Division of Cardiology, University of Colorado School of Medicine, Aurora (G.G.S.).
Université de Paris, Assistance Publique-Hôpitaux de Paris, Hôpital Bichat, France (P.G.S.).
Circulation. 2020 May 19;141(20):1608-1617. doi: 10.1161/CIRCULATIONAHA.120.046524. Epub 2020 Mar 29.
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.
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-C) for cholesterol content in lipoprotein(a).
At baseline, median lipoprotein(a) and LDL-C 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) (=0.0021), and tended to associate with baseline quartile of LDL-C (=0.06); VTE tended to associate with baseline quartile of lipoprotein(a) (=0.06), but not LDL-C (=0.85). Alirocumab reduced risk of PAD events (hazard ratio [HR], 0.69 [95% CI, 0.54-0.89]; =0.004), with nonsignificantly fewer VTE events (HR, 0.67 [95% CI, 0.44-1.01]; =0.06). Reduction in PAD events with alirocumab was associated with baseline quartile of lipoprotein(a) (=0.03), but not LDL-C (=0.50). With alirocumab, the change from baseline to Month 4 in lipoprotein(a), but not LDL-C, was associated with the risk of VTE and the composite of VTE and PAD events.
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.
急性冠状动脉综合征患者存在外周动脉疾病（PAD）事件和静脉血栓栓塞（VTE）的风险。PCSK9（脯氨酸羧肽酶/枯草溶菌素 9）抑制剂可降低脂蛋白（a）和低密度脂蛋白胆固醇（LDL-C）水平。我们的目的是确定 PCSK9 抑制剂是否会降低急性冠状动脉综合征后 PAD 事件或 VTE 的风险，以及这种作用是否与脂蛋白（a）或 LDL-C 水平有关。
这是一项针对 ODYSSEY OUTCOMES 随机临床试验（急性冠状动脉综合征后心血管结局评估）的预设分析，该试验在 18924 名正在接受强化或最大耐受他汀类药物治疗的近期急性冠状动脉综合征患者中进行，这些患者被随机分配至 PCSK9 抑制剂阿利西尤单抗或安慰剂组。在一项预设分析中，评估了 PAD 事件（严重肢体缺血、肢体血运重建或缺血性截肢）和 VTE（深静脉血栓形成或肺栓塞）。LDL-C 校正了脂蛋白（a）中的胆固醇含量。
在基线时，脂蛋白（a）和 LDL-C 的中位数分别为 21 和 75mg/dL；使用阿利西尤单抗，中位数相对降低分别为 23.5%和 70.6%。在安慰剂组中，246 例患者发生 PAD 事件，92 例患者发生 VTE。PAD 事件的风险与脂蛋白（a）的基线四分位相关（=0.0021），且与 LDL-C 的基线四分位相关（=0.06）的趋势；VTE 与脂蛋白（a）的基线四分位相关（=0.06），但与 LDL-C 无关（=0.85）。阿利西尤单抗降低了 PAD 事件的风险（危险比[HR]，0.69[95%CI，0.54-0.89]；=0.004），但 VTE 事件的风险无显著降低（HR，0.67[95%CI，0.44-1.01]；=0.06）。阿利西尤单抗降低 PAD 事件的风险与脂蛋白（a）的基线四分位相关（=0.03），但与 LDL-C 无关（=0.50）。阿利西尤单抗治疗后 4 个月时，脂蛋白（a）的变化与 VTE 风险和 VTE 及 PAD 事件的复合终点相关，而 LDL-C 无此关联。
在接受他汀类药物治疗的近期急性冠状动脉综合征患者中，PAD 事件的风险与脂蛋白（a）水平有关，阿利西尤单抗可降低 PAD 事件的风险，尤其是脂蛋白（a）水平较高的患者。需要进一步研究以确认 VTE 的风险是否与脂蛋白（a）水平及其降低有关。注册：网址：https://www.clinicaltrials.gov；唯一标识符：NCT01663402。
