‘Treat-to-target is key’: Allopurinol noninferior to febuxostat for gout when properly dosed
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Allopurinol is noninferior to febuxostat for gout when dosed appropriately as part of a treat-to-target strategy, according to data presented at ACR Convergence 2021.
The data emphasize the significance of following the American College of Rheumatology or EULAR treatment recommendations, as opposed to guidelines from the American College of Physicians, which “does not recognize” the importance of treat-to-target, the presenter said.
“There is a big controversy in the gout treatment world between the American College of Rheumatology and EULAR, which are the experts in rheumatology in Europe and the United States, versus the American College of Physicians,” James O’Dell, MD, of the University of Nebraska Medical Center, in Omaha, told attendees at a virtual press conference. “The American College of Physicians does not recognize how important it is to treat gout to a target of a low uric acid level.”
“After all, when your uric acid level is above a certain level — and that level of 6.8 milligrams per deciliter — you start precipitating out gout crystals all over your body, literally,” he added. “They show up in joints as the most painful thing you've ever had in your life, frequently starting in the toes, ankles, knees and later can involve every joint in your body. We don't want that to happen to our patients, so the strategy recommended by the American College of Rheumatology is treat to target.”
To compare the efficacy and safety of the two most common urate lowering medications — allopurinol and febuxostat — in gout management, O’Dell and colleagues conducted a multicenter, randomized, double-blind, non-inferiority trial.
“Because, after all, febuxostat is 19 times more expensive than allopurinol,” O’Dell said.
The researchers also aimed to test how successful both drugs can be as part of a dedicated treat-to-target strategy. The 72-week trial enrolled 940 patients with gout — and a serum urate concentration of at least 6.8 mg/dL — from 21 sites, who were then randomized 1:1 to receive either allopurinol or febuxostat. By design, more than one-third of the patients had chronic kidney disease.
The trial included three phases: Urate lowering therapy titration from weeks 0 to 24, maintenance therapy from weeks 25 to 48, and observation with continued stable urate lowering therapy from weeks 49 to 72. Patients received initial doses of either 100 mg of allopurinol, with a maximum titration to 800 mg, or 40 mg of febuxostat, with maximum titration to 120 mg. The maximum febuxostat titration was later reduced to 80 mg in 2019 as per FDA request.
“Unfortunately, unless you are seen by a rheumatologist – and most our patients are not – that essentially never happens in practice,” O’Dell said. “The most common dose, overwhelmingly, is the physician gives the patient 300 milligrams of allopurinol and never monitors how effective that is, whether they need more or whether they need less. So, treat the target is a key thing that we study. The primary hypothesis was that allopurinol would be noninferior to febuxostat in this trial.”
Patients received anti-inflammatory prophylaxis, chosen by site investigator, according to 2012 ACR guidelines until the start of phase three. The primary endpoint was the proportion of patients experiencing one or more flares during phase three, with a pre-specified margin of more than 8% difference defining noninferiority. Secondary endpoints included efficacy and tolerability in stage 3 chronic kidney disease, the proportion achieving a serum urate concentration of less than 6 mg/dL at the end of phase two, and serious adverse events.
According to the researchers, a total of 20% of participants withdrew prior to completion, with similar proportions in each treatment arm. In phase three, 35% of patients treated with allopurinol had one or more flares, compared with 42% in the febuxostat group (P < .001 for non-inferiority). Overall, 80% of patients achieved the serum urate target of less than 6 mg/dL — with 92% reaching less than 6.8 mg/dL — during phase two, with no differences between the treatment groups.
Similarly, there were no differences between the treatment arms regarding serious adverse events, including cardiovascular events, in those with or without chronic kidney disease.
“Our trial was able to show in gout patients, including gout patients with chronic kidney disease, that you can safely use either allopurinol or febuxostat,” O’Dell said. “If you do that, and you use it in a treat-to-target approach — in other words you titrate the dose of your allopurinol or febuxostat until that patient gets below 6 — then you control the vast majority of your patients.”
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O’Dell J. Abstract 1900. Presented at: ACR Convergence 2021; November 5-9, 2021 (virtual meeting).
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