Up-titration of allopurinol in patients with gout
Introduction
Gout is a common condition with an overall prevalence in the UK of 1.4% rising to over 6% in the over 65 years age group [1], [2]. Incidence of gout in the UK has been stable for the past two decades; however, the disease burden of gout is expected to increase due to increasing life expectancy and a predicted rise in the UK population that is over 60 years of age from 14 million in 2010 to 18.6 million by 2026 [3], [4]. The European League against Rheumatism (EULAR) published guidelines in 2006, making a series of recommendations for the management of gout, including titration of urate-lowering therapy to achieve a serum urate target level <6.0 mg/dL [5]. The American College of Rheumatology guidelines published in 2012 recommend a target serum urate level <6.0 mg/dL in all patients but recognised that lowering serum urate level below 5.0 mg/dL may be required for durable improvements in severe disease manifestations such as tophaceous deposits [6].
Allopurinol is currently the first-line urate-lowering therapy prescribed for patients with chronic gout, and guidelines recommend starting at a low dose and titrating this upwards until a target urate level is reached. In the UK, approximately 30% of patients with gout are regularly prescribed allopurinol [7], and it is recognised that a significant proportion of these patients do not achieve the EULAR target of serum urate level <6.0 mg/dL. A postal survey in UK primary care practices showed that 23% of patients with gout taking allopurinol had urate levels >6.0 mg/dL [8]. In a US review of 15,596 patients with gout, only 30% met the specified urate target level, and of those prescribed allopurinol, 40% did not have the urate level checked after completing their first allopurinol prescription [9]. A survey of UK GPs found that 86% of GPs felt confident in the diagnosis and management of gout [10], but despite this confidence, achievement of the EULAR target levels remains poor. This is potentially due to a lack of awareness of the targets for therapy, concerns about side effects of allopurinol dose increases and infrequent monitoring of urate levels.
The Febuxostat versus Allopurinol Streamlined Trial (FAST) [ISRCTN72443728] fulfils a European Medicines Agency requirement for a post-licensing cardiovascular safety study of febuxostat and compares the cardiovascular safety of febuxostat with allopurinol. Febuxostat is a more potent urate-lowering treatment than 300 mg of allopurinol [11], [12]. Therefore, as recruited patients were already taking allopurinol, in order to allow a fair comparison of cardiovascular safety, the study design forced up-titration of allopurinol dose until the serum urate level was below the EULAR target prior to randomisation. An exact conversion of 6.0 mg/dL is 357 µmol/L and this was the cutoff urate level used in FAST.
Analysis of patients recruited into FAST gives an insight into the use of allopurinol in this population and provides important information on the response to allopurinol dose increases, how this therapy is tolerated and what factors might influence patients’ response to allopurinol.
Section snippets
Methods
FAST patients were recruited in Scotland, England and Denmark. Potential patients were identified by searches from primary care databases undertaken by study nurses. Eligible patients were aged over 60 years, prescribed allopurinol for symptomatic hyperuricaemia (clinical diagnosis) and had at least one additional cardiovascular risk factor. Patients with significantly impaired renal function (eGFR < 30 mL/min) were excluded. Patients meeting the inclusion criteria attended for a screening
Results
Of the 400 patients, 144 (36%) had urate levels ≥357 µmol/L at screening and therefore required up-titration of their allopurinol dose. The baseline characteristics of these two groups are shown in the Table.
Patients who required up-titration of allopurinol were significantly more likely to be male (p = 0.002), have a higher body mass index (BMI) (p = 0.026), have higher alcohol intake (p < 0.05), be prescribed a diuretic (p = 0.015) and were taking a lower dose of allopurinol (p < 0.005)
Discussion
The 2006 EULAR guidelines proposed 12 key recommendations to improve the management of patients with gout, including three recommendations for urate-lowering therapy [5]. Allopurinol is recommended as first-line urate-lowering therapy and should be started at a low dose (100 mg daily) with the daily dose to be increased by 100 mg every 1–2 weeks as required. The British Rheumatology Society published guidelines in 2007 with similar recommendations except advising an even lower target urate level
Conclusion
Analysis of pre-randomisation data for the first 400 FAST patients has shown that only 64% of patients were controlled on their baseline dose of allopurinol. A total of 144 patients required one or more up-titrations of allopurinol and 97% of these patients ultimately achieved the EULAR urate target level of <357 µmol/L. Historical guidelines advocate caution with higher doses of allopurinol; however, our data shows that in patients already taking allopurinol, generally only modest dose
Ethical approval
The FAST trial has ethical approval in the UK and Denmark (REC Ref: 11/AL/0311). All participants in the FAST trial provided written informed consent.
T.M.M. holds research grants from Novartis, Pfizer, Ipsen and Menarini; is currently or has been the principal investigator on trials paid for by Pfizer, Novartis, Ipsen and Menarini; and has been paid consulting or speakers fees by Pfizer, Novartis, Kaiser Permanente, Takeda, Recordati, Servier, Menarini, and AstraZeneca in the previous 3 years.
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2016, International Journal of Medical InformaticsCitation Excerpt :The core advice of these guidelines is to lower and maintain serum uric acid (sUA) to ≤6 mg/dL (0.36 mmol/L; British Guidelines recommend ≤5 mg/dL (0.30 mmol/L)) [3], and to increase the dose of allopurinol, the predominantly used ULT, slowly until this is achieved. Remarkably, if these guidelines are followed, and ULT is commenced carefully, acute gout attacks will ultimately cease and the damaging effects of monosodium-urate deposits in joints and tissues will be avoided or minimised [7]. A study has shown that negative experiences and mistaken beliefs of patients with gout were major barriers to patients seeking information and advice about gout, and also impacted on their adherence to therapy [8].
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All listed authors fulfil the requirements for authorship and agree to submission of the manuscript in its current form.
The FAST trial is funded by Menarini and is sponsored by the University of Dundee. IPSEN pharmaceuticals funded the initial protocol development. Both IPSEN and Menarini are permitted an observer at steering committee meetings.
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Members of the FAST study group are listed at the end of the article.