在 14 项随机的 2 期和 3 期对照临床试验的 3340 例患者中，没有发现与阿利西尤单抗治疗相关的神经认知不良事件：一项个体患者数据的荟萃分析。

No evidence of neurocognitive adverse events associated with alirocumab treatment in 3340 patients from 14 randomized Phase 2 and 3 controlled trials: a meta-analysis of individual patient data.

机构信息

Department of Psychiatry, University of Miami Miller School of Medicine, 1120 NW 14th Street, Suite 1450, Miami, FL, USA.

Barrow Neurological Institute, 350 W Thomas Rd, Phoenix, AZ 85013, USA.

出版信息

Eur Heart J. 2018 Feb 1;39(5):374-381. doi: 10.1093/eurheartj/ehx661.

AIMS

Despite patient reports of neurocognitive disorders with lipid-lowering treatments (LLTs), large clinical trials have found no significant association between neurocognitive disorders and LLTs. We assessed incidence of neurocognitive treatment-emergent adverse events (TEAEs) from 14 Phase 2 and 3 trials of the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor alirocumab.

METHODS AND RESULTS

Patients (most on background maximally tolerated statin) received alirocumab 75/150 mg every 2 weeks (n = 3340; 4029 patient-years of exposure), placebo (n = 1276), or ezetimibe (n = 618). Data were pooled by the control used. Neurocognitive TEAEs were reported by 22 (0.9%) alirocumab-treated patients vs. 9 (0.7%) with placebo in placebo-controlled trials [hazard ratio (HR) 1.24, 95% confidence interval (CI) 0.57-2.68] and 10 (1.2%) with alirocumab vs. 8 (1.3%) with ezetimibe in ezetimibe-controlled trials (HR 0.81, 95% CI 0.32-2.08). Rates of neurocognitive TEAEs were similar in patients receiving alirocumab with LDL cholesterol (LDL-C) levels <25 mg/dL (<0.65 mmol/L; n = 5/839; 0.6%; 0.5/100 patient-years) vs. ≥25 mg/dL (n = 26/2501; 1.0%; 0.8/100 patient-years). One patient (0.1%; ezetimibe-controlled pool) receiving alirocumab had a neurocognitive TEAE leading to discontinuation vs. two (0.2%) patients receiving placebo and three (0.4%) patients receiving ezetimibe. Neurocognitive TEAE incidence was also similar between alirocumab and controls when stratified by age.

CONCLUSIONS

Neurocognitive TEAE incidences were low (≤1.2%), with no significant differences between alirocumab vs. controls up to 104 weeks. No association was found between neurocognitive TEAEs and LDL-C <25 mg/dL based on the completed Phase 2 and 3 trials examined, although long-term effects of very low LDL-C levels induced by PCSK9 inhibitors are currently unknown.

目的

尽管有患者报告降脂治疗（LLT）后出现神经认知障碍，但大型临床试验并未发现神经认知障碍与 LLT 之间存在显著关联。我们评估了前蛋白转化酶枯草溶菌素/ kexin 9（PCSK9）抑制剂阿利西尤单抗的 14 项 2 期和 3 期试验中神经认知治疗出现的不良事件（TEAEs）的发生率。

方法和结果

患者（大多数正在接受最大耐受剂量的他汀类药物治疗）接受阿利西尤单抗 75/150mg，每 2 周一次（n=3340；4029 患者年暴露）、安慰剂（n=1276）或依折麦布（n=618）治疗。按所用对照药物汇总数据。在安慰剂对照试验中，22 例（0.9%）阿利西尤单抗治疗患者和 9 例（0.7%）安慰剂治疗患者报告有神经认知 TEAEs[风险比（HR）1.24，95%置信区间（CI）0.57-2.68]；在依折麦布对照试验中，10 例（1.2%）阿利西尤单抗治疗患者和 8 例（1.3%）依折麦布治疗患者报告有神经认知 TEAEs（HR 0.81，95%CI 0.32-2.08）。在 LDL 胆固醇（LDL-C）水平<25mg/dL（<0.65mmol/L；n=5/839；0.6%；0.5/100 患者年）的患者中，阿利西尤单抗组的神经认知 TEAEs 发生率与 LDL-C 水平≥25mg/dL（n=26/2501；1.0%；0.8/100 患者年）的患者相似。在接受阿利西尤单抗治疗的患者中，有 1 例（0.1%；依折麦布对照药物组）因神经认知 TEAEs 导致停药，而接受安慰剂治疗的患者有 2 例（0.2%）和接受依折麦布治疗的患者有 3 例（0.4%）。按年龄分层时，阿利西尤单抗与对照药物之间的神经认知 TEAEs 发生率也相似。