{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T15:16:29Z","timestamp":1783005389818,"version":"3.54.5"},"reference-count":39,"publisher":"MDPI AG","issue":"13","license":[{"start":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T00:00:00Z","timestamp":1782950400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["JCM"],"abstract":"<jats:p>Background: Dyslipidemia is a modifiable risk factor and predictive biomarker for acute ischemic stroke (AIS) that necessitates early, aggressive lipid-lowering therapy to achieve target low-density lipoprotein cholesterol (LDL-C) levels for primary and secondary prevention. In certain patients, this can be difficult to achieve with statins alone. Proprotein convertase subtilisin\/kexin type 9 inhibitor (PCSK9i) lipid-lowering agents may improve outcomes when introduced early. This review assessed whether early PCSK9i administration (within 3 weeks of AIS) reduced early neurological deterioration (END), recurrent stroke\/transient ischemic attack (TIA), poor functional outcomes, and mortality. Methods: This systematic review and meta-analysis included randomized clinical trials (RCTs) and observational studies. Random-effects meta-analysis and subgroup and sensitivity analyses were used to assess whether effects differed by treatment timing (\u226472 vs. &gt;72 h) and study design. Results: Eight studies (three randomized clinical trials) in East Asian cohorts were included. Early PCSK9i initiation significantly reduced END compared with usual care (odds ratio [OR]: 0.39; 95% confidence interval [CI]: 0.26\u20130.57). Stroke\/TIA recurrence and all-cause mortality within 6 months of stroke were also significantly reduced in the PCSK9i group (OR: 0.47; 95% CI: 0.28\u20130.77 and OR: 0.33; 95% CI: 0.15\u20130.72, respectively), and early initiation was associated with a greater likelihood of good functional outcomes at 90 days (OR: 2.28; 95% CI: 1.48\u20133.51). Sensitivity analyses yielded consistent results. Conclusions: Early PCSK9i initiation within 3 weeks of AIS onset was associated with lower rates of END, recurrent stroke\/TIA, and mortality, although the certainty of evidence was limited by the small number of included studies and the predominantly observational data. Outcomes did not differ significantly by initiation timing within this period. Large-scale trials in diverse populations are needed to define the optimal initiation window and long-term clinical effects.<\/jats:p>","DOI":"10.3390\/jcm15135169","type":"journal-article","created":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T14:43:14Z","timestamp":1783003394000},"page":"5169","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Clinical Outcomes of Early Administration of Proprotein Convertase Subtilisin\/Kexin Type 9 Inhibitors in East Asian Patients with Acute Ischemic Stroke: A Systematic Review and Meta-Analysis"],"prefix":"10.3390","volume":"15","author":[{"ORCID":"https:\/\/orcid.org\/0009-0003-6148-4686","authenticated-orcid":false,"given":"Sarah","family":"Alqhtani","sequence":"first","affiliation":[{"name":"College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Jeddah 21423, Saudi Arabia"},{"name":"Ministry of National Guard\u2013Health Affairs, Jeddah 11426, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Hannah","family":"Abid","sequence":"additional","affiliation":[{"name":"College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Jeddah 21423, Saudi Arabia"},{"name":"Ministry of National Guard\u2013Health Affairs, Jeddah 11426, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0004-2871-5363","authenticated-orcid":false,"given":"Montaha","family":"Almatrafi","sequence":"additional","affiliation":[{"name":"College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Jeddah 21423, Saudi Arabia"},{"name":"Ministry of National Guard\u2013Health Affairs, Jeddah 11426, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Amal","family":"Bamehriz","sequence":"additional","affiliation":[{"name":"College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Jeddah 21423, Saudi Arabia"},{"name":"Ministry of National Guard\u2013Health Affairs, Jeddah 11426, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Shatha","family":"Alqurashi","sequence":"additional","affiliation":[{"name":"College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Jeddah 21423, Saudi Arabia"},{"name":"Ministry of National Guard\u2013Health Affairs, Jeddah 11426, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ahmed","family":"Alkhiri","sequence":"additional","affiliation":[{"name":"Neuroscience Center of Excellence, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0009-0005-6561-9183","authenticated-orcid":false,"given":"Norah","family":"Alqhtani","sequence":"additional","affiliation":[{"name":"College of Medicine, Ibn Sina National College for Medical Studies, Jeddah 22421, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gadi","family":"Sindi","sequence":"additional","affiliation":[{"name":"College of Medicine, King Saud Bin Abdulaziz University for Health Sciences, Jeddah 21423, Saudi Arabia"},{"name":"Ministry of National Guard\u2013Health Affairs, Jeddah 11426, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kamal","family":"Bin Salama","sequence":"additional","affiliation":[{"name":"Ministry of National Guard\u2013Health Affairs, Jeddah 11426, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2937-1548","authenticated-orcid":false,"given":"Faris","family":"Alzahrani","sequence":"additional","affiliation":[{"name":"Ministry of National Guard\u2013Health Affairs, Jeddah 11426, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9884-2243","authenticated-orcid":false,"given":"Adel","family":"Alhazzani","sequence":"additional","affiliation":[{"name":"Neuroscience Center of Excellence, King Faisal Specialist Hospital and Research Center, Riyadh 11211, Saudi Arabia"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"1968","published-online":{"date-parts":[[2026,7,2]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"2064","DOI":"10.1161\/STR.0b013e318296aeca","article-title":"An updated definition of stroke for the 21st century: A statement for healthcare professionals from the American Heart Association\/American Stroke Association","volume":"44","author":"Sacco","year":"2013","journal-title":"Stroke"},{"key":"ref_2","doi-asserted-by":"crossref","unstructured":"Zhou, L., Zhang, H., Wang, S., Zhao, H., Li, Y., Han, J., Zhang, H., Li, X., and Qu, Z. (2024). PCSK-9 inhibitors: A new direction for the future treatment of ischemic stroke. Front. Pharmacol., 14.","DOI":"10.3389\/fphar.2023.1327185"},{"key":"ref_3","doi-asserted-by":"crossref","first-page":"139","DOI":"10.12997\/jla.2024.13.2.139","article-title":"Dyslipidemia treatment and cerebrovascular disease: Evidence regarding the mechanism of stroke","volume":"13","author":"Ha","year":"2024","journal-title":"J. Lipid Atheroscler."},{"key":"ref_4","doi-asserted-by":"crossref","first-page":"3322","DOI":"10.1161\/STROKEAHA.115.011164","article-title":"Lipids and cerebrovascular disease: Research and practice","volume":"46","author":"Yaghi","year":"2015","journal-title":"Stroke"},{"key":"ref_5","doi-asserted-by":"crossref","first-page":"165","DOI":"10.1007\/s40265-024-01995-9","article-title":"Long-term efficacy and tolerability of PCSK9 targeted therapy: A review of the literature","volume":"84","author":"Schonck","year":"2024","journal-title":"Drugs"},{"key":"ref_6","doi-asserted-by":"crossref","first-page":"310","DOI":"10.2174\/0115672026332171240624100802","article-title":"Effects of PCSK9 inhibitors on early neurologic deterioration in patients with acute non-cardioembolism without hemorrhagic transformation after intravenous thrombolysis","volume":"21","author":"Lei","year":"2024","journal-title":"Curr. Neurovasc. Res."},{"key":"ref_7","doi-asserted-by":"crossref","first-page":"197","DOI":"10.1007\/s40263-024-01145-5","article-title":"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","volume":"39","author":"Tian","year":"2025","journal-title":"CNS Drugs"},{"key":"ref_8","doi-asserted-by":"crossref","unstructured":"Li, Z., Zhu, L., Xu, Y., Zhang, Y., Liu, Y., Sun, H., Li, S., Wang, M., Jiang, T., and Zhou, J. (2024). Pleiotropic effects of PCSK9 inhibitors on cardio-cerebrovascular diseases. Biomedicines, 12.","DOI":"10.3390\/biomedicines12122729"},{"key":"ref_9","doi-asserted-by":"crossref","first-page":"529","DOI":"10.1136\/jnnp-2023-332392","article-title":"PCSK9 inhibitors reduced early recurrent stroke in patients with symptomatic intracranial atherosclerotic stenosis","volume":"95","author":"Wu","year":"2024","journal-title":"J. Neurol. Neurosurg. Psychiatry"},{"key":"ref_10","doi-asserted-by":"crossref","unstructured":"Kim, J., Hong, U., Yoon, C.W., Bae, J.W., Rha, J.-H., and Park, H.-K. (2024). PCSK9 inhibitor in acute ischemic stroke patient receiving mechanical thrombectomy: Early outcomes and safety. Front. Neurol., 15.","DOI":"10.3389\/fneur.2024.1375609"},{"key":"ref_11","doi-asserted-by":"crossref","first-page":"l4898","DOI":"10.1136\/bmj.l4898","article-title":"RoB 2: A revised tool for assessing risk of bias in randomised trials","volume":"366","author":"Sterne","year":"2019","journal-title":"BMJ"},{"key":"ref_12","doi-asserted-by":"crossref","unstructured":"Lo, C.K., Mertz, D., and Loeb, M. (2014). Newcastle-Ottawa Scale: Comparing reviewers\u2019 to authors\u2019 assessments. BMC Med. Res. Methodol., 14.","DOI":"10.1186\/1471-2288-14-45"},{"key":"ref_13","unstructured":"(2024). Review Manager (RevMan) [Computer Program], The Cochrane Collaboration. Available online: https:\/\/revman.cochrane.org."},{"key":"ref_14","doi-asserted-by":"crossref","unstructured":"Wan, X., Wang, W., Liu, J., and Tong, T. (2014). Estimating the sample mean and standard deviation from the sample size, median, range and\/or interquartile range. BMC Med. Res. Methodol., 14.","DOI":"10.1186\/1471-2288-14-135"},{"key":"ref_15","doi-asserted-by":"crossref","unstructured":"Qiu, X., Liang, Y., Wei, Y., Lu, M., Mei, Y., Tang, S., Tang, J., Liang, J., and Liang, J. (2024). Evolocumab for early reduction of LDL-C levels in patients with acute ischemic stroke: A randomized controlled trial. Front. Neurol., 15.","DOI":"10.3389\/fneur.2024.1454608"},{"key":"ref_16","first-page":"625","article-title":"Effect of proprotein convertase subtilisin\/kexin type 9 inhibitor combined with rosuvastatin on lipid levels and short-term prognosis in patients with acute ischemic stroke","volume":"57","author":"Zhou","year":"2024","journal-title":"Chin. J. Neurol."},{"key":"ref_17","doi-asserted-by":"crossref","first-page":"302","DOI":"10.1007\/s11239-023-02925-4","article-title":"Real-world effectiveness and safety of evolocumab in very high-risk atherosclerotic cardiovascular disease patients with acute ischemic stroke","volume":"57","author":"Zhang","year":"2024","journal-title":"J. Thromb. Thrombolysis"},{"key":"ref_18","first-page":"2940","article-title":"Effect of PCSK9 inhibitors on early neurological deterioration in patients with branch atheromatous disease","volume":"103","author":"Zhu","year":"2023","journal-title":"Chin. Med. J. (Engl.)"},{"key":"ref_19","doi-asserted-by":"crossref","first-page":"1713","DOI":"10.1056\/NEJMoa1615664","article-title":"Evolocumab and clinical outcomes in patients with cardiovascular disease","volume":"376","author":"Sabatine","year":"2017","journal-title":"N. Engl. J. Med."},{"key":"ref_20","doi-asserted-by":"crossref","first-page":"106057","DOI":"10.1016\/j.jstrokecerebrovasdis.2021.106057","article-title":"Efficacy and safety of PCSK9 inhibitors in stroke prevention","volume":"30","author":"Moustafa","year":"2021","journal-title":"J. Stroke Cerebrovasc. Dis."},{"key":"ref_21","doi-asserted-by":"crossref","first-page":"2054","DOI":"10.1161\/CIRCULATIONAHA.119.043826","article-title":"Effect of alirocumab on stroke in ODYSSEY OUTCOMES","volume":"140","author":"Jukema","year":"2019","journal-title":"Circulation"},{"key":"ref_22","doi-asserted-by":"crossref","first-page":"1400","DOI":"10.1001\/jama.2026.3277","article-title":"Evolocumab to reduce first major cardiovascular events in patients without known significant atherosclerosis and with diabetes: Results from the VESALIUS-CV trial","volume":"335","author":"Marston","year":"2026","journal-title":"JAMA"},{"key":"ref_23","doi-asserted-by":"crossref","unstructured":"Hosseini, K., Soleimani, H., Maleki, S., Nasrollahizadeh, A., Tayebi, S., Nelson, J., and Heffron, S.P. (2024). Early administration of proprotein convertase subtilisin\/kexin type 9 (PCSK9) inhibitors in patients with acute coronary syndrome: A systematic review and meta-analysis. BMC Cardiovasc. Disord., 24.","DOI":"10.1186\/s12872-024-04057-w"},{"key":"ref_24","doi-asserted-by":"crossref","first-page":"1","DOI":"10.31083\/j.rcm.2019.01.31812","article-title":"A short review of proprotein convertase subtilisin\/kexin type 9 inhibitors","volume":"20","author":"Alali","year":"2019","journal-title":"Rev. Cardiovasc. Med."},{"key":"ref_25","first-page":"CD011748","article-title":"PCSK9 monoclonal antibodies for the primary and secondary prevention of cardiovascular disease","volume":"4","author":"Schmidt","year":"2017","journal-title":"Cochrane Database Syst. Rev."},{"key":"ref_26","doi-asserted-by":"crossref","first-page":"I134","DOI":"10.1093\/eurheartjsupp\/suac099","article-title":"Reduction of cerebrovascular and peripheral events with PCSK9 inhibitors: Does it just depend on the lowering of the low-density lipoprotein?","volume":"24","author":"Cesaro","year":"2022","journal-title":"Eur. Heart J. Suppl."},{"key":"ref_27","doi-asserted-by":"crossref","unstructured":"Xiao, J., Zhang, S.Q., Shu, H.G., Chen, X., Zhou, L.Q., Shang, K., Qin, C., Xu, W.H., and Tian, D.S. (2023). PCSK9 inhibition reduces low-density lipoprotein cholesterol and stabilizes the plaque in ischemic stroke patients with severe intracranial atherosclerotic stenosis. Res. Sq.","DOI":"10.21203\/rs.3.rs-2038721\/v1"},{"key":"ref_28","doi-asserted-by":"crossref","first-page":"391","DOI":"10.1016\/S0166-2236(99)01401-0","article-title":"Pathobiology of ischaemic stroke: An integrated view","volume":"22","author":"Dirnagl","year":"1999","journal-title":"Trends Neurosci."},{"key":"ref_29","doi-asserted-by":"crossref","first-page":"181","DOI":"10.1016\/j.neuron.2010.07.002","article-title":"The science of stroke: Mechanisms in search of treatments","volume":"67","author":"Moskowitz","year":"2010","journal-title":"Neuron"},{"key":"ref_30","doi-asserted-by":"crossref","first-page":"e035651","DOI":"10.1161\/JAHA.124.035651","article-title":"Evaluation of intensive statins and proprotein convertase subtilisin\/kexin type 9 inhibitors on intracranial artery plaque stability: A prospective single-arm study","volume":"14","author":"Zeng","year":"2025","journal-title":"J. Am. Heart Assoc."},{"key":"ref_31","first-page":"2098","article-title":"Inhibition of proprotein convertase subtilisin\/kexin type 9 attenuates neuronal apoptosis following focal cerebral ischemia via apolipoprotein E receptor 2 downregulation in hyperlipidemic mice","volume":"42","author":"Wang","year":"2018","journal-title":"Int. J. Mol. Med."},{"key":"ref_32","doi-asserted-by":"crossref","first-page":"e213768","DOI":"10.1212\/WNL.0000000000213768","article-title":"Estimated theoretical benefit of aggressive LDL lowering in patients with symptomatic intracranial atherosclerosis","volume":"105","author":"Siegler","year":"2025","journal-title":"Neurology"},{"key":"ref_33","doi-asserted-by":"crossref","first-page":"257","DOI":"10.1007\/s00062-011-0107-0","article-title":"Comment on: Stenting versus aggressive medical therapy for intracranial arterial stenosis","volume":"21","author":"Henkes","year":"2011","journal-title":"Clin. Neuroradiol."},{"key":"ref_34","doi-asserted-by":"crossref","first-page":"1187","DOI":"10.1212\/01.wnl.0000208404.94585.b2","article-title":"Prospective study of symptomatic atherothrombotic intracranial stenoses: The GESICA study","volume":"66","author":"Mazighi","year":"2006","journal-title":"Neurology"},{"key":"ref_35","doi-asserted-by":"crossref","unstructured":"Wu, L., Kong, Q., Huang, H., Xu, S., Qu, W., Zhang, P., Yu, Z., and Luo, X. (2023). Effect of PCSK9 inhibition in combination with statin therapy on intracranial atherosclerotic stenosis: A high-resolution MRI study. Front. Aging Neurosci., 15.","DOI":"10.3389\/fnagi.2023.1127534"},{"key":"ref_36","unstructured":"ClinicalTrials.gov (2026, May 20). Trial of PCSK9 Inhibition in Patients with Acute Stroke and Symptomatic Intracranial Atherosclerosis (TOPICAL-MRI). Identifier: NCT05001984, Available online: https:\/\/clinicaltrials.gov\/study\/NCT05001984."},{"key":"ref_37","unstructured":"ClinicalTrials.gov (2026, May 20). The Effect of Intensive Statin in Ischemic Stroke with Intracranial Atherosclerotic Plaques (INSIST-HRMRI). Identifier: NCT03753555, Available online: https:\/\/clinicaltrials.gov\/study\/NCT03753555."},{"key":"ref_38","unstructured":"ClinicalTrials.gov (2026, May 20). Improving Blood Lipid Management in Symptomatic Intracranial Atherosclerotic Stenosis on Clinical Outcome (sICASBLM). Identifier: NCT05397405, Available online: https:\/\/clinicaltrials.gov\/study\/NCT05397405."},{"key":"ref_39","doi-asserted-by":"crossref","first-page":"n71","DOI":"10.1136\/bmj.n71","article-title":"The PRISMA 2020 statement: An updated guideline for reporting systematic reviews","volume":"372","author":"Page","year":"2021","journal-title":"BMJ"}],"container-title":["Journal of Clinical Medicine"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/13\/5169\/pdf","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2026,7,2]],"date-time":"2026-07-02T14:47:31Z","timestamp":1783003651000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.mdpi.com\/2077-0383\/15\/13\/5169"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2026,7,2]]},"references-count":39,"journal-issue":{"issue":"13","published-online":{"date-parts":[[2026,7]]}},"alternative-id":["jcm15135169"],"URL":"https:\/\/doi.org\/10.3390\/jcm15135169","relation":{},"ISSN":["2077-0383"],"issn-type":[{"value":"2077-0383","type":"electronic"}],"subject":[],"published":{"date-parts":[[2026,7,2]]}}}