Frailty as an independent predictor of cancer therapy–related cardiac dysfunction in older cardio-oncology patients

Background Frailty reflects reduced physiological reserve and increased vulnerability to physiological stressors and is frequently encountered in cardio-oncology populations. However, whether baseline frailty independently predicts cancer therapy–related cardiac dysfunction (CTRCD) in patients exposed to cardiotoxic anticancer treatments remains insufficiently defined. Purpose To examine the association between baseline frailty status and subsequent CTRCD in patients undergoing cardiotoxic cancer therapy. Methods We conducted a retrospective observational study of 130 consecutive patients (median age 73 years) treated with anticancer therapies classified as moderate or high cardiotoxic risk according to the Heart Failure Association–International Cardio-Oncology Society (HFA–ICOS) risk stratification and followed in a dedicated cardio-oncology program. Baseline frailty was assessed using the Geriatric-8 (G8) screening tool and categorized as frail or non-frail according to established cut-offs. CTRCD was defined according to the 2022 ESC Cardio-Oncology Guidelines as a ≥10-percentage-point reduction in left ventricular ejection fraction to <50% and/or a relative decrease in global longitudinal strain of >15% from baseline. The primary endpoint was time to first CTRCD event. CTRCD-free survival was estimated using Kaplan–Meier methods. Associations between frailty and CTRCD were evaluated using Cox proportional hazards regression. Multivariable models were adjusted for age, sex, baseline left ventricular ejection fraction, cancer stage, cumulative anthracycline exposure, and major cardiovascular comorbidities. To account for competing mortality, sensitivity analysis was performed using Fine–Gray competing risk models, treating death as a competing event. Median follow-up was 50 months. Results At baseline, 45 patients (35%) were classified as frail based on the G8 score. During follow-up, CTRCD occurred more frequently in frail than non-frail patients (62% vs. 32%). Time-to-event analysis demonstrated shorter CTRCD-free survival in frail patients, with early and sustained separation of Kaplan–Meier curves. In univariable Cox analysis, frailty was associated with an increased risk of CTRCD (hazard ratio [HR] 2.21, 95% confidence interval [CI] 1.39–3.52). This association remained significant after multivariable adjustment (adjusted HR 2.03, 95% CI 1.24–3.31), confirming frailty as an independent prognostic factor. Sensitivity analysis using Fine–Gray models showed a higher cumulative incidence of CTRCD among frail patients after accounting for competing mortality, with consistent effect estimates. Conclusions Among patients exposed to potentially cardiotoxic cancer therapies, baseline frailty independently predicts CTRCD. Incorporation of frailty assessment into routine cardio-oncology evaluation may improve risk stratification and support individualized monitoring and preventive strategies.