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. 2021 Apr;8(2):1027-1038.
doi: 10.1002/ehf2.12765. Epub 2020 Dec 30.

Prognostic impacts of serum uric acid levels in patients with chronic heart failure: insights from the CHART-2 study

Takahide Fujihashi  1 , Yasuhiko Sakata  1   2 , Kotaro Nochioka  1   2 , Masanobu Miura  1 , Ruri Abe  1 , Shintaro Kasahara  1 , Masayuki Sato  1 , Hajime Aoyanagi  1 , Shinsuke Yamanaka  1 , Hideka Hayashi  1 , Takashi Shiroto  1 , Koichiro Sugimura  1 , Jun Takahashi  1 , Satoshi Miyata  3 , Hiroaki Shimokawa  1   2   3 ; CHART-2 Investigators
Affiliations

Prognostic impacts of serum uric acid levels in patients with chronic heart failure: insights from the CHART-2 study

Takahide Fujihashi et al. ESC Heart Fail. 2021 Apr.

Abstract

Aims: Prognostic impacts of serum uric acid (UA) levels in patients with chronic heart failure (CHF) remain inconclusive, especially for the whole range of serum UA levels.

Methods and results: In the Chronic Heart Failure Registry and Analysis in the Tohoku District-2 (CHART-2) study, we enrolled 4652 consecutive patients with CHF and classified them into four groups based on baseline serum UA levels by the Classification and Regression Tree: G1 (<3.8 mg/dL, N = 313), G2 (3.8-7.1 mg/dL, N = 3070), G3 (7.2-9.2 mg/dL, N = 1018), and G4 (>9.2 mg/dL, N = 251). Mean age was 71 ± 12, 69 ± 12, 68 ± 13, and 69 ± 15 years in G1, G2, G3, and G4, respectively (P < 0.001). During the median follow-up of 6.3 years, in G1, G2, G3, and G4, 111 (35%), 905 (29%), 370 (36%), and 139 (55%) patients died and 79 (25%), 729 (24%), 300 (29%), and 115 (46%) experienced heart failure hospitalization, respectively (both P < 0.001). G1 was characterized by a significantly high prevalence of women as compared with G2, G3, and G4 (59%, 32%, 24%, and 23%, respectively). Serum creatinine levels (0.8 ± 0.4, 0.9 ± 0.4, 1.2 ± 0.6, and 1.4 ± 0.8 mg/dL, respectively), prevalence of atrial fibrillation (34%, 39%, 45%, and 50%, respectively), and diuretics use (36%, 45%, 67%, and 89%, respectively) increased from G1, G2, G3 to G4 (all P < 0.001), while left ventricular ejection fraction decreased from G1, G2, G3 to G4 (59 ± 15, 58 ± 15, 54 ± 15, and 52 ± 17%, respectively, P < 0.001). Multivariable Cox proportional hazards models showed that, as compared with G2, both G1 and G4 had increased incidence of all-cause death [adjusted hazard ratio (aHR) 1.34, 95% confidence interval (CI) 1.08-1.67, P = 0.009; aHR 1.28, 95% CI 1.02-1.61, P = 0.037, respectively] and heart failure admission (aHR 1.39, 95% CI 1.09-1.78, P = 0.008 and aHR 1.35, 95% CI, 1.06-1.71, P = 0.014, respectively). This U-shaped relationship was evident in the elderly patients. Furthermore, abnormal transitions to either higher or lower levels of serum UA from G2 were associated with increased mortality (aHR 1.29, 95% CI 1.06-1.57, P = 0.012; aHR 1.57, 95% CI 1.12-2.20, P = 0.009).

Conclusions: These results demonstrate that serum UA levels have the U-shaped prognostic effects and abnormal transitions to either higher or lower levels are associated with poor prognosis in the elderly patients with CHF.

Keywords: Biomarker; Heart failure; Prognosis; Uric acid.

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Conflict of interest statement

The Department of Evidence‐Based Cardiovascular Medicine, Tohoku University Graduate School of Medicine is supported in part by unrestricted research grants from Daiichi Sankyo (Tokyo, Japan), Bayer Yakuhin (Osaka, Japan), Kyowa Hakko Kirin (Tokyo, Japan), Novartis Pharma (Tokyo, Japan), Dainippon Sumitomo Pharma (Osaka, Japan), Astellas Pharma (Tokyo, Japan), AstraZeneca (Osaka, Japan), Chugai Pharmaceutical (Tokyo, Japan), GlaxoSmithKline (Tokyo, Japan), Kowa Pharmaceutical (Tokyo, Japan), Mitsubishi Tanabe Pharma (Osaka, Japan), Mochida Pharmaceutical (Tokyo, Japan), MSD (Tokyo, Japan), Nippon Boehringer Ingelheim (Tokyo, Japan), Otsuka Pharmaceutical (Tokyo, Japan), Shionogi (Osaka, Japan), and Takeda Pharmaceutical (Osaka, Japan). H. S. has received lecture fees from Bayer Yakuhin (Osaka, Japan) and Daiichi Sankyo (Tokyo, Japan).

Figures

Figure 1
Figure 1
Study flowchart. CHART, Chronic Heart Failure Registry and Analysis in the Tohoku District‐2.
Figure 2
Figure 2
Kaplan–Meier curves and unadjusted and adjusted hazard ratio by univariable and multivariable Cox proportional regression analysis for (A) all‐cause death and (B) HF admission among patients with HF by serum UA levels at baseline. Covariates used in this analysis were age, sex, BMI, heart rate, NYHA III/IV, HF admission, hypertension, diabetes mellitus, atrial fibrillation, stroke, cancer, drinking history, ischaemic heart disease, LVEF, haemoglobin, creatinine, ACE‐I/ARBs, beta‐blockers, calcium channel blockers, diuretics, statins. ACE‐Is, angiotensin‐converting‐enzyme inhibitors; ARBs, angiotensin II receptor blockers, BMI, body mass index; CI, confidence interval; HF, heart failure; HR, hazard ratio; LVEF, left ventricular ejection fraction; NYHA, New York Heart Association.
Figure 3
Figure 3
Cubic spline curves of additive Cox proportional hazard regression models for (A) All‐cause death and (B) HF admission. HF, heart failure; UA, uric acid.
Figure 4
Figure 4
Comparisons of incidence rates by serum UA levels for (A) CV death and (B) non‐CV death. AMI, acute myocardial infarction; CV, cardiovascular; HF, heart failure; UA, uric acid.
Figure 5
Figure 5
Subgroup analysis with multivariable Cox proportional regression models for the prognostic relevance of serum UA levels with all‐cause death by (A) age, (B) sex, (C) LVEF, (D) eGFR in patients with HF, (E) CONUT score < 2 or ≥ 2, (F) ischaemic heart disease, (G) use of diuretics, and (H) use of UA lowering agents. CI, confidence interval; CONUT, controlling nutritional status; eGFR, estimated glomerular filtration rate; HF, heart failure; HR, hazard ratio; LVEF, left ventricular ejection fraction; UA, uric acid.
Figure 6
Figure 6
Kaplan–Meier curves and forest plots in multivariable Cox proportional hazards models for cumulative all‐cause death in G2 patients at baseline with serum UA levels both at baseline and 1 year for (A) overall population and (B) subpopulation with use of UA lowering drugs at neither baseline nor 1 year. HF, heart failure; HR, hazard ratio; UA, uric acid.
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