PCSK9 inhibition reduces low-density lipoprotein cholesterol and stabilizes the plaque in ischemic stroke patients with severe intracranial atherosclerotic stenosis

Abstract Background: Proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors have been shown to reduce cardiovascular events. However, their effects on intracranial atherosclerotic plaque remain elusive. The prospective study aims to investigate the effect of adding PCSK9 inhibition to statin therapy on intracranial atherosclerotic plaque features in those ischemic stroke patients with severe intracranial atherosclerotic stenosis (ICAS) using high-resolution vessel wall magnetic resonance imaging (HRVW-MRI). Methods: In our single-center study, a total of 29 patients with high-grade ICAS (PCSK9i group, n=19; control group, n=10) were included. HRVW-MRI scans at baseline and 3-6 months posttreatment were performed. The clinical characteristics and plaque features including plaque area, plaque burden, enhancement ratio, eccentricity, percent wall volume (PWV) and degree of stenosis were investigated. Results: Compared with statin monotherapy, the least-squares mean percentage reduction low-density lipoprotein cholesterol (LDL-C) with PCSK9 inhibitor add-on therapy was 71% at 1 month, 69% at 3 months and 64% at 6 months (p<0.001 for all comparisons). Fifteen patients (51.7%) completed HRVW-MRI at both baseline and follow-up. A significant reduction in plaque enhancement ratio (-13.7%, 95% CI, -27.2% to 0.3%) and degree of stenosis (-11.7%, 95% CI, -23.3% to -0.1%) was observed in PCSK9i group but not in control group (37.7%, 95% CI, -14.6% to 221%, p=0.024 and 16.0%, 95% CI, -7.6% to 39.6%, p=0.027, respectively). The plaque area, plaque burden, eccentricity and PWV did not change significantly during the follow-up. Among those patients, the median follow-up duration was 11 months (IQR, 9-14), most (28/29, 96.6%) did not suffer from stroke during the follow-up, with no statistical difference in median National Institutes of Health Stroke Scale (NIHSS) and Modified Rankin Scale (mRS) scores between the groups. Conclusion: Inhibition of PCSK9 added to high-intensity statin therapy can lower the LDL-C levels, slow down the progression of stenosis and stabilize plaque in patients with severe ICAS. These findings provide insight into the benefit of lowering LDL-C levels below current recommendation targets with the PCSK9 inhibitor add-on therapy in patients with high-grade ICAS. Trial registration: Clinicaltrial.gov, NCT04847752, registered April 19, 2021, https://www.clinicaltrials.gov/ct2/show/NCT04847752.