Sildenafil and Kidney Function in Heart Failure with Preserved Ejection Fraction.

Abstract

Chronic kidney disease (CKD) worsens the prognosis for people with heart failure with preserved ejection fraction (HFpEF). In the RELAX trial, sildenafil decreased estimated glomerular filtration rate (eGFR) compared to placebo despite favorable kidney effects in preclinical models. Since acute eGFR decline precedes long-term kidney benefits for select medications, we assessed the influence of sildenafil on acute and chronic eGFR slopes. The RELAX trial randomized 216 participants to placebo or sildenafil and assessed 24-week changes in cardiopulmonary exercise testing, cardiovascular imaging, and laboratory data. We applied linear mixed modeling to calculate the total, acute (0-12 weeks), and chronic (3-24 weeks) eGFR slopes by treatment. Using regression modeling, we assessed respective associations between eGFR slope and baseline data and clinical endpoints. We repeated the analyses using a binary outcome based on a substantial (≥20%) decline in eGFR. The mean baseline eGFR was 60.8 ml/min/1.73 m2, and the mean eGFR slope during follow-up was -3.21 ml/min/1.73 m2/year. Sildenafil did not alter total eGFR slope compared to placebo (difference +0.47 ml/min/1.73 m2/year, 95% CI -6.63 - 7.57 ml/min/1.73 m2/year). Sildenafil users tended to experience a more negative acute eGFR slope (difference -3.15 ml/min/1.73 m2/year) and more positive chronic slope (+2.06 ml/min/1.73 m2/year) compared to placebo, but neither difference reached statistical significance. Baseline NT-proBNP and loop diuretic use were associated with worse eGFR trajectory regardless of treatment. Substantial eGFR decline was associated with increase in endothelin-1 and a greater risk of hospitalization or death (HR 2.34, 95% CI 1.21-4.53, p=0.01). Sildenafil induced an acute effect on eGFR without change in the overall eGFR slope after 24 weeks in a HFpEF cohort, suggesting lack of long-term risk related to early reduction in eGFR after initiating treatment. Long-term studies are needed to determine the effect of sildenafil on kidney function in HFpEF.