Objective To compare the impact of ezetimibe and proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors on cardiovascular outcomes in adults taking maximally tolerated statin therapy or who are statin intolerant. Design Network meta-analysis. Data sources Medline, EMBASE, and Cochrane Library up to 31 December 2020. Eligibility criteria for selecting studies Randomised controlled trials of ezetimibe and PCSK9 inhibitors with ≥500 patients and follow-up of ≥6 months. Main outcome measures We performed frequentist fixed-effects network meta-analysis and GRADE (grading of recommendations, assessment, development, and evaluation) to assess certainty of evidence. Results included relative risks (RR) and absolute risks per 1000 patients treated for five years for non-fatal myocardial infarction (MI), non-fatal stroke, all-cause mortality, and cardiovascular mortality. We estimated absolute risk differences assuming constant RR (estimated from network meta-analysis) across different baseline therapies and cardiovascular risk thresholds; the PREDICT risk calculator estimated cardiovascular risk in primary and secondary prevention. Patients were categorised at low to very high cardiovascular risk. A guideline panel and systematic review authors established the minimal important differences (MID) of 12 per 1000 for MI and 10 per 1000 for stroke. Results We identified 14 trials assessing ezetimibe and PCSK9 inhibitors among 83 660 adults using statins. Adding ezetimibe to statins reduced MI (RR 0.87 (95% confidence interval 0.80 to 0.94)) and stroke (RR 0.82 (0.71 to 0.96)) but not all-cause mortality (RR 0.99 (0.92 to 1.06)) or cardiovascular mortality (RR 0.97 (0.87 to 1.09)). Similarly, adding PCSK9 inhibitor to statins reduced MI (0.81 (0.76 to 0.87)) and stroke (0.74 (0.64 to 0.85)) but not all-cause (0.95 (0.87 to 1.03)) or cardiovascular mortality (0.95 (0.87 to 1.03)). Among adults with very high cardiovascular risk, adding PCSK9 inhibitor was likely to reduce MI (16 per 1000) and stroke (21 per 1000) (moderate to high certainty); whereas adding ezetimibe was likely to reduce stroke (14 per 1000), but the reduction of MI (11 per 1000) (moderate certainty) did not reach MID. Adding ezetimibe to PCSK9 inhibitor and statin may reduce stroke (11 per 1000), but the reduction of MI (9 per 1000) (low certainty) did not reach MID. Adding PCSK9 inhibitors to statins and ezetimibe may reduce MI (14 per 1000) and stroke (17 per 1000) (low certainty). Among adults with high cardiovascular risk, adding PCSK9 inhibitor probably reduced MI (12 per 1000) and stroke (16 per 1000) (moderate certainty); adding ezetimibe probably reduced stroke (11 per 1000), but the reduction in MI did not achieve MID (8 per 1000) (moderate certainty). Adding ezetimibe to PCSK9 inhibitor and statins did not reduce outcomes beyond MID, while adding PCSK9 inhibitor to ezetimibe and statins may reduce stroke (13 per 1000). These effects were consistent in statin-intolerant patients. Among moderate and low cardiovascular risk groups, adding PCSK9 inhibitor or ezetimibe to statins yielded little or no benefit for MI and stroke. Conclusions Ezetimibe or PCSK9 inhibitors may reduce non-fatal MI and stroke in adults at very high or high cardiovascular risk who are receiving maximally tolerated statin therapy or are statin-intolerant, but not in those with moderate and low cardiovascular risk. Statistical code and dataset are available from the corresponding author at safinmc@gmail.com.

中文翻译：

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PCSK9抑制剂和依折麦布联合或不联合他汀类药物治疗降低心血管风险：系统评价和网络荟萃分析

目的比较依折麦布和前蛋白转化酶枯草溶菌素/kexin 9 (PCSK9) 抑制剂对接受最大耐受他汀类药物治疗或他汀类药物不耐受的成人心血管结局的影响。设计网络荟萃分析。数据来源 Medline、EMBASE 和 Cochrane 图书馆，截至 2020 年 12 月 31 日。 选择研究的资格标准 依折麦布和 PCSK9 抑制剂的随机对照试验，≥500 名患者，随访时间≥6 个月。主要结果测量 我们进行了常客固定效应网络荟萃分析和 GRADE（推荐、评估、开发和评估的分级）来评估证据的确定性。结果包括每 1000 名接受五年治疗的非致死性心肌梗死 (MI)、非致死性卒中、全因死亡率、和心血管死亡率。我们估计了不同基线治疗和心血管风险阈值之间的恒定 RR（从网络荟萃分析估计）的绝对风险差异；PREDICT 风险计算器估计了一级和二级预防中的心血管风险。患者被归类为低到非常高的心血管风险。一个指南小组和系统评价作者确定了 MI 的最小重要差异 (MID) 为每 1000 人 12 人，卒中每 1000 人 10 人。结果 我们在 83 660 名使用他汀类药物的成年人中确定了 14 项评估依折麦布和 PCSK9 抑制剂的试验。在他汀类药物中添加依折麦布可降低 MI（RR 0.87（95% 置信区间 0.80 至 0.94））和卒中（RR 0.82（0.71 至 0.96）），但不能降低全因死亡率（RR 0.99（0.92 至 1.06））或心血管死亡率（RR 0.97（0.87 至 1.09））。同样，在他汀类药物中添加 PCSK9 抑制剂可降低 MI（0.81（0.76 至 0.87））和中风（0.74（0.64 至 0.85）），但不能降低全因死亡率（0.95（0.87 至 1.03））或心血管死亡率（0.95（0.87 至 1.03）） ）。在心血管风险极高的成年人中，添加 PCSK9 抑制剂可能会降低 MI（每 1000 人 16 人）和中风（每 1000 人 21 人）（中等至高度确定性）；而加入依折麦布可能会减少卒中（每 1000 人 14 人），但 MI 减少（每 1000 人 11 人）（中等确定性）并未达到 MID。在 PCSK9 抑制剂和他汀类药物中添加依折麦布可减少卒中（每 1000 人 11 人），但 MI 减少率（每 1000 人 9 人）（低确定性）并未达到 MID。在他汀类药物和依折麦布中添加 PCSK9 抑制剂可减少 MI（每 1000 人 14 人）和中风（每 1000 人 17 人）（低确定性）。在心血管高危人群中，添加 PCSK9 抑制剂可能减少 MI（每 1000 人 12 人）和中风（每 1000 人 16 人）（中等确定性）；添加依折麦布可能会减少卒中（每 1000 人 11 人），但 MI 的减少并未达到 MID（每 1000 人 8 人）（中等确定性）。将依折麦布添加到 PCSK9 抑制剂和他汀类药物中并不会降低 MID 以外的结果，而将 PCSK9 抑制剂添加到依折麦布和他汀类药物中可能会减少中风（每 1000 人中有 13 人）。这些效果在他汀类药物不耐受的患者中是一致的。在中度和低度心血管风险组中，将 PCSK9 抑制剂或依折麦布添加到他汀类药物中对 MI 和中风几乎没有或没有益处。结论 依折麦布或 PCSK9 抑制剂可降低接受最大耐受他汀类药物治疗或他汀类药物不耐受的具有极高或高心血管风险的成人的非致命性 MI 和卒中，但不适用于中度和低心血管风险的人。统计代码和数据集可从通讯作者 safinmc@gmail.com 获得。