BACKGROUND The relationship between cholesterol levels and risk of venous thromboembolism (VTE) is uncertain. We set out to determine the effect of PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibition on the risk of VTE, explore potential mechanisms, and examine the efficacy in subgroups with clinically and genetically defined risk. METHODS We performed a post hoc analysis of the FOURIER trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk) testing whether evolocumab reduces the risk of VTE events (deep venous thrombosis or pulmonary embolism). Data from FOURIER and ODYSSEY OUTCOMES (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome During Treatment with Alirocumab) were then combined in a meta-analysis to assess the class effect of PCSK9 inhibition on the risk of VTE. We also analyzed baseline lipids in FOURIER to investigate potential mechanisms explaining the reduction in VTE with evolocumab. Last, an exploratory genetic analysis was performed in FOURIER to determine whether a VTE polygenic risk score could identify high-risk patients who would derive the greatest VTE reduction from evolocumab. RESULTS In FOURIER, the hazard ratio (HR) for VTE with evolocumab was 0.71 (95% CI, 0.50-1.00; P=0.05), with no effect in the 1st year (HR, 0.96 [95% CI, 0.57-1.62]) but a 46% reduction (HR, 0.54 [95% CI, 0.33-0.88]; P=0.014) beyond 1 year. A meta-analysis of FOURIER and ODYSSEY OUTCOMES demonstrated a 31% relative risk reduction in VTE with PCSK9 inhibition (HR, 0.69 [95% CI, 0.53-0.90]; P=0.007). There was no relation between baseline low-density lipoprotein cholesterol levels and magnitude of VTE risk reduction. In contrast, in patients with higher baseline lipoprotein(a) (Lp[a]) levels, evolocumab reduced Lp(a) by 33 nmol/L and risk of VTE by 48% (HR, 0.52 [95% CI, 0.30-0.89]; P=0.017), whereas, in patients with lower baseline Lp(a) levels, evolocumab reduced Lp(a) by only 7 nmol/L and had no effect on VTE risk (Pinteraction 0.087 for HR; Pheterogeneity 0.037 for absolute risk reduction). Modeled as a continuous variable, there was a significant interaction between baseline Lp(a) concentration and magnitude of VTE risk reduction (Pinteraction=0.04). A polygenic risk score identified patients who were at >2-fold increased risk for VTE and who derived greater relative (Pinteraction=0.04) and absolute VTE reduction (Pheterogeneity=0.009) in comparison with those without high genetic risk. CONCLUSIONS PCSK9 inhibition significantly reduces the risk of VTE. Lp(a) reduction may be an important mediator of this effect, a finding of particular interest given the ongoing development of potent Lp(a) inhibitors.

中文翻译：

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PCSK9（前蛋白转化酶枯草杆菌蛋白酶/Kexin 9 型）抑制对静脉血栓栓塞风险的影响。


背景胆固醇水平与静脉血栓栓塞（VTE）风险之间的关系尚不确定。我们着手确定 PCSK9（前蛋白转化酶枯草杆菌蛋白酶/kexin 9 型）抑制对 VTE 风险的影响，探索潜在机制，并检查在具有临床和遗传定义风险的亚组中的疗效。方法 我们对 FOURIER 试验（高风险受试者中 PCSK9 抑制的进一步心血管结果研究）进行了事后分析，测试 evolocumab 是否可以降低 VTE 事件（深静脉血栓形成或肺栓塞）的风险。然后将来自 FOURIER 和 ODYSSEY OUTCOMES（Alirocumab 治疗期间急性冠脉综合征后心血管结果的评估）的数据合并到一项荟萃分析中，以评估 PCSK9 抑制对 VTE 风险的类别效应。我们还分析了 FOURIER 中的基线血脂，以研究解释 evolocumab 减少 VTE 的潜在机制。最后，在 FOURIER 中进行了探索性遗传分析，以确定 VTE 多基因风险评分是否可以识别出能够从 evolocumab 中获得最大 VTE 降低的高风险患者。结果 在 FOURIER 中，evolocumab 治疗 VTE 的风险比 (HR) 为 0.71（95% CI，0.50-1.00；P=0.05），第一年没有效果（HR，0.96 [95% CI，0.57-1.62]） ），但 1 年后降低 46%（HR，0.54 [95% CI，0.33-0.88]；P=0.014）。 FOURIER 和 ODYSSEY OUTCOMES 的荟萃分析表明，抑制 PCSK9 可使 VTE 相对风险降低 31%（HR，0.69 [95% CI，0.53-0.90]；P=0.007）。基线低密度脂蛋白胆固醇水平与 VTE 风险降低程度之间没有关系。 相比之下，在基线脂蛋白(a) (Lp[a])水平较高的患者中，evolocumab 将 Lp(a) 降低 33 nmol/L，并将 VTE 风险降低 48%（HR，0.52 [95% CI，0.30-0.89]） ]；P=0.017），而在基线 Lp(a) 水平较低的患者中，evolocumab 仅使 Lp(a) 降低 7 nmol/L，并且对 VTE 风险没有影响（HR 的 Pinteraction 为 0.087；绝对风险的异质性为 0.037）减少）。作为连续变量建模，基线 Lp(a) 浓度与 VTE 风险降低程度之间存在显着的交互作用（Pinteraction=0.04）。多基因风险评分确定了与无高遗传风险的患者相比，VTE 风险增加 2 倍以上的患者，以及相对 (Pinteraction=0.04) 和绝对 VTE 降低 (Pheterogenity=0.009) 更大的患者。结论 PCSK9 抑制可显着降低 VTE 风险。 Lp(a) 减少可能是这种效应的重要介导因素，考虑到强效 Lp(a) 抑制剂的不断发展，这一发现特别令人感兴趣。