PharmacotherapyOriginal researchEffect of Prophylaxis on Gout Flares After the Initiation of Urate-Lowering Therapy: Analysis of Data From Three Phase III Trials
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
References (38)
- et al.
Selectivity of febuxostat, a novel non-purine inhibitor of xanthine oxidase/xanthine dehydrogenase
Life Sci
(2005) - et al.
Asymptomatic hyperuricemiaRisks and consequences in the Normative Aging Study
Am J Med
(1987) - et al.
Monosodium urate microcrystals induce cyclooxygenase-2 in human monocytes
Blood
(1998) Effective management of gout: An analogy
Am J Med
(1998)- et al.
EULAR evidence based recommendations for goutPart II: Management. Report of a task force of the EULAR Standing Committee for International Clinical Studies Including Therapeutics (ESCISIT)
Ann Rheum Dis
(2006) - et al.
A retrospective study of the relationship between serum urate level and recurrent attacks of gouty arthritis: Evidence for reduction of recurrent gouty arthritis with antihyperuricemic therapy
Arthritis Rheum
(2004) - et al.
Determinants of the clinical outcomes of gout during the first year of urate-lowering therapy
Nucleosides Nucleotides Nucleic Acids
(2008) The effect of allopurinol (HPP) in the treatment of gout
Arthritis Rheum
(1965)- et al.
Evaluation of uricosuric agents in chronic gout
Ann Rheum Dis
(1957) - et al.
Allopurinol in the treatment of uraemic patients with gout
Ann Rheum Dis
(1967)
Results of a clinical trial of G-28315, a sulfoxide analog of phenylbutazone, as a uricosuric agent in gouty subjects
Arthritis Rheum
Effect of allopurinol (4-hydroxypyrazolo-(3,4-D)pyrimidine) on serum and urinary uric acid in primary and secondary gout
Am J Med
Febuxostat compared with allopurinol in patients with hyperuricemia and gout
N Engl J Med
Effects of febuxostat versus allopurinol and placebo in reducing serum urate in subjects with hyperuricemia and gout: A 28-week, phase III, randomized, double-blind, parallel-group trial
Arthritis Rheum
The urate-lowering efficacy and safety of febuxostat in the treatment of the hyperuricemia of gout: The CONFIRMS trial
Arthritis Res Ther
Management of acute and chronic gouty arthritis: Present state-of-the-art
Drugs
Colchicine for prophylaxis of acute flares when initiating allopurinol for chronic gouty arthritis
J Rheumatol
Prophylactic colchicine therapy of intercritical goutA placebo-controlled study of probenecid-treated patients
Arthritis Rheum
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2020, Seminars in Arthritis and RheumatismCitation Excerpt :Patients should be provided with a prophylactic anti-inflammatory medication along with the initiation of ULT when feasible. Although other anti-inflammatories used to treat acute flare may be suitable, low doses of colchicine (0.6 mg once or twice daily) are commonly used, as they are most likely to be tolerated for the 3–9 months of the initial ULT required to reduce the risk of gout flares below pre-treatment levels [58]. Even more important than when treating acute flares, chronically-dosed colchicine should be adjusted for renal function and for co-administration of drugs that are metabolized by the same pathways (hepatic CYP3A4 and P-gp in the gut).