Comparative Effectiveness of Allopurinol and Febuxostat in Gout Management

O'Dell, James Robert; Brophy, Mary; Pillinger, Michael H.; Neogi, Tuhina; Palevsky, Paul M.; Wu, Hongwei; Davis-Karim, Anne; Newcomb, Jeff; Ferguson, Ryan; Pittman, David J.; Cannon, Grant W.; Taylor, Thomas H.; Terkeltaub, Robert; Cannella, Amy C.; England, Bryant R.; Helget, Lindsay N.; Mikuls, Ted R.

doi:10.1056/evidoa2100028

Cited by 39 publications

(52 citation statements)

References 33 publications

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“…This advantage is valid at the time of randomization (the index date) and can be sustained when all events are counted after randomization during the entire trial period, without biased follow-up (for example, from participants dropping out or switching treatment). However, all gout trials to date, including the pivotal trials in Table 1 , started counting flare events (as a primary end point in one trial 27 and a secondary end point in the other trials 24 – 26 , 33 ) at a specific time that was substantially after the time of randomization (that is, a post-randomization landmark time), and they also had notable dropout rates (Table 1 ). Such post-randomization analysis (also called landmark analysis) 34 resets the trial ‘clock’, by moving the index date from the time of randomization to the landmark time.…”

Section: Landmark Analysis Can Bias Resultsmentioning

confidence: 99%

“…Some of these trials have reported an increased risk of flares with the investigational product in the early stages of the trial 24 – 26 , but the approach of reporting the flare experience over the entire period of the trial has not been adopted (Table 2 ). The comparative efficacy trial of febuxostat and allopurinol published in early 2022 is the first ULT trial to report gout flares as the primary end point 27 . However, this primary end point (the proportion of participants experiencing one or more flares) only covered the third phase of the study (weeks 49 to 72), after urate-lowering had been established, but not for the entirety of the trial or for the first phase (weeks 0 to 24) or second phase (weeks 25 to 48) individually.…”

Section: How Are Flares Assessed In Trials?mentioning

confidence: 99%

“…However, this primary end point (the proportion of participants experiencing one or more flares) only covered the third phase of the study (weeks 49 to 72), after urate-lowering had been established, but not for the entirety of the trial or for the first phase (weeks 0 to 24) or second phase (weeks 25 to 48) individually. Nevertheless, flare rate (as opposed to risk proportion), one of the trial’s pre-specified secondary end points, was reported over the entire period as well as for each of the three phases 27 .…”

Section: How Are Flares Assessed In Trials?mentioning

confidence: 99%

“…These analytic approaches 27 are in contrast to those used in trials of other interventions with time-dependent (non-proportional) effects (Table 3 ). For example, similar time-dependent trade-offs arise with the use of initially intrusive interventions, such as transplantation, surgeries or other invasive procedures, which can have immediate adverse effects — even mortality, initially — but subsequently lead to benefits among those who survive.…”

Section: How Are Flares Assessed In Trials?mentioning

confidence: 99%

“…These difficulties can be mitigated by the use of highly effective anti-inflammatory flare prophylaxis and gradual dose escalation of ULT 17 . The duration of prophylaxis has varied substantially in gout trials to date, ranging from nearly zero prophylaxis 25 to prophylaxis for up to 11 months 27 (Table 1 ). We recommend prophylaxis for a duration of 3–6 months as a minimum, as recommended in the ACR guideline for the management of gout 19 .…”

Section: Solutions and Associated Issuesmentioning

confidence: 99%

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When underlying biology threatens the randomization principle — initial gout flares of urate-lowering therapy

2022

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Flare is the dominant feature of gout and occurs because of inflammatory response to monosodium urate crystals; prevention of gout flares should be the major goal of gout care. However, a paradoxical increase in the risk of flare following initiation of urate-lowering therapy presents considerable challenges for proving the expected long-term benefits of flare prevention in clinical trials. Nevertheless, excluding from enumeration flares that occur in the initial post-randomization period (which can last several months to 1 year) can threaten the core benefits of randomization: the characteristics of the remaining participants can differ from those who were randomized, introducing potential bias from confounding (both measured and unmeasured); participants who drop out or die are excluded from the analysis, introducing potential selection bias; and, finally, ignoring initial flares underestimates participants’ experience during the trial. This Perspective discusses these issues and recommends measures that will allow for high-level evidence that preserves the randomization principle, to satisfy methodological scrutiny and generate robust evidence-based guidelines for gout care.

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Section: Landmark Analysis Can Bias Resultsmentioning

confidence: 99%

Section: How Are Flares Assessed In Trials?mentioning

confidence: 99%

Section: How Are Flares Assessed In Trials?mentioning

confidence: 99%

Section: How Are Flares Assessed In Trials?mentioning

confidence: 99%

Section: Solutions and Associated Issuesmentioning

confidence: 99%

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When underlying biology threatens the randomization principle — initial gout flares of urate-lowering therapy

2022

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Serum Urate and Its Association With Gout Flares

Gaffo

2024

JAMA

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Gout is a chronic illness that has been underappreciated and poorly understood. Despite being more prevalent than rheumatoid arthritis and lupus, 1,2 gout has traditionally lagged behind these other diseases in research and quality of care. In addition, poor clinical management of gout is associated with increased cardiovascular morbidity and mortality, chronic kidney disease, and metabolic syndrome. These associations have been described as forming part of a comorbidity cluster in need of treatment optimization. 3 The intensely painful attacks of inflammatory arthritis known as gout flares are the main clinical manifestation of the disease, and their decrease in frequency and intensity is what matters most to patients. 4 Elevated serum urate levels above the saturation point (6.8 mg/dL at 37 °C, the definition of hyperuricemia) and the deposition of monosodium urate crystals in joints and periarticular tissues lead to activation of the innate immune system and the acute arthritis characteristic of gout. 5 Since the role of the uric acid molecule was recognized in the pathogenesis of gout, an association between circulating serum urate levels and clinical manifestations of gout was assumed. However, the evidence to support this assumption has been scarce. This issue became more controversial when the clinical guidelines for gout management were updated and were contradictory to the major rheumatology recommendations, which were still based on treating to a serum urate target using urate-lowering therapies. [6][7][8] Since then, concerns about the value of serum urate as a biomarker for gout severity and treatment response have increased, despite serum urate being used for decades for this purpose in the rheumatology practice community. Consequently, the need to generate evidence about the best strategy for secondary prevention of gout clinical manifestations is a priority.In this issue of JAMA, McCormick et al used data from the UK Biobank to study the association between a baseline level of serum urate and the subsequent risk of flares among 3613 patients with gout followed up for a mean of 8.3 years. 9 The primary analysis used a reference serum urate category of less than 6 mg/dL (the treat-to-target threshold recommended by most treatment guidelines) and studied the rate ratios of gout flares associated with 1.0-mg/dL increase categories over the reference value up to 10 mg/dL or higher. The results showed that all the categories above 6 mg/dL were associated with significantly increased rate ratios of gout flares, starting with 3.37 for the 6.0 to 6.9 mg/dL category up to 11.42 for the 10 mg/dL or higher category. These increased rate ratio associations did not vary meaningfully

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Superiority of Low‐Dose Benzbromarone Add‐On to Low‐Dose Febuxostat Compared With Febuxostat Monotherapy in Gout With Combined‐Type Hyperuricemia

Xue,

Sun,

Yan

et al. 2024

Arthritis Care & Research

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ObjectiveThere is unmet need for simpler ULT regimens that achieve serum urate target and improve overall quality of gout care. We report a comparative effectiveness trial of febuxostat monotherapy vs. benzbromarone add‐on to low dose febuxostat in gout specifically with combined renal urate underexcretion and overload.MethodsA prospective, randomized trial was conducted on subjects with a combined type of hyperuricemia and eGFR above 60 ml/min/1.73 m2, 1:1 randomly assigned to febuxostat and benzbromarone combination therapy (initially febuxostat 20mg/day, with benzbromarone 25mg/day added onto 20 mg/day febuxostat if not at target) or febuxostat monotherapy (initially 20mg daily, escalating to 40mg daily if not at target). Primary end point at 12 weeks was proportion achieving serum urate (SU) level < 360μmol/L. Other outcomes included altered liver and kidney function, new‐onset urolithiasis, and gout flares.ResultsThere were 250 participants randomized; with 219 completing 12‐week treatment. More febuxostat and benzbromarone combination group subjects achieved SU target compared to febuxostat monotherapy group subjects (75.5% vs. 47.7%; OR 3.37 [95% CI 1.90, 5.98]). Safety profiles were comparable between the two groups.ConclusionSimply adding on low‐dose benzbromarone (25 mg/day) to low‐dose (20 mg/day) febuxostat showed superior urate lowering to febuxostat monotherapy in gout with a combined‐type hyperuricemia. For selected patients, expedited achievement of serum urate target in over 75% of subjects, using one titration step and low XOI and uricosuric doses, is a potential alternative to standard ULT regimens.This article is protected by copyright. All rights reserved.

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Comparative Effectiveness of Allopurinol and Febuxostat in Gout Management

Cited by 39 publications

References 33 publications

When underlying biology threatens the randomization principle — initial gout flares of urate-lowering therapy

When underlying biology threatens the randomization principle — initial gout flares of urate-lowering therapy

Serum Urate and Its Association With Gout Flares

Superiority of Low‐Dose Benzbromarone Add‐On to Low‐Dose Febuxostat Compared With Febuxostat Monotherapy in Gout With Combined‐Type Hyperuricemia

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