Changes in frailty based on minimally important difference and the impact of spironolactone on frailty in heart failure with preserved ejection fraction: insights from the TOPCAT trial

Abstract

Background The minimally important difference (MID) for frailty variation associated with adverse outcomes remains unknown in patients with heart failure and preserved ejection fraction (HFpEF), and whether spironolactone can ameliorate frailty progression in this population remains unclear. Methods We analysed data from 1767 participants in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist trial. The MID for frailty was calculated using an anchor-based approach, with the EuroQol-Visual Analogue Scale (EQ-VAS) as the anchor. Frailty index (FI), defined as a 35-item cumulative deficit score, and EQ-VAS were assessed at baseline and 1-year follow-up. The primary composite outcome (cardiovascular death, aborted cardiac arrest or heart failure hospitalisation) was assessed from the 1-year follow-up visit. Adjusted Cox proportional hazards models evaluated the link between FI changes (ΔFI≥MID) and the primary outcome. Longitudinal FI changes were analysed using linear mixed-effects models to evaluate spironolactone’s effect. Results The MID for the FI was 0.03 points. An FI reduction ≥MID was associated with a lower risk of the primary composite outcome (aHR, 0.63; 95%CI 0.48 to 0.82), all-cause mortality (aHR, 0.57; 95%CI 0.42 to 0.76) and heart failure hospitalisation (aHR, 0.55; 95%CI 0.40 to 0.75) after adjusting for baseline FI, age, sex, New York Heart Association class, smoking status and treatment assignment. No between-group difference in FI change was observed with spironolactone versus placebo (aOR, 0.85; 95%CI 0.67 to 1.09). Conclusions Frailty improvement exceeding the 0.03 FI threshold predicts better prognosis in HFpEF, underscoring the value of routine assessment. Spironolactone use was associated with neutral effects on frailty progression in our analysis, suggesting potential safety in this vulnerable population.