PreventIon of CArdiovascular Events in iSchemic Stroke Patients With High Risk of Cerebral HemOrrhage

Study Overview
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Brief Summary
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Through this study, the investigators are to prove that Cilostazol effectively prevent cardiovascular events in ischemic stroke patients with high risk of cerebral hemorrhage, along with no significant increase in the risk of occurrence of hemorrhagic side effects. The primary hypothesis of this study is; Cilostazol alone or with probucol will reduce the risk of cerebral hemorrhage without increase of cardiovascular events compared to aspirin in the ischemic stroke patients with symptomatic or asymptomatic old cerebral hemorrhage. This study will prove the superiority of cilostazol on the prevention of cerebral hemorrhagic events without increasing the cardiovascular events against aspirin and the superiority of probucol on the prevention of overall cardiovascular events.

Detailed Description
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It has been generally accepted that 'old age' and 'hypertension' may be risk factors not only for cerebral infarction but also for cerebral hemorrhage. Usually 40 to 60 percent of recurrent strokes after cerebral hemorrhage cases are cerebral infarction; and 5 to 10 percent of recurrent stroke after cerebral infarction cases are cerebral hemorrhage. Consequently, for the reasons described above, hemorrhagic side effects including cerebral hemorrhage have been a great concern, in the usage of antiplatelet agent or anticoagulant for the secondary prevention in the patients with cerebral infarction. It is reported that the occurrence of cerebral hemorrhage tends to increase in cases of accompanying lacunar infarction which occurs more frequently in Asians than in Westerners, or periventricular ischemic change which increasingly occurs with ageing. Accordingly, the point is that the occurrence of cerebral hemorrhage should be primarily considered in the treatment of cerebral infarction, along with the phenomenon of an ageing population both in Asian countries including Korea. Nevertheless, so far there has been no clinical research regarding secondary prevention of stroke, particularly considering the risk of occurrence of hemorrhage in cerebral infarction cases. However, according to a recent study, when phosphodiesterase inhibitors including Cilostazol are used independently, or in combination with aspirin, secondary prevention can be improved without increasing the occurrence of hemorrhagic side effects. Considering this, if it is proved that the agent, Cilostazol, could decrease the risk of occurrence of stoke, along with no significant increase in the risk of occurrence of hemorrhagic side effects, by selecting a patent group with a high risk of cerebral hemorrhage, the agent (Cilostazol) may be recognized as an unique antiplatelet agent applicable to old-aged patient with cerebral infarction who have a certain risk of cerebral hemorrhage. High risk of cerebral hemorrhage is defined as presence of history of cerebral hemorrhage with appropriate neuroimage findings or presence of asymptomatic old cerebral hemorrhage findings(equal or more than 8mm) or multiple microbleeds on the GRE images. 1600 ischemic stroke patients with high risk of cerebral hemorrhage will be recruited and they are randomized into four groups (cilostazol plus probucol, aspirin plus probucol, cilostazol and aspirin) by 2X2 factorial design. IMT and ABI will be measured every year during follow-up period and the results will be compared with the baseline data. The change of IMT and ABI will be analyzed with the occurrence of cardiovascular events. The study will finish at least 1 year after the recruit of 1600th patients. Until the finish, all patients will continuously take study medications and visit every 3months at the study site. Brain MRI including FLAIR and GRE will be done at the final visits.

Official Title
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A Multicenter, Double Blind, Factorial Design, Phase IV Trial to Compare the Efficacy and Safety of Cilostazol Long-term Treatment With Aspirin in Ischemic Stroke Patients With High Risk of Cerebral Hemorrhage for the Prevention of Cerebral Hemorrhage and Cardiovascular Events and to Compare the Preventive Effect of Probucol in the Same Patient Group With Non-drug User Group for the Prevention of Cardiovascular Events

Conditions
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Brain Ischemia, Intracranial Hemorrhages

Intervention / Treatment
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* Drug: Cilostazol
* Drug: Probucol
* Drug: Aspirin
* Drug: placebo of cilostazol
* Drug: placebo of aspirin
* Device: ankle-brachial index (ABI)
* Device: intima-medial thickness (IMT)
* Device: new asymptomatic brain hemorrhage
* Device: new ischemic lesions on follow-up FLAIR images


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Patients with transient ischemic attack (TIA) or ischemic stroke within 180 days prior to screening - Adult aged 20 years or older High risk of hemorrhagic stroke (history of intracranial hemorrhage or imaging evidence of previous intracranial hemorrhage) Informed consent Exclusion Criteria: Clinical diagnosis of myocardial infarction or coronary intervention within 4 weeks Bleeding tendency Pregnant or breast-feeding woman Hemorrhagic stroke within 6 months Patient who was taking antithrombotic medication other than aspirin and does not agree to change the previous medication Severe cardiovascular disease such as cardiomyopathy or congestive heart failure Life expectancy less than one year Contraindication to long term aspirin use Enrolled in other clinical trial within 30 days

Ages Eligible for Study
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Minimum Age: 20 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Factorial Assignment
Masking: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Cilostazol+ Probucol<br>100mg cilostazol bid plus probucol plus placebo of aspirin | Drug: Cilostazol<br>* Cilostazol 100mg bid<br>* Other names: Pletaal produced by Korea Otsuka Pharmaceutical company;Drug: Probucol<br>* Probucol 250mg bid<br>* Other names: Probucol is produced by Otsuka Pharmaceutical;Drug: placebo of aspirin<br>* same size and shape of active aspirin 100mg<br>Device: ankle-brachial index (ABI)<br>* measurement of ABI every years during follow up<br>Device: intima-medial thickness (IMT)<br>* ultrasound measured IMT of both common carotid arteries<br>* Other names: change of maximal IMT and mean IMT;Device: new asymptomatic brain hemorrhage<br>* asymptomatic macrobleedings or microbleedings on GRE images<br>Device: new ischemic lesions on follow-up FLAIR images<br>* any new ischemic lesions<br>|
| Active Comparator: Aspirin + Probucol<br>aspirin plus placebo cilostazol plus probucol | Drug: Probucol<br>* Probucol 250mg bid<br>* Other names: Probucol is produced by Otsuka Pharmaceutical;Drug: Aspirin<br>* Aspirin 100mg qd<br>Drug: placebo of cilostazol<br>* same shape and size of active cilostazol<br>Device: ankle-brachial index (ABI)<br>* measurement of ABI every years during follow up<br>Device: intima-medial thickness (IMT)<br>* ultrasound measured IMT of both common carotid arteries<br>* Other names: change of maximal IMT and mean IMT;Device: new asymptomatic brain hemorrhage<br>* asymptomatic macrobleedings or microbleedings on GRE images<br>Device: new ischemic lesions on follow-up FLAIR images<br>* any new ischemic lesions<br>|
| Experimental: Cilostazol<br>cilostazol plus placebo of aspirin | Drug: Cilostazol<br>* Cilostazol 100mg bid<br>* Other names: Pletaal produced by Korea Otsuka Pharmaceutical company;Drug: placebo of aspirin<br>* same size and shape of active aspirin 100mg<br>Device: ankle-brachial index (ABI)<br>* measurement of ABI every years during follow up<br>Device: intima-medial thickness (IMT)<br>* ultrasound measured IMT of both common carotid arteries<br>* Other names: change of maximal IMT and mean IMT;Device: new asymptomatic brain hemorrhage<br>* asymptomatic macrobleedings or microbleedings on GRE images<br>Device: new ischemic lesions on follow-up FLAIR images<br>* any new ischemic lesions<br>|
| Active Comparator: Aspirin<br>aspirin plus placebo of cilostazol | Drug: Aspirin<br>* Aspirin 100mg qd<br>Drug: placebo of cilostazol<br>* same shape and size of active cilostazol<br>Device: ankle-brachial index (ABI)<br>* measurement of ABI every years during follow up<br>Device: intima-medial thickness (IMT)<br>* ultrasound measured IMT of both common carotid arteries<br>* Other names: change of maximal IMT and mean IMT;Device: new asymptomatic brain hemorrhage<br>* asymptomatic macrobleedings or microbleedings on GRE images<br>Device: new ischemic lesions on follow-up FLAIR images<br>* any new ischemic lesions<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to the first occurrence of cerebral hemorrhage |  | time since randomization; follow-up period is 1.0 to 5.5 years | 
| Time to the first occurence of composite cardiovascular events |  | time since randomization; follow-up period is 1.0 to 5.5 years | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time to the first occurrence of stroke |  | time since randomization; follow-up period is 1.0 to 5.5 years | 
| Time to the first occurrence of ischemic stroke |  | time since randomization; follow-up period is 1.0 to 5.5 years | 
| Time to the first occurence of myocardial infarction |  | time since randomization; follow-up period is 1.0 to 5.5 years | 
| Time to the first occurence of other designated vascular events |  | time since randomization; follow-up period is 1.0 to 5.5 years | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Ischemic Stroke, Intracranial Hemorrhage, Cilostazol, Probucol