Do uric acid levels continue to increase as heart failure worsens?

Comment by InpharmD Researcher

Uric acid levels may increase as patients’ New York Heart Association functional class increases. However, available data shows that increased uric acid levels may be more of a predictive factor in heart failure risk and worse prognosis.
Background

A 2020 systematic review and meta-analysis discussed the prognostic value of uric acid (UA) levels in heart failure (HF) patients regardless of their coexisting kidney function, as higher UA levels were associated with poorer prognosis and adverse outcomes. Thus, the present review and meta-analysis (11 trials; N= 16,088) examined whether lowering serum UA (SUA) levels with UA-lowering agents has an effect on mortality, cardiovascular (CV) events, and left ventricular ejection fraction (LVEF) in patients with HF. Interestingly, the overall findings showed that allopurinol treatment did not result in measurable clinical benefits. Instead, allopurinol treatment was associated with a significantly increased risk for all-cause mortality (hazard ratio [HR]: 1.24, 95% confidence interval [CI], 1.04-1.49, p= 0.02) and a 42% increased risk in CV mortality (HR: 1.42, 95% CI, 1.11-1.81, p= 0.005). Moreover, there was a trend toward increased CV hospitalization with allopurinol treatment (HR: 1.21, 95% CI, 0.95-1.53, p= 0.12). Nonetheless, these findings need to be interpreted with caution given a high level of heterogeneity (heterogeneity X2= 37.3, I2= 73%, p<0.001). [1]

A 2017 review assessed the association between serum uric acid levels and multiple health outcomes, including heart failure. Five meta-analyses of observational studies were used to assess heart failure incidence in a total population of 427,917 patients; the association was considered to be highly suggestive, with an increased risk of heart failure with high serum uric acid levels (relative risk 1.65 (95% confidence interval 1.41 to 1.94). [2]

A 2020 review evaluated pathophysiological connections between elevated serum uric acid and heart failure with a focus on its prognostic impact. Approximately half of the patients with heart failure have a serum uric acid concentration above the upper limit normal based on results from a recent study by Palazzuoli et al. (Table 2). Additionally, serum uric acid levels can predict morbidity and mortality in mild to moderate and advanced heart failure cases, and evidence suggests that moderately elevated serum uric acid levels are independently associated with increased risk of adverse outcomes in patients with acute and chronic heart failure. [3]

References:

[1] Kanbay M, Afsar B, Siriopol D, et al. Effect of Uric Acid-Lowering Agents on Cardiovascular Outcome in Patients With Heart Failure: A Systematic Review and Meta-Analysis of Clinical Studies. Angiology. 2020;71(4):315-323. doi:10.1177/0003319719897509
[2] Li X, Meng X, Timofeeva M, et al. Serum uric acid levels and multiple health outcomes: umbrella review of evidence from observational studies, randomised controlled trials, and Mendelian randomisation studies [published correction appears in BMJ. 2017 Aug 8;358:j3799]. BMJ. 2017;357:j2376. Published 2017 Jun 7. doi:10.1136/bmj.j2376
[3] Tedeschi A, Agostoni P, Pezzuto B, et al. Role of comorbidities in heart failure prognosis Part 2: Chronic kidney disease, elevated serum uric acid. Eur J Prev Cardiol. 2020;27(2_suppl):35-45. doi:10.1177/2047487320957793

Literature Review

A search of the published medical literature revealed 2 studies investigating the researchable question:

Do uric acid levels continue to increase as heart failure worsens?

Level of evidence

C - Multiple studies with limitations or conflicting results  Read more→



Please see Tables 1-2 for your response.


 

Serum Uric Acid level in the severity of Congestive Heart Failure (CHF)

Design

Retrospective chart review

N= 285

Objective

To find out the relationship between serum uric acid levels in the severity of Heart failure (HF)

Study Groups

Hyperuricemic (n= 169)

Normouricemics (n= 116)

Inclusion Criteria

Congestive HF consecutively admitted to Cardiology Department, Lady Reading Hospital Peshawar

Exclusion Criteria

Secondary hyperuricemia, like drugs, malignancies, uremia and other conditions with rapid cell turnovers live psoriasis

Methods

All patients were subjected to a detailed history and examination. Serum uric acid level was measured, after overnight fasting by enzymatic methods using the chemical analyzer.

Duration

From March 1st to August 2016

Outcome Measures

Serum uric acid levels and severity of congestive heart failure

Baseline Characteristics

 

Hyperuricemic (n= 169)

Normouricemics (n= 116) p-value

 

 

Age, years

 54 ± 2.8   -    

Male

141 (83.43%) 47 (40.51%) -    

BMI, kg/m2

24.6 ± 07 22.9 ± 09 0.168    

Systolic blood pressure, mmHg

153 ± 32 156 ± 32 -    

Diastolic blood pressure, mmHg

87 ± 21 86 ± 19    
Mean heart rate, bpm

73.9 ± 3.6

67.5 ± 2 0.239    
Brain natriuretic peptide, pg/ml

206 ± 13

79.8 ± 9 <0.001    

Risk factor

Hypertension

Diabetes Mellitus

Hyperlipidemia

Current smoking

 

113 (66.86%)

78 (46.15%)

37 (21.89%)

13 (7.69%)

 

75 (64.65%)

41 (35.34%)

28 (24.13%)

7 (6.03%)

 

0.432

0.064

0.086

0.932

   

Drugs

Beta-blocker

Diuretics

ACEi/ARB

Digitalis

 

39 (23.07%)

79

163

19

 

21 (18.10%)

43

103

17

 

0.187

<0.001

0.643

0.051

   

Etiology

Ischemic heart disease

Valvular heart disease

 

88

76

 

69

74

 

0.167

0.976

   

Results

Serum uric acid (SUA) levels and severity of congestive heart failure (n= 285)

SUA, mg/dL NYHA I NYHA II NYHA III NYHA IV  Total 

<6

3 (1.05%) 40 (14.03%) 27 (9.47%) 5 (1.75%) 75 (26.31%)

6 - 8

1 (0.35%) 37 (12.98%) 28 (9.82%) 24 (8.42%) 90 (31.57%)

8.1 - 12

1 (0.35%) 36 (12.63%) 30 (10.52%) 30 (10.52%) 97 (34.93%)

>12

0 (0%) 1 (0.35%) 8 (2.80%) 14 (4.91%) 23 (8.07%)

Total

5 (1.75%) 114 (40%) 93 (32.63%) 73 (25.61%) 285 (100%)

Mean serum uric acid (SUA) levels are 7.79 mg/dL ± 2.47. Out of 285, 59.29% met the definition of hyperuricemia (defined as a serum UA level >7.0 mg/dL) of which 83.43% were male. Most of the hyperuricemic patients (62.13%) had a mean age of 57 ± 4.5 years. Mean SUA levels increased significantly with NYHA class.

A significant correlation was found between uric acid level and BNP (p≤ 0.001), and the use of diuretics (p≤ 0.001). 

Adverse Events

N/A

Study Author Conclusions

High serum uric acid was observed in 59.29% of patients with CHF. The observed significant correlation between UA level and some established prognostic markers in these patients may indicate that serum UA could provide additional prognostic information in this population. SUA as a marker can be measured anywhere at a low cost to help identify high-risk patients with CHF. Lowering uric acid is expected to be a new approach for the prevention and therapy of HF.

InpharmD Researcher Critique

The study is subject to the limitations inherent to retrospective analysis, and presented data only represents a single institution's experience. The authors noted that the study was able to examine the extent of hyperuricemia but not the duration of hyperuricemia.



References:

Khan A, Shah MH, Khan S, et al. Serum uric acid level in the severity of congestive heart failure (CHF). Pak J Med Sci. 2017;33(2):330-334. doi:10.12669/pjms.332.11779

 

Prevalence of Hyperuricemia in Patients With Acute Heart Failure With Either Reduced or Preserved Ejection Fraction

Design

Prospective, single-center study

N= 331

Objective

To evaluate the significance of uric acid in acute heart failure attributed to heart failure with reduced ejection fraction (HFrEF) versus heart failure with preserved ejection fraction (HFpEF)

Study Groups

Reduced (n= 173)

Preserved (n= 151)

Inclusion Criteria

Consecutive patients screened from the Diur-HF Trial (NCT01441245), admitted with dyspnea and primary diagnosis of acute heart failure with evidence of volume overload, within <24 hours from hospital presentation in Diur-HF Trial, typical signs and symptoms of heart failure (dyspnea, edema, rales, third heart sound, jugular turgor, lung congestion on chest x-ray, and B-type natriuretic peptide [BNP] levels >100 pg/mL)

Exclusion Criteria

End-stage renal disease or need for renal replacement therapy (dialysis or ultrafiltration), recent myocardial infarction, systolic blood pressure <90 mm Hg, serum creatinine level >4 mg/dL, sepsis, systemic inflammatory disease, severe liver disease, or neoplastic disease

Methods

Prospectively collected data are retrospectively analyzed. Patients were assigned to 2 groups based on ejection fraction: HFrEF (EF <50%) and HFpEF (EF ≥50%). Hyperuricemia was defined as a uric acid level ≥7 mg/dL in men and ≥6 mg/dL in women. Uric acid measurement was evaluated by an enzymatic colorimetric test. Cox regression analysis was used to assess independent relations between hyperuricemia and the primary endpoint for each group. The analysis was adjusted for age, gender, chronic kidney disease, hypertension, diabetes, dyslipidemia, atrial fibrillation, and smoking.

Duration

Screening: January 2011 to February 2016

Follow-up: 6 months after discharge

Outcome Measures

Primary outcome: Composite of heart failure rehospitalization and death

Secondary outcome: Association of hyperuricemia in regard to the primary outcome

Baseline Characteristics

 

Reduced (n= 173)

Preserved (n= 151)

p-value

Median age, years

77 (75 to 84) 80 (78 to 83) 0.04

Female

102 (59%) 113 (75%) 0.004

Uric acid, mg/dL

11.5 (10.1 to 13) 11.4 (10.1 to 12.8) 0.37

Hyperuricemia

74 (43%) 86 (57%) 0.01

Age and uric acid levels were specified as median values, but values in parentheses were not specified to be ranges or interquartile ranges.

Results

Endpoint

Reduced (n= 173)

Preserved (n= 151)

p-value

Heart failure death or rehospitalization 111 (64%) 91 (60%) 0.55

Hyperuricemia

Univariate HR (95% CI); p-value

Multivariate HR (95% CI); p-value



1.48 (1.02 to 2.15); 0.04

1.24 (0.81 to 1.9); 0.31



2.25 (1.44 to 3.5); <0.001

2.75 (1.52 to 5); 0.001

 

Kaplan-Meier survival curves showed increased event-free survival in patients with normal uric acid levels compared to hyperuricemia in both HFrEF and HFpEF (p= 0.03 and p< 0.001, respectively).

Adverse Events

N/A

Study Author Conclusions

Hyperuricemia is associated with hospitalization and death in both HFrEF and in HFpEF; however, only in HFpEF hyperuricemia is the only independent item after multivariate adjustment.

InpharmD Researcher Critique

Prevalence of hyperuricemia was significantly higher in the HFpEF group compared to the HFrEF group. Additionally, increased uric acid levels appear to be associated with worse heart failure outcomes for HFpEF patients based on multivariate analysis. Assessment for potential metabolic confounders for UA was limited in the study.



References:

Palazzuoli A, Ruocco G, De Vivo O, et al. Prevalence of hyperuricemia in patients with acute heart failure with either reduced or preserved ejection fraction. Am J Cardiol. 2017;120(7):1146-1150. doi:10.1016/j.amjcard.2017.06.057