stenosis (grade 0); mild, < 50% stenosis (grade 1); moderate, > 50% stenosis (grade 2); severe, partial distal flow loss (grade 3); and occlusion without distal flow (grade 4). 10 Significant stenosis in both extra-and intracranial arteries was defined as a stenosis diameter > 50% and grade 2.…”