medwireNews: Escalation of allopurinol to above creatinine clearance (CrCL)-based doses is effective for achieving target serum urate levels in patients with gout, study findings suggest.
Despite US Food and Drug Administration approval of allopurinol doses of up to 800 mg/day, doses above 300 mg/day are rarely used, the researchers report, citing physician inertia and concerns over adverse events as possible reasons.
In their randomized trial, 69% of 90 patients with gout whose allopurinol dose was escalated over a 12-month period achieved a target urate level below 6 mg/dL, compared with 32% of 93 gout patients who remained on the same dose.
Prior to randomization, the patients had all been taking at least a CrCL-based dose of allopurinol for a month or more and had serum urate levels of 6 mg/dL or above.
For those in the dose escalation group, allopurinol was increased monthly by 50 mg/day if CrCL was below 60 mL/min and by 100 mg/day for those with CrCL at or above this level. Dose escalation continued until urate levels were below 6 mg/dL on three consecutive visits or adverse events occurred.
Urate levels in these patients fell by an average of 1.5 mg/dL, from 7.18 mg/dL at baseline to 5.7 mg/dL after dose escalation. This was a significant 1.2 mg/dL improvement compared with the patients who remained on the same dose of allopurinol, whose urate levels fell by 0.34 mg/dL, on average, from 7.13 mg/dL to 6.9 mg/dL.
Lisa Stamp (University of Otago, Christchurch, New Zealand) and colleagues note that despite the lower urate levels, dose escalation did not significantly reduce gout flares or activity compared with no escalation.
They explain in the Annals of the Rheumatic Diseases that escalation of allopurinol had to be slow because about half of the participants had chronic kidney disease with CrCL below 60 mL/minute, so average urate levels below 6 mg/dL were not reached until month 7 and therefore a longer follow-up period may be needed for a difference in flare rates to show.
They see this high prevalence of chronic kidney disease in their study population as a key strength, however. This, together with a high level of comorbid conditions and a 44% rate of severe gout, means the patients were “representative of people with gout” and that the findings reflect “real-life clinical practice” and are “generalisable to other gout populations,” they write.
There were a number of serious adverse events – 35 in 22 patients receiving dose escalation and 43 in 25 controls – with cardiac disorders being the most common. But only a single occurrence of increased international normalized ratio in one dose escalation patient was deemed related to allopurinol, and none of the 10 deaths, five in each group, were due to the drug.
Mild treatment-emergent liver function abnormalities occurred, but at a similar rate in each group. Gamma glutamyl transferase elevations occurred more often in patients in the dose escalation group, but there were only a small number of higher-grade abnormalities, compared with the control group.
The researchers conclude: “[I]n people with gout, including those with kidney impairment, who tolerate CrCl-based doses of allopurinol but fail to reach target urate, gradual [dose escalation] to achieve target urate is effective and well-tolerated.”
By Lucy Piper
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