BACKGROUND The PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor evolocumab reduced low-density lipoprotein cholesterol and cardiovascular events in the FOURIER trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Subjects With Elevated Risk). We investigated the efficacy and safety of evolocumab in patients with peripheral artery disease (PAD) as well as the effect on major adverse limb events. METHODS FOURIER was a randomized trial of evolocumab versus placebo in 27 564 patients with atherosclerotic disease on statin therapy followed for a median of 2.2 years. Patients were identified as having PAD at baseline if they had intermittent claudication and an ankle brachial index of <0.85, or if they had a prior peripheral vascular procedure. The primary end point was a composite of cardiovascular death, myocardial infarction, stroke, hospital admission for unstable angina, or coronary revascularization. The key secondary end point was a composite of cardiovascular death, myocardial infarction, or stroke. An additional outcome of interest was major adverse limb events defined as acute limb ischemia, major amputation, or urgent peripheral revascularization for ischemia. RESULTS Three thousand six hundred forty-two patients (13.2%) had PAD (1505 with no prior myocardial infarction or stroke). Evolocumab significantly reduced the primary end point consistently in patients with PAD (hazard ratio [HR] 0.79; 95% confidence interval [CI], 0.66-0.94; P=0.0098) and without PAD (HR 0.86; 95% CI, 0.80-0.93; P=0.0003; Pinteraction=0.40). For the key secondary end point, the HRs were 0.73 (0.59-0.91; P=0.0040) for those with PAD and 0.81 (0.73-0.90; P<0.0001) for those without PAD (Pinteraction=0.41). Because of their higher risk, patients with PAD had larger absolute risk reductions for the primary end point (3.5% with PAD, 1.6% without PAD) and the key secondary end point (3.5% with PAD, 1.4% without PAD). Evolocumab reduced the risk of major adverse limb events in all patients (HR, 0.58; 95% CI, 0.38-0.88; P=0.0093) with consistent effects in those with and without known PAD. There was a consistent relationship between lower achieved low-density lipoprotein cholesterol and lower risk of limb events (P=0.026 for the beta coefficient) that extended down to <10 mg/dL. CONCLUSIONS Patients with PAD are at high risk of cardiovascular events, and PCSK9 inhibition with evolocumab significantly reduced that risk with large absolute risk reductions. Moreover, lowering of low-density lipoprotein cholesterol with evolocumab reduced the risk of major adverse limb events. CLINICAL TRIAL REGISTRATION URL: https://www.clinicaltrials.gov. Unique identifier: NCT01764633.

中文翻译：

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Evolocumab降低低密度脂蛋白胆固醇并改善周围动脉疾病患者的结果：FOURIER试验的见解（对PCSK9抑制的高风险受试者进行了进一步的心血管结局研究）。

背景技术在FOURIER试验（具有较高风险的受试者进行PCSK9抑制的进一步心血管结局研究）中，PCSK9（原蛋白转化酶枯草杆菌蛋白酶/ kexin 9型）抑制剂evolocumab降低了低密度脂蛋白胆固醇和心血管事件。我们调查了evolocumab在外周动脉疾病（PAD）患者中的功效和安全性，以及对主要不良肢体事件的影响。方法FOURIER是依他汀类药物治疗27 564例动脉粥样硬化患者的evolocumab与安慰剂的随机试验，中位时间为2.2年。如果患者的间歇性lau行和踝臂指数<0.85，或者先前有外周血管手术，则被确定为基线PAD。主要终点是心血管疾病死亡的综合因素，心肌梗塞，中风，因不稳定型心绞痛而入院或冠状动脉血运重建。关键的次要终点是心血管死亡，心肌梗塞或中风的综合因素。另一个令人感兴趣的结果是严重的肢体不良事件，定义为急性肢体缺血，大面积截肢或因缺血引起的紧急外周血运重建。结果362例患者（13.2％）患有PAD（1505例既往无心肌梗塞或中风）。Evolocumab显着降低了PAD患者的主要终点（危险比[HR] 0.79; 95％置信区间[CI]，0.66-0.94; P = 0.0098）和无PAD患者（HR 0.86; 95％CI，0.80-0.93） ； P = 0.0003；互动= 0.40）。对于关键的次要终点，PAD患者的HR为0.73（0.59-0.91; P = 0.0040），而HR为0.81（0.73-0.90; P <0）。不含PAD的用户（0001）（互动= 0.41）。由于PAD患者的风险较高，因此其主要终点（主要为PAD的患者为3.5％，没有PAD的患者为1.6％）和主要次要终点（PAD的患者为3.5％，PAD的患者为1.4％）的绝对风险降低幅度更大。Evolocumab降低了所有患者发生重大不良肢体事件的风险（HR，0.58； 95％CI，0.38-0.88； P = 0.0093），在有和无PAD的患者中疗效一致。降低的低密度脂蛋白胆固醇水平与肢体事件的风险降低（β系数为P = 0.026）之间存在一致的关系，肢体事件的风险降低到<10 mg / dL。结论PAD患者有发生心血管事件的高风险，而依伐洛单抗对PCSK9的抑制显着降低了该风险，并且绝对风险大大降低。而且，evolocumab降低低密度脂蛋白胆固醇可降低发生严重不良肢体事件的风险。临床试验注册网址：https：//www.clinicaltrials.gov。唯一标识符：NCT01764633。