Spironolactone reduced heart failure hospitalizations (HR 0.77; 95% CI 0.62-0.96; P=0.021), an effect that could not be solely attributed to potential diuretic effects.
RCT (n=1,767)
Yes
Does spironolactone reduce recurrent heart failure hospitalizations independently of its diuretic and renal effects in patients with HFpEF?
The reduction in heart failure hospitalizations with spironolactone in HFpEF cannot be solely attributed to its diuretic effects, suggesting other mechanisms of benefit.
Effect estimate: HR 0.77 (95% CI 0.62-0.96)
p-value: p=0.021
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 Δ: -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.
Kalogeropoulos et al. (2020) conducted an RCT in Heart failure with preserved ejection fraction (n=1,767). Spironolactone vs. Placebo was evaluated on Heart failure hospitalizations (HR 0.77, 95% CI 0.62-0.96, p=0.021). Spironolactone reduced heart failure hospitalizations (HR 0.77; 95% CI 0.62-0.96; P=0.021), an effect that could not be solely attributed to potential diuretic effects.