Diuretic and renal effects of spironolactone and heart failure hospitalizations: aTOPCATAmericas analysis

Aims It is unclear whether spironolactone reduced heart failure (HF) hospitalizations in the Treatment of Preserved Cardiac Function Heart Failure with an Aldosterone Antagonist (TOPCAT) trial through potential diuretic or other effects. We examined the effects of spironolactone on weight, diuretic use, and renal function, and their subsequent impact on outcomes. Methods and results We analysed data from TOPCAT Americas (1767 patients with HF and preserved ejection fraction; 886 in spironolactone, 881 in placebo arm). We used mixed-effects models for serial data and shared frailty models to identify determinants of recurrent HF hospitalizations among baseline and serial parameters. There were 800 HF hospitalizations after a median of 3.0 years. Despite more weight loss with spironolactone initially, weight trajectories overlapped after 12 months. Daily furosemide dose (time-averaged Delta: -4.8% vs. +11.6%,P < 0.001) and thiazide use (-4.3% vs. +1.7%;P = 0.003) decreased with spironolactone; however, angiotensin-converting enzyme inhibitor (ACEI)/angiotensin receptor blocker (ARB) use decreased also (-13.1% vs. -7.3%;P = 0.004). Serum creatinine increased more with spironolactone (+12.5% vs. +3.5%;P < 0.001). In time-updated models, loop diuretic dose [hazard ratio (HR) per doubling 1.21; 95% confidence interval (CI) 1.10-1.32;P < 0.001], creatinine (HR per doubling 1.28; 95% CI 1.04-1.40;P = 0.019), and ACEI/ARB use (HR 0.82; 95% CI 0.67-1.00;P = 0.048) were associated with HF hospitalizations. However, the effect of spironolactone on HF hospitalizations persisted (HR 0.77; 95% CI 0.62-0.96;P = 0.021) in these models. Results were similar for cardiovascular mortality and time to first HF hospitalization. Conclusions In TOPCAT Americas, the benefit of spironolactone on outcomes could not be solely attributed to potential diuretic effects, suggesting the presence of non-diuretic mechanisms.