Background: In the FOURIER trial (Further Cardiovascular Outcomes Research With PCSK9 Inhibition in Patients With Elevated Risk), the PCSK9 (proprotein convertase subtilisin/kexin type 9) inhibitor evolocumab reduced low-density lipoprotein cholesterol (LDL-C) and cardiovascular risk. It is not known whether the efficacy of evolocumab is modified by baseline inflammatory risk. We explored the efficacy of evolocumab stratified by baseline high-sensitivity C-reactive protein (hsCRP). We also assessed the importance of inflammatory and residual cholesterol risk across the range of on-treatment LDL-C concentrations.

Methods: Patients (n=27 564) with stable atherosclerotic cardiovascular disease and LDL-C ≥70 mg/dL on a statin were randomly assigned to evolocumab versus placebo and followed for a median of 2.2 years (1.8–2.5). The effects of evolocumab on the primary end point of cardiovascular death, myocardial infarction, stroke, hospitalization for unstable angina or coronary revascularization, and the key secondary end point of cardiovascular death, myocardial infarction, or stroke were compared across strata of baseline hsCRP (<1, 1–3, and >3 mg/dL). Outcomes were also assessed across values for baseline hsCRP and 1-month LDL-C in the entire trial population. Multivariable models adjusted for variables associated with hsCRP and 1-month LDL-C were evaluated.

Results: A total of 7981 (29%) patients had a baseline hsCRP<1 mg/L, 11 177 (41%) had a hsCRP 1 to 3 mg/L, and 8337 (30%) had a hsCRP >3 mg/L. Median (interquartile range) baseline hsCRP was 1.8 (0.9–3.6) mg/L and levels were not altered by evolocumab (change at 48 weeks of –0.2 mg/dL [–1.0 to 0.4] in both treatment arms). In the placebo arm, patients in higher baseline hsCRP categories experienced significantly higher 3-year Kaplan-Meier rates of the primary and key secondary end points: 12.0%, 13.7%, and 18.1% for the primary end point (P_trend<0.0001) and 7.4%, 9.1%, and 13.2% for the key secondary end point (P_trend<0.0001) for categories of <1, 1 to 3, and >3 mg/dL, respectively. The relative risk reductions for the primary end point and key secondary end point with evolocumab were consistent across hsCRP strata (P-interactions>0.15 for both). In contrast, the absolute risk reductions with evolocumab tended to be greater in patients with higher hsCRP: 1.6%, 1.8%, and 2.6% and 0.8%, 2.0%, and 3.0%, respectively, for the primary and key secondary end points across hsCRP strata. In adjusted analyses of the association between LDL-C and hsCRP levels and cardiovascular risk, both LDL-C and hsCRP were independently associated with the primary outcome (P<0.0001 for each).

Conclusions: LDL-C reduction with evolocumab reduces cardiovascular events across hsCRP strata with greater absolute risk reductions in patients with higher-baseline hsCRP. Event rates were lowest in patients with the lowest hsCRP and LDL-C.

Clinical Trial Registration: URL: https://www.clinicaltrials.gov. Unique identifier: NCT01764633.

背景：在FOURIER试验（对风险较高的患者进行PCSK9抑制的进一步心血管结果研究）中，PCSK9（前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（LDL-C）和心血管疾病的风险。尚不知道基线炎症风险是否会改变evolocumab的疗效。我们探讨了由基线高敏C反应蛋白（hsCRP）分层的evolocumab的疗效。我们还评估了在治疗中LDL-C浓度范围内炎症和残留胆固醇风险的重要性。

方法：将具有稳定的动脉粥样硬化性心血管疾病且他汀类药物的LDL-C≥70 mg / dL的患者（n = 27 564）随机分配至evolocumab与安慰剂组，随访时间中位数为2.2年（1.8-2.5）。在基线hsCRP的各个层次比较了evolocumab对心血管死亡，心肌梗塞，中风，不稳定型心绞痛或冠状动脉血运重建住院的主要终点的影响以及心血管死亡，心肌梗塞或中风的关键次要终点的影响（< 1、1-3和> 3 mg / dL）。还评估了整个试验人群中基线hsCRP和1个月LDL-C值的结果。评估了针对与hsCRP和1个月LDL-C相关的变量进行调整的多变量模型。

结果：共有7981名患者（29％）的基线hsCRP <1 mg / L，11 177名患者（41％）的hsCRP为1至3 mg / L，8337名患者（30％）的hsCRP> 3 mg / L L. 基线hsCRP中位数（四分位数范围）为1.8（0.9-3.6）mg / L，但依伏洛单抗没有改变其水平（两个治疗组在48周时的变化为–0.2 mg / dL [–1.0至0.4]）。在安慰剂组中，基线hsCRP类别较高的患者，主要和主要次要终点的3年Kaplan-Meier比率显着更高：主要终点为12.0％，13.7％和18.1％（P_趋势<0.0001）关键次要终点分别为7.4％，9.1％和13.2％（P_趋势<0.0001）分别用于<1、1至3和> 3 mg / dL的类别。在hsCRP层次上，使用evolocumab的主要终点和主要次要终点的相对风险降低是一致的（两者P相互作用均大于0.15）。相比之下，hsCRP较高的患者使用evolocumab的绝对风险降低趋势往往更大：在整个主要和次要终点，分别为1.6％，1.8％和2.6％和0.8％，2.0％和3.0％ hsCRP层。在对LDL-C和hsCRP水平与心血管风险之间关系的调整分析中，LDL-C和hsCRP均与主要结局独立相关（每项P <0.0001）。

结论： evolocumab降低LDL-C可以降低hsCRP阶层的心血管事件，并且基线hsCRP较高的患者绝对风险的降低更大。hsCRP和LDL-C最低的患者中事件发生率最低。

临床试验注册： URL：https://www.clinicaltrials.gov。唯一标识符：NCT01764633。