Prognostic Value of Albuminuria and Influence of Spironolactone in Heart Failure With Preserved Ejection Fraction: The TOPCAT Trial

Abstract

Background: Albuminuria predicts adverse events in heart failure with preserved ejection fraction. No therapies to date have reduced albuminuria in heart failure with preserved ejection fraction. Methods and Results: We analyzed 1175 participants from the Americas from the TOPCAT study (Treatment of Preserved Cardiac Function Heart Failure With an Aldosterone Antagonist) with urinary albumin:creatinine ratio (UACR) measurements at baseline. We examined the association of UACR with the primary outcome (cardiovascular death, aborted cardiac arrest, or heart failure hospitalization) and its individual components, all-cause mortality, and several safety end points using multivariable-adjusted Cox regression. We evaluated whether spironolactone reduced albuminuria at the 1-year visit in a subpopulation (N=744). Thirty-five percent had microalbuminuria, 13% had macroalbuminuria, and 80% were receiving angiotensin-converting enzyme inhibitors or angiotensin receptor blockers. Increasing UACR was associated with male sex, higher systolic blood pressure, diabetes mellitus, and renal dysfunction. Macroalbuminuria (hazard ratio, 1.67; 95% CI, 1.22–2.28) and microalbuminuria (hazard ratio, 1.47; 95% CI, 1.15–1.86) were independently associated with the TOPCAT primary end point (compared with normoalbuminuria). Adjusting for placebo response, spironolactone reduced albuminuria by 39% in all participants at the 1-year visit compared with baseline (geometric mean ratio, 0.61; 95% CI, 0.49–0.77) and by 76% (geometric mean ratio, 0.24; 95% CI, 0.10–0.56) among those with macroalbuminuria. Reducing UACR by 50% was independently associated with a reduction in heart failure hospitalization (hazard ratio, 0.90; P =0.017) and all-cause mortality (hazard ratio, 0.91; P =0.019). The change in UACR was significantly associated with change in systolic blood pressure ( P =0.001). Conclusions: In TOPCAT, albuminuria was independently associated with worse cardiovascular outcomes. Spironolactone significantly reduced albuminuria compared with placebo. Reducing albuminuria was independently associated with improved outcomes. Clinical Trial Registration: URL: https://www.clinicaltrials.gov . Unique identifier: NCT00094302.