Serum Uric Acid, Influence of Sacubitril/Valsartan, and Cardiovascular Outcomes in Heart Failure with Preserved Ejection Fraction: PARAGON-HF.

AIMS To determine the prognostic value of serum uric acid (SUA) on outcomes in heart failure with preserved ejection fraction (HFpEF), and whether sacubitril/valsartan reduces SUA and SUA-related therapies. METHODS AND RESULTS We analyzed 4795 participants from PARAGON-HF. We related baseline hyperuricemia (using assay definitions) to the primary outcome (CV death and total HF hospitalization). Between baseline and 4 months, we assessed the association between changes in SUA and Kansas City Cardiomyopathy Questionnaire overall summary score (KCCQ-OSS) and other cardiac biomarkers. We simultaneously adjusted for baseline and time-updated SUA to determine whether lowering SUA was associated with clinical benefit. Average age was 73 ± 8 years and 52% were women. After multivariable adjustment, hyperuricemia was associated with increased risk for the primary outcome (rate ratio 1.61, 95%CI 1.37, 1.90). The treatment effect of sacubitril/valsartan for the primary endpoint was not significantly modified by hyperuricemia (p-interaction = 0.14). Sacubitril/valsartan reduced SUA -0.38 mg/dL (95%CI: -0.45, -0.31) compared with valsartan at 4 months, with greater effect in those with elevated SUA vs. normal SUA (-0.51 vs. -0.32 mg/dL) (p-interaction = 0.031). Sacubitril/valsartan reduced the odds of initiating SUA-related treatments by 32% during follow-up (p < 0.001). After multivariable adjustment, change in SUA was inversely associated with change in KCCQ-OSS and directly associated with high-sensitivity Troponin T (p < 0.05). Time-updated SUA was a stronger predictor of adverse outcomes than baseline SUA. CONCLUSIONS SUA independently predicted adverse outcomes in HFpEF. Sacubitril/valsartan reduced SUA and related therapy initiation compared to valsartan. Reducing SUA was associated with improved outcomes.