PCSK9 Inhibitor for Intracranial Atherosclerosis Related Acute Ischemic Stroke

Summary

This study is a prospective, multicenter, double-blind, randomized, placebo-controlled clinical trial designed to evaluate whether early administration of PCSK9 inhibitors can effectively improve functional outcomes at 90 days in patients with ischemic stroke (AIS) associated with intracranial atherosclerotic stenosis (ICAS), primarily assessed using the modified Rankin Scale at 90 days.

Timeline

Start

2026-09-01

Primary completion

2028-12-31

Completion

2029-12-31

Publications

• Results Zhao W, Li S, Li C, Wu C, Wang J, Xing L, Wan Y, Qin J, Xu Y, Wang R, Wen C, Wang A, Liu L, Wang J, Song H, Feng W, Ma Q, Ji X; TREND Investigators. Effects of Tirofiban on Neurological Deterioration in Patients With Acute Ischemic Stroke: A Randomized Clinical Trial. JAMA Neurol. 2024 Jun 1;81(6):594-602. doi: 10.1001/jamaneurol.2024.0868.
• Results Tao C, Liu T, Cui T, Liu J, Li Z, Ren Y, Zhao X, Xie F, Li J, Wang H, Huang L, Li J, Wen J, Zeng J, Zhu J, Li Z, Li D, Hu X, Huang B, Wang J, Zhang C, Ye B, Hou Y, Gan Y, Sun H, Guan F, Shao Y, Liu Z, Ou Z, Fan S, Wang Y, Zhai H, Ni C, Wang H, Zhang C, Zhao Y, Wang G, Zhu Y, Li R, Sun J, Hu H, Cui J, Wang L, Zhang C, Song J, Jing X, Wang A, Wang J, Xu P, Qureshi AI, Nguyen TN, Nogueira RG, Saver JL, Hu W; ASSET-IT Investigators. Early Tirofiban Infusion after Intravenous Thrombolysis for Stroke. N Engl J Med. 2025 Sep 25;393(12):1191-1201. doi: 10.1056/NEJMoa2503678. Epub 2025 Jul 4.
• Results Wang C, Gu H, Huo X, Yuan B, Li S, Xu J, Jiang Y, Jing J, Yao X, Li Z, Long F, Ma Z, Zhuang X, Xu L, Jin Y, Huang W, Zhang Y, Wen J, Wang A, Pan Y, Ye W, Yu W, Cheng A, Wang M, Dong Q, Xu A, Wang N, Yang Y, Meng X, Liu L, Zhao X, Li H, Miao Z, Li Z, Wang Y; TASTE-2 investigators. Edaravone dexborneol versus placebo on functional outcomes in patients with acute ischaemic stroke undergoing endovascular thrombectomy (TASTE-2): randomised controlled trial. BMJ. 2026 Jan 7;392:e086850. doi: 10.1136/bmj-2025-086850.
• Results Writing Committee for the PEARL Investigators; Yang X, He X, Xu Y, Pan D, Li K, Chen Y, Zhu Y, Pan Y, Yi T, Zhang M, Peng H, Huang W, Li D, Feng J, Chen J, Lu W, Liao B, Xie Y, Liao B, Yang L, Tang L, Han B, Liu Y, Lin P, Chen J, Liang Y, Li D, Weng G, Huang H, Li H, Li C, Peng Z, Li H, He B, Xue R, Bao M, Sun H, Hou H, Zhou H, Xiao Y, Li J, Zhang W, Chen X, Yan W, Pi Y, Deng Z, Wang J, Xie D, Liu M, Li H, Peng Q, Fang W, Lin X, Chen Z, Li H, Lin Y, Lin Q, Xiao S, Miao Z, Wang D, Nguyen TN, Nogueira RG, Liu Y, Tang Y; PEARL investigators. Intra-Arterial Alteplase After Successful Endovascular Reperfusion in Acute Stroke: The PEARL Randomized Clinical Trial. JAMA. 2025 Oct 13;334(19):1728-39. doi: 10.1001/jama.2025.16876. Online ahead of print.
• Results Kim J, Hong U, Yoon CW, Bae JW, Rha JH, Park HK. PCSK9 inhibitor in acute ischemic stroke patient receiving mechanical thrombectomy: early outcomes and safety. Front Neurol. 2024 May 16;15:1375609. doi: 10.3389/fneur.2024.1375609. eCollection 2024.
• Results Liu L, Chen W, Zhou H, Duan W, Li S, Huo X, Xu W, Huang L, Zheng H, Liu J, Liu H, Wei Y, Xu J, Wang Y; Chinese Stroke Association Stroke Council Guideline Writing Committee. Chinese Stroke Association guidelines for clinical management of cerebrovascular disorders: executive summary and 2019 update of clinical management of ischaemic cerebrovascular diseases. Stroke Vasc Neurol. 2020 Jun;5(2):159-176. doi: 10.1136/svn-2020-000378. Epub 2020 Jun 18.
• Results Prabhakaran S, Gonzalez NR, Zachrison KS, Adeoye O, Alexandrov AW, Ansari SA, Chapman S, Czap AL, Dumitrascu OM, Ishida K, Jadhav AP, Johnson B, Johnston KC, Khatri P, Kimberly WT, Lee VH, Leslie-Mazwi TM, Mac Grory B, Madsen TE, Menon B, Mistry EA, Park S, Parker S, Perez de la Ossa N, Reeves M, Saiz T, Scott PA, Schwartzberg D, Sheth SA, Sporns PB, Times S, Tjoumakaris S, Wolfe SQ, Yaghi S; Peer Review Committee. 2026 Guideline for the Early Management of Patients With Acute Ischemic Stroke: A Guideline From the American Heart Association/American Stroke Association. Stroke. 2026 Jan 26. doi: 10.1161/STR.0000000000000513. Online ahead of print.
• Results Sun Y, Lv Q, Guo Y, Wang Z, Huang R, Gao X, Han Y, Yao Z, Zheng M, Luo S, Li Y, Gu X, Zhang Y, Wang J, Hong L, Ma X, Su G, Sheng J, Lai C, Shen A, Wang M, Zhang W, Wu S, Zheng Z, Li J, Zhong T, Wang Y, He L, Du X, Ma CS. Recaticimab as Add-On Therapy to Statins for Nonfamilial Hypercholesterolemia: The Randomized, Phase 3 REMAIN-2 Trial. J Am Coll Cardiol. 2024 Nov 12;84(20):2037-2047. doi: 10.1016/j.jacc.2024.09.012.
• Results Xu M, Wang Z, Zhang Y, Liu Y, Huang R, Han X, Yao Z, Sun J, Tian F, Hu X, Ma L, Lai C, Zhang X, Sheng J, Han Q, Jin C, Luo L, Zhao R, Li L, Xu B, Yin D, Luo S, Ge X, Liu Z, Yang P, Huang Z, Li T, Feng W, Wu Y, Ling Z, Ma L, Lv C, Deng C, Wei W, Wang Y, Yan L, Ge J; REMAIN-1 Investigators. Recaticimab Monotherapy for Nonfamilial Hypercholesterolemia and Mixed Hyperlipemia: The Phase 3 REMAIN-1 Randomized Trial. J Am Coll Cardiol. 2024 Nov 12;84(20):2026-2036. doi: 10.1016/j.jacc.2024.07.035. Epub 2024 Oct 9.
• Results Liu J, Li Y, Tian W, Cao H, Li X, Cheng L, Ji X, Liu J. Effects of PCSK9 inhibitor evolocumab on preventing early neurological deterioration in acute ischemic stroke patients with or without large artery atherosclerosis: a subgroup analysis of a randomized trial. BMC Neurol. 2025 Oct 17;25(1):431. doi: 10.1186/s12883-025-04434-8.
• Results Wu L, Zhang B, Li C, Zhuang Z, Liu K, Chen H, Zhu S, Zhu J, Dai Z, Huang H, Jiang Y. PCSK9 inhibitors reduced early recurrent stroke in patients with symptomatic intracranial atherosclerotic stenosis. J Neurol Neurosurg Psychiatry. 2024 May 14;95(6):529-535. doi: 10.1136/jnnp-2023-332392.
• Results Tian W, Cao H, Li X, Gong X, Yu X, Li D, Xie J, Bai Y, Zhang D, Li X, Xu P, Liu J, Zhang B, Ji X, Dong H. Adjunctive PCSK9 Inhibitor Evolocumab in the Prevention of Early Neurological Deterioration in Non-cardiogenic Acute Ischemic Stroke: A Multicenter, Prospective, Randomized, Open-Label, Clinical Trial. CNS Drugs. 2025 Feb;39(2):197-208. doi: 10.1007/s40263-024-01145-5. Epub 2025 Jan 5.
• Results Zeng W, Zhou F, Zhao H, Wang Y, Chen J, Lu J, Zheng D, Kuang J, Yuan D, Zhou J, Shi C, Zhao X, Leng X, Yan B, Tan Z. Evaluation of Intensive Statins and Proprotein Convertase Subtilisin/Kexin Type 9 Inhibitors on Intracranial Artery Plaque Stability: A Prospective Single-Arm Study. J Am Heart Assoc. 2025 Jan 21;14(2):e035651. doi: 10.1161/JAHA.124.035651. Epub 2025 Jan 17.
• Results Hu X, Liu Y, Yuan W, Zhang Z, Li S, Cheng A, Yu Q, Guo H, Zou Y, Li M, Liu C, Xu Y, Xu W. Evolocumab Added to Statin Is Associated With Intracranial Atherosclerotic Plaque Regression Compared With Statin Alone. J Am Heart Assoc. 2025 Aug 19;14(16):e041251. doi: 10.1161/JAHA.124.041251. Epub 2025 Aug 18.
• Results Jukema JW, Zijlstra LE, Bhatt DL, Bittner VA, Diaz R, Drexel H, Goodman SG, Kim YU, Pordy R, Reiner Z, Roe MT, Tse HF, Montenegro Valdovinos PC, White HD, Zeiher AM, Szarek M, Schwartz GG, Steg PG; ODYSSEY OUTCOMES Investigators. Effect of Alirocumab on Stroke in ODYSSEY OUTCOMES. Circulation. 2019 Dec 17;140(25):2054-2062. doi: 10.1161/CIRCULATIONAHA.119.043826. Epub 2019 Nov 11.
• Results Sabatine MS, Giugliano RP, Keech AC, Honarpour N, Wiviott SD, Murphy SA, Kuder JF, Wang H, Liu T, Wasserman SM, Sever PS, Pedersen TR; FOURIER Steering Committee and Investigators. Evolocumab and Clinical Outcomes in Patients with Cardiovascular Disease. N Engl J Med. 2017 May 4;376(18):1713-1722. doi: 10.1056/NEJMoa1615664. Epub 2017 Mar 17.
• Results Wang L, Wang Z, Shi J, Jiang Q, Wang H, Li X, Hao D. Inhibition of proprotein convertase subtilisin/kexin type 9 attenuates neuronal apoptosis following focal cerebral ischemia via apolipoprotein E receptor 2 downregulation in hyperlipidemic mice. Int J Mol Med. 2018 Oct;42(4):2098-2106. doi: 10.3892/ijmm.2018.3797. Epub 2018 Jul 31.
• Results Zheng Y, Zhu T, Li G, Xu L, Zhang Y. PCSK9 inhibitor protects against ischemic cerebral injury by attenuating inflammation via the GPNMB/CD44 pathway. Int Immunopharmacol. 2024 Jan 5;126:111195. doi: 10.1016/j.intimp.2023.111195. Epub 2023 Dec 4.
• Results Luo Y, Yuan L, Liu Z, Dong W, Huang L, Liao A, Xie Y, Liu R, Lan W, Cai Y, Zhu W. Inhibition of PCSK9 Protects against Cerebral Ischemia-Reperfusion Injury via Attenuating Microcirculatory Dysfunction. Neurochem Res. 2024 Nov 16;50(1):10. doi: 10.1007/s11064-024-04272-z.
• Results Punch E, Klein J, Diaba-Nuhoho P, Morawietz H, Garelnabi M. Effects of PCSK9 Targeting: Alleviating Oxidation, Inflammation, and Atherosclerosis. J Am Heart Assoc. 2022 Feb;11(3):e023328. doi: 10.1161/JAHA.121.023328. Epub 2022 Jan 20.
• Results Gutierrez J, Turan TN, Hoh BL, Chimowitz MI. Intracranial atherosclerotic stenosis: risk factors, diagnosis, and treatment. Lancet Neurol. 2022 Apr;21(4):355-368. doi: 10.1016/S1474-4422(21)00376-8. Epub 2022 Feb 7.
• Results Park TH, Lee JK, Park MS, Park SS, Hong KS, Ryu WS, Kim DE, Park MS, Choi KH, Kim JT, Kang J, Kim BJ, Han MK, Lee J, Cha JK, Kim DH, Kim JG, Lee SJ, Cho YJ, Kwon JH, Shin DI, Yeo MJ, Sohn SI, Hong JH, Lee JS, Choi JC, Kim WJ, Lee BC, Yu KH, Oh MS, Park JM, Kang K, Lee KB, Lee J, Gorelick PB, Bae HJ. Neurologic deterioration in patients with acute ischemic stroke or transient ischemic attack. Neurology. 2020 Oct 20;95(16):e2178-e2191. doi: 10.1212/WNL.0000000000010603. Epub 2020 Aug 14.
• Results Glavan M, Liu J, Sampaio Silva G, Nguyen TN, Zhou J, Sestan N, Kimberly WT, Sheth KN. Endovascular thrombectomy for acute stroke: evolving eligibility criteria and adjunct therapies. Lancet Neurol. 2026 Jan;25(1):61-76. doi: 10.1016/S1474-4422(25)00356-4.
• Results 《中国卒中中心报告》编写组. 《中国卒中中心报告 2020》概要.中国脑血管病杂志. 2021;18(11):737-743.

Drugs

Indications