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 [12
] 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 [42
The prior RCTs comparing febuxostat and allopurinol [34
] 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 [13
] 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 [8
] likely by depletion of excessive miscible and non-miscible (crystalline) extracellular urate pools characteristic of gout patients [46
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 ). 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 [34
]. 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 [13
], 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 [34
]. In the entire febuxostat development program [13
], 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 [34
] 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 [34
]. 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 [24
], 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.