Association Between Immune Checkpoint Inhibitors With Cardiovascular Events and Atherosclerotic Plaque

Abstract

Background: 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.

Methods: 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.

Results: 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]; 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 2 years (adjusted hazard ratio, 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%/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.

Conclusions: 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.

Keywords: atherosclerosis; immunomodulation; plaque, atherosclerotic.

Figure 1.

Flow diagram.

Figure 2.. Kaplan Meier curves of the cumulative hazard for atherosclerotic cardiovascular events.

Panel A shows the cumulative hazard for the composite cardiovascular outcome. The individual components of the primary outcome are also shown in Panel B, C and D. Cases (those treated with an ICI) are marked with red, and controls (not treated with an ICI) are marked with blue.

Figure 3.. Cardiovascular events in the case-crossover study.

Panel A shows the composite cardiovascular outcomes in the two-year period pre-and post-immune checkpoint inhibitor. Panel A includes the cardiovascular event rates per 100 person years from two-year prior to the start of an immune checkpoint inhibitor to two-year after starting an immune checkpoint inhibitor. The individual components of the primary outcome are also shown. Panel B shows the composite cardiovascular outcomes in the one-year period pre-and post-immune checkpoint inhibitor.