Dr. Inna Lutsenko, ESO Social Media and PR Committee
Department of Neurology, Hietzing Hospital, Vienna, Austria
Twitter: @inna_lutsenko

By Dr. Inna Lutsenko

In future ESO blog articles we will try to recall the events and clinical trials of past ESO Conferences and today we are coming back to 2017, when the clinical trial PICASSO was presented at the opening Plenary session by the principal investigators, Prof. Sun U Kwon and Prof. Eun-Jae Lee of the Asan Medical Center, Seoul, Republic of Korea.

It is well known that stroke burden and mortality are higher in Asian countries than in non-Asian countries (1) and that Asian people are more susceptible to intracerebral hemorrhage as well as to microangiopathies. Antiplatelet treatment such as aspirin is the main approach in the secondary stroke prevention but it is simultaneously increasing the cerebral hemorrhage risk in the Asian population (2) together with statins (3). Hence, the need for other lipid-lowering medications for the Asian cohort was emphasized and the clinical trial named PICASSO (The Prevention of Cardiovascular Events in Ischemic Stroke Patients with High Risk of Cerebral Hemorrhage) was designed in Korea. PICASSO aimed to assess the efficacy of cilostazol compared to aspirin in the prevention of major vascular events and the efficacy of probucol, which was added either to aspirin or to the cilostazol group.

Cilostazol, a type III phosphodiesterase inhibitor, can improve endothelial dysfunction and decrease platelet aggregation (7), thus demonstrating a number of activities that may contribute to its efficacy in stroke prevention. Favorable characteristics of cilostazol include inhibition of smooth muscle proliferation, induction of vasodilatation and reduction of inflammation (5).

Probucol is an antioxidative and lipid-lowering medication that lowers HDL-C levels but does not worsen atherosclerosis, having, in contrast, strong antiatherosclerotic and antiaging effects, prevents restenosis, and has been used to treat atherosclerotic cardiovascular diseases and xanthomas (6,8). If patients have used high doses of statins but their LDL‐C still does not meet the target standard or if low doses of statins cause LDL‐C intolerance, other drugs, such as PU, must be combined (8).

The 2 by 2 factorial randomized trial design was a model for the PICASSO trial, which was comparing the efficacy of cilostazol or probucol to placebo in 1512 patients with a non-cardioembolic ischaemic stroke, TIA at an increased risk of intracerebral hemorrhage due to previous hemorrhage or multiple microhemorrhages in brain imaging (4). 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 centralized blocks stratified by center (9).

The study found that in patients with non-cardioembolic ischemic stroke with a high risk of future hemorrhage, cilostazol was non-inferior to aspirin in preventing a composite of cardiovascular events, but not superior to aspirin in reducing cerebral hemorrhage (4). Adding probucol to cilostazol or aspirin reduced the incidence of the cerebrovascular events but did not reduce the risk of cerebral hemorrhage.

In this population, probucol significantly reduced the risk of recurrent cardiovascular events, offering a potential new treatment for secondary prevention of ischaemic stroke in patients at an increased risk of cerebral hemorrhage (9). Although this requires confirmation in other clinical populations, it offers an exciting new treatment approach in these difficult patients at risk of both major forms of stroke.

“Probucol treatment in addition to standard lipid regimen may be more efficacious than standard lipid treatment, although more further research is needed,” commented Prof. Lee.

1. Qureshi AI, Mendelow AD, Hanley DF. Intracerebral hemorrhage. Lancet 2009; 373: 1632–44. DOI: 10.1016/S0140-6736(09)60371-8
2. Lee M, Saver JL, Hong KS, Rao NM, Wu YL, Ovbiagele B. Risk-benefit profile of long-term dual- versus single-antiplatelet therapy among patients with ischemic stroke: a systematic review and meta-analysis. Ann Intern Med 2013; 159: 463–70.DOI: 10.7326/0003-4819-159-7-201310010-00006
3. McKinney JS, Kostis WJ. Statin therapy and the risk of intracerebral hemorrhage: a meta-analysis of 31 randomized controlled trials. Stroke 2012; 43: 2149–56. DOI: 10.1161/STROKEAHA.112.655894
4. 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. PMID: 31856691.
5. Aoki C, Hattori Y, Tomizawa A, Jojima T, Kasai K. Anti-inflammatory role of cilostazol in vascular smooth muscle cells in vitro and in vivo. J Atheroscler Thromb 2010; 17: 503–09.
6. Lang L, Zhang J, Zheng D, Gao H. Probucol will become a new model for treating cerebral infarction with a high risk of hemorrhage: A narrative review. Brain Circ. 2023 Nov 30;9(4):222-227. doi: 10.4103/bc.bc_44_23. PMID: 38284116; PMCID: PMC10821687.
7. Masayasu Matsumoto. Cilostazol in secondary prevention of stroke: Impact of the Cilostazol Stroke Prevention Study, Atherosclerosis Supplements
8. Lang, Liguo1,2; Zhang, Jianying1; Zheng, Dongju3; Gao, Huanmin1. Probucol will become a new model for treating cerebral infarction with a high risk of hemorrhage: A narrative review. Brain Circulation 9(4):p 222-227, Oct–Dec 2023. | DOI: 10.4103/bc.bc_44_23
9. Kim BJ, Lee EJ, Kwon SU, Park JH, Kim YJ, Hong KS, Wong LK, Yu S, Hwang YH, Lee JS, Lee J. Prevention of cardiovascular events in Asian patients with ischaemic stroke at high risk of cerebral haemorrhage (PICASSO): a multicentre, randomised controlled trial. The Lancet Neurology. 2018 Jun 1;17(6):509-18.
10. ESOC 2017 Materials: Sun Kwon PICASSO Trial at ESOC 2017–pLfVE