Serum uric acid, influence of sacubitril–valsartan, and cardiovascular outcomes in heart failure with preserved ejection fraction: PARAGON‐HF

Abstract

Aims This study aimed to determine the prognostic value of serum uric acid (SUA) on outcomes in heart failure (HF) with preserved ejection fraction (HFpEF), and whether sacubitril–valsartan reduces SUA and use of SUA‐related therapies. Methods and results We analysed 4795 participants from the Prospective Comparison of ARNI [angiotensin receptor–neprilysin inhibitor] with ARB [angiotensin‐receptor blockers] Global Outcomes in HF with Preserved Ejection Fraction (PARAGON‐HF) trial. We related baseline hyperuricaemia (using age and gender adjusted assay definitions) to the primary outcome [cardiovascular (CV) death and total HF hospitalizations]. We assessed the associations between changes in SUA and Kansas City Cardiomyopathy Questionnaire Overall Summary Score (KCCQ‐OSS) and other cardiac biomarkers from baseline to 4 months. We simultaneously adjusted for baseline and time‐updated SUA to determine whether lowering SUA was associated with clinical benefit. The mean (± standard deviation) age of patients was 73 ± 8 years and 52% were women. After multivariable adjustment, hyperuricaemia was associated with increased risk for the primary outcome [rate ratio 1.61, 95% confidence interval (CI) 1.37–1.90]. The treatment effect of sacubitril–valsartan for the primary endpoint was not significantly modified by hyperuricaemia (P‐value for interaction = 0.14). Sacubitril–valsartan reduced SUA by 0.38 mg/dL (95% CI 0.31−0.45) compared with valsartan at 4 months, with greater effect in those with elevated SUA vs. normal SUA (−0.51 mg/dL vs. −0.32 mg/dL) (P‐value for 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 Serum uric acid independently predicted adverse outcomes in HFpEF. Sacubitril–valsartan reduced SUA and the initiation of related therapy compared with valsartan. Reductions in SUA were associated with improved outcomes.

The importance of including uric acid in the definition of metabolic syndrome when assessing the mortality risk

“…Indeed, animal models have shown that decreasing uric acid levels can prevent or reverse MS features [20], probably because hyperuricemia can induce endothelial dysfunction [21] and/or oxidative changes in adipocytes [22], which are typical stigmata of MS. Interestingly, all these features are increasingly described in HF with preserved ejection fraction (HFpEF), pointing to the existence of an inflammatory-metabolic phenotype [23]. A recent subanalysis from the PARAGON-HF trial demonstrated that hyperuricaemia was associated with an increased risk of adverse cardiovascular outcomes (CVM and HF hospitalisation) [24], suggesting that SUA may be a relevant therapeutic target also in HFpEF.…”

“…Clearer identification of the patient phenotype in which SUA might have a greater impact on mortality could avoid further confusion in the future. Noteworthy, the risk of CVM may increase with SUA levels lower than those currently used in clinical practice to define the risk of gout [24]. This is of utmost importance, since there is an urgent need to develop and implement prevention and treatment strategies (e.g., lifestyle programs, diets, and pharmacotherapies) to reduce the CV burden.…”

Sacubitril/valsartan for patients with heart failure with preserved ejection fraction: what will the FDA decide? Author’s reply

“…The results of the PARAGON-HF trail are also of great importance for the redefinition of the heart failure classification, as suggested by the experts [1]. The last subanalyses of the trial also revealed the beneficial effect of ARNI on the serum uric acid level which was independently associated with increased risk for primary outcomes (rate ratio, 1.61; 95% CI, 1.37-1.9) [2], and the beneficial effect of the pulse pressure, a marker of arterial stiffness [3].…”

Hyperurikämie, Gicht und Herz – eine kritische Diskussion im Licht der aktuellen Literatur

“…Es gibt Hinweise dafür, dass diese Substanzen ebenfalls eine gewisse Harnsäuresenkung bewirken; man könnte vorsichtig optimistisch formulieren, dass dies eventuell für Patienten mit Herzinsuffizienz (gezeigt für Patienten mit Herzinsuffizienz und erhaltener Ejektionsfraktion, sog. HFpEF) und Gicht eine Option darstellt [31]. Bei Patienten mit einer Herzinsuffizienz muss aus symptomatischen (nicht aus prognostischen Gründen!)…”