Frailty and pre-frailty identify long-term heart failure and MACCE in patients with cancer: a longitudinal cohort study

Background Frailty is increasingly recognized as a determinant of adverse outcomes in heart failure (HF), yet its prognostic significance in patients with cancer—a growing population at risk of cardiovascular disease—remains insufficiently defined. Whether pre-frailty already confers excess long-term HF and cardiovascular risk is unknown. Purpose To investigate the association of frailty and pre-frailty with long-term heart failure and major adverse cardiac and cerebrovascular events (MACCE) in patients with cancer. Methods In this longitudinal analysis of the UK Biobank, 52,285 patients with cancer (baseline 2006–2010; follow-up through October 31, 2022) were categorized as non-frail (n=27,083), pre-frail (n=22,942), or frail (n=2,260) using the validated frailty phenotype (weight loss, exhaustion, low physical activity, slow gait speed, reduced grip strength). The primary endpoint was incident MACCE. Secondary analyses examined incident heart failure and all-cause mortality. Time-to-event analyses were performed using Kaplan–Meier estimates and multivariable Cox proportional hazards models adjusting for age, sex, obesity, smoking, socioeconomic deprivation, diabetes, hypertension, COPD, and tumor type. Results Frailty burden was substantial: 43.9% were pre-frail and 4.3% frail. Over a mean follow-up of 4.5 years, MACCE occurred in 31.0% of non-frail, 37.3% of pre-frail, and 52.5% of frail individuals (p<0.001). Incident heart failure demonstrated a marked graded increase across frailty strata (2.7% vs. 4.1% vs. 8.0%; p<0.001). Kaplan–Meier curves showed early and progressive separation for both HF and MACCE (log-rank p<0.001). After multivariable adjustment, pre-frailty (HR 1.10, 95% CI 1.02–1.18; p=0.010) and frailty (HR 1.21, 95% CI 1.07–1.38; p=0.002) independently predicted MACCE. Frailty was strongly associated with incident HF and cardiovascular mortality, independent of traditional cardiometabolic risk factors. Conclusions Frailty and even pre-frailty define a high-risk heart failure and cardiovascular phenotype among patients with cancer. These findings highlight frailty assessment as a potential tool for early HF risk stratification and multidisciplinary prevention strategies in cardio-oncology and survivorship care.Figure 1Figure 2