Investigate the efficacy and safety of proprotein convertase subtilisin/kexin type 9 inhibitors (PCSK9i) on stroke prevention. PCSK9i reduce low-density lipoprotein cholesterol (LDL-C) and lipoprotein a (LpA) levels. Their efficacy in reducing the risk of major cardiovascular events has been shown in multiple randomized clinical trials (RCT). However, clinical equipoise remains on the magnitude and mechanisms by which PCSK9i decrease the risk of stroke. We performed a systematic search of biomedical databases from inception to January 15, 2024, to identify RCTs that investigated the efficacy of PCSK9i versus placebo for major cardiovascular event prevention. The primary outcome was total stroke. The safety outcome was the risk of adverse neurological events, as defined by each trial. Effect size was represented by risk ratio (RR), and analysis was done using random-effects meta-analysis. Heterogeneity was assessed by I and Cochrane Q statistics. Meta-regression analyses were performed to assess the association between LDL-C and LpA reduction and stroke risk. Overall, 20 studies with 93,093 patients were included. The quality of the evidence was moderate and heterogeneity for all comparisons was low (I <25%). The mean age was 60.1 years for the PCSK9i group and 59.6 years for the placebo group, with a mean follow-up time of 60.1 weeks. PCSK9i reduced the LDL-C levels by 11% and LpA levels by 8%. PCSK9i were associated with a significant reduction in stroke risk (RR 0.75, 95% CI 0.66-0.86, I=0%), without an increase in mortality (RR 0.97, 95% CI 0.87-1.08, I=0%). The risk of adverse neurological events was similar between groups (RR 0.99, 95% CI 0.84-1.18, I=11%). In meta-regression analyses, the stroke risk was not associated with the magnitude of the effect of PCSK9i on LDL-C (LDL C β=-0.01, 95% CI=-0.03-0.02) and LpA (β=-0.01, 95% CI=-0.06-0.04) levels. PCSK9i significantly reduced the stroke risk, without increasing mortality or the risk of adverse neurological events. Our findings also suggest that the beneficial effect of PCSK9i on stroke risk is mediated by LDL-C- and LpA-independent mechanisms.

中文翻译：

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PCSK9 抑制剂预防卒中的功效和安全性：系统评价和荟萃分析

研究前蛋白转化酶枯草杆菌蛋白酶/kexin 9 型抑制剂 (PCSK9i) 对预防中风的功效和安全性。PCSK9i 降低低密度脂蛋白胆固醇 (LDL-C) 和脂蛋白 a (LpA) 水平。它们在降低主要心血管事件风险方面的功效已在多项随机临床试验 (RCT) 中得到证实。然而，对于 PCSK9i 降低中风风险的程度和机制，临床仍处于平衡状态。我们对从成立到 2024 年 1 月 15 日的生物医学数据库进行了系统检索，以确定研究 PCSK9i 与安慰剂在预防重大心血管事件方面的功效的随机对照试验。主要结局是总卒中。安全性结果是每项试验所定义的不良神经系统事件的风险。效应大小以风险比（RR）表示，并使用随机效应荟萃分析进行分析。通过 I 和 Cochrane Q 统计来评估异质性。进行荟萃回归分析以评估 LDL-C 和 LpA 降低与中风风险之间的关联。总体而言，纳入了 20 项研究，涉及 93,093 名患者。证据质量中等，所有比较的异质性较低（I <25%）。PCSK9i 组的平均年龄为 60.1 岁，安慰剂组为 59.6 岁，平均随访时间为 60.1 周。PCSK9i 使 LDL-C 水平降低 11%，LpA 水平降低 8%。PCSK9i 与中风风险显着降低相关（RR 0.75，95% CI 0.66-0.86，I = 0%），而不增加死亡率（RR 0.97，95% CI 0.87-1.08，I = 0%）。各组之间不良神经系统事件的风险相似（RR 0.99，95% CI 0.84-1.18，I = 11%）。在荟萃回归分析中，卒中风险与 PCSK9i 对 LDL-C（LDL C β=-0.01，95% CI=-0.03-0.02）和 LpA（β=-0.01，95）的影响程度无关。 % CI=-0.06-0.04）水平。PCSK9i 显着降低了中风风险，而不增加死亡率或不良神经事件的风险。我们的研究结果还表明，PCSK9i 对中风风险的有益作用是由 LDL-C 和 LpA 独立机制介导的。