Long-term cardiovascular events after immune checkpoint inhibitor therapy: a nationwide propensity-matched cohort study

Background

Immune checkpoint inhibitors (ICIs) have transformed cancer outcomes and are increasingly used. As survival improves, long-term cardiovascular complications have emerged as an important concern. Beyond immune-mediated myocarditis, accumulating evidence suggests broader cardiovascular effects, yet real-world data remain limited by short follow-up, lack of appropriate cancer controls, and residual confounding from established cardiotoxic therapies, leaving long-term ICI-associated cardiovascular risk incompletely defined.

Purpose

To define the long-term cardiovascular risk associated with ICI therapy using a nationwide, population-based cohort with robust matching and extended follow-up.

Methods

We conducted a retrospective nationwide cohort study using the Taiwan National Health Insurance Research Database. Adults initiating ICI therapy between 2019 and 2022, during ICI reimbursement era, were compared with cancer patients between 2016 and 2018 without ICI exposure. Patients with prior anthracyclines or anti-HER2 therapy were excluded.

Major adverse cardiovascular events (MACE) were defined as a composite of heart failure hospitalization, myocardial infarction, ischemic stroke, or cardiovascular death. Additional cardiovascular outcomes included individual MACE components, coronary artery disease, arrhythmias, peripheral artery disease, and venous thromboembolism. Propensity score matching balanced demographic, cardiovascular and oncologic variables. Hazard ratios were estimated using Cox proportional hazards models at one- and three-year follow-up.

Results

After propensity score matching, 3,615 ICI-treated patients were compared with 7,230 cancer controls(Table 1). ICI therapy was associated with a higher risk of MACE, with incidence rates of 12.1 versus 6.0 per 100 person-years at one year, corresponding to an almost two-fold increased risk (hazard ratio [HR] 1.94, 95% confidence interval [CI] 1.66–2.26) that persisted at three years (HR 1.89, 95% CI 1.66–2.15). Elevated risks were observed across heart failure hospitalization, coronary artery disease, ischemic stroke, arrhythmias, peripheral artery disease, and cardiovascular death at both one-year and three-year follow-up(Figure 1).

Venous thromboembolism was the strongest signal associated with ICI exposure, with a more than three-fold increased risk at one year (HR 3.45, 95% CI 2.81–4.24), driven by elevated risks of deep vein thrombosis (HR 3.25, 95% CI 2.61–4.06) and pulmonary embolism (HR 5.64, 95% CI 3.35–9.51), and persisting through three years (HR 3.52, 95% CI 2.94–4.21)(Figure 1).

Conclusions

In this nationwide propensity-matched cohort, increased risks of MACE, cardiovascular death, heart failure hospitalization, coronary artery disease, ischemic stroke, and venous thromboembolism persisted through three years, underscoring that ICI-associated cardiovascular risk is long-term, broad in spectrum, and clinically meaningful.  Figure 1