Immune checkpoint inhibitors are associated with peripheral artery disease in cancer patients.

Abstract

Immune checkpoint inhibitors (ICIs) have revolutionized cancer therapy and improved survival across multiple malignancies. Although associations with cardiovascular events have been described, the relationship between ICIs and peripheral artery disease (PAD) remains unclear. The study aimed to determine whether ICI treatment is associated with PAD, chronic limb-threatening ischemia (CLTI), or lower extremity amputation (LEA) in patients with cancer. We conducted a retrospective multicenter cohort study using the TriNetX Analytics platform to identify cancer patients treated with ICIs or non-ICI therapies between 2005 and 2025. Propensity score matching (1:1) was performed to balance baseline characteristics. Outcomes included PAD, CLTI, LEA within five years. Kaplan-Meier analyses assessed survival probabilities, and hazard ratios (HRs) with 95% confidence intervals (CIs) were calculated using Cox models. Subgroup analyses evaluated outcomes across different ICI classes and within at-risk groups with hypertension, hyperlipidemia, diabetes, or smoking history. The matched cohort included 66,766 patients treated with ICIs and 66,766 controls. Kaplan-Meier analysis showed a lower 5-year PAD-free survival in the ICI group (73.6% vs 81.7%; P < .001). On multivariable analysis, although the risks of CLTI and LEA were similar, ICI treatment was associated with increased risk of PAD (HR, 1.59; 95% CI, 1.53-1.64). Consistently, an increased risk of PAD was demonstrated across all ICI classes: programmed cell death protein-1 inhibitors (HR, 1.56; 95% CI, 1.47-1.55), programmed cell death ligand-1 inhibitors (HR, 1.48; 95% CI, 1.36-1.61), and cytotoxic T-lymphocyte associated protein 4 (cytotoxic T-lymphocyte-associated antigen-4) inhibitors (HR, 1.58; 95% CI, 1.43-1.74). Among at-risk patients (n = 27,932), Kaplan-Meier analysis showed a lower 5-year PAD-free survival in the ICI group (70.3% vs 80.2%; P < .001) and ICI treatment was associated with an increased risk of PAD (HR, 1.64; 95% CI, 1.58-1.71) and LEA (HR, 1.85; 95% CI, 1.32-2.61). Furthermore, a higher risk of PAD was demonstrated across each ICI class among at-risk patients: programmed cell death protein-1 inhibitors (HR, 1.64; 95% CI, 1.57-1.71), programmed death ligand-1 inhibitors (HR, 1.64; 95% CI, 1.51-1.78), and CTLA-4 inhibitors (HR, 1.82; 95% CI, 1.60-2.06). In this multicenter cohort of adults with cancer, ICI therapy appears to be associated with increased risks of PAD and LEA, particularly among individuals with preexisting vascular risk factors. These findings suggest that ICI may contribute to PAD and highlight the need for vascular assessment and monitoring in patients receiving ICIs.