Upfront immune checkpoint inhibitors and long-term risk of major adverse cardiovascular events: a population-based propensity-matched cohort study

Background Immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, but prior observational studies reported large relative increases in atherosclerotic cardiovascular events post-exposure. These estimates may be confounded by differences in treatment line and cumulative prior therapy. Purpose To evaluate the risk of major adverse cardiovascular events (MACE) in cancer patients treated with ICIs compared to matched patients treated with targeted regimens or epirubicin. Methods Using linked administrative databases, we conducted a retrospective, population-based cohort study of adults initiating upfront systemic treatment for melanoma, lung, or breast cancer (2012–2024). The exposure group (ICIs) was matched 1:1 with controls receiving targeted regimens (Melanoma: BRAF/MEK; Lung: EGFR/ALK/ROS1/RET/MET) or epirubicin (Breast). Matching was based on sex, cancer site, and stage. The primary outcome (MACE) was a composite of acute myocardial infarction, stroke, or coronary revascularization (CABG/PCI), with death as a competing risk. Patients were followed from date of initiation of systemic treatment until the earliest of 5 years thereafter, death, loss of insurance eligibility (+7 days), or March 31, 2025. Crude mortality was assessed via Kaplan-Meier curves, and the Aalen-Johansen estimate was used for MACE incidence. Cause-specific hazards regression adjusting for age, hypertension, diabetes (DM), ischemic heart disease (IHD), heart failure (HF), atrial fibrillation (AF), stroke, peripheral arterial disease (PAD), and chronic obstructive pulmonary disease (COPD) was used to estimate the adjusted hazard ratio (HR) of the composite outcome in the ICI group relative to controls. Results Among 9,478 patients (4,739 matched pairs; 66.8% female; 76.1% lung, 17.2% breast, 6.7% melanoma), ICI recipients were slightly younger (median 67 vs. 69 years) with a higher baseline prevalence of IHD, PAD, and HF, but similar rates of HTN, DM, and stroke. Over mean follow-up of 463 days, there were 5,624 (59.3%) deaths and 3,514 (37.1%) MACE events. The median survival at 3 years was 31.4% (95% CI 29.8%-33.1%) in the ICI group and 40.2% (95% CI 38.7%-41.7%) for controls. The crude 3-year incidence of MACE was similar between groups (4.0%, 95% CI 3.4%-4.7% vs. 3.2%, 95% CI 2.7%-3.8%, p= 0.34). After multivariable adjustment, the cause-specific HR for MACE for the ICI group relative to controls was 1.34, 95% CI 1.07-1.67, p= 0.01). Conclusion After adjustment, ICI therapy was associated with a 34% higher hazard of MACE compared to controls. Notably, this hazard ratio is lower than estimates from earlier observational studies that did not restrict to upfront treatment. These findings support proactive cardiovascular risk assessment and optimization in long-term survivors while reinforcing that the excess risk is modest and should not deter use of these life-prolonging therapies.HR for ICI-treated individuals vs. controls