{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T15:53:35Z","timestamp":1790178815711,"version":"4.1.0"},"reference-count":26,"publisher":"Ovid Technologies (Wolters Kluwer Health)","issue":"10","content-domain":{"domain":["www.ahajournals.org"],"crossmark-restriction":true},"short-container-title":["Stroke"],"published-print":{"date-parts":[[2021,10]]},"abstract":"<jats:sec>\n            <jats:title>Background and Purpose:<\/jats:title>\n            <jats:p>Statins were shown to increase hemorrhagic stroke (HS) in patients with a first cerebrovascular event in 2006 (SPARCL), likely due to off-target antithrombotic effects, but continued to sometimes be used in patients with elevated HS risk due to absence of alternative medications. Recently, the PCSK9Is (proprotein convertase subtilisin kexin 9 inhibitors) have become available as a potent lipid-lowering class with potentially less hemorrhagic propensity.<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Methods:<\/jats:title>\n            <jats:p>We performed a systematic comparative meta-analysis assessing HS rates across all completed statin and PCSK9I randomized clinical trials with treatment &gt;3 months, following PRISMA guidelines. In addition to HS rates across all trials, causal relation was probed by evaluating for dose-response relationships by medication (low versus high medication dose\/potency) and by presence and type of preceding brain vascular events at inception (none versus ischemic stroke\/transient ischemic attack versus HS).<\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Results:<\/jats:title>\n            <jats:p>\n              The systematic review identified 36 statin randomized clinical trials (204\u2009918 patients) and 5 PCSK9I randomized clinical trials (76\u2009140 patients). Across all patient types and all medication doses\/potencies, statins were associated with increased HS: relative risk 1.15,\n              <jats:italic>P<\/jats:italic>\n              =0.04; PCSK9Is were not (\n              <jats:italic>P<\/jats:italic>\n              =0.77). In the medication dose\/potency analysis, higher dose\/potency statins (7 trials, 62\u2009204 patients) were associated with magnified HS risk: relative risk, 1.53;\n              <jats:italic>P<\/jats:italic>\n              =0.002; higher dose\/potency PCSK9Is (1 trial, 27\u2009564 patients) were not (\n              <jats:italic>P<\/jats:italic>\n              =0.99). In the type of index brain vascular injury analysis for statins (5 trials, 9772 patients), prior ischemic stroke\/transient ischemic attack was associated with a magnified risk of HS: relative risk, 1.43;\n              <jats:italic>P<\/jats:italic>\n              =0.04; and index intracerebral hemorrhage was associated with an extremely high effect estimate of risk of recurrent HS: hazard ratio, 4.06. For PCSK9Is, prior ischemic stroke\/transient ischemic attack (1 trial, 5337 patients) was not associated with increased HS risk (\n              <jats:italic>P<\/jats:italic>\n              =0.97).\n            <\/jats:p>\n          <\/jats:sec>\n          <jats:sec>\n            <jats:title>Conclusions:<\/jats:title>\n            <jats:p>Statins increase the risk of HS in a medication dose- and type of index brain vascular injury-dependent manner; PCSK9Is do not increase HS risk. PCSK9Is may be a preferred lipid-lowering medication class in patients with elevated HS risk, including patients with prior HS.<\/jats:p>\n          <\/jats:sec>","DOI":"10.1161\/strokeaha.121.034576","type":"journal-article","created":{"date-parts":[[2021,6,22]],"date-time":"2021-06-22T09:00:12Z","timestamp":1624352412000},"page":"3142-3150","update-policy":"https:\/\/doi.org\/10.1161\/crossmarkpolicy","source":"Crossref","is-referenced-by-count":82,"title":["Lipid-Lowering Therapy and Hemorrhagic Stroke Risk"],"prefix":"10.1161","volume":"52","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-3117-2046","authenticated-orcid":true,"given":"Borja E.","family":"Sanz-Cuesta","sequence":"first","affiliation":[{"name":"Department of Neurology, Olive View \u2013 UCLA Medical Center, Sylmar, CA (B.E.S.-C)."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-9141-2251","authenticated-orcid":true,"given":"Jeffrey L.","family":"Saver","sequence":"additional","affiliation":[{"name":"Department of Neurology, UCLA, Los Angeles, CA (J.L.S.)."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"276","reference":[{"key":"e_1_3_6_2_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(04)15690-0"},{"key":"e_1_3_6_3_2","doi-asserted-by":"publisher","DOI":"10.1212\/01.wnl.0000296277.63350.77"},{"key":"e_1_3_6_4_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(09)70058-4"},{"key":"e_1_3_6_5_2","doi-asserted-by":"publisher","DOI":"10.1161\/CIRCULATIONAHA.112.145334"},{"key":"e_1_3_6_6_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.atherosclerosis.2016.03.010"},{"key":"e_1_3_6_7_2","doi-asserted-by":"publisher","DOI":"10.1097\/MOL.0000000000000505"},{"key":"e_1_3_6_8_2","doi-asserted-by":"publisher","DOI":"10.1097\/MD.0000000000014400"},{"key":"e_1_3_6_9_2","doi-asserted-by":"publisher","DOI":"10.1001\/jama.283.15.2008"},{"key":"e_1_3_6_10_2","doi-asserted-by":"publisher","DOI":"10.1161\/STR.0b013e318296aeca"},{"key":"e_1_3_6_11_2","doi-asserted-by":"publisher","DOI":"10.1111\/ane.12540"},{"key":"e_1_3_6_12_2","doi-asserted-by":"publisher","DOI":"10.1002\/jrsm.1411"},{"key":"e_1_3_6_13_2","first-page":"463","article-title":"Significant reduction in the LDL cholesterol increases the risk of intracerebral hemorrhage: a systematic review and meta-analysis of 33 randomized controlled trials.","volume":"12","author":"Cheng Y","year":"2020","unstructured":"Cheng, Y, Qiao, L, Jiang, Z, Dong, X, Feng, H, Gui, Q, Lu, Y, Liang, Y. Significant reduction in the LDL cholesterol increases the risk of intracerebral hemorrhage: a systematic review and meta-analysis of 33 randomized controlled trials. Am J Transl Res. 2020;12:463\u2013477.","journal-title":"Am J Transl Res"},{"key":"e_1_3_6_14_2","doi-asserted-by":"publisher","DOI":"10.1177\/1756286419864830"},{"key":"e_1_3_6_15_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1615664"},{"key":"e_1_3_6_16_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1801174"},{"key":"e_1_3_6_17_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1501031"},{"key":"e_1_3_6_18_2","doi-asserted-by":"publisher","DOI":"10.1056\/NEJMoa1701488"},{"key":"e_1_3_6_19_2","doi-asserted-by":"publisher","DOI":"10.1161\/STROKEAHA.119.027759"},{"key":"e_1_3_6_20_2","doi-asserted-by":"publisher","DOI":"10.1016\/S0140-6736(17)32290-0"},{"key":"e_1_3_6_21_2","doi-asserted-by":"publisher","DOI":"10.1111\/ene.12273"},{"key":"e_1_3_6_22_2","doi-asserted-by":"publisher","DOI":"10.1136\/jnnp-2018-318483"},{"key":"e_1_3_6_23_2","doi-asserted-by":"publisher","DOI":"10.1097\/MD.0000000000004950"},{"key":"e_1_3_6_24_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.wneu.2017.12.020"},{"key":"e_1_3_6_25_2","doi-asserted-by":"publisher","DOI":"10.1055\/s-0038-1676863"},{"key":"e_1_3_6_26_2","doi-asserted-by":"publisher","DOI":"10.1016\/j.biopha.2018.09.164"},{"key":"e_1_3_6_27_2","doi-asserted-by":"publisher","DOI":"10.1016\/S1474-4422(18)30145-5"}],"container-title":["Stroke"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.ahajournals.org\/doi\/full\/10.1161\/STROKEAHA.121.034576","content-type":"unspecified","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2024,5,13]],"date-time":"2024-05-13T14:55:38Z","timestamp":1715612138000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.ahajournals.org\/doi\/10.1161\/STROKEAHA.121.034576"}},"subtitle":["Comparative Meta-Analysis of Statins and PCSK9 Inhibitors"],"short-title":[],"issued":{"date-parts":[[2021,10]]},"references-count":26,"journal-issue":{"issue":"10","published-print":{"date-parts":[[2021,10]]}},"alternative-id":["10.1161\/STROKEAHA.121.034576"],"URL":"https:\/\/doi.org\/10.1161\/strokeaha.121.034576","relation":{},"ISSN":["0039-2499","1524-4628"],"issn-type":[{"value":"0039-2499","type":"print"},{"value":"1524-4628","type":"electronic"}],"subject":[],"published":{"date-parts":[[2021,10]]},"assertion":[{"value":"2021-02-09","order":0,"name":"received","label":"Received","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-04-30","order":1,"name":"accepted","label":"Accepted","group":{"name":"publication_history","label":"Publication History"}},{"value":"2021-06-22","order":2,"name":"published","label":"Published","group":{"name":"publication_history","label":"Publication History"}}]}}