Clinical trial NCT01013532: PreventIon of CArdiovascular Events in iSchemic Stroke Patients With High Risk of Cerebral HemOrrhage
Official title: 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
Study type: INTERVENTIONAL
Overall status: UNKNOWN
Phase: PHASE4
Conditions: Brain Ischemia
Intracranial Hemorrhages
Keywords: Ischemic Stroke
Intracranial Hemorrhage
Cilostazol
Probucol
Lead sponsor: Asan Medical Center
Sponsor class: OTHER
Collaborators: name: Korea Otsuka Pharmaceutical Co., Ltd.
First posted: 2009-11-13
Enrollment: 1600
Sex: ALL
Minimum age (years): 20
Standard ages: ADULT
OLDER_ADULT
Accepts healthy volunteers: no
Allocation: RANDOMIZED
Intervention model: FACTORIAL
Primary purpose: PREVENTION

Brief summary: 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: 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.

Eligibility criteria: 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

Primary outcomes:
measure: Time to the first occurrence of cerebral hemorrhage
timeFrame: time since randomization; follow-up period is 1.0 to 5.5 years
measure: Time to the first occurence of composite cardiovascular events
timeFrame: time since randomization; follow-up period is 1.0 to 5.5 years
Secondary outcomes:
measure: Time to the first occurrence of stroke
timeFrame: time since randomization; follow-up period is 1.0 to 5.5 years
measure: Time to the first occurrence of ischemic stroke
timeFrame: time since randomization; follow-up period is 1.0 to 5.5 years
measure: Time to the first occurence of myocardial infarction
timeFrame: time since randomization; follow-up period is 1.0 to 5.5 years
measure: Time to the first occurence of other designated vascular events
timeFrame: time since randomization; follow-up period is 1.0 to 5.5 years
Other outcomes:
measure: Incidence rate of major and non-major hemorrhagic event
timeFrame: time since randomization; follow-up period is 1.0 to 5.5 years
measure: Rate of asymptomatic hemorrhage in GRE (microhemorrhage or macrohemorrhage)
timeFrame: at final visit, follow-up MRI will be checked at the final visit
measure: Rate of new asymptomatic cerebral infarction lesion in FLAIR
timeFrame: at final visit, follow-up MRI will be checked at the final visit
measure: Change of ankle-brachial index
timeFrame: at final visit;follow-up period is 1.0 to 5.5 years
measure: The effect of the size of common carotid artery(CCA) including plaque on the occurrence of cardiovascular events
timeFrame: at final visit;follow-up period is 1.0 to 5.5 years
measure: Time to all deaths including vascular and non-vascular deaths
timeFrame: time since randomization; follow-up period is 1.0 to 5.5 years
measure: Incidence rate of dementia diagnosed after initiation of the trial
timeFrame: time since randomization; follow-up period is 1.0 to 5.5 years
Locations:
city: Hong Kong
country: China
facility: Pamela Youde Nethersole Eastern Hospital
state: Hong Kong
city: Hong Kong
country: China
facility: Queen Elizabeth Hospital
state: Hong Kong
city: Hong Kong
country: China
facility: United Christian Hospital
state: Hong Kong
city: Shatin, NT
country: China
facility: Prince of Wales Hospital
state: Hong Kong
city: Cheongju
country: Korea, Republic of
facility: Chungbuk National University Hospital
state: Chungbuk
city: Cheonan
country: Korea, Republic of
facility: Soonchunhyang University Cheonan Hospital
state: Chungcheongnam-do
city: Wonju
country: Korea, Republic of
facility: Wonju Christian Hospital
state: Gangwon-do
city: Gyeonggi-do
country: Korea, Republic of
facility: Kwandong University College of Medicine Myongji Hospital
state: Goyang
city: Jinju
country: Korea, Republic of
facility: Gyeongsang National University Hospital
state: Gyengsangnam-do
city: Ansan
country: Korea, Republic of
facility: Korea University Ansan Hospital
state: Gyeonggi-do
city: Bucheon
country: Korea, Republic of
facility: Soonchunhyang University Bucheon Hospital
state: Gyeonggi-do
city: Goyang-si
country: Korea, Republic of
facility: National Health Insurance Corporation Ilsan Hoapital
state: Gyeonggi-do
city: Goyang
country: Korea, Republic of
facility: Inje University Ilsan Paik Hospital
state: Gyeonggi-do
city: Guri
country: Korea, Republic of
facility: Hanyang University Guri Hospital
state: Gyeonggi-do
city: Seongnam-si
country: Korea, Republic of
facility: Bundang Medical Center, CHA University
state: Gyeonggi-do
city: Uijeongbu
country: Korea, Republic of
facility: Uijeongbu St. Mary's Hospital
state: Gyeonggi-do
city: Changwon
country: Korea, Republic of
facility: Samsung changwon Medical Center
state: Gyeongsangnam-do
city: Iksan
country: Korea, Republic of
facility: Wonkwang University Hospital
state: Jeonbuk
city: Jeonju-si
country: Korea, Republic of
facility: Chonbuk National University Hospital
state: Jeonbuk
city: Chuncheon
country: Korea, Republic of
facility: Kangwon National University Hospital
state: Kangwon-do
city: Changwon
country: Korea, Republic of
facility: Chang Won Fatima hospital
state: Kyeongsangnam-do
city: Goyang
country: Korea, Republic of
facility: Dongguk University International Hospital
state: Kyoungki-do
city: Anyang
country: Korea, Republic of
facility: Hallym University Sacred Heart Hospital
state: Kyunggi
city: Seongnam
country: Korea, Republic of
facility: Seoul National University Bundang Hospital
state: Kyunggi
city: Suwon
country: Korea, Republic of
facility: Ajou University Hospital
state: Kyunggi
city: Busan
country: Korea, Republic of
facility: Kosin University Gospel Hospital
city: Busan
country: Korea, Republic of
facility: Inje University Pusan Paik Hospital
city: Busan
country: Korea, Republic of
facility: Pusan National University Hospital
city: Busan
country: Korea, Republic of
facility: Dong-A University Hospital
city: Daegu
country: Korea, Republic of
facility: Keimyung University Dongsan Center
city: Daegu
country: Korea, Republic of
facility: Daegu Fatima Hospital
city: Daejon
country: Korea, Republic of
facility: Eulji University Hospital
city: Deagu
country: Korea, Republic of
facility: Dongsan Medical Center
city: Deagu
country: Korea, Republic of
facility: Kyungpook National University Hospital
city: Deagu
country: Korea, Republic of
facility: Yeungnam University Medical Center
city: Deagu
country: Korea, Republic of
facility: Deagu Catholic University Hospital
city: Deajeon
country: Korea, Republic of
facility: Chungnam National University Hospital
city: Deajeon
country: Korea, Republic of
facility: Deajeon St.Mary's Hospital, The Catholic University of Korea
city: GwangJu
country: Korea, Republic of
facility: Chosun University Hospital
city: Gwangju
country: Korea, Republic of
facility: Chonnam National University Hospital
city: Incheon
country: Korea, Republic of
facility: Gachon University Gil Hoapital
city: Inchon
country: Korea, Republic of
facility: Inha University Hospital
city: Pusan
country: Korea, Republic of
facility: Wallace Memorial Baptist Hospital
city: Seoul
country: Korea, Republic of
facility: National Medical Center
city: Seoul
country: Korea, Republic of
facility: Kangbuk Samsung Hospital
city: Seoul
country: Korea, Republic of
facility: Severance Hospital
city: Seoul
country: Korea, Republic of
facility: Kyung Hee University Medical Center
city: Seoul
country: Korea, Republic of
facility: Hanyang University Medical Center
city: Seoul
country: Korea, Republic of
facility: Kangdong Sacred Heart Hospital, Hallym University
city: Seoul
country: Korea, Republic of
facility: Gangnam Severance Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul Medical Center
city: Seoul
country: Korea, Republic of
facility: Korea University Anam Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul St.Mary's Hospital
city: Seoul
country: Korea, Republic of
facility: Asan Medical Center
city: Seoul
country: Korea, Republic of
facility: Inje University Sanggye Paik Hospital
city: Seoul
country: Korea, Republic of
facility: Konkuk Univ. Hospital
city: Seoul
country: Korea, Republic of
facility: St. Mary's Hospital
city: Seoul
country: Korea, Republic of
facility: Hangang Sacred Heart Hospital
city: Seoul
country: Korea, Republic of
facility: Kangnam Sacred Heart Hospital, Hallym University College of Medicine
city: Seoul
country: Korea, Republic of
facility: Korea University Guro Hospital
city: Seoul
country: Korea, Republic of
facility: Seoul National University Borame Hospital
city: Seoul
country: Korea, Republic of
facility: Ewha Womans University Medical Center
city: Seoul
country: Korea, Republic of
facility: Eulji Hospital
city: Seoul
country: Korea, Republic of
facility: Chung-Ang University Medical Center
city: Seoul
country: Korea, Republic of
facility: Seoul National University Hospital
city: Seoul
country: Korea, Republic of
facility: Soonchunhyang University Hospital
city: Ulsan
country: Korea, Republic of
facility: Ulsan University Hospital
city: Manila
country: Philippines
facility: Manila Doctors Hospital
city: Manila
country: Philippines
facility: University of Santo Tomas
city: Pasig
country: Philippines
facility: The Medical City
city: Quezon City
country: Philippines
facility: St. Luke's Medical Center
Study officials:
affiliation: Departement of Neurology, Asan Medical Center
name: Sun U. Kwon, MD, PhD
role: PRINCIPAL_INVESTIGATOR
References:
citation: Park JH, Lee J, Kwon SU, Sung Kwon H, Hwan Lee M, Kang DW. Elevated Pulse Pressure and Recurrent Hemorrhagic Stroke Risk in Stroke With Cerebral Microbleeds or Intracerebral Hemorrhage. J Am Heart Assoc. 2022 Feb;11(3):e022317. doi: 10.1161/JAHA.121.022317. Epub 2021 Nov 15.
citation: Cho KH, Kwon SU, Lee JS, Yu S, Cho AH. Newly diagnosed diabetes has high risk for cardiovascular outcome in ischemic stroke patients. Sci Rep. 2021 Jun 21;11(1):12929. doi: 10.1038/s41598-021-92349-y.
citation: Park HK, Lee JS, Kim BJ, Park JH, Kim YJ, Yu S, Hwang YH, Rha JH, Heo SH, Ahn SH, Seo WK, Park JM, Lee JH, Kwon JH, Sohn SI, Jung JM, Kwon SU, Hong KS; PICASSO investigators. Cilostazol versus aspirin in ischemic stroke with cerebral microbleeds versus prior intracerebral hemorrhage. Int J Stroke. 2021 Dec;16(9):1019-1030. doi: 10.1177/1747493020941273. Epub 2020 Jul 14.
citation: Lee EJ, Kwon SU, Park JH, Kim YJ, Hong KS, Yu S, Hwang YH, Lee JS, Lee J, Rha JH, Heo SH, Ahn SH, Seo WK, Park JM, Lee JH, Kwon JH, Sohn SI, Jung JM, Kim HY, Kim EG, Kim SH, Cha JK, Park MS, Nam HS, Kang DW; PICASSO Investigators. Changes in High-Density Lipoprotein Cholesterol and Risks of Cardiovascular Events: A Post Hoc Analysis from the PICASSO Trial. J Stroke. 2020 Jan;22(1):108-118. doi: 10.5853/jos.2019.02551. Epub 2020 Jan 31.
citation: Kim BJ, Kwon SU, Park JH, Kim YJ, Hong KS, Wong LKS, Yu S, Hwang YH, Lee JS, Lee J, Rha JH, Heo SH, Ahn SH, Seo WK, Park JM, Lee JH, Kwon JH, Sohn SI, Jung JM, Navarro JC, Kim HY, Kim EG, Kim S, Cha JK, Park MS, Nam HS, Kang DW; PICASSO Investigators. Cilostazol Versus Aspirin in Ischemic Stroke Patients With High-Risk Cerebral Hemorrhage: Subgroup Analysis of the PICASSO Trial. Stroke. 2020 Mar;51(3):931-937. doi: 10.1161/STROKEAHA.119.023855. Epub 2019 Dec 20.
citation: Kim BJ, Lee EJ, Kwon SU, Park JH, Kim YJ, Hong KS, Wong LKS, Yu S, Hwang YH, Lee JS, Lee J, Rha JH, Heo SH, Ahn SH, Seo WK, Park JM, Lee JH, Kwon JH, Sohn SI, Jung JM, Navarro JC, Kang DW; PICASSO investigators. Prevention of cardiovascular events in Asian patients with ischaemic stroke at high risk of cerebral haemorrhage (PICASSO): a multicentre, randomised controlled trial. Lancet Neurol. 2018 Jun;17(6):509-518. doi: 10.1016/S1474-4422(18)30128-5.
citation: Park TH, Lee JS, Park SS, Ko Y, Lee SJ, Lee KB, Lee J, Kang K, Park JM, Choi JC, Kim DE, Cho YJ, Kim JT, Kim DH, Cha JK, Han MK, Lee J, Oh MS, Yu KH, Lee BC, Bae HJ, Hong KS. Safety and efficacy of intravenous recombinant tissue plasminogen activator administered in the 3- to 4.5-hour window in Korea. J Stroke Cerebrovasc Dis. 2014 Aug;23(7):1805-12. doi: 10.1016/j.jstrokecerebrovasdis.2014.04.027. Epub 2014 Jun 21.