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Randomized Controlled Trial
. 2018 Mar;20(3):514-522.
doi: 10.1002/ejhf.1056. Epub 2017 Nov 30.

Sacubitril/valsartan reduces serum uric acid concentration, an independent predictor of adverse outcomes in PARADIGM-HF

Ulrik M Mogensen  1   2 , Lars Køber  2 , Pardeep S Jhund  1 , Akshay S Desai  3 , Michele Senni  4 , Søren L Kristensen  1   2 , Andrej Dukát  5 , Chen-Huan Chen  6 , Felix Ramires  7 , Martin P Lefkowitz  8 , Margaret F Prescott  8 , Victor C Shi  8 , Jean L Rouleau  9 , Scott D Solomon  3 , Karl Swedberg  10 , Milton Packer  11 , John J V McMurray  1 ; PARADIGM-HF Investigators and Committees
Affiliations
Randomized Controlled Trial

Sacubitril/valsartan reduces serum uric acid concentration, an independent predictor of adverse outcomes in PARADIGM-HF

Ulrik M Mogensen et al. Eur J Heart Fail. 2018 Mar.

Abstract

Aims: Elevated serum uric acid concentration (SUA) has been associated with an increased risk of cardiovascular disease, but this may be due to unmeasured confounders. We examined the association between SUA and outcomes as well as the effect of sacubitril/valsartan on SUA in patients with heart failure with reduced ejection fraction (HFrEF) in PARADIGM-HF.

Methods and results: The association between SUA and the primary composite outcome of cardiovascular death or heart failure (HF) hospitalization, its components, and all-cause mortality was examined using Cox regression analyses among 8213 patients using quintiles (Q1-Q5) of SUA adjusted for baseline prognostic variables including estimated glomerular filtration rate (eGFR), diuretic dose, and log N-terminal pro-brain natriuretic peptide. Change in SUA from baseline over 12 months was also evaluated in each treatment group. Patients in Q5 (SUA ≥8.6 mg/dL) compared with Q1 (<5.4 mg/dL) were younger (62.8 vs. 64.2 years), more often male (88.7% vs. 63.1%), had lower systolic blood pressure (119 vs. 123 mmHg), lower eGFR (57.4 vs. 76.6 mL/min/1.73 m2 ), and greater diuretic use. Higher SUA was associated with a higher risk of the primary outcome (adjusted hazard ratios) Q5 vs. Q1 = 1.28 [95% confidence intervals (1.09-1.50), P = 0.003], cardiovascular death [1.44 (1.11-1.77), P = 0.001], HF hospitalization [1.37 (1.11-1.70), P = 0.004], and all-cause mortality [1.36 (1.13-1.64), P = 0.001]. Compared with enalapril, sacubitril/valsartan reduced SUA by 0.24 (0.17-0.32) mg/dL over 12 months (P < 0.0001). Sacubitril/valsartan improved outcomes, irrespective of SUA concentration.

Conclusion: Serum uric acid concentration was an independent predictor of worse outcomes after multivariable adjustment in patients with HFrEF. Compared with enalapril, sacubitril/valsartan reduced SUA and improved outcomes irrespective of SUA.

Keywords: Angiotensin; Heart failure; Mortality; Neprilysin; Uric acid.

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Figures

Figure 1
Figure 1
Cumulative probability of the primary endpoint according to quintile (Q) of uric acid concentration at randomization. CV, cardiovascular; HF, heart failure.
Figure 2
Figure 2
Associations between serum uric acid level at randomization and outcomes. Adjusted for the following baseline variables: age, sex, race, region, systolic blood pressure, heart rate, ejection fraction, New York Heart Association class, history of heart failure (HF) hospitalization, duration of HF, atrial fibrillation, diabetes, body mass index, prior myocardial infarction, prior stroke, estimated glomerular filtration rate, haemoglobin, sodium, albumin, randomized treatment (sacubitril/valsartan), diuretic dose, and log N‐terminal pro‐brain natriuretic peptide. The reference is 7.0 mg/dL. CV, cardiovascular.
Figure 3
Figure 3
Effect of study drug on serum uric acid concentration. *P < 0.001 for sacubitril/valsartan vs. placebo in a repeated measures mixed model, with baseline score as a covariate, and treatment, region, time, and treatment by time interaction as fixed effects. During the first run‐in all patients received enalapril but changed to sacubitril/valsartan during the second run‐in, as illustrated below the curves.
Figure 4
Figure 4
Point prevalence of serum uric acid (SUA) according to randomized treatment * P < 0.001. Grey bars illustrate number of patients with measurements at each time point.
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