Association Between Immune Checkpoint Inhibitors With Cardiovascular Events and Atherosclerotic Plaque.
Association Between Immune Checkpoint Inhibitors With Cardiovascular Events and Atherosclerotic Plaque.
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DOI：
10.1161/circulationaha.120.049981
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发表时间：
2020-12-15
期刊：
影响因子：
37.8
通讯作者：
Neilan TG
中科院分区：
文献类型：
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作者：
Drobni ZD;Alvi RM;Taron J;Zafar A;Murphy SP;Rambarat PK;Mosarla RC;Lee C;Zlotoff DA;Raghu VK;Hartmann SE;Gilman HK;Gong J;Zubiri L;Sullivan RJ;Reynolds KL;Mayrhofer T;Zhang L;Hoffmann U;Neilan TG
免疫检查点抑制剂（ICI）治疗范围不断扩大的癌症。一致的基础数据表明，这些相同的检查点是动脉粥样硬化的关键负调节因子。因此，我们的目的是测试ICI是否与加速动脉粥样硬化和动脉粥样硬化相关的心血管事件的风险较高。该研究位于一个单一的学术医疗中心。主要分析评估了2842名患者和2842名对照者的ICI暴露是否与动脉粥样硬化性心血管事件相关，并与年龄、心血管事件史和癌症类型相匹配。在第二种设计中，进行了病例交叉分析，“风险期”定义为治疗后两年，“对照期”定义为治疗前两年。主要结局是动脉粥样硬化性心血管事件（心肌梗死、冠状动脉血运重建和缺血性卒中）的复合终点。次要结局包括主要结局的各个组成部分。此外，在一项成像子研究（n=40）中，比较了开始ICI之前和之后的动脉粥样硬化斑块进展率。对所有研究指标和结局进行盲法判定。在配对队列研究中，开始ICI后心血管事件的风险增加3倍（HR，3.3 [95%CI，2.0-5.5]; P<0.001）。主要结局的各个组成部分也有类似的增加。在病例交叉研究中，2年时心血管事件也从1.37/100人-年增加到6.55/100人-年（调整后的HR为4.8 [95%CI为3.5-6.5]; P<0.001）。在影像学研究中，ICI组主动脉斑块总体积的进展率高出3倍以上（从术前的2.1%/年增加到术后的6.7%/年）。使用ICI和动脉粥样硬化斑块进展增加之间的这种关联在同时使用他汀类药物或皮质类固醇时减弱。心血管事件在开始ICI后更高，可能由动脉粥样硬化的加速进展介导。在接受ICI的患者中，应考虑在治疗前、治疗期间和治疗后优化心血管风险因素并提高心血管风险意识。
Immune checkpoint inhibitors (ICI) treat an expanding range of cancers. Consistent basic data suggest that these same checkpoints are critical negative regulators of atherosclerosis. Therefore, our objectives were to test whether ICIs were associated with accelerated atherosclerosis and a higher risk of atherosclerosis-related cardiovascular events. The study was situated in a single academic medical center. The primary analysis evaluated whether exposure to an ICI was associated with atherosclerotic cardiovascular events in 2842 patients and 2842 controls, matched by age, a history of cardiovascular events and cancer type. In a second design, a case-crossover analysis was performed with an “at-risk period” defined as the two-year period after and the “control period” as the two-year prior to treatment. The primary outcome was a composite of atherosclerotic cardiovascular events (myocardial infarction, coronary revascularization and ischemic stroke). Secondary outcomes included the individual components of the primary outcome. Additionally, in an imaging sub-study (n=40), the rate of atherosclerotic plaque progression was compared from before and after starting an ICI. All study measures and outcomes were blindly adjudicated. In the matched cohort study, there was a 3-fold higher risk for cardiovascular events after starting an ICI (HR, 3.3 [95% CI, 2.0–5.5]; P<0.001). There was a similar increase in each of the individual components of the primary outcome. In the case-crossover, there was also an increase in cardiovascular events from 1.37 to 6.55 per 100 person-years at two years (adjusted HR, 4.8 [95% CI, 3.5–6.5]; P<0.001). In the imaging study, the rate of progression of total aortic plaque volume was >3-fold higher with ICIs (from 2.1%/year pre-to 6.7%/year post). This association between ICI use and increased atherosclerotic plaque progression was attenuated with concomitant use of statins or corticosteroids. Cardiovascular events were higher after initiation of ICIs, potentially mediated by accelerated progression of atherosclerosis. Optimization of cardiovascular risk factors and increased awareness of cardiovascular risk, prior to, during and after treatment, should be considered among patients on an ICI.