Adjunctive PCSK9 Inhibitor Evolocumab in the Prevention of Early Neurological Deterioration in Non-cardiogenic Acute Ischemic Stroke: A Multicenter, Prospective, Randomized, Open-Label, Clinical Trial.

Background: Early neurological deterioration (END) is associated with a poor prognosis in acute ischemic stroke (AIS). Effectively lowering low-density lipoprotein cholesterol (LDL-C) can improve the stability of atherosclerotic plaque and reduce post-stroke inflammation, which may be an effective means to lower the incidence of END. The objective of this study was to determine the preventive effects of evolocumab on END in patients with non-cardiogenic AIS.

Methods: This was a multicenter, prospective, open-label, blinded-endpoint clinical trial. Participants with AIS within 24 h were randomly assigned to either the group receiving combination therapy of evolocumab and atorvastatin, which is a 3-hydroxy-3-methyl glutaryl coenzyme A (HMG-CoA) reductase inhibitor, i.e., a "statin" (PI group), or the group receiving atorvastatin monotherapy (AT group). The primary outcome was END within 7 days, defined as a 2-point increase in the National Institutes of Health Stroke Scale (NIHSS) score or a 1-point increase in motor function within 24 h-7 days from the onset of AIS. Secondary outcomes included LDL-C target achievement rate on day 7 (≤ 1.8 mmol/L with a reduction exceeding 50% from baseline), inflammatory factors (interleukin [IL]-6, IL-8, and tumor necrosis factor [TNF]-α) before and after 7 days of treatment, and stroke-related death with 7 days. Safety endpoints included any adverse events.

Results: Patients with AIS (n = 272) were randomly assigned to the PI (n = 136) or AT (n = 136) groups. Within 7 days, 18 (13.2%) and 33 (24.3%) patients experienced END in the PI and AT groups, respectively (relative risk [RR] -0.90; 95% confidence interval [CI]: -1.59 to -0.22; p = 0.010). On the seventh day, LDL-C target achievement rate in the PI and AT groups was 74.3% and 14.7%, respectively (RR 3.27; 95% CI: 2.40-4.15; p = 0.001). Changes in IL-6 over 7 days were significantly lower in the PI group compared with the AT group, respectively (median 1.02 [range -1.91, 5.47] versus 2.54 [-0.83, 15.20]; p = 0.033). On the 90th day of follow-up, 83.1% and 65.4% of patients had a modified Rankin Scale score ≤ 2 in the PI and AT groups, respectively (RR 0.51; 95% CI: 0.66-2.66; p = 0.001). There was no significant difference in stroke recurrence between the two groups within 90 days (RR -1.72; 95% CI: -4.57 to 1.13; p = 0.237). Regarding adverse events, 15 and 22 patients in the PI and AT groups, respectively, experienced slight abnormalities in liver and kidney function laboratory values during the 7-day treatment period (odds ratio 0.62; 95% CI: 0.30-1.29; p = 0.203), but no serious adverse events were observed in either group.

Conclusion: These results suggest that the combination therapy of evolocumab and atorvastatin within 24 h of AIS onset may effectively reduce the incidence of END compared with atorvastatin monotherapy. Additionally, in the early stages of AIS, this combination therapy can reduce blood LDL-C levels, and inhibit IL-6 elevation, potentially improving the prognosis of patients with AIS within 90 days.

Trial Registration: China Clinical Trials Registry (No: ChicTR2200059445, 29 April 2022, https://www.chictr.org.cn/ ).