Cardiovascular Imaging Research Center, Department of Radiology and Division of Cardiology (Z.D.D., R.M.A., J.T., A.Z., V.K.R., S.E.H., H.K.G., J.G., T.M., U.H., T.G.N.), Massachusetts General Hospital, Harvard Medical School, Boston.
Cardiovascular Imaging Research Group, Heart and Vascular Center, Semmelweis University, Budapest, Hungary (Z.D.D.).
Circulation. 2020 Dec 15;142(24):2299-2311. doi: 10.1161/CIRCULATIONAHA.120.049981. Epub 2020 Oct 2.
Immune checkpoint inhibitors (ICIs) 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 2-year period after and the control period as the 2-year period before 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. In addition, in an imaging substudy (n=40), the rate of atherosclerotic plaque progression was compared from before to after the ICI was started. 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 (hazard ratio, 3.3 [95% CI, 2.0-5.5]; <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 2 years (adjusted hazard ratio, 4.8 [95% CI, 3.5-6.5]; <0.001). In the imaging study, the rate of progression of total aortic plaque volume was >3-fold higher with ICIs (from 2.1%/y before 6.7%/y after). 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 before, during, and after treatment should be considered among patients on an ICI.
免疫检查点抑制剂（ICI）可治疗多种癌症。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控因子。因此，我们的目标是检验 ICI 是否与动脉粥样硬化加速和动脉粥样硬化相关心血管事件风险增加相关。
本研究位于一家学术型医疗中心。主要分析评估了 2842 例患者和 2842 例匹配的对照者（年龄、心血管事件史和癌症类型匹配）接受 ICI 治疗后，其动脉粥样硬化性心血管事件的发生情况。在第二种设计中，采用病例交叉设计，将风险期定义为治疗后 2 年，对照期定义为治疗前 2 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）的复合结局。次要结局包括主要结局的各个组成部分。此外，在影像学亚研究（n=40）中，比较了开始 ICI 前后动脉粥样硬化斑块进展的速度。所有研究指标和结局均进行了盲法裁决。
在匹配队列研究中，开始使用 ICI 后心血管事件的风险增加了 3 倍（风险比，3.3[95%CI，2.0-5.5]；<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 年内心血管事件也从 1.37 增至 6.55/100 人年（校正后的风险比，4.8[95%CI，3.5-6.5]；<0.001）。在影像学研究中，主动脉总斑块体积的进展速度在使用 ICI 后增加了 3 倍以上（从治疗前的 2.1%/年增加至治疗后的 6.7%/年）。ICI 使用与动脉粥样硬化斑块进展加速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。
ICI 起始后心血管事件发生率更高，可能是由动脉粥样硬化进展加速介导的。在开始 ICI 治疗之前、期间和之后，应考虑优化心血管危险因素并提高对心血管风险的认识。
