Early acute declines in estimated glomerular filtration rate (eGFR) are a recognized phenomenon after initiating several cardiovascular and renal therapies. Less is known about how often these early declines occur after starting a mineralocorticoid receptor antagonist (MRA) and whether such changes alter the clinical benefit of MRA therapy in patients with heart failure with preserved ejection fraction (HFpEF). The present analysis used data from the TOPCAT trial Americas regional subgroup to describe the frequency, prognostic relevance, and treatment implications of early eGFR changes following spironolactone initiation.
This is a post-hoc analysis of 1,648 participants enrolled in the TOPCAT trial from the Americas. The analysis defined an early eGFR dip as a ≥15% decrease in eGFR between baseline and week 4 after randomization. Landmark analyses were performed to assess the association between early eGFR changes, randomized treatment assignment (spironolactone versus placebo), and the trial primary composite endpoint, defined as cardiovascular death, heart failure hospitalization, or aborted cardiac arrest.
Within the first 4 weeks after treatment initiation, 431 of 1,648 patients (26%) experienced an acute decrease in eGFR meeting the prespecified threshold. The decline was more frequent among participants randomized to spironolactone: 269 of 817 patients (33%) on spironolactone versus 162 of 831 patients (20%) on placebo. The odds ratio for an early eGFR dip with spironolactone versus placebo was 1.97 (95% confidence interval 1.58–2.47), demonstrating a nearly twofold greater likelihood of an early eGFR decrease after starting the MRA.
An acute eGFR decrease occurring early after randomization was independently associated with a higher risk of subsequent cardiovascular events. This adverse prognostic association was observed irrespective of treatment arm, indicating that an early decline in renal function carried increased risk whether patients received spironolactone or placebo.
Despite the higher incidence of early eGFR declines with spironolactone, treatment with spironolactone appeared to reduce the risk of the primary composite cardiovascular outcome compared with placebo. Reported hazard ratios for spironolactone versus placebo were 0.75 (95% CI 0.53–1.08) among participants who experienced an early eGFR dip and 0.80 (95% CI 0.64–1.00) among those without an early eGFR dip. The interaction P value for differential treatment effect by presence versus absence of early eGFR decline was Pinteraction = .81, indicating no statistical evidence that the benefit of spironolactone differed according to early eGFR change.
A complementary analysis evaluating the relationship across magnitudes of eGFR decline found that, at any given magnitude of decline, the risk of the primary endpoint remained consistently lower with spironolactone compared with placebo (Pinteraction = .64).
Key clinical takeaways from this TOPCAT Americas post-hoc analysis are:
Early acute eGFR decreases of ≥15% are common after initiating spironolactone in patients with HFpEF, occurring in about one-third of treated patients within 4 weeks.
An early eGFR decline independently signals higher subsequent cardiovascular risk, regardless of whether patients received spironolactone or placebo.
Importantly, the occurrence of an early modest eGFR decline did not appear to negate the observed benefit of spironolactone on the trial primary composite outcome. There was no statistical interaction between early eGFR decline and the effect of spironolactone on outcomes.
Therefore, an acute eGFR decrease early after initiation of an MRA should not automatically prompt discontinuation of spironolactone. Clinical decisions should weigh the modestly increased likelihood of an early eGFR decline against the potential cardiovascular benefits observed with spironolactone.
This analysis is derived from the TOPCAT trial (ClinicalTrials.gov identifier NCT00094302). It represents a post-hoc assessment of the Americas regional subgroup of the randomized controlled trial. The abstract provides key results and effect estimates; full methodological details, additional subgroup data, and extended analyses beyond the abstract were not reported in the source summary. Clinicians should interpret these findings in the context of the full trial report and individual patient circumstances.