美国休斯敦卫理公会医院德贝基心脏和血管中心Safi U Khan团队研究了PCSK9抑制剂和依折麦布联合或不联合他汀治疗降低心血管风险的效果。2022年5月4日出版的《英国医学杂志》发表了这项成果。

为了比较依折麦布和前蛋白转化酶枯草杆菌素/可欣9型（PCSK9）抑制剂对服用最大耐受他汀类药物或他汀类药物不耐受的成人心血管结局的影响，研究组在Medline、EMBASE和Cochrane图书馆等大型数据库中检索截至2020年12月31日的相关文献，筛选出关于依折麦布和PCSK9抑制剂、≥500例患者、随访结果≥6个月的随机对照试验，进行网络荟萃分析。

研究组进行了频度固定效应网络荟萃分析和评分（推荐分级、评估、发展和定值），以评估证据的确定性。结局包括每1000名接受五年治疗的患者非致命性心肌梗死（MI）、非致命性中风、全因死亡和心血管死亡的相对风险（RR）和绝对风险。

研究组假设不同基线治疗和心血管风险阈值的RR恒定（通过网络荟萃分析估计），并估计绝对风险差异；预测风险计算器估计了一级和二级预防中的心血管风险。将患者按低到极高的心血管风险进行分层。一个指导小组和系统评价作者确定最小重要差异（MID），即心肌梗死为12/1000例，中风为10/1000例。

研究组在83项研究中确定了14项评估依折麦布和PCSK9抑制剂的试验，共83660名成年人使用他汀类药物。在他汀类药物中添加依折麦布可降低心肌梗死（RR为0.87）和中风（0.82）的发生率，但不能降低全因死亡率（0.99）或心血管死亡率（0.97）。类似地，在他汀类药物中添加PCSK9抑制剂可降低心肌梗死（0.81）和中风（0.74）发生率，但不能降低全因死亡率（0.95）或心血管死亡率（0.95）。

在心血管风险极高的成年人中，添加PCSK9抑制剂可能会减少心肌梗死（16/1000）和中风（21/1000）（中高度确定性）的发生率；而添加依折麦布可能会减少中风（14/1000）发生率，但心肌梗死（11/1000）的减少（中度确定）并未达到MID。在PCSK9抑制剂和他汀类药物中添加依折麦布可能会减少中风（11/1000）发生率，但心肌梗死（9/1000）的减少（低确定性）并未达到MID。

在他汀类药物和依折麦布中添加PCSK9抑制剂可以减少心肌梗死（14/1000）和中风（17/1000）的发生率（低确定性）。在心血管风险较高的成年人中，添加PCSK9抑制剂可能会降低心肌梗死（12/1000）和中风（16/1000）的发生率（中度确定）；添加依折麦布可能会减少中风（11/1000）率，但心肌梗死（8/1000）的减少并未达到MID（中度确定）。

在PCSK9抑制剂和他汀类药物中添加依折麦布不会降低超过MID的预后，而在依折麦布和他汀类药物中添加PCSK9抑制剂可能会降低中风率（13/1000）。这些结果在他汀类药物不耐受患者中是一致的。在中、低心血管风险组中，在他汀类药物中添加PCSK9抑制剂或依折麦布对心肌梗死和中风几乎没有益处。

研究结果表明，在接受最大耐受他汀类药物治疗或他汀类药物不耐受的心血管风险极高或较高的成年人中，添加依折麦布或PCSK9抑制剂可能会减少非致命性心肌梗死和中风的发生率，但在心血管风险中等或较低的人中则不会。

附：英文原文

Title: PCSK9 inhibitors and ezetimibe with or without statin therapy for cardiovascular risk reduction: a systematic review and network meta-analysis

Author: Safi U Khan, Siva H Yedlapati, Ahmad N Lone, Qiukui Hao, Gordon Guyatt, Nicolas Delvaux, Geertruida E (Trudy) Bekkering, Per Olav Vandvik, Irbaz Bin Riaz, Sheyu Li, Bert Aertgeerts, Nicolas Rodondi

Issue&Volume: 2022/05/04

Abstract:

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 83660 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.

DOI: 10.1136/bmj-2021-069116

Source: https://www.bmj.com/content/377/bmj-2021-069116