Elsevier

Clinical Therapeutics

Volume 32, Issue 14, December 2010, Pages 2386-2397
Clinical Therapeutics

Pharmacotherapy
Original research
Effect of Prophylaxis on Gout Flares After the Initiation of Urate-Lowering Therapy: Analysis of Data From Three Phase III Trials

https://doi.org/10.1016/j.clinthera.2011.01.008Get rights and content

Abstract

Background

Use of urate-lowering therapy (ULT), such as febuxostat or allopurinol, is recommended for the long-term management of hyperuricemia in patients with gout to reduce the incidence of acute flares. Because of the paradoxical relationship between early use of ULT and the increased incidence of gout flares, prophylaxis with either low-dose colchicine or NSAIDs has been recommended, although there have been concerns about the long-term prophylactic use of these agents.

Objectives

The present analysis examined flare rates during the 3 Phase III trials of febuxostat based on mean postbaseline serum urate (sUA) concentrations and duration of prophylaxis. Adverse events (AEs) were assessed by prophylaxis with colchicine or naproxen.

Methods

This investigator-initiated, post hoc reanalysis of data on gout flares from the 3 randomized, placebo-controlled, Phase III trials evaluated the proportion of patients requiring treatment for gout flares at 4-week intervals based on mean postbaseline sUA concentrations <6.0 and ≥6.0 mg/dL. The 3 trials enrolled males or females aged 18–85 years who had a diagnosis of gout and a baseline sUA concentration ≥8.0 mg/dL. Patients received ULT (febuxostat or allopurinol) or placebo for 6 months or 1 year and flare prophylaxis with colchicine 0.6 mg/d or naproxen 250 mg BID for 8 weeks or 6 months. The prophylactic regimen was chosen at the discretion of the investigator, based on renal function and known intolerance to either drug. Patients with an estimated creatinine clearance <50 mL/min were not to receive naproxen. AEs were summarized based on prophylaxis with colchicine or naproxen.

Results

The 3 trials enrolled a total of 4101 patients with gout. The majority were white (80.1%), male (94.5%), and obese (body mass index ≥30 kg/m2) (62.8%). The mean duration of gout ranged from 10.9–11.9 years, and the mean baseline sUA concentration ranged from 9.6–9.9 mg/dL. Flare rates increased sharply (up to 40%) at the end of 8 weeks of prophylaxis and then declined gradually, whereas flare rates were consistently low (range, 3%–5%) at the end of 6 months of prophylaxis. Mean postbaseline sUA concentrations were correlated with flare rates; by the end of each study, patients with a mean postbaseline sUA concentration <6.0 mg/dL had fewer flares than did those with a mean postbaseline sUA concentration ≥6.0 mg/dL. There were differences in rates of AEs between prophylaxis groups, but the rates did not increase with increased duration of prophylaxis.

Conclusion

This analysis of gout flare data from the 3 Phase III trials of febuxostat found that flare prophylaxis for up to 6 months during the initiation of ULT appeared to provide greater benefit than flare prophylaxis for 8 weeks, with no increase in AEs.

Introduction

Urate-lowering therapy (ULT) is indicated for individuals with hyperuricemia (serum urate [sUA] concentration >6.8 mg/dL) and gout who have had multiple acute flares and/or developed such complications as tophaceous deposits.1 Acute gout flares are known to occur as a consequence of the initiation of ULT and effective reduction of sUA concentrations.2 In fact, the greater the reduction in sUA, the more likely a flare.3 This paradox of gout treatment was noted during the clinical development of uricosuric agents and allopurinol, generally in uncontrolled trials involving small numbers of patients,4, 5, 6, 7, 8 and was confirmed in the febuxostat clinical trial program.9, 10, 11

To help prevent flares, it is recommended that initiation of ULT be accompanied by low-dose colchicine or NSAIDs.1, 12 Before the febuxostat clinical trial program, the limited amount of data on flare prophylaxis from clinical trials left concerns about chronic use of these agents. Only 2 randomized controlled trials that examined the benefits and tolerability of colchicine prophylaxis during 6 months of ULT with allopurinol13 and probenecid14 reported significant reductions in the frequency and severity of acute attacks in patients receiving colchicine compared with those receiving ULT only. In the allopurinol/colchicine study, in which colchicine 0.6 mg was administered BID, overall rates of acute gout flares were 33% in the allopurinol/colchicine group and 77% in the allopurinol/placebo group (P = 0.008).13 The only significant difference in adverse events (AEs) was an increase in diarrhea among patients receiving colchicine compared with those receiving allopurinol alone. In the other study, in which probenecid was administered with colchicine 0.5 mg TID, the annual rate of acute gout flares was 2.3 in the probenecid/colchicine group and 6.0 in the probenecid/placebo group (P < 0.05).14 Patients receiving colchicine had higher rates of gastrointestinal AEs than did those who received probenecid alone.14

Febuxostat is a selective xanthine oxidase inhibitor15 that is approved for the treatment of hyperuricemia in patients with gout in the United States, Canada, South Korea, and Europe.16 Three double-blind clinical trials compared the use of febuxostat and allopurinol for up to 1 year in a total of >4000 patients and provided evidence regarding the relationship between gout flares, use of ULT, and use of flare prophylaxis.9, 10, 11 Although these trials were not designed to assess different prophylactic regimens in a blinded, controlled manner, they were the largest trials of ULT to examine the impact of both colchicine and the NSAID naproxen on flare rates over different durations of prophylaxis. In addition, 2 open-label extension trials examined the benefits of long-term ULT (up to 5 years) on flare rates and found that use of ULT for >1 year was associated with near-elimination of gout flares.17, 18

The present analysis examined flare rates in the 3 Phase III trials of febuxostat, based on mean postbaseline sUA concentrations and the duration of prophylaxis. AEs were assessed by prophylaxis with colchicine or naproxen.

Section snippets

Patients and Methods

This was an investigator-initiated, post hoc reanalysis of data on gout flares from the 3 Phase III randomized controlled trials of febuxostat—FACT (Febuxostat Versus Allopurinol Control Trial in Subjects With Gout) (NCT00102440),9 APEX (Allopurinol- and Placebo-Controlled, Efficacy Study of Febuxostat) (NCT00174915),10 and CONFIRMS (A Phase 3, Randomized, Multicenter, Double-Blind, Allopurinol-Controlled Study Assessing the Efficacy and Safety of Oral Febuxostat in Subjects With Gout) (NCT00430248

Demographic and Baseline Characteristics

Across the Phase III studies, the majority of patients were white (80.1%), male (94.5%), and obese (body mass index ≥30 kg/m2) (62.8%) (Table II). The mean duration of gout ranged from 10.9–11.9 years, and the mean baseline sUA concentration ranged from 9.6–9.9 mg/dL. Of the 760 patients in FACT, 416 (54.7%) received gout flare prophylaxis with colchicine and 339 (44.6%) received prophylaxis with naproxen. Of the 1072 patients in APEX, 577 (53.8%) received prophylaxis with colchicine and 490

Discussion

Hyperuricemia (sUA >6.8 mg/dL), the underlying pathophysiology in gout, leads to the supersaturation of body fluids with urate. Under permissive conditions, such as decreased temperature or lack of protein binding, urate crystal formation and deposition may occur.23 However, the majority of hyperuricemic individuals never experience a gout flare.24, 25, 26 The reasons for this are not clear. Several additional clinical risk factors for the development of gout have been identified, including

Conclusions

The results of this post hoc analysis suggest that prophylaxis with low-dose colchicine or naproxen reduced the risk of gout flares after the initiation of ULT. Based on the difference in flare rates in CONFIRMS compared with FACT and APEX, 6 months of prophylaxis may impart a greater benefit than 2 months, with no associated increase in AEs.

Acknowledgments

FACT, APEX, and CONFIRMS were funded by TAP Pharmaceutical Products, Inc, now a part of Takeda Global Research and Development Center, Inc. This was an investigator-initiated reanalysis. Dr. Wortmann has served as a speaker and consultant for Takeda Global Research and Development Center. He was provided with all data for the reanalysis and was not paid for being an author. His authorship is in full compliance with Dartmouth Medical School academic guidelines for authorship, and all authors met

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