Frailty redefines the prognostic value of multimorbidity in heart failure

Background Multimorbidity is common and associated with adverse outcomes in heart failure (HF). However, its prognostic value across frailty states is uncertain, particularly whether comorbidities continue to stratify risk once frailty develops. Aims To evaluate whether frailty modifies the association of multimorbidity in HF. Methods A retrospective cohort study of HF patients. Multimorbidity was quantified using 26 conditions and categorized as low (≤4), intermediate (5-7), or high (>8). Frailty was defined using a multimodal construct integrating functional, nutritional, and biochemical domains. All-cause mortality was assessed using Cox models with frailty-multimorbidity interaction testing. Charlson Comorbidity Index (CCI) was used for validation. Results Among 18,058 patients (median age 74 years; 62% male; 64% frail), 57% died over a median follow-up of 4.0 years (IQR 1.3-7.7). Multimorbidity burden comprised 31% low, 48% intermediate, and 22% high. Frailty was associated with a 91% higher mortality risk (adjusted HR 1.91; 95% CI 1.85-2.00). Compared with low multimorbidity, intermediate and high burden were associated with an independent 8% and 20% higher mortality risks, respectively (95% CI 1.02-1.14 and 1.13-1.27; both p<.001). However, the association of multimorbidity differed by frailty such that among non-frail patients, intermediate and high multimorbidity increased mortality by 18% and 42% whereas in frail patients, the association was attenuated, with no excess risk for intermediate burden and only 13% increase for high burden (p-for-interaction <.001). Findings were consistent using CCI, though differed among females and HFpEF. Conclusion Frailty fundamentally redefines risk in HF, while multimorbidity stratifies prognosis only when physiological reserve is preserved. Figure 1: Adjusted Association Between Multimorbidity Burden and Mortality Risk by Frailty Status - Restricted cubic spline models demonstrating the adjusted association between multimorbidity burden and mortality risk in frail and non-frail patients. Left panel - shows the relationship between comorbidity count and mortality risk. Right panel - depicts the association for the CCI. All models are adjusted for age, sex, left ventricular ejection fraction (LVEF), and guideline-directed medical therapy (GDMT). Hazard ratios are presented with 95% confidence intervals. Figure 2: Kaplan-Meier Survival by Comorbidity Burden in Frail vs Non-Frail Patients - Top: shows survival stratified by comorbidity burden quartiles among frail patients; Bottom shows the same among non-frail patients.Figure 1Figure 2