Background: 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. 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 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. Results: 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. 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, prior to, during and after treatment,
should be considered among patients on an ICI.
