Inclisiran effectively, safely lowers LDL in patients with prior cerebrovascular disease
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Inclisiran effectively and safely lowered LDL in patients with hyperlipidemia and prior cerebrovascular disease, according to a pooled analysis of the three ORION trials presented at the National Lipid Association Scientific Sessions.
“Patients with hyperlipidemia and established cerebrovascular disease are at an increased risk of future strokes or other cardiovascular events. In ischemic stroke survivors, treatment with statins and inhibitors of PCSK9 reduce recurrent cardiovascular events including stroke,” R. Scott Wright, MD, consultant in the divisions of structural heart disease and preventive cardiology and professor of medicine at Mayo Clinic, and colleagues wrote in a poster abstract. “With guidelines increasingly advocating lower LDL-C goals, add-on lipid-lowering therapies to statins may be required.”
The ORION trials were phase 3, double-blind, randomized, placebo-controlled trials that evaluated the safety and efficacy of inclisiran (Leqvio, Novartis) in patients with heterozygous FH (ORION-9), atherosclerotic CVD (ORION-10 and ORION-11) or ASCVD risk equivalent (ORION-11).
As Healio previously reported, the ORION-9 trial demonstrated that patients with heterozygous FH treated with inclisiran in had reductions in LDL at 510 days and in the average of 90 days and 540 days, independent of their underlying genotype; ORION-10 showed that LDL reductions with twice yearly inclisiran were sustained in in high-risk patients with ASCVD; and the findings from ORION-11 indicated that twice yearly inclisiran injections also achieved durable LDL reduction in patients with ASCVD or ASCVD risk equivalents.
A prior pooled analysis of the three trials found that inclisiran safely lowered LDL in patients with ASCVD, heterozygous FH and ASCVD risk equivalents by 55% at 510 days and by 52% in the average of 90 days and 540 days compared with placebo.
For this pooled analysis of the ORION trials, researchers assessed the efficacy and safety of inclisiran in a subgroup of participants with prior cerebrovascular disease defined as ischemic stroke, carotid artery stenosis of more than 70% or percutaneous or surgical carotid artery revascularization.
The co-primary endpoints were the percentage change in LDL from baseline to 510 days and the time-adjusted percentage change in LDL from baseline after day 90 to 540.
Key secondary endpoints included absolute change in LDL from baseline to 510 days and time-adjusted absolute change in LDL from baseline from day 90 to 540.
A total of 202 ORION trial participants with prior cerebrovascular disease were included in the analysis. Most participants had prior ischemic stroke.
Researchers observed the mean difference in LDL reduction for inclisiran compared with placebo from baseline to 510 days was 55.2% (95% CI, –64.5 to –45.9), and a similar difference in time-adjusted change from baseline from day 90 to 540 (P for all < .0001).
The difference in absolute mean reduction in LDL with inclisiran was 1.6 mmol/L compared with placebo (95% CI, 1.8-1.3) and the difference in time-adjusted absolute change was 1.5 mmol/L from day 90 to 540 (95% CI, 1.7-1.3).
Researchers also observed a 33.4% difference in mean change in total cholesterol; a 48.7% difference in mean change in non-HDL; a 44% difference in mean change in apolipoprotein B and a 23.3% difference in mean change in in lipoprotein(a), all favoring inclisiran compared with placebo.
Treatment emergent adverse events and treatment emergent serious adverse events occurred at similar frequency in the inclisiran and placebo groups in the cerebrovascular subgroups and in the overall cohort.
“In patients with established cerebrovascular disease, a twice-yearly dosing with inclisiran (after the initial and 3-month doses) provided sustained additional LDL-C reduction of [approximately] 55%,” the researchers wrote in the poster abstract. “Inclisiran was well tolerated in patients with established cerebrovascular disease, with a safety profile consistent with that observed in the overall Phase III trial population; a modest excess of treatment emergent adverse events at the injection site were reported with inclisiran, but all were mild or moderate in severity.”
The CV benefits of inclisiran are being evaluated in the ongoing ORION-4 trial, according to the poster.
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Wright SR, et al. Abstract 26. Presented at: National Lipid Association Scientific Sessions; June 2-5, 2022; Scottsdale, Arizona (hybrid meeting).
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