Prevention of cardiovascular events in Asian patients with ischaemic stroke at high risk of cerebral haemorrhage (PICASSO)

a multicentre, randomised controlled trial

PICASSO Investigators

Research output: Contribution to journalArticle

12 Citations (Scopus)

Abstract

Background: The optimal treatment for patients with ischaemic stroke with a high risk of cerebral haemorrhage is unclear. We assessed the efficacy and safety of cilostazol versus aspirin, with and without probucol, in these patients. Methods: In this randomised, controlled, 2 × 2 factorial trial, we enrolled patients with ischaemic stroke with a history of or imaging findings of intracerebral haemorrhage or two or more microbleeds from 67 centres in three Asian countries. Patients were randomly assigned (1:1:1:1) to receive oral cilostazol (100 mg twice a day), aspirin (100 mg once a day), cilostazol plus probucol (250 mg twice a day), or aspirin plus probucol with centralised blocks stratified by centre. Cilostazol versus aspirin was investigated double-blinded; probucol treatment was open-label, but the outcome assessor was masked to assignment. The co-primary outcomes were incidence of the composite of stroke, myocardial infarction, or vascular death (efficacy) and incidence of haemorrhagic stroke (safety), which were assessed in intention-to-treat and modified intention-to-treat populations. Efficacy was analysed with a non-inferiority test and a superiority test if non-inferiority was satisfied. Safety was assessed with a superiority test only. This trial is registered with ClinicalTrials.gov, NCT01013532. Findings: Between Aug 1, 2009, and Aug 31, 2015, we randomly assigned 1534 patients to one of the four study groups, of whom 1512 were assessed for the co-primary endpoints. During a median follow-up of 1·9 years (IQR 1·0–3·0), the incidence of composite vascular events was 4·27 per 100 person-years in patients who received cilostazol and 5·33 per 100 person-years in patients who received aspirin (HR 0·80, 95% CI 0·57–1·11; non-inferiority p=0·0077; superiority p=0·18). Incidence of cerebral haemorrhage was 0·61 per 100 person-years in patients who received cilostazol and 1·20 per 100 person-years in those who received aspirin (HR 0·51, 97·5% CI 0·20–1·27; superiority p=0·18). The incidence of vascular events was 3·91 per 100 person-years in the probucol group compared with 5·75 per 100 person-years in the non-probucol group (HR 0·69, 95% CI 0·50–0·97; superiority p=0·0316). The incidence of cerebral haemorrhage was 0·72 per 100 person-years in the probucol group and 1·11 per 100 person-years in the non-probucol group (HR 0·65, 97·5% CI 0·27–1·57; p=0·55). Adverse events were similar across the four study groups; the most common events were dizziness, headache, diarrhoea, and constipation. Interpretation: In patients with ischaemic stroke at high risk of cerebral haemorrhage, cilostazol was non-inferior to aspirin for the prevention of cardiovascular events, but did not reduce the risk of haemorrhagic stroke. Addition of probucol to aspirin or cilostazol could be beneficial for reducing the incidence of cardiovascular events. Funding: Korea Otsuka Pharmaceutical.

Original languageEnglish
Pages (from-to)509-518
Number of pages10
JournalThe Lancet Neurology
Volume17
Issue number6
DOIs
Publication statusPublished - 2018 Jun 1

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Cerebral Hemorrhage
Probucol
Aspirin
Randomized Controlled Trials
Stroke
Incidence
Blood Vessels
Safety
cilostazol
Dizziness
Constipation
Korea
Headache
Diarrhea
Myocardial Infarction
Therapeutics

ASJC Scopus subject areas

  • Clinical Neurology

Cite this

@article{257f025fad3e48cfad4153f24a5d7ebc,
title = "Prevention of cardiovascular events in Asian patients with ischaemic stroke at high risk of cerebral haemorrhage (PICASSO): a multicentre, randomised controlled trial",
abstract = "Background: The optimal treatment for patients with ischaemic stroke with a high risk of cerebral haemorrhage is unclear. We assessed the efficacy and safety of cilostazol versus aspirin, with and without probucol, in these patients. Methods: In this randomised, controlled, 2 × 2 factorial trial, we enrolled patients with ischaemic stroke with a history of or imaging findings of intracerebral haemorrhage or two or more microbleeds from 67 centres in three Asian countries. Patients were randomly assigned (1:1:1:1) to receive oral cilostazol (100 mg twice a day), aspirin (100 mg once a day), cilostazol plus probucol (250 mg twice a day), or aspirin plus probucol with centralised blocks stratified by centre. Cilostazol versus aspirin was investigated double-blinded; probucol treatment was open-label, but the outcome assessor was masked to assignment. The co-primary outcomes were incidence of the composite of stroke, myocardial infarction, or vascular death (efficacy) and incidence of haemorrhagic stroke (safety), which were assessed in intention-to-treat and modified intention-to-treat populations. Efficacy was analysed with a non-inferiority test and a superiority test if non-inferiority was satisfied. Safety was assessed with a superiority test only. This trial is registered with ClinicalTrials.gov, NCT01013532. Findings: Between Aug 1, 2009, and Aug 31, 2015, we randomly assigned 1534 patients to one of the four study groups, of whom 1512 were assessed for the co-primary endpoints. During a median follow-up of 1·9 years (IQR 1·0–3·0), the incidence of composite vascular events was 4·27 per 100 person-years in patients who received cilostazol and 5·33 per 100 person-years in patients who received aspirin (HR 0·80, 95{\%} CI 0·57–1·11; non-inferiority p=0·0077; superiority p=0·18). Incidence of cerebral haemorrhage was 0·61 per 100 person-years in patients who received cilostazol and 1·20 per 100 person-years in those who received aspirin (HR 0·51, 97·5{\%} CI 0·20–1·27; superiority p=0·18). The incidence of vascular events was 3·91 per 100 person-years in the probucol group compared with 5·75 per 100 person-years in the non-probucol group (HR 0·69, 95{\%} CI 0·50–0·97; superiority p=0·0316). The incidence of cerebral haemorrhage was 0·72 per 100 person-years in the probucol group and 1·11 per 100 person-years in the non-probucol group (HR 0·65, 97·5{\%} CI 0·27–1·57; p=0·55). Adverse events were similar across the four study groups; the most common events were dizziness, headache, diarrhoea, and constipation. Interpretation: In patients with ischaemic stroke at high risk of cerebral haemorrhage, cilostazol was non-inferior to aspirin for the prevention of cardiovascular events, but did not reduce the risk of haemorrhagic stroke. Addition of probucol to aspirin or cilostazol could be beneficial for reducing the incidence of cardiovascular events. Funding: Korea Otsuka Pharmaceutical.",
author = "{PICASSO Investigators} and Kim, {Bum Joon} and Lee, {Eun Jae} and Kwon, {Sun U.} and Park, {Jong Ho} and Kim, {Yong Jae} and Hong, {Keun Sik} and Wong, {Lawrence K.S.} and Sungwook Yu and Hwang, {Yang Ha} and Lee, {Ji Sung} and Juneyoung Lee and Rha, {Joung Ho} and Heo, {Sung Hyuk} and Ahn, {Sung Hwan} and Seo, {Woo Keun} and Park, {Jong Moo} and Lee, {Ju Hun} and Kwon, {Jee Hyun} and Sohn, {Sung Il} and Jin-Man Jung and Navarro, {Jose C.} and Kang, {Dong Wha} and Kwon, {Sun U.} and Juneyoung Lee and Kang, {Dong Wha} and Rha, {Joung Ho} and Park, {Jong Moo} and Lee, {Yong Seok} and Lee, {Ju Hun} and Kim, {Yong Jae} and Hong, {Keun Sik} and Yu, {Kyung Ho} and Sohn, {Sung Il} and Ahn, {Seong Hwan} and Cha, {Jae Kwan} and Park, {Man Seok} and Kim, {Jong S.} and Yoon, {Byung Woo} and Lee, {Byung Chul} and Nam, {Cheong Mo} and Koo, {Ja Seong} and Nam, {Hyo Seok} and Park, {Kwang Yeol} and Kim, {Dae Hyun} and Nah, {Hyun Wook} and Cho, {Yong Jin} and Kim, {Dong Eog} and Han, {Moon Ku} and Lee, {Kyung Bok} and Kyung-Hee Cho",
year = "2018",
month = "6",
day = "1",
doi = "10.1016/S1474-4422(18)30128-5",
language = "English",
volume = "17",
pages = "509--518",
journal = "The Lancet Neurology",
issn = "1474-4422",
publisher = "Lancet Publishing Group",
number = "6",

}

TY - JOUR

T1 - Prevention of cardiovascular events in Asian patients with ischaemic stroke at high risk of cerebral haemorrhage (PICASSO)

T2 - a multicentre, randomised controlled trial

AU - PICASSO Investigators

AU - Kim, Bum Joon

AU - Lee, Eun Jae

AU - Kwon, Sun U.

AU - Park, Jong Ho

AU - Kim, Yong Jae

AU - Hong, Keun Sik

AU - Wong, Lawrence K.S.

AU - Yu, Sungwook

AU - Hwang, Yang Ha

AU - Lee, Ji Sung

AU - Lee, Juneyoung

AU - Rha, Joung Ho

AU - Heo, Sung Hyuk

AU - Ahn, Sung Hwan

AU - Seo, Woo Keun

AU - Park, Jong Moo

AU - Lee, Ju Hun

AU - Kwon, Jee Hyun

AU - Sohn, Sung Il

AU - Jung, Jin-Man

AU - Navarro, Jose C.

AU - Kang, Dong Wha

AU - Kwon, Sun U.

AU - Lee, Juneyoung

AU - Kang, Dong Wha

AU - Rha, Joung Ho

AU - Park, Jong Moo

AU - Lee, Yong Seok

AU - Lee, Ju Hun

AU - Kim, Yong Jae

AU - Hong, Keun Sik

AU - Yu, Kyung Ho

AU - Sohn, Sung Il

AU - Ahn, Seong Hwan

AU - Cha, Jae Kwan

AU - Park, Man Seok

AU - Kim, Jong S.

AU - Yoon, Byung Woo

AU - Lee, Byung Chul

AU - Nam, Cheong Mo

AU - Koo, Ja Seong

AU - Nam, Hyo Seok

AU - Park, Kwang Yeol

AU - Kim, Dae Hyun

AU - Nah, Hyun Wook

AU - Cho, Yong Jin

AU - Kim, Dong Eog

AU - Han, Moon Ku

AU - Lee, Kyung Bok

AU - Cho, Kyung-Hee

PY - 2018/6/1

Y1 - 2018/6/1

N2 - Background: The optimal treatment for patients with ischaemic stroke with a high risk of cerebral haemorrhage is unclear. We assessed the efficacy and safety of cilostazol versus aspirin, with and without probucol, in these patients. Methods: In this randomised, controlled, 2 × 2 factorial trial, we enrolled patients with ischaemic stroke with a history of or imaging findings of intracerebral haemorrhage or two or more microbleeds from 67 centres in three Asian countries. Patients were randomly assigned (1:1:1:1) to receive oral cilostazol (100 mg twice a day), aspirin (100 mg once a day), cilostazol plus probucol (250 mg twice a day), or aspirin plus probucol with centralised blocks stratified by centre. Cilostazol versus aspirin was investigated double-blinded; probucol treatment was open-label, but the outcome assessor was masked to assignment. The co-primary outcomes were incidence of the composite of stroke, myocardial infarction, or vascular death (efficacy) and incidence of haemorrhagic stroke (safety), which were assessed in intention-to-treat and modified intention-to-treat populations. Efficacy was analysed with a non-inferiority test and a superiority test if non-inferiority was satisfied. Safety was assessed with a superiority test only. This trial is registered with ClinicalTrials.gov, NCT01013532. Findings: Between Aug 1, 2009, and Aug 31, 2015, we randomly assigned 1534 patients to one of the four study groups, of whom 1512 were assessed for the co-primary endpoints. During a median follow-up of 1·9 years (IQR 1·0–3·0), the incidence of composite vascular events was 4·27 per 100 person-years in patients who received cilostazol and 5·33 per 100 person-years in patients who received aspirin (HR 0·80, 95% CI 0·57–1·11; non-inferiority p=0·0077; superiority p=0·18). Incidence of cerebral haemorrhage was 0·61 per 100 person-years in patients who received cilostazol and 1·20 per 100 person-years in those who received aspirin (HR 0·51, 97·5% CI 0·20–1·27; superiority p=0·18). The incidence of vascular events was 3·91 per 100 person-years in the probucol group compared with 5·75 per 100 person-years in the non-probucol group (HR 0·69, 95% CI 0·50–0·97; superiority p=0·0316). The incidence of cerebral haemorrhage was 0·72 per 100 person-years in the probucol group and 1·11 per 100 person-years in the non-probucol group (HR 0·65, 97·5% CI 0·27–1·57; p=0·55). Adverse events were similar across the four study groups; the most common events were dizziness, headache, diarrhoea, and constipation. Interpretation: In patients with ischaemic stroke at high risk of cerebral haemorrhage, cilostazol was non-inferior to aspirin for the prevention of cardiovascular events, but did not reduce the risk of haemorrhagic stroke. Addition of probucol to aspirin or cilostazol could be beneficial for reducing the incidence of cardiovascular events. Funding: Korea Otsuka Pharmaceutical.

AB - Background: The optimal treatment for patients with ischaemic stroke with a high risk of cerebral haemorrhage is unclear. We assessed the efficacy and safety of cilostazol versus aspirin, with and without probucol, in these patients. Methods: In this randomised, controlled, 2 × 2 factorial trial, we enrolled patients with ischaemic stroke with a history of or imaging findings of intracerebral haemorrhage or two or more microbleeds from 67 centres in three Asian countries. Patients were randomly assigned (1:1:1:1) to receive oral cilostazol (100 mg twice a day), aspirin (100 mg once a day), cilostazol plus probucol (250 mg twice a day), or aspirin plus probucol with centralised blocks stratified by centre. Cilostazol versus aspirin was investigated double-blinded; probucol treatment was open-label, but the outcome assessor was masked to assignment. The co-primary outcomes were incidence of the composite of stroke, myocardial infarction, or vascular death (efficacy) and incidence of haemorrhagic stroke (safety), which were assessed in intention-to-treat and modified intention-to-treat populations. Efficacy was analysed with a non-inferiority test and a superiority test if non-inferiority was satisfied. Safety was assessed with a superiority test only. This trial is registered with ClinicalTrials.gov, NCT01013532. Findings: Between Aug 1, 2009, and Aug 31, 2015, we randomly assigned 1534 patients to one of the four study groups, of whom 1512 were assessed for the co-primary endpoints. During a median follow-up of 1·9 years (IQR 1·0–3·0), the incidence of composite vascular events was 4·27 per 100 person-years in patients who received cilostazol and 5·33 per 100 person-years in patients who received aspirin (HR 0·80, 95% CI 0·57–1·11; non-inferiority p=0·0077; superiority p=0·18). Incidence of cerebral haemorrhage was 0·61 per 100 person-years in patients who received cilostazol and 1·20 per 100 person-years in those who received aspirin (HR 0·51, 97·5% CI 0·20–1·27; superiority p=0·18). The incidence of vascular events was 3·91 per 100 person-years in the probucol group compared with 5·75 per 100 person-years in the non-probucol group (HR 0·69, 95% CI 0·50–0·97; superiority p=0·0316). The incidence of cerebral haemorrhage was 0·72 per 100 person-years in the probucol group and 1·11 per 100 person-years in the non-probucol group (HR 0·65, 97·5% CI 0·27–1·57; p=0·55). Adverse events were similar across the four study groups; the most common events were dizziness, headache, diarrhoea, and constipation. Interpretation: In patients with ischaemic stroke at high risk of cerebral haemorrhage, cilostazol was non-inferior to aspirin for the prevention of cardiovascular events, but did not reduce the risk of haemorrhagic stroke. Addition of probucol to aspirin or cilostazol could be beneficial for reducing the incidence of cardiovascular events. Funding: Korea Otsuka Pharmaceutical.

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U2 - 10.1016/S1474-4422(18)30128-5

DO - 10.1016/S1474-4422(18)30128-5

M3 - Article

VL - 17

SP - 509

EP - 518

JO - The Lancet Neurology

JF - The Lancet Neurology

SN - 1474-4422

IS - 6

ER -