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Wolfgang Koenig, MD has received consulting fees and lecture fees from AstraZeneca, Novartis and Amgen; consulting fees from Pfizer, the Medicines Company, DalCor Pharmaceuticals, Genentech, Esperion, OMEICOS, Novo Nordisk, LIB Therapeutics, Kowa, Corvidia Therapeutics and Daiichi Sankyo; lecture fees from Berlin- Chemie, Bristol-Myers Squibb and Sanofi; and grant support and provision of reagents from Singulex, Abbott, Roche Diagnostics and Dr. Beckmann Pharma. Novartis Pharma AG, Basel, Switzerland. Patients with hyperlipidemia and established cerebrovascular disease (CeVD) are at increased risk of future strokes or other cardiovascular events (1). In ischemic stroke survivors, statins and inhibitors of proprotein convertase subtilisin/kexin type 9 (PCSK9) reduce recurrent cardiovascular events, including stroke (2,3). With guidelines advocating increasingly lower low-density lipoprotein cholesterol (LDL-C) goals, adding lipid-lowering therapies to statins may be needed. Inclisiran, a first-in-class small interfering RNA targeting PCSK9 messenger RNA, when added to maximally tolerated statin therapy for patients with established CeVD, may provide further LDL-C lowering, with a convenient, infrequent dosing schedule (4). To assess the efficacy and safety of inclisiran in patients with established CeVD. This was a post hoc analysis of patients with heterozygous familial hypercholesterolemia or atherosclerotic cardiovascular disease or its risk equivalents and established CeVD (ischemic stroke, carotid artery stenosis by angiography or ultrasound greater than 70%, and/or percutaneous or surgical carotid artery revascularization) from ORION-9 (NCT03397121), ORION-10 (NCT03399370), and ORION-11 (NCT03400800), randomized 1:1 to receive inclisiran sodium 300 mg (equivalent to 284mg inclisiran) or placebo at Day 1, Day 90, and 6 monthly thereafter to Day 540. Evaluations included LDL-C percentage change from baseline to Day 510 and corresponding time-averaged percentage change from baseline after Day 90 to Day 540; safety was assessed over 540 days. Of 202 patients with established CeVD at baseline, 90.0% (99/110) of patients receiving inclisiran and 84.8% (78/92) on placebo reported prior ischemic stroke; others reported prior carotid artery stenosis and/or carotid revascularization (Table 1). Mean (95% CI) placebo- corrected LDL-C percentage change from baseline at Day 510 with inclisiran was −55.2% (−64.5 to −45.9); corresponding time-averaged change from baseline between Days 90 and 540 was −55.2% (−62.4 to −47.9) (P less than 0.0001 for both; Table 2). Treatment-emergent adverse events (TEAEs) and serious TEAEs were more frequent with inclisiran vs placebo. Clinically relevant injection site TEAEs were more frequent with inclisiran (3.6% [4/110]) vs placebo (0% [0/92]) and none was severe. Few patients had clinically relevant laboratory measurements (Table 2). In patients with established CeVD, twice-yearly dosing with inclisiran (after the initial and 3-month doses) provided a sustained additional LDL-C reduction of ∼55% and a modest increase in mild/moderate injection site TEAEs. The cardiovascular benefits of inclisiran in patients with established CeVD are being evaluated in ongoing trials. [ABSTRACT FROM AUTHOR]