BACKGROUND Patients with acute coronary syndrome are at risk for peripheral artery disease (PAD) events and venous thromboembolism (VTE). PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitors reduce lipoprotein(a) and low-density lipoprotein cholesterol (LDL-C) levels. Our objective was to ascertain whether PCSK9 inhibition reduces the risk of PAD events or VTE after acute coronary syndrome, and if such effects are related to levels of lipoprotein(a) or LDL-C. METHODS This was a prespecified analysis of the ODYSSEY OUTCOMES randomized clinical trial (Evaluation of Cardiovascular Outcomes After an Acute Coronary Syndrome), which was conducted in 18 924 patients with recent acute coronary syndrome on intensive or maximum-tolerated statin treatment who were randomized to the PCSK9 inhibitor alirocumab or placebo. In a prespecified analysis, PAD events (critical limb ischemia, limb revascularization, or amputation for ischemia) and VTE (deep vein thrombosis or pulmonary embolism) were assessed. LDL-C was corrected (LDL-Ccorrected) for cholesterol content in lipoprotein(a). RESULTS At baseline, median lipoprotein(a) and LDL-Ccorrected were 21 and 75 mg/dL, respectively; with alirocumab, median relative reductions were 23.5% and 70.6%, respectively. PAD events and VTE occurred in 246 and 92 patients, respectively. In the placebo group, risk of PAD events was related to baseline quartile of lipoprotein(a) (Ptrend=0.0021), and tended to associate with baseline quartile of LDL-Ccorrected (Ptrend=0.06); VTE tended to associate with baseline quartile of lipoprotein(a) (Ptrend=0.06), but not LDL-Ccorrected (Ptrend=0.85). Alirocumab reduced risk of PAD events (hazard ratio [HR], 0.69 [95% CI, 0.54-0.89]; P=0.004), with nonsignificantly fewer VTE events (HR, 0.67 [95% CI, 0.44-1.01]; P=0.06). Reduction in PAD events with alirocumab was associated with baseline quartile of lipoprotein(a) (Ptrend=0.03), but not LDL-Ccorrected (Ptrend=0.50). With alirocumab, the change from baseline to Month 4 in lipoprotein(a), but not LDL-Ccorrected, was associated with the risk of VTE and the composite of VTE and PAD events. CONCLUSIONS In statin-treated patients with recent acute coronary syndrome, risk of PAD events is related to lipoprotein(a) level and is reduced by alirocumab, particularly among those with high lipoprotein(a). Further study is required to confirm whether risk of VTE is related to lipoprotein(a) level and its reduction with alirocumab. Registration: URL: https://www.clinicaltrials.gov; Unique identifier: NCT01663402.

中文翻译：

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急性冠脉综合征后的外周动脉疾病和静脉血栓栓塞事件：脂蛋白 (a) 的作用和 Alirocumab 的修饰：ODYSSEY OUTCOMES 随机临床试验的预设分析。

背景 急性冠脉综合征患者有发生外周动脉疾病 (PAD) 事件和静脉血栓栓塞 (VTE) 的风险。PCSK9（前蛋白转化酶枯草杆菌蛋白酶/kexin 9 型）抑制剂可降低脂蛋白 (a) 和低密度脂蛋白胆固醇 (LDL-C) 水平。我们的目标是确定 PCSK9 抑制是否会降低急性冠脉综合征后 PAD 事件或 VTE 的风险，以及这种影响是否与脂蛋白 (a) 或 LDL-C 的水平有关。方法 这是对 ODYSSEY OUTCOMES 随机临床试验（急性冠脉综合征后心血管结局评估）的预设分析，该试验在 18 924 名近期接受强化或最大耐受他汀类药物治疗的急性冠脉综合征患者中进行，这些患者被随机分配至PCSK9 抑制剂 alirocumab 或安慰剂。在预先指定的分析中，评估了 PAD 事件（严重肢体缺血、肢体血运重建或缺血截肢）和 VTE（深静脉血栓形成或肺栓塞）。根据脂蛋白 (a) 中的胆固醇含量对 LDL-C 进行校正 (LDL-Ccorrected)。结果 基线时，中位脂蛋白 (a) 和 LDL-C 校正值分别为 21 和 75 mg/dL；使用 alirocumab 时，中位相对减少分别为 23.5% 和 70.6%。PAD 事件和 VTE 分别发生在 246 和 92 名患者中。在安慰剂组中，PAD 事件的风险与脂蛋白 (a) 的基线四分位数相关（Ptrend=0.0021），并倾向于与 LDL-C 校正的基线四分位数相关（Ptrend=0.06）；VTE 倾向于与脂蛋白 (a) 的基线四分位数相关（Ptrend=0.06），但与 LDL-C 校正（Ptrend=0.85）无关。Alirocumab 降低了 PAD 事件的风险（风险比 [HR]，0.69 [95% CI，0.54-0.89]；P=0.004），VTE 事件较少（HR，0.67 [95% CI，0.44-1.01]；P= 0.06）。使用 alirocumab 减少 PAD 事件与脂蛋白 (a) 的基线四分位数相关（Ptrend=0.03），但与 LDL-C 校正（Ptrend=0.50）无关。使用 alirocumab 时，脂蛋白 (a) 从基线到第 4 个月的变化与 VTE 的风险以及 VTE 和 PAD 事件的复合风险相关，但未校正的 LDL-C。结论 在接受他汀类药物治疗的近期急性冠脉综合征患者中，PAD 事件的风险与脂蛋白 (a) 水平相关，并且通过 alirocumab 降低，尤其是在那些具有高脂蛋白 (a) 的患者中。需要进一步研究以确认 VTE 风险是否与脂蛋白 (a) 水平及其使用 alirocumab 的降低有关。注册：网址：https：//www.clinicaltrials.gov; 唯一标识符：NCT01663402。