Immune checkpoint inhibitors and atherosclerotic cardiovascular events: a retrospective cohort study

Abstract Background Immune checkpoint inhibitors (ICI) are cancer therapies that have improved the prognoses of over 20 different tumour types (1). However, ICIs have been increasingly recognised to associate with major atherosclerotic cardiovascular events (MACE) in cancer survivorship (2). Purpose This study aimed to determine the incidence and predictors for MACE among cancer patients treated with ICIs. Methods We performed a single-centre retrospective analysis of consecutive ambulatory cancer patients treated with ICIs between 2018 and 2020. Demographics, baseline cardiovascular risk factors (CVRF), medication history, cancer history and ICI regimen were determined from electronic medical records. The primary endpoint of MACE, defined as a composite of acute myocardial infarction, coronary revascularization, ischaemic stroke, and acute limb ischaemia, was determined from case note review. Cox proportional multivariable modelling was performed to determine predictors for MACE using significant variables on univariate analysis (p<0.20) and variables of clinical relevance including CVRFs and use of dual ICI therapy. Time to first MACE analysis was undertaken; in those without MACE, date of death or last follow-up was used as the censoring date. Subgroup analysis was performed among patients with stage 1-3 cancer who were treated with (neo)adjuvant ICI therapy and expected to have favourable long-term prognoses. Results The study cohort included 366 patients (median age 66 years (58,73), 63% male). There were 238 patients (65%) with non-small cell lung cancer and 65 (17.8%) had prior history of atherosclerotic cardiovascular disease (ASCVD). A total of 26 patients (7.1%) experienced 27 MACE (7 myocardial infarction, 1 coronary revascularization, 13 ischaemic stroke, 6 acute limb ischaemia) over median follow up of 1.9 years (0.6,3.2). During the study, there were 226 (61.8%) cancer-related deaths; there were no cardiac deaths. On multivariable analysis, MACE was independently associated with history of ASCVD (hazard ratio [HR] 4.49, 95% CI 1.92-10.49, p<0.01) and hypertension (HR 2.57, 95% CI 1.07-6.17, p=0.04). When limited to those with stage 1-3 cancer, 16 patients (11.0%) developed MACE among a cohort of 145 patients. History of ASCVD was the only variable associated with MACE on subgroup analysis (HR 3.79, 95% 1.25-11.49, p=0.02). Conclusion Among an unselected cohort of cancer patients treated with ICIs, an increased risk of MACE was observed among patients with a history of ASCVD or hypertension. Patients undergoing ICI therapy with concomitant ASCVD or hypertension should be identified and their modifiable CVRFs aggressively treated.