Cerebral Infarction
Conditions
Keywords
Infarction, Cerebral, Cilostazol, Aspirin Resistance
Brief summary
This study will recruit 316 ischemic stroke patients taking aspirin. They will be randomly assigned into cilostazol group or placebo group. Every patients will take 200mg of cilostazol a day or placebo for 1 month. The primary outcome variable of this study is rate of biochemical aspirin resistance on the Ultra Rapid Platelet Function Assay-ASA.
Detailed description
\[Goal\] To reveal the effect and safety of additional cilostazol for overcoming biochemical aspirin resistance. \[Trial Design\] Double-Blind, Placebo-Controlled, Randomized, Multicenter Trial \[Participants\] Ischemic stroke patients taking aspirin \[Methods\] * Double-Blind, Placebo-Controlled, Randomized, Multicenter Trial * Investigational product: Cilostazol 200mg (100mg twice per day) * Concomitant medication: Aspirin 100 mg per day * Medication Duration: 1 month \[Outcome Variables\] Primary Outcome Variable: • the proportion of patients with aspirin reaction units (ARUs) values ≥550 on the Ultra Rapid Platelet Function Assay-ASA Secondary outcome variables: * the proportion of patients with ARUs values ≥500 on the Ultra Rapid Platelet Function Assay-ASA * ARUs values * Bleeding time (BT) * Fatal or major bleeding complications * Any bleeding complications
Interventions
DRUGplacebo
placebo 1 tablet twice a day matching for cilostazol
DRUGCilostazol
cilostazol 100mg twice a day for 4 weeks
Sponsors
Korea Otsuka Pharmaceutical Co., Ltd.
Asan Medical Center
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
TREATMENT
Masking
QUADRUPLE (Subject, Caregiver, Investigator, Outcomes Assessor)
Eligibility
Sex/Gender
ALL
Age
35 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Symptomatic cerebral infarction documented on MRI or CT * More than 35 years of age * Patients taking aspirin 100mg a day for 2 weeks or more before randomization
Exclusion criteria
* Patients taking any antiplatelets other than aspirin within 2 weeks before randomization * Patients taking any anticoagulants within 2 weeks before randomization * Patients taking thrombolytic therapy within 2 weeks before randomization * Patients taking any NSAIDs within 2 weeks before randomization * Patients who need to take NSAIDs regularly (e.g. rheumatic arthritis). * Bleeding diathesis * Chronic liver disease (ALT \> 100 or AST \> 100) or chronic renal disease (creatinine \> 3.0mg/dl) * Anemia (hemoglobin \< 10mg/dl) or thrombocytopenia (platelet count less than 100,000/mm3) * Pregnant or lactating patients * Patients scheduled for angioplasty or revascularization procedures within 4 weeks * Patients scheduled for any surgery or invasive procedures within 4 weeks * Patients having acute coronary syndrome
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Aspirin Resistance (ARU ≥ 550) | 4 weeks after treatment | The number of patients with aspirin reaction units (ARUs) values ≥ 550 on the Ultra Rapid Platelet Function Assay-ASA among the recruited patients |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Bleeding Time (BT) | 4 weeks after reatment | for evaluation of the extent of the bleeding time prolongation by additional cilostazol |
| Fatal or Major Bleeding Complications; | events ocurred during study medication after randomization | Fatal or life-threatening bleeding was defined as any fatal bleeding event, a drop in hemoglobin of ≥ 50g/L, or significant hypotension with need for inotropic agents, symptomatic intracranial hemorrhage, or transfusion of ≥ 4 units of red-blood cells or equivalent amount of whole blood. Major bleeding was defined as significantly disabling bleedings, intraocular bleeding leading to significant visual loss, or bleeding requiring transfusion of ≤ 3 units of red-blood cells or equivalent amount of whole blood |
| Aspirin Resistance (ARU ≥ 500) | 4 weeks after reatment | The number of participants with ARUs values ≥500 on the Ultra Rapid Platelet Function Assay-ASA; ARUs values |
| Difference of Post-treatment ARU and Baseline ARU | baseline ARU measured at the randomization and post-treatment ARU measured at the 4weeks treatment with study medication | summation of change of ARU (posttreatment ARU - baseline ARU) of individual patients |
| Post-treatment ARU | after 4 weeks treatment | mean of ARU value of individual participants after 4 weeks treatment |
| Any Bleeding Complications | events ocurred during study medication after randomization | any bleeding events causing medical attention |
Countries
South Korea
Participant flow
Recruitment details
244 patients with subacute or chronic ischemic stroke were recruited from outpatient clinics of 5 comprehensive stroke centers of Korea
Pre-assignment details
Patients with aspirin therapy were recruited due to subacute or chronic ischemic stroke. The patients should have taken aspirin 100mg per day at least 2 weeks before randomization
Participants by arm
| Arm | Count |
|---|---|
| Cilostazol Cilostazol 100mg twice per day | 125 |
| Placebo matching placebo to cilostazol | 119 |
| Total | 244 |
Withdrawals & dropouts
| Period | Reason | FG000 | FG001 |
|---|---|---|---|
| Overall Study | Lost to Follow-up | 1 | 1 |
| Overall Study | poor compliance | 8 | 6 |
| Overall Study | Withdrawal by Subject | 8 | 3 |
Baseline characteristics
| Characteristic | Total | Cilostazol | Placebo |
|---|---|---|---|
| Age, Categorical <=18 years | 0 Participants | 0 Participants | 0 Participants |
| Age, Categorical >=65 years | 98 Participants | 50 Participants | 48 Participants |
| Age, Categorical Between 18 and 65 years | 146 Participants | 75 Participants | 71 Participants |
| Age Continuous | 62.02 years STANDARD_DEVIATION 10.095 | 61.24 years STANDARD_DEVIATION 10.198 | 62.83 years STANDARD_DEVIATION 9.963 |
| Region of Enrollment Korea, Republic of | 244 participants | 125 participants | 119 participants |
| Sex: Female, Male Female | 77 Participants | 36 Participants | 41 Participants |
| Sex: Female, Male Male | 167 Participants | 89 Participants | 78 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — |
| other Total, other adverse events | 7 / 125 | 2 / 119 |
| serious Total, serious adverse events | 0 / 125 | 0 / 119 |
Outcome results
Primary
Aspirin Resistance (ARU ≥ 550)
The number of patients with aspirin reaction units (ARUs) values ≥ 550 on the Ultra Rapid Platelet Function Assay-ASA among the recruited patients
Time frame: 4 weeks after treatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cilostazol | Aspirin Resistance (ARU ≥ 550) | 9 participants |
| Placebo | Aspirin Resistance (ARU ≥ 550) | 11 participants |
Comparison: We assumed that the prevalence of AR would be 12 % among ischemic stroke patients who were treated with aspirin 100 per day. The prevalence could be reduced to 4% with additional cilostazol therapyp-value: 0.654Chi-squared
Secondary
Any Bleeding Complications
any bleeding events causing medical attention
Time frame: events ocurred during study medication after randomization
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cilostazol | Any Bleeding Complications | 0 participants |
| Placebo | Any Bleeding Complications | 0 participants |
Secondary
Aspirin Resistance (ARU ≥ 500)
The number of participants with ARUs values ≥500 on the Ultra Rapid Platelet Function Assay-ASA; ARUs values
Time frame: 4 weeks after reatment
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cilostazol | Aspirin Resistance (ARU ≥ 500) | 20 participants |
| Placebo | Aspirin Resistance (ARU ≥ 500) | 28 participants |
Secondary
Bleeding Time (BT)
for evaluation of the extent of the bleeding time prolongation by additional cilostazol
Time frame: 4 weeks after reatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cilostazol | Bleeding Time (BT) | 113 seconds | Standard Deviation 38.5 |
| Placebo | Bleeding Time (BT) | 106 seconds | Standard Deviation 34.2 |
Secondary
Difference of Post-treatment ARU and Baseline ARU
summation of change of ARU (posttreatment ARU - baseline ARU) of individual patients
Time frame: baseline ARU measured at the randomization and post-treatment ARU measured at the 4weeks treatment with study medication
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cilostazol | Difference of Post-treatment ARU and Baseline ARU | -7.8 change of ARU measured | Standard Deviation 77.6 |
| Placebo | Difference of Post-treatment ARU and Baseline ARU | 12.1 change of ARU measured | Standard Deviation 71.1 |
Secondary
Fatal or Major Bleeding Complications;
Fatal or life-threatening bleeding was defined as any fatal bleeding event, a drop in hemoglobin of ≥ 50g/L, or significant hypotension with need for inotropic agents, symptomatic intracranial hemorrhage, or transfusion of ≥ 4 units of red-blood cells or equivalent amount of whole blood. Major bleeding was defined as significantly disabling bleedings, intraocular bleeding leading to significant visual loss, or bleeding requiring transfusion of ≤ 3 units of red-blood cells or equivalent amount of whole blood
Time frame: events ocurred during study medication after randomization
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| Cilostazol | Fatal or Major Bleeding Complications; | 0 participants |
| Placebo | Fatal or Major Bleeding Complications; | 0 participants |
Secondary
Post-treatment ARU
mean of ARU value of individual participants after 4 weeks treatment
Time frame: after 4 weeks treatment
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Cilostazol | Post-treatment ARU | 454.8 ARU | Standard Deviation 52.8 |
| Placebo | Post-treatment ARU | 473.6 ARU | Standard Deviation 63.9 |