Category: Rheumatology

“Febuxostat Compared with Allopurinol in Patients with Hyperuricemia and Gout”

aka the Febuxostat versus Allopurinol Controlled Trial (FACT)

N Engl J Med. 2005 Dec 8;353(23):2450-61. [free full text]
—

Gout is thought to affect approximately 3% of the US population, and its prevalence appears to be rising. Gout occurs due to precipitation of monosodium urate crystals from supersaturated body fluids. Generally, the limit of solubility is 6.8 mg/dL, but local factors such as temperature, pH, and other solutes can lower this threshold. A critical element in the treatment of gout is the lowering of the serum urate concentration below the limit of solubility, and generally, the accepted target is 6.0 mg/dL. The xanthine oxidase inhibitor allopurinol is the most commonly used urate-lowering pharmacologic therapy. Allopurinol rarely can have severe or life-threatening side effects, particularly among patients with renal impairment. Thus drug companies have sought to bring to market other xanthine oxidase inhibitors such as febuxostat (trade name Uloric). In this chronic and increasingly burdensome disease, a more efficacious drug with fewer exclusion criteria and fewer side effects would be a blockbuster.

The study enrolled adults with gout and a serum urate concentration of ≥ 8.0 mg/dL. Exclusion criteria included serum Cr ≥ 1.5 mg/dL or eGFR < 50 ml/min (due to this being a relative contraindication for allopurinol use) as well as a the presence of various conditions or use of various drugs that would affect urate metabolism and/or clearance of the trial drugs. (Patients already on urate-lowering therapy were given a two week washout period prior to randomization.) Patients were randomized to treatment for 52 weeks with either febuxostat 80mg PO daily, febuxostat 120mg PO daily, or allopurinol 300mg PO daily. Because the initiation of urate-lowering therapy places patients at increased risk of gout flares, patients were placed on prophylaxis with either naproxen 250mg PO BID or colchicine 0.6mg PO daily for the first 8 weeks of the study. The primary endpoint was a serum urate level of < 6.0 mg/dL at weeks 44, 48, and 52. Selected secondary endpoints included percentage reduction in serum urate from baseline at each visit, percentage reduction in area of a selected tophus, and prevalence of acute gout flares weeks requiring treatment.

762 patients were randomized. Baseline characteristics were statistically similar among all three groups. A majority of the patients were white males age 50+ who drank alcohol. Average serum urate was slightly less than 10 mg/dL. The primary endpoint (urate < 6.0 at the last three monthly measurements) was achieved in 53% of patients taking febuxostat 80mg, 62% of patients taking febuxostat 120mg, and 21% of patients taking allopurinol 300mg (p < 0.001 for each febuxostat groups versus allopurinol). Regarding selected secondary endpoints:

1) The percent reduction in serum urate from baseline at the final visit was 44.73 ± 19.10 in the febuxostat 80mg group, 52.52 ± 19.91 in the febuxostat 120mg group, and 32.99 ± 15.33 in the allopurinol 300mg group (p < 0.001 for each febuxostat group versus allopurinol, and p < 0.001 for febuxostat 80mg versus 120mg). 2) The percentage reduction in area of a single selected tophus was assessed in 156 patients who had tophi at baseline. At week 52, the median percentage reduction in tophus area was 83% in febuxostat 80mg patients, 66% in febuxostat 120mg patients, and 50% in allopurinol patients (no statistical difference per authors, p values not reported). Additionally, there was no significant reduction in tophus count in any of the groups. 3) During weeks 1-8 (in which acute gout flare prophylaxis was scheduled), 36% of patients in the febuxostat 120mg sustained a flare, whereas only 22% of the febuxostat 80mg group and 21% of the allopurinol group sustained a flare (p < 0.001 for both pairwise comparisons versus febuxostat 120mg). During weeks 9-52 (in which acute gout flare prophylaxis was no longer scheduled), a similar proportion of patients in each treatment group sustained an acute flare of gout (64% in the febuxostat 80mg group, 70% in the febuxostat 120mg group, and 64% in the allopurinol group). Finally, the incidence of treatment-related adverse events was similar among all three groups (see Table 3). Treatment was most frequently discontinued in the febuxostat 120mg group (98 patients, versus 88 patients in the febuxostat 80mg group and 66 patients in the allopurinol group; p = 0.003 for comparison between febuxostat 120mg and allopurinol).

In summary, this large RCT of urate-lowering therapy among gout patients found that febuxostat, dosed at either 80mg or 120mg PO daily, was more efficacious than allopurinol 300mg in reducing serum urate to below 6.0 mg/dL. Febuxostat was not superior to allopurinol with respect to the tested clinical outcomes of tophus size reduction, tophus count, and acute gout flares. Safety profiles were similar among the three regimens.

The authors note that the incidence of gout flares during and after the prophylaxis phase of the study “calls attention to a well-described paradox with important implications for successful management of gout: the risk of acute gout flares is increased early in the course of urate-lowering treatment” and the authors suggest that there is “a role for more sustained prophylaxis during the initiation of urate-lowering therapy than was provided here” (2458).

A limitation of this study is that its comparator group, allopurinol 300mg PO daily, may not have represented optimal use of the drug. Allopurinol should be uptitrated q2-4 weeks to the minimum dose required to maintain the goal serum urate of < 6.0 mg/dL (< 5.0 if tophi are present). According to UpToDate, “a majority of gout patients require doses of allopurinol exceeding 300 mg/day in order to maintain serum urate < 6.0 mg/dL.” In the United States allopurinol has been approved for doses of up to 800 mg daily. The authors state that “titration of allopurinol would have compromised the blinding of the study” (2459) but this is not true – blinded protocolized titration of study or comparator drugs has been performed in numerous other RCTs and could have been achieved simply at greater cost to and effort from the study sponsor (which happens to be the drug company TAP Pharmaceuticals). The likelihood that such titration would have shifted the results toward a null effect does not go unnoted. Another limitation is the relatively short duration of the trial – follow-up may have been insufficient to establish superiority in clinical outcomes, given the chronic nature of the disease.

In the UK, the National Institute for Health and Care Excellence (NICE), the agency tasked with assessing cost-effectiveness of various medical therapies, recommended as of 2008 that febuxostat be used for the treatment of hyperuricemia in gout “only for people who are intolerant of allopurinol or for whom allopurinol is contraindicated.”

Of note, a recent study funded by Takeda Pharmaceuticals demonstrated the non-inferiority of febuxostat relative to allopurinol with respect to rates of adverse cardiovascular events in patient with gout and major pre-existing cardiovascular conditions.

Allopurinol started at 100mg PO daily and titrated gradually to goal serum urate is the current general practice in the US. However, patients of Chinese, Thai, Korean, or “another ethnicity with similarly increased frequency of HLA-B*5801” should be tested for HLA-B*5801 prior to initiation of allopurinol therapy, as those patients are at increased risk of a severe cutaneous adverse reaction to allopurinol.

Further Reading/References:
1. FACT @ ClinicalTrials.gov
2. UpToDate “Pharmacologic urate-lowering therapy and treatment of tophi in patients with gout”
3. NICE: “Febuxostat for the management of hyperuricemia in people with gout”
4. “Cardiovascular Safety of Febuxostat or Allopurinol in Patients with Gout.” N Engl J Med. 2018 Mar 29;378(13):1200-1210.

Summary by Duncan F. Moore, MD

Image Credit: James Gilray, US Public Domain, via Wikimedia Commons