Spironolactone, Early Acute eGFR Changes, and Clinical Outcomes in Patients with Heart Failure with Preserved Ejection Fraction: Insights from TOPCAT Americas

Background and Aims Early acute changes in estimated glomerular filtration rate (eGFR) have been well described with renin-angiotensin-system inhibitors and sodium-glucose cotransporter-2 inhibitors, but less is known about the frequency, prognostic relevance, and implications of these changes after mineralocorticoid receptor antagonist (MRA) initiation in patients with heart failure with preserved ejection fraction (HFpEF). Methods We performed a post-hoc analysis of 1,648 patients enrolled in the TOPCAT Americas region, defining an early eGFR dip as a ≥15% decrease in eGFR between baseline and week 4. Landmark analyses assessed the association of eGFR changes, treatment, and cardiovascular death, HF hospitalization, or aborted cardiac arrest. Results Within 4 weeks of treatment initiation, 431 (26%) patients experienced acute eGFR decrease with a higher proportion of patients assigned to spironolactone (269 [33%]) compared with placebo (162 [20%]) (OR 1.97; 95% CI 1.58-2.47). An acute eGFR decrease was independently associated with higher risk of subsequent cardiovascular outcomes, irrespective of treatment arm. However, treatment with spironolactone appeared beneficial in reducing the primary cardiovascular outcome irrespective of the presence (HR 0.75 [0.53-1.08]) or absence (0.80 [0.64-1.00]) of early eGFR decrease (pinteraction=0.81). At any given magnitude of eGFR decline, risk of the primary endpoint was consistently lower with spironolactone compared with placebo (pinteraction=0.64). Conclusions Early acute eGFR changes were common and adversely prognostic in patients with HFpEF. Spironolactone treatment was beneficial in improving cardiovascular outcomes, despite a modest increase in the likelihood of acute eGFR decrease. An acute eGFR decrease early after MRA initiation should not automatically prompt treatment discontinuation.