Abstract
Objective. To systematically review available literature on treatment of hyperuricemia (HU) as a measure of preventing gouty arthritis, renal disease, or cardiovascular events in asymptomatic patients.
Methods. A systematic literature search was conducted in the Cochrane Library, Medline, Embase, clinical trials registries of the World Health Organization and the US National Institutes of Health, and abstracts from American College of Rheumatology/European League Against Rheumatism meetings, for interventional studies involving adults with no history of gouty arthritis, who were treated for HU. Outcomes of interest included gouty arthritis, renal disease (i.e., renal insufficiency, urate nephropathy, nephrolithiasis), and cardiovascular events (i.e., myocardial infarction, heart failure, ischemic stroke).
Results. A total of 3 studies met the inclusion criteria, 2 studies assessing the prevention of renal disease and 1 study evaluating the potential for delaying progression of preexisting renal disease. In hyperuricemic patients without renal disease, treatment resulted in increased estimated glomerular filtration rate. In hyperuricemic patients with preexisting renal disease, treatment resulted in no significant elevation of serum creatinine over a 1-year followup. However, differences in renal function between the treatment and no-treatment groups were not statistically significant in any of the identified studies.
Conclusion. Very limited data are available on the treatment of HU in asymptomatic patients. There is currently insufficient empiric evidence to suggest that lowering serum uric acid level in asymptomatic patients with HU can prevent gouty arthritis, renal disease, or cardiovascular events.
This article is part of the 3e (Evidence, Expertise, Exchange) Initiative on Diagnosis and Management of Gout1. The objective of the current work was to systematically review the available literature concerning 1 of the 10 selected questions as an evidence base for generating the recommendations. This review relates to the question: Can we prevent gouty arthritis, renal disease, and cardiovascular events by lowering serum uric acid levels in patients with asymptomatic hyperuricemia? If yes, what should be the target levels?
The clinical significance of elevated serum uric acid as a harbinger of various diseases is unclear. Large observational cohort studies have demonstrated an association between hyperuricemia (HU) and an increased risk of gout, although the number of affected patients in these studies was generally small, and their uric acid levels very high2,3. An association with adverse renal and cardiovascular (CV) outcomes has also been suggested. Specifically, HU has been shown to have a predictive and prognostic value as a marker in patients with hypertension4,5, heart failure6, cardiovascular disease7, cerebrovascular disease8, metabolic syndrome9, and renal disease10,11. However, it remains unclear whether treatment of HU can prevent its associated adverse outcomes of gouty arthritis, renal disease, or CV events in asymptomatic patients. A systematic review of the literature was conducted to address this question as an evidence base for developing clinical practice recommendations.
MATERIALS AND METHODS
The research question was used to generate the PICO (Population, Intervention, Comparison, Outcome), a concept suggested by the Cochrane Collaboration as a tool in conducting systematic literature reviews. The target population was defined as adults (age > 18 years) with elevated serum uric acid level but without history of gouty arthritis. The intervention of interest included any uric acid-lowering therapy, and comparators could be no treatment or placebo. The included outcomes were gouty arthritis (including tophi), renal disease, encompassing renal insufficiency, urate nephropathy and nephrolithiasis, and CV events, including myocardial infarction, heart failure and ischemic cerebrovascular stroke. Included study types were randomized controlled trials, case controlled studies, cohort studies, and case series. Studies involving congenital, malignant, or iatrogenic causes of HU were excluded. Articles written in a language other than English or a language in which at least 1 member of the 3e bibliographic group was fluent (Dutch, German, French, and Spanish) were excluded.
A systematic search was conducted using the Cochrane Library, OVID Medline (1948 to October 2011), and Embase (1980 to October 2011). The search strategy was devised with the help of an experienced librarian (LF) (for the complete search strategy, see online supplementary data available from www.3egout.com). Clinical trials registries of the World Health Organization (WHO) and the US National Institutes of Health (NIH), as well as abstracts from the American College of Rheumatology (ACR) and European League Against Rheumatism meetings (EULAR) (2010–2011) were also searched. Search results were reviewed by 2 reviewers (OV, MW), who also extracted the relevant data. Risk of bias was assessed using the Cochrane Collaboration risk of bias tool12.
RESULTS
A total of 1683 articles were identified as well as 4 abstracts from the ACR and EULAR meetings and 7 entries from the clinical trials registries of the WHO and NIH (Figure 1). After detailed review, only 3 studies met the inclusion criteria, none of which pertained to the prevention of gouty arthritis or CV events (Table 1). Two studies13,14 assessed the prevention of renal disease by treating HU in asymptomatic patients, and 1 study15 evaluated the potential for delaying progression of renal disease by treating HU in patients with preexisting renal dysfunction. The limited number of identified studies precluded a subsequent metaanalysis. All 3 studies were deemed to have high risk of bias based on lack of allocation concealment and lack of blinding of both participants and outcome assessors (for more details see online supplementary data available from www.3egout.com).
Kanbay, et al (2007)13 conducted an open single-arm trial in which 48 patients with HU and normal renal function were treated with a xanthine oxidase inhibitor (allopurinol 300 mg per day) for 3 months. Their renal function and plasma urate levels were monitored and compared to a group of 21 non-HU patients. A total of 10 patients dropped out of the study, of which 1 was due to rash in the treatment group. After 3 months of treatment there was a significant decrease in the mean serum uric acid level in the HU group compared to baseline (8.0 ± 0.76 mg/dl to 5.5 ± 1.2 mg/dl; p < 0.05). The mean estimated glomerular filtration rate (eGFR) of patients on treatment increased (79.2 ± 31.9 ml/min to 92.9 ± 36.8 ml/min; p < 0.05) with an associated decrease of their serum creatinine (1.24 ± 0.36 mg/dl to 1.14 ± 0.32 mg/dl; p < 0.05). There was no significant change in urine protein excretion in the treatment group compared to baseline. At 3 months there were no statistically significant differences between the treatment and no-treatment groups with respect to eGFR, serum creatinine, and urine protein excretion.
In a subsequent open-label randomized trial by Kanbay, et al (2011)14, 72 HU patients with normal renal function were randomized to either a xanthine oxidase inhibitor (allopurinol 300 mg per day) or to no treatment and were followed for 4 months with monitoring of renal function. No adverse outcomes were reported. At the end of 4 months there was a significant reduction in uric acid level in those treated with the xanthine oxidase inhibitor (8.3 ± 1.1 mg/dl to 5.8 ± 1.5 mg/dl; p < 0.05) compared to baseline. The mean eGFR in the treatment group increased (86.3 ± 19.4 ml/min to 89.6 ± 12.6 ml/min; p = 0.001), but with no significant change in urine protein excretion compared to baseline. There was also no statistically significant difference between the treatment and no-treatment groups with respect to these variables.
The third included study, Siu, et al (2006)15, recruited patients with HU who had a baseline renal disease defined as serum creatinine between 120 and 400 µmol/l and/or 24-h urine protein excretion > 0.5 g. Their definition of HU was uric acid > 7.6 µmol/l (compared to 7 µmol/l in the other 2 studies). This was an open-label, randomized study in which 54 patients were randomized to receive either xanthine oxidase inhibitor (allopurinol, dosed at 200 mg per day when serum creatinine was ≤ 150 µmol/l, and 100 mg per day if serum creatinine was > 150 µmol/l) or no treatment. They were followed at 12 months with measurement of renal function. Other medications such as antihypertensive and lipid-lowering agents were allowed to be adjusted during the study at clinician’s discretion. They reported 1dropout from the treatment group due to a skin reaction. After 12 months of treatment, patients receiving a xanthine oxidase inhibitor had a significant reduction in uric acid level (9.75 ± 1.18 mg/dl to 5.88 ± 1.01 mg/dl; p < 0.05). There was no significant change in serum creatinine in the treatment group compared to baseline (1.64 ± 0.63 mg/dl to 1.99 ± 0.92 mg/dl; p > 0.05), while in the no-treatment group there was a significant increase (1.86 ± 0.69 mg/dl to 2.89 ± 0.96 mg/dl; p < 0.05) suggesting worsening renal function. There was no significant change in urine protein excretion in either of the 2 groups compared to baseline. Comparing the 2 groups at 12 months, there were no statistically significant differences with respect to serum creatinine and urine protein excretion.
DISCUSSION
This systematic review summarizes and evaluates the existing evidence on treating HU in patients with no history of gouty arthritis. Combined with expert opinion from the panel of rheumatologists taking part in the 3e Initiative, these results served as an evidence base for generating 1 of the 10 clinical recommendations on the management of gout.
The findings of this systematic review highlight the paucity of empiric data relating to the treatment of HU as a measure of preventing its previously identified clinical associations with gouty arthritis, renal disease, and CV events. It also illustrates the lack of a uniform definition of HU in the medical literature. This, to some extent, likely reflects the difficulty of establishing an epidemiologically-based reference distribution of uric acid levels in a population because levels appear to change over time and vary among different populations and geographic locations16.
The definition of asymptomatic HU was a topic of some debate among the 3e group participants. In principle, primary prevention of a disease in an asymptomatic person implies the absence of any history of this disease in the individual. Thus, from a purist perspective, patients with history of any associated sequela of HU should be excluded from the definition of asymptomatic HU. However, since the prevention and management of gout was the main objective of the 3e working group, the eventual agreed-upon definition was limited to patients with HU but no history of gouty arthritis. Patients with preexisting CV or renal disease were included in the definition of asymptomatic HU.
The 3 identified studies related only to the prevention of renal insufficiency. However, the duration of these studies (12 months or less) is likely too short to properly assess the target outcomes, and the small sample sizes are most likely underpowered for their specified outcomes. Although the Kanbay, et al studies13,14 demonstrated an increase in eGFR with xanthine oxidase inhibitor in patients with HU, these were patients with no preexisting renal dysfunction and a normal baseline eGFR. The increase in eGFR in this context is of unclear clinical significance, particularly considering the short study duration.
The study by Siu, et al15, while demonstrating no significant increase in serum creatinine after 1 year treatment with xanthine oxidase inhibitor in patients with preexisting renal disease, was also limited by small sample size and short followup duration. Results were also confounded by the noncontrolled use of other medications with potential renal as well as uric acid effects on metabolism, such as anti-hypertensive and lipid-lowering agents.
Finally, it must be emphasized that the treatment of HU carries risks of potential adverse events, some of which are not inconsequential17. Some of the uric acid-lowering medications carry the specific warning that they are not recommended for the treatment of asymptomatic hyperuricemia18,19. This is highlighted in other recent recommendations for the management of gout20. Citing the paucity of empiric data, the 2012 ACR guidelines for management of gout did not address the pharmacological management of asymptomatic HU21.
Notwithstanding the lack of empiric evidence for pharmacological treatment of asymptomatic HU, experts in the 3e group suggested that lifestyle advice on diet, weight loss, and exercise could still be part of the management of these patients. This suggestion is based on the existing evidence for the health benefits of these nonpharmacological interventions, including their effect on uric acid levels and gout22,23,24.
In summary, HU has been associated with an increased risk of gouty arthritis in large observational studies, although the number of affected patients in these studies is generally small and their uric acid level is significantly elevated. In addition, an associated risk of renal disease and CV events has also been described. However, the available interventional data on treating HU in asymptomatic patients is extremely sparse and fraught with limitations. Therefore, pharmacological treatment of asymptomatic hyperuricemia cannot be recommended at present for the prevention of gouty arthritis, renal disease, or CV events. Further interventional studies are required to determine the potential clinical benefits of this preventive approach.
Footnotes
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The authors acknowledge the work of all members of the 3e scientific committees and all participants in the national meetings. This article is derived from the 3e Gout program, which was sponsored by AbbVie Inc. Margaux Orange, Paris, France, provided logistical and administrative support for the 3e Gout meetings; this work was funded by AbbVie Inc. AbbVie employees were present during the 3e meetings, but did not influence the scientific discussions. AbbVie did not review the content or have influence on this manuscript.