Effect of C-Reactive Protein on Lipoprotein(a)-Associated Cardiovascular Risk in Optimally Treated Patients With High-Risk Vascular Disease A Prespecified Secondary Analysis of the ACCELERATE Trial
Effect of C-Reactive Protein on Lipoprotein(a)-Associated Cardiovascular Risk in Optimally Treated Patients With High-Risk Vascular Disease A Prespecified Secondary Analysis of the ACCELERATE Trial
复制标题
DOI：
10.1001/jamacardio.2020.2413
复制
发表时间：
2020-10-01
期刊：
影响因子：
24
通讯作者：
Nicholls, Stephen J.
中科院分区：
文献类型：
--
作者：
Puri, Rishi;Nissen, Steven E.;Nicholls, Stephen J.
重要性 尽管脂蛋白(a) (Lp[a]) 是动脉粥样硬化性心血管疾病的致病遗传危险因素，但目前尚不清楚哪些患有动脉粥样硬化性心血管疾病的患者能从降低Lp(a) 中获益最多。二级预防期间炎症是否可以调节 Lp(a) 相关的心血管 (CV) 风险尚不清楚。 目的 在 CV 疾病高风险患者中，检查经过最佳治疗的患者中 Lp(a) 相关的 CV 风险是否受全身炎症调节。 设计、设置和参与者 对使用 Evacetrapib 抑制胆固醇酯转移蛋白的临床效果进行双盲、多中心随机临床评估的预先指定的二次事后分析血管结局高风险（ACCELERATE）试验于2012年10月1日至2013年12月31日期间进行；该研究于 2015 年 10 月 12 日终止。该研究在 36 个国家的 543 家学术和社区医院进行，研究对象为 12092 名心血管疾病高危患者（急性冠状动脉综合征、中风、外周动脉疾病或合并冠状动脉疾病的 2 型糖尿病），治疗期间可测量 Lp(a) 和高敏 C 反应蛋白 (hsCRP) 水平。本事后分析的统计分析于 2018 年 9 月 26 日至 2020 年 3 月 28 日进行。 干预措施 参与者接受 evacetrapib 130mg/d 或匹配的安慰剂。 主要结果和措施 ACCELERATE 试验发现 evacetrapib 对 30 个月的主要不良心血管事件（心血管死亡、心肌梗塞 [MI]、中风、冠状动脉血运重建，或因不稳定心绞痛住院）。该二次分析评估了不同 Lp(a) 水平的 CV 死亡率、MI 和中风率。 结果 对 10 503 名患者（8135 名男性；8561 名白人；10 134 名同时接受他汀类药物治疗的患者；平均 [SD] 年龄，64.6 [9.4] 岁）测量了高敏 C 反应蛋白和 Lp(a) 水平。在完全调整的分析中，在 hsCRP 为 2mg/L 或更高但不低于 2mg/L 的患者中，Lp(a) 的五分位数增加与更高的死亡率、MI 和卒中发生率显着相关（交互作用 P = 0.006）。仅当 hsCRP 水平为 2mg/L 或更高时，log Lp(a) 水平每增加一个单位，与 CV 死亡、非致命性 MI 或中风的风险增加 13% 相关（交互作用 P = .008）。当 hsCRP 水平为 2mg/L 或更高但不低于 2mg/L 时，Lp(a) 五分位的增加与首次 CV 死亡、MI 或中风的时间之间也存在显着的阶梯关系（对数秩 P < .001）。 ACCELERATE 安慰剂治疗组的敏感性分析仅在 hsCRP 为 2mg/L 或更高的组中得出类似的显着相关性。 结论和相关性 当 hsCRP 水平为 2mg/L 或更高但不低于 2mg/L 时，治疗期间升高的 Lp(a) 水平与心血管死亡、心肌梗死和中风相关。这一发现表明，尽管接受了最佳药物治疗，但仍有残留全身炎症的患者降低 Lp(a) 具有潜在益处。
IMPORTANCE Although lipoprotein(a) (Lp[a]) is a causal genetic risk factor for atherosclerotic cardiovascular disease, it remains unclear which patients with established atherosclerotic cardiovascular disease stand to benefit the most from Lp(a) lowering. Whether inflammation can modulate Lp(a)-associated cardiovascular (CV) risk during secondary prevention is unknown.OBJECTIVE To examine whether Lp(a)-associated CV risk is modulated by systemic inflammation in optimally treated patients at high risk of CV disease.DESIGN, SETTING, AND PARTICIPANTS A prespecified secondary post hoc analysis of the double-blind, multicenter randomized clinical Assessment of Clinical Effects of Cholesteryl Ester Transfer Protein Inhibition With Evacetrapib in Patients at a High Risk for Vascular Outcomes (ACCELERATE) trial was conducted between October 1, 2012, and December 31, 2013; the study was terminated October 12, 2015. The study was conducted at 543 academic and community hospitals in 36 countries among 12 092 patients at high risk of CV disease (acute coronary syndrome, stroke, peripheral arterial disease, or type 2 diabetes with coronary artery disease) with measurable Lp(a) and high-sensitivity C-reactive protein (hsCRP) levels during treatment. Statistical analysis for this post hoc analysis was performed from September 26, 2018, to March 28, 2020.INTERVENTIONS Participants received evacetrapib, 130mg/d, or matching placebo.MAIN OUTCOMES AND MEASURES The ACCELERATE trial found no significant benefit or harm of evacetrapib on 30-month major adverse cardiovascular events (CV death, myocardial infarction [MI], stroke, coronary revascularization, or hospitalization for unstable angina). This secondary analysis evaluated rates of CV death, MI, and stroke across levels of Lp(a).RESULTS High-sensitivity C-reactive protein and Lp(a) levels were measured in 10 503 patients (8135 men; 8561 white; 10 134 received concurrent statins; mean [SD] age, 64.6 [9.4] years). In fully adjusted analyses, in patients with hsCRP of 2mg/L or more but not less than 2mg/L, increasing quintiles of Lp(a) were significantly associated with greater rates of death, MI, and stroke (P = .006 for interaction). Each unit increase in log Lp(a) levels was associated with a 13% increased risk of CV death, nonfatal MI, or stroke only in those with hsCRP levels of 2mg/L or more (P = .008 for interaction). There was also a significant stepwise relationship between increasing Lp(a) quintiles and time to first CV death, MI, or stroke (log-rank P < .001) when hsCRP levels were 2mg/L or more but not less than 2mg/L. Sensitivity analyses in the ACCELERATE placebo-treated group yielded similar significant associations exclusively in the group with hsCRP of 2mg/L or more.CONCLUSIONS AND RELEVANCE Elevated Lp(a) levels during treatment are related to CV death, MI, and stroke when hsCRP levels are 2mg/L or more but not less than 2mg/L. This finding suggests a potential benefit of lowering Lp(a) in patients with residual systemic inflammation despite receipt of optimal medical therapy.