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.

Background To determine whether high-risk plaque as detected by coronary computed tomography angiography (CTA) permits improved early diagnosis of acute coronary syndrome (ACS) independent to the presence of significant CAD in acute chest pain patients. Objectives The primary aim was to determine whether high-risk plaque features, as detected by CTA in the emergency department, may improve diagnostic certainty of ACS independent and incremental to the presence of significant CAD and clinical risk assessment in patients with acute chest pain but without objective evidence of myocardial ischemia or myocardial infarction. Methods We included patients randomized to the CCTA arm of ROMICAT II trial. Readers assessed coronary CTA qualitatively for the presence of non-obstructive CAD (1-49% stenosis), significant CAD (≥50% or ≥70% stenosis), and the presence of at least 1 of the high-risk plaque features (positive remodeling, low < 30 Hounsfield Units plaque, napkin-ring sign, spotty calcium). In logistic regression analysis, we determined the association of high-risk plaque with ACS [myocardial infarction (MI) or unstable angina pectoris (UAP)] during the index hospitalization and whether this was independent of significant CAD and clinical risk assessment. Results Overall 37 of 472 patients who underwent coronary CTA with diagnostic image quality (mean age 53.9±8.0 years, 52.8% men) had ACS (7.8%; MI n=5, UAP n=32)]. CAD was present in 262 (55.5%) patients [non-obstructive CAD 217 (46.0%) patients, significant CAD with ≥50% stenosis 45 (9.5%) patients]. High-risk plaques were more frequent in patients with ACS and remained a significant predictor of ACS (OR 8.9, 95% CI 1.8-43.3, p=0.006) after adjusting for ≥50% stenosis (OR 38.6, 95% CI 14.2-104.7, p<0.001) and clinical risk assessment (age, gender, number of cardiovascular risk factors). Similar results were observed after adjusting for ≥70% stenosis. Conclusions In patients presenting to the ED with acute chest pain but negative initial electrocardiogram and troponin, presence of high-risk plaque on coronary CTA increases the likelihood of ACS independent of significant CAD and clinical risk assessment (age, gender, and number of cardiovascular risk factors).

clinicaltrials.gov Indentifier: NCT01174550.