Frailty Attenuates the Prognostic Value of Multimorbidity in Heart Failure – Insights From the Largest Tertiary Center in the Middle East

OBJECTIVE 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 30.5% low, 48% intermediate, and 21.5% 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). CCI analyses was consistent, though differed among females and HFpEF. CONCLUSION Frailty fundamentally attenuates risk in HF, while multimorbidity stratifies prognosis only when physiological reserve is preserved.