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Abstract
Background: END (Early Neurologic Deterioration) significantly elevates the risk of morbidity and mortality. While numerous studies have investigated END following hemorrhagic transformation post-thrombolysis in acute cerebral infarction research on END without hemorrhagic transformations in patients with acute cerebral infarction due to non-cardiogenic embolism remains scarce.
Aim:: This study aimed to elucidate the impact of PCSK9 inhibitors on early neurological deterioration (END) in patients with acute non-cardioembolism cerebral infarction without hemorrhagic transformation post-intravenous thrombolysis. Additionally it aimed to identify risk factors associated with END in patients suffering from this type of stroke. Objective:: The objective of this study is to investigate the effect of PCSK9 inhibitors on early neurologic deterioration (END) in patients with acute non-cardiogenic cerebral infarction without hemorrhagic transformation after intravenous thrombolysis and identify associated risk factors for END in this patient population. Methods: In this retrospective case-control study the data of consecutive patients who underwent intravenous thrombolysis after AIS (acute ischemic stroke) without hemorrhagic transformation during hospitalization at the Stroke Center of The Fifth Affiliated Hospital of Sun Yat-sen University between January 2018 to February 2023 were retrieved and assessed. An increase of >2 in the National Institutes of Health Stroke Scale (NIHSS) within 7 days after admission was defined as END. Results: This study included 250 patients (56 males 22.4%) they were 63.34±12.901 years old. There were 41 patients in the END group and 209 in the non-END group. The usage rate of PCSK9 inhibitors was significantly different between the END group and non-END group (29.268% vs 58.852% P<0.001). The White blood cell count (WBC) and homocysteine levels showed a significant difference between the two groups (all P<0.05). Patients not using PCSK9 inhibitors (OR=0.282 95%CI: 0.127-0.593) and white blood cell count (OR=1.197, 95%CI: 1.085-1.325) were independently associated with END. Receiver-operating characteristic curve analysis suggested that the sensitivity specificity and area under the curve for PCSK9 inhibitors used for END were 88.9%, 80.7% and 0.648 respectively. Conclusion: The use of PCSK9 inhibitors can reduce the incidence of early neurological deterioration in patients with acute non-cardioembolism and non-hemorrhagic transformation after intravenous thrombolysis.[1]
Feigin VL, Stark BA, Johnson CO, et al. Global, regional, and national burden of stroke and its risk factors, 1990–2019: A systematic analysis for the Global Burden of Disease Study 2019. Lancet Neurol 2021; 20(10): 795-820.
[http://dx.doi.org/10.1016/S1474-4422(21)00252-0] [PMID: 34487721]
[http://dx.doi.org/10.1016/S1474-4422(21)00252-0] [PMID: 34487721]
[2]
Powers WJ, Rabinstein AA, Ackerson T, et al. Guidelines for the early management of patients with acute ischemic stroke: 2019 update to the 2018 guidelines for the early management of acute ischemic stroke: A guideline for healthcare professionals from the american heart association/american stroke association. Stroke 2019; 50(12): e344-418.
[http://dx.doi.org/10.1161/STR.0000000000000211] [PMID: 31662037]
[http://dx.doi.org/10.1161/STR.0000000000000211] [PMID: 31662037]
[3]
Hankey GJ. Stroke. Lancet 2017; 389(10069): 641-54.
[http://dx.doi.org/10.1016/S0140-6736(16)30962-X] [PMID: 27637676]
[http://dx.doi.org/10.1016/S0140-6736(16)30962-X] [PMID: 27637676]
[4]
Seners P, Turc G, Oppenheim C, Baron JC. Incidence, causes and predictors of neurological deterioration occurring within 24 h following acute ischaemic stroke: A systematic review with pathophysiological implications. J Neurol Neurosurg Psychiatry 2015; 86(1): 87-94.
[http://dx.doi.org/10.1136/jnnp-2014-308327] [PMID: 24970907]
[http://dx.doi.org/10.1136/jnnp-2014-308327] [PMID: 24970907]
[5]
Lyden P. Using the national institutes of health stroke scale. Stroke 2017; 48(2): 513-9.
[http://dx.doi.org/10.1161/STROKEAHA.116.015434] [PMID: 28077454]
[http://dx.doi.org/10.1161/STROKEAHA.116.015434] [PMID: 28077454]
[6]
Dai Z, Cao H, Wang F, et al. Impacts of stress hyperglycemia ratio on early neurological deterioration and functional outcome after endovascular treatment in patients with acute ischemic stroke. Front Endocrinol 2023; 14: 1094353.
[http://dx.doi.org/10.3389/fendo.2023.1094353] [PMID: 36777360]
[http://dx.doi.org/10.3389/fendo.2023.1094353] [PMID: 36777360]
[7]
Adams HP Jr, Bendixen BH, Kappelle LJ, et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke 1993; 24(1): 35-41.
[http://dx.doi.org/10.1161/01.STR.24.1.35] [PMID: 7678184]
[http://dx.doi.org/10.1161/01.STR.24.1.35] [PMID: 7678184]
[8]
Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA guideline on the management of blood cholesterol. J Am Coll Cardiol 2019; 73(24): e285-350.
[http://dx.doi.org/10.1016/j.jacc.2018.11.003] [PMID: 30423393]
[http://dx.doi.org/10.1016/j.jacc.2018.11.003] [PMID: 30423393]
[9]
Touboul PJ, Hennerici MG, Meairs S, et al. Mannheim carotid intima-media thickness and plaque consensus (2004-2006-2011). An update on behalf of the advisory board of the 3rd, 4th and 5th watching the risk symposia, at the 13th, 15th and 20th European Stroke Conferences, Mannheim, Germany, 2004, Brussels, Belgium, 2006, and Hamburg, Germany, 2011. Cerebrovasc Dis 2012; 34(4): 290-6.
[http://dx.doi.org/10.1159/000343145] [PMID: 23128470]
[http://dx.doi.org/10.1159/000343145] [PMID: 23128470]
[10]
Zhou M, Wang H, Zeng X, et al. Mortality, morbidity, and risk factors in China and its provinces, 1990–2017: A systematic analysis for the Global Burden of Disease Study 2017. Lancet 2019; 394(10204): 1145-58.
[http://dx.doi.org/10.1016/S0140-6736(19)30427-1] [PMID: 31248666]
[http://dx.doi.org/10.1016/S0140-6736(19)30427-1] [PMID: 31248666]
[11]
Wu S, Wu B, Liu M, et al. Stroke in China: Advances and challenges in epidemiology, prevention, and management. Lancet Neurol 2019; 18(4): 394-405.
[http://dx.doi.org/10.1016/S1474-4422(18)30500-3] [PMID: 30878104]
[http://dx.doi.org/10.1016/S1474-4422(18)30500-3] [PMID: 30878104]
[12]
Zi W, Song J, Kong W, et al. Tirofiban for stroke without large or medium-sized vessel occlusion. N Engl J Med 2023; 388(22): 2025-36.
[http://dx.doi.org/10.1056/NEJMoa2214299] [PMID: 37256974]
[http://dx.doi.org/10.1056/NEJMoa2214299] [PMID: 37256974]
[13]
Feigin VL, Nguyen G, Cercy K, et al. Global, regional, and country-specific lifetime risks of stroke, 1990 and 2016. N Engl J Med 2018; 379(25): 2429-37.
[http://dx.doi.org/10.1056/NEJMoa1804492] [PMID: 30575491]
[http://dx.doi.org/10.1056/NEJMoa1804492] [PMID: 30575491]
[14]
Sharma A, Pandit AK, Mishra B, et al. Early neurological deterioration in acute ischemic stroke. Ir J Med Sci 2024; 193(2): 949-55.
[http://dx.doi.org/10.1007/s11845-023-03485-5] [PMID: 37561387]
[http://dx.doi.org/10.1007/s11845-023-03485-5] [PMID: 37561387]
[15]
Korompoki E, Ntaios G, Tountopoulou A, et al. Quality indicators and clinical outcomes of acute stroke: results from a prospective multicenter registry in greece (SUN4P). J Clin Med 2024; 13(3): 917.
[http://dx.doi.org/10.3390/jcm13030917] [PMID: 38337611]
[http://dx.doi.org/10.3390/jcm13030917] [PMID: 38337611]
[16]
Deb P, Sharma S, Hassan KM. Pathophysiologic mechanisms of acute ischemic stroke: An overview with emphasis on therapeutic significance beyond thrombolysis. Pathophysiology 2010; 17(3): 197-218.
[http://dx.doi.org/10.1016/j.pathophys.2009.12.001] [PMID: 20074922]
[http://dx.doi.org/10.1016/j.pathophys.2009.12.001] [PMID: 20074922]
[17]
Seners P, Turc G, Maïer B, Mas JL, Oppenheim C, Baron JC. Incidence and predictors of early recanalization after intravenous thrombolysis. Stroke 2016; 47(9): 2409-12.
[http://dx.doi.org/10.1161/STROKEAHA.116.014181] [PMID: 27462117]
[http://dx.doi.org/10.1161/STROKEAHA.116.014181] [PMID: 27462117]
[18]
Smith CJ, Emsley HCA, Gavin CM, et al. Peak plasma interleukin-6 and other peripheral markers of inflammation in the first week of ischaemic stroke correlate with brain infarct volume, stroke severity and long-term outcome. BMC Neurol 2004; 4(1): 2.
[http://dx.doi.org/10.1186/1471-2377-4-2] [PMID: 14725719]
[http://dx.doi.org/10.1186/1471-2377-4-2] [PMID: 14725719]
[19]
O’Donoghue ML, Fazio S, Giugliano RP, et al. Lipoprotein(a), PCSK9 inhibition, and cardiovascular risk. Circulation 2019; 139(12): 1483-92.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.118.037184] [PMID: 30586750]
[http://dx.doi.org/10.1161/CIRCULATIONAHA.118.037184] [PMID: 30586750]
[20]
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; 126: 111195.
[http://dx.doi.org/10.1016/j.intimp.2023.111195] [PMID: 38048667]
[http://dx.doi.org/10.1016/j.intimp.2023.111195] [PMID: 38048667]
[21]
Seidah NG, Prat A. The multifaceted biology of PCSK9. Endocr Rev 2022; 43(3): 558-82.
[http://dx.doi.org/10.1210/endrev/bnab035] [PMID: 35552680]
[http://dx.doi.org/10.1210/endrev/bnab035] [PMID: 35552680]
[22]
Giugliano RP, Pedersen TR, Saver JL, et al. Stroke prevention with the PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitor evolocumab added to statin in high-risk patients with stable atherosclerosis. Stroke 2020; 51(5): 1546-54.
[http://dx.doi.org/10.1161/STROKEAHA.119.027759] [PMID: 32312223]
[http://dx.doi.org/10.1161/STROKEAHA.119.027759] [PMID: 32312223]
[23]
Alloubani A, Nimer R, Samara R. Relationship between hyperlipidemia, cardiovascular disease and stroke: A systematic review. Curr Cardiol Rev 2021; 17(6): e051121189015.
[http://dx.doi.org/10.2174/1573403X16999201210200342] [PMID: 33305711]
[http://dx.doi.org/10.2174/1573403X16999201210200342] [PMID: 33305711]
[24]
Zanda G, Varbella F. Stabilization of vulnerable plaque in the ACS patient: Evidence from HUYGENS studies. Eur Heart J Suppl 2023; 25 (Suppl. C): C106-8.
[http://dx.doi.org/10.1093/eurheartjsupp/suad013] [PMID: 37125301]
[http://dx.doi.org/10.1093/eurheartjsupp/suad013] [PMID: 37125301]
[25]
Ahmad P, Alvi SS, Iqbal D, Khan MS. Insights into pharmacological mechanisms of polydatin in targeting risk factors-mediated atherosclerosis. Life Sci 2020; 254: 117756.
[http://dx.doi.org/10.1016/j.lfs.2020.117756] [PMID: 32389832]
[http://dx.doi.org/10.1016/j.lfs.2020.117756] [PMID: 32389832]
[26]
Paciullo F, Momi S, Gresele P. PCSK9 in haemostasis and thrombosis: Possible pleiotropic effects of PCSK9 inhibitors in cardiovascular prevention. Thromb Haemost 2019; 119(3): 359-67.
[http://dx.doi.org/10.1055/s-0038-1676863] [PMID: 30605918]
[http://dx.doi.org/10.1055/s-0038-1676863] [PMID: 30605918]
[27]
Qi Z, Hu L, Zhang J, et al. PCSK9 (proprotein convertase subtilisin/kexin 9) enhances platelet activation, thrombosis, and myocardial infarct expansion by binding to platelet CD36. Circulation 2021; 143(1): 45-61.
[http://dx.doi.org/10.1161/CIRCULATIONAHA.120.046290] [PMID: 32988222]
[http://dx.doi.org/10.1161/CIRCULATIONAHA.120.046290] [PMID: 32988222]
[28]
Iadecola C, Anrather J. The immunology of stroke: from mechanisms to translation. Nat Med 2011; 17(7): 796-808.
[http://dx.doi.org/10.1038/nm.2399] [PMID: 21738161]
[http://dx.doi.org/10.1038/nm.2399] [PMID: 21738161]
[29]
Galea I. The blood–brain barrier in systemic infection and inflammation. Cell Mol Immunol 2021; 18(11): 2489-501.
[http://dx.doi.org/10.1038/s41423-021-00757-x] [PMID: 34594000]
[http://dx.doi.org/10.1038/s41423-021-00757-x] [PMID: 34594000]
[30]
Zera KA, Buckwalter MS. The local and peripheral immune responses to stroke: implications for therapeutic development. Neurotherapeutics 2020; 17(2): 414-35.
[http://dx.doi.org/10.1007/s13311-020-00844-3] [PMID: 32193840]
[http://dx.doi.org/10.1007/s13311-020-00844-3] [PMID: 32193840]
[31]
DeLong JH, Ohashi SN, O’Connor KC, Sansing LH. Inflammatory responses after ischemic stroke. Semin Immunopathol 2022; 44(5): 625-48.
[http://dx.doi.org/10.1007/s00281-022-00943-7] [PMID: 35767089]
[http://dx.doi.org/10.1007/s00281-022-00943-7] [PMID: 35767089]
[32]
Marfella R, Prattichizzo F, Sardu C, et al. Evidence of an anti-inflammatory effect of PCSK9 inhibitors within the human atherosclerotic plaque. Atherosclerosis 2023; 378: 117180.
[http://dx.doi.org/10.1016/j.atherosclerosis.2023.06.971] [PMID: 37422356]
[http://dx.doi.org/10.1016/j.atherosclerosis.2023.06.971] [PMID: 37422356]
[33]
Moustafa B, Testai FD. Efficacy and Safety of PCSK9 inhibitors in stroke prevention. J Stroke Cerebrovasc Dis 2021; 30(11): 106057.
[http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2021.106057] [PMID: 34450482]
[http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2021.106057] [PMID: 34450482]
[34]
Nardi K, Milia P, Eusebi P, Paciaroni M, Caso V, Agnelli G. Admission leukocytosis in acute cerebral ischemia: Influence on early outcome. J Stroke Cerebrovasc Dis 2012; 21(8): 819-24.
[http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2011.04.015] [PMID: 21703875]
[http://dx.doi.org/10.1016/j.jstrokecerebrovasdis.2011.04.015] [PMID: 21703875]
[35]
Kollikowski AM, Schuhmann MK, Nieswandt B, Müllges W, Stoll G, Pham M. Local leukocyte invasion during hyperacute human ischemic stroke. Ann Neurol 2020; 87(3): 466-79.
[http://dx.doi.org/10.1002/ana.25665] [PMID: 31899551]
[http://dx.doi.org/10.1002/ana.25665] [PMID: 31899551]
[36]
Shi Z, Guan Y, Huo YR, et al. Elevated total homocysteine levels in acute ischemic stroke are associated with long-term mortality. Stroke 2015; 46(9): 2419-25.
[http://dx.doi.org/10.1161/STROKEAHA.115.009136] [PMID: 26199315]
[http://dx.doi.org/10.1161/STROKEAHA.115.009136] [PMID: 26199315]
[37]
Zhang T, Jiang Y, Zhang S, et al. The association between homocysteine and ischemic stroke subtypes in Chinese. Medicine 2020; 99(12): e19467.
[http://dx.doi.org/10.1097/MD.0000000000019467] [PMID: 32195946]
[http://dx.doi.org/10.1097/MD.0000000000019467] [PMID: 32195946]
[38]
Zhang H, Huang J, Zhou Y, Fan Y. Association of homocysteine level with adverse outcomes in patients with acute ischemic stroke: a meta-analysis. Curr Med Chem 2021; 28(36): 7583-91.
[http://dx.doi.org/10.2174/0929867328666210419131016] [PMID: 33874865]
[http://dx.doi.org/10.2174/0929867328666210419131016] [PMID: 33874865]
[39]
Fu HJ, Zhao LB, Xue JJ, et al. Elevated serum homocysteine (Hcy) levels may contribute to the pathogenesis of cerebral infarction. J Mol Neurosci 2015; 56(3): 553-61.
[http://dx.doi.org/10.1007/s12031-015-0497-6] [PMID: 25682236]
[http://dx.doi.org/10.1007/s12031-015-0497-6] [PMID: 25682236]
[40]
Esse R, Barroso M, Tavares de Almeida I, Castro R. The contribution of homocysteine metabolism disruption to endothelial dysfunction: state-of-the-art. Int J Mol Sci 2019; 20(4): 867.
[http://dx.doi.org/10.3390/ijms20040867] [PMID: 30781581]
[http://dx.doi.org/10.3390/ijms20040867] [PMID: 30781581]
[41]
Zaric BL, Obradovic M, Bajic V, Haidara MA, Jovanovic M, Isenovic ER. Homocysteine and hyperhomocysteinaemia. Curr Med Chem 2019; 26(16): 2948-61.
[http://dx.doi.org/10.2174/0929867325666180313105949] [PMID: 29532755]
[http://dx.doi.org/10.2174/0929867325666180313105949] [PMID: 29532755]
[42]
Spence JD, Yi Q, Hankey GJ. B vitamins in stroke prevention: time to reconsider. Lancet Neurol 2017; 16(9): 750-60.
[http://dx.doi.org/10.1016/S1474-4422(17)30180-1] [PMID: 28816120]
[http://dx.doi.org/10.1016/S1474-4422(17)30180-1] [PMID: 28816120]
[43]
Martí-Carvajal AJ, Solà I, Lathyris D, Dayer M. Homocysteine-lowering interventions for preventing cardiovascular events. Cochrane Database Syst Rev 2017; 8(8): CD006612.
[PMID: 28816346]
[PMID: 28816346]
[44]
Macchi C, Banach M, Corsini A, Sirtori CR, Ferri N, Ruscica M. Changes in circulating pro-protein convertase subtilisin/kexin type 9 levels experimental and clinical approaches with lipid-lowering agents. Eur J Prev Cardiol 2019; 26(9): 930-49.
[http://dx.doi.org/10.1177/2047487319831500] [PMID: 30776916]
[http://dx.doi.org/10.1177/2047487319831500] [PMID: 30776916]
[45]
Ganguly P, Alam SF. Role of homocysteine in the development of cardiovascular disease. Nutr J 2015; 14(1): 6.
[http://dx.doi.org/10.1186/1475-2891-14-6] [PMID: 25577237]
[http://dx.doi.org/10.1186/1475-2891-14-6] [PMID: 25577237]
[46]
Škovierová H, Vidomanová E, Mahmood S, et al. The molecular and cellular effect of homocysteine metabolism imbalance on human health. Int J Mol Sci 2016; 17(10): 1733.
[http://dx.doi.org/10.3390/ijms17101733] [PMID: 27775595]
[http://dx.doi.org/10.3390/ijms17101733] [PMID: 27775595]
[47]
Kwon HM, Lee YS, Bae HJ, Kang DW. Homocysteine as a predictor of early neurological deterioration in acute ischemic stroke. Stroke 2014; 45(3): 871-3.
[http://dx.doi.org/10.1161/STROKEAHA.113.004099] [PMID: 24448992]
[http://dx.doi.org/10.1161/STROKEAHA.113.004099] [PMID: 24448992]
[48]
Cao YX, Li S, Liu HH, Li JJ. Impact of PCSK9 monoclonal antibodies on circulating hs-CRP levels: A systematic review and meta-analysis of randomised controlled trials. BMJ Open 2018; 8(9): e022348.
[http://dx.doi.org/10.1136/bmjopen-2018-022348] [PMID: 30287608]
[http://dx.doi.org/10.1136/bmjopen-2018-022348] [PMID: 30287608]
[49]
Barale C, Melchionda E, Morotti A, Russo I. PCSK9 biology and its role in atherothrombosis. Int J Mol Sci 2021; 22(11): 5880.
[http://dx.doi.org/10.3390/ijms22115880] [PMID: 34070931]
[http://dx.doi.org/10.3390/ijms22115880] [PMID: 34070931]