Gout is an increasingly common disorder 12345 characterized by hyperuricemia (serum urate concentration (sUA) exceeding 6.8 mg/dL, the limit of urate solubility) and by acute and chronic consequences of urate crystal deposition: episodic gout flares, deforming gouty arthropathy, tophi, and urolithiasis 6. Long-term management of recurrent or progressive gout focuses on urate-lowering therapy (ULT) aimed at maintaining sUA in a sub-saturating range, often chosen as <6.0 mg/dL 789101112. Achievement of this goal results in eventual cessation (and even reversal) of urate crystal deposition and clinical signs and symptoms 8910111314. Pharmacological approaches to ULT have, for over 40 years, involved either enhancement of renal uric acid excretion with a uricosuric, such as probenecid, or inhibition of urate production with the purine base analogue allopurinol, a xanthine oxidase (XO) inhibitor. In the United States, over 90% of ULT prescriptions are for allopurinol, approved at doses up to 800 mg daily but rarely (<5% of patients) prescribed at doses exceeding 300 mg daily 1516.

Several recent publications 7891011161718 have documented poor urate-lowering (UL) efficacy and/or clinical outcomes in gout patients, including progression to gout-related disability and impaired quality of life 7192021. Gout patients also have high incidences of major comorbidities that may be associated with hyperuricemia or gout or both 22. Thus, gout patients not only suffer potentially disabling and deforming arthritic disease, but are also at high risk for cardiovascular (CV) 23242526272829 and metabolic disorders 2930.

Febuxostat, a non-purine analogue XO inhibitor 31, has recently received regulatory approval in the United States for treatment of hyperuricemia in gout patients 32. Three published randomized controlled trials (RCTs) in subjects with gout and baseline sUA ≥ 8.0 mg/dL 333435 have established superior UL efficacy (proportion of subjects achieving sUA <6.0 mg/dL) for febuxostat (in daily doses from 80 to 240 mg) compared with placebo 3335 or with allopurinol 300 mg daily 3435. Overall rates of adverse events (AEs) were similar across treatment groups in these studies 333435, but CV disorders, although uncommon, occurred numerically more often in febuxostat- than allopurinol-treated. Subjects who experienced these events had a prior history of CV disease (CVD) and/or underlying CV risk factors. This imbalance was not statistically significant or explained by known actions of febuxostat but warranted further study.

Here we report results of the CONFIRMS trial, a Phase 3, double-blind RCT further examining the comparative UL efficacy and safety of febuxostat and allopurinol in a greater number of gout subjects than the total participating in prior comparative trials 3435. The three-fold objectives of this study were: 1) to compare the UL efficacy of febuxostat at a dose of 40 mg with that of allopurinol at doses most commonly utilized in clinical practice; 2) to evaluate UL efficacies of 80 mg and 40 mg daily doses of febuxostat compared with that of allopurinol in subjects with mild or moderate renal impairment; and 3) to gain prospective, uniformly reviewed information regarding the safety of these agents, particularly their comparative CV safety.

In a previous RCT in subjects with gout 33, the UL efficacy of febuxostat at a daily dose of 40 mg was superior to that of placebo. Here, the UL efficacy of febuxostat 40 mg was confirmed as comparable to that of allopurinol 300 mg. At all levels of renal function studied, daily dosing of febuxostat 80 mg was superior in UL efficacy to that of febuxostat 40 mg or allopurinol. However, in subjects with impaired renal function, febuxostat 40 mg was also superior to allopurinol 300 mg daily (mild renal impairment) or 200 mg daily (moderate renal impairment), suggesting that treatment with either dose of febuxostat is more likely to achieve sUA <6.0 mg/dL than is allopurinol treatment at the reduced doses widely recommended for such individuals 41. Indicators of higher body urate pools (baseline presence of tophi or sUA ≥ 10.0 mg/dL) were also identified as factors reducing rates of responsiveness to ULT.

If goal range urate levels are not achieved and maintained with febuxostat 40 mg daily or allopurinol, the current data suggest that dose titration to febuxostat 80 mg would be a rational alternative to increasing allopurinol doses beyond 300 mg. In fact, RCT evidence to support the safety and efficacy of allopurinol administered at doses exceeding 300 mg daily is limited to a recent four-month trial in which 13 of 17 subjects (eCLcr ≥ 50 ml/minute) failing to achieve sUA <5.0 mg/dL while receiving allopurinol 300 mg daily safely reached this efficacy endpoint when treated with 600 mg daily 42.

Failure to achieve sUA <6.0 mg/dL among individuals with or without renal impairment receiving guideline-recommended doses of allopurinol has been documented 43. The common practice of prescribing allopurinol at a fixed daily dose of 300 mg for gout patients with mildly impaired or normal renal function and less for those with moderate renal impairment 121844 may further decrease the likelihood of achieving sUA <6.0 mg/dL. In this study, there was no titration of allopurinol doses; subjects were assigned the standard daily dose of 300 mg unless they had moderate renal impairment. For this reason and due to the paucity of controlled data cited above 42, we are reluctant to speculate as to whether allopurinol dose escalation would have safely increased the proportion of subjects who achieved target sUA 4245.

The prior RCTs comparing febuxostat and allopurinol 3435 did not establish significant differences between these agents in the clinical outcomes of flare rate and tophus size reductions in the first 6 to 12 months of treatment. As such, clinical outcomes were not endpoints in the current trial. Nevertheless, subjects who had successfully completed prior the long-term open-label UL studies 1314 and then enrolled in CONFIRMS had reduced rates of baseline tophi and, during the additional six months of ULT, showed higher rates of UL efficacy and reduced rates of gout flares compared with those who did not have prior trial participation. These data support the concept that persistent UL to sub-saturating sUA eventually results in relief of clinical symptoms of both acute (flares) and chronic (tophi) gout 81012 likely by depletion of excessive miscible and non-miscible (crystalline) extracellular urate pools characteristic of gout patients 4647.

In all treatment groups, rates of gout flares requiring treatment diminished slowly after Month 2 and did not affect more than 15% of subjects per month after Week 8 of the study (Figure 2). This result contrasts with sharp increases in flare rates (30% to 40% of subjects per month) encountered after cessation of flare prophylaxis at Month 2 in prior comparative RCTs 3435. These results seem likely due to differences in the duration of prophylaxis and are in accord with the results of an RCT that established the efficacy of colchicine flare prophylaxis during the first six months after initiation of allopurinol therapy 48. We thus recommend gout flare prophylaxis co-therapy for at least the first six months of ULT.

As in prior febuxostat clinical trials 1314333435, no severe rashes or hypersensitivity reactions were observed during febuxostat treatment in the current trial. In these trials, serum transaminase elevations (≥three times upper limit of normal) were numerically more frequent with febuxostat than with allopurinol, but neither concurrent serum bilirubin levels exceeding 2 mg/dL nor clinically-manifested liver-related symptoms were encountered 3435. In the entire febuxostat development program 1314333435, neither febuxostat nor allopurinol treatment was associated with combined serum transaminase and bilirubin increases, except when explained by cholecystitis or by bile duct obstruction due to stones or malignancy. Nevertheless, administration of allopurinol or febuxostat to a gout population with significant rates of obesity, metabolic syndrome, and alcohol use 3435 is accompanied by liver function test abnormalities more frequently than is placebo administration 35. Consequently, we recommend periodic liver function testing during treatment with either febuxostat or allopurinol.

A lack of significant differences in overall rates of AEs or of the most frequently occurring treatment emergent AEs across febuxostat and allopurinol treatment groups in CONFIRMS recapitulate safety results previously reported 3435. In addition, in this study encompassing a greater number of subjects than all prior febuxostat/allopurinol RCTs combined, no significant differences between treatment groups were observed in the rates of reported CV AEs, adjudicated APTC, or non-APTC events. Gout and hyperuricemia are strongly associated with CVD and CVD-related death 24252627282949, and all subjects who experienced adjudicated CV events had prior medical histories or risk factors for CVD. Thus, despite the fact that the small number of severe CV AEs encountered in febuxostat/allopurinol comparative RCTs did not identify a differential CV risk of these agents, we recommend continued attention to monitoring and management of CV health, particularly among gout patients at high risk for CV events.

Results of the CONFIRMS trial establish equivalent UL efficacy for febuxostat 40 mg daily and allopurinol 300/200 mg daily. At all levels of renal function studied, UL efficacy of febuxostat 80 mg daily was superior to that of febuxostat 40 mg or allopurinol 300/200 mg, and was comparably safe. In subjects with mildly or moderately impaired renal function, however, febuxostat 40 mg daily was significantly more effective in lowering sUA than allopurinol. At the doses studied, safety of febuxostat and allopurinol, including CV safety, was comparable. Febuxostat, at 40 mg or 80 mg daily, offers a well-tolerated UL alternative to allopurinol, particularly for patients with mild or moderate renal impairment.

AE: adverse event; APTC: Antiplatelet Trialists Collaboration; BMI: body mass index; CI: confidence interval; CV: cardiovascular; CVD: cardiovascular disease; eCLcr: estimated creatinine clearance; mITT: modified intent-to-treat; RCT: randomized controlled trial; sUA: serum urate; UL: urate lowering; ULT: urate-lowering therapy; XO: xanthine oxidase.

MAB has served as a consultant for Takeda Global Research & Development Center, Inc. and Savient Pharmaceuticals (>$10,000) and for Biocryst Pharmaceuticals, Regeneron Pharmaceuticals, Proctor & Gamble, Inc., and URL Pharma (<$10,000). LRE has received consulting fees from Takeda Global Research & Development Center, Inc. (<$10,000). HRS has received consulting fees (<$10,000) from Takeda Global Research & Development Center, Inc., Savient Pharmaceuticals, Regeneron Pharmaceuticals, Pfizer, Inc., Xoma, Centocor, Inc., and has received research grants from Takeda Global Research & Development Center, Inc., CherryPharm, and Wyeth Pharmaceuticals (now a part of Pfizer, Inc.). AFW has served as a consultant for Takeda Global Research & Development Center, Inc.(>$10,000), Abbott Laboratories, Amgen, Inc., Bristol-Myers Squibb Company, Centocor, Inc., Eli Lilly and Company, GlaxoSmithKline, Pfizer, Inc., Wyeth Pharmaceuticals, and Genetech, Inc. (all <$10,000). PM and EL are currently employees of Takeda Global Research & Development Center, Inc., Deerfield, IL, USA. They were employees of TAP Pharmaceutical Products Inc. at the time of the study conduct and analysis. CL was an employee of TAP Pharmaceutical Products Inc. at the time of the study conduct and analysis.

MAB and PM made substantial contributions to the conception and design of the study; acquisition, analysis and interpretation of the data; drafting and revising of the manuscript; and gave final approval for publication. HRS participated in the analysis and interpretation of the data; drafting and revising of the manuscript; and gave final approval for publication. LRE and AFW were involved in drafting and revising the manuscript; and gave final approval for publication. EL and CL contributed to the conception and design of the study; analysis and interpretation of the data; drafting and revising of the manuscript; and gave final approval for publication.