A new standard of care? Studies on febuxostat in the management of hyperuricemia with and without gout.

Gout is one of the most common rheumatic diseases worldwide. Its rising prevalence, pronounced economic burden for society, and significant toll on patients’ lives make it of central concern for physicians and patients alike. The clinical symptoms of gout are because of the formation of monosodium urate crystals in soft tissues and joints. This occurs when serum uric acid (sUA) levels rise above 7.0 mg/dL, the limit of solubility for monosodium urate in plasma, which also defines the metabolic disorder hyperuricemia. Known to be one of the main risk factors for gout, hyperuricemia has also been postulated to be a causative factor in cardiovascular disease. Although not all patients with hyperuricemia develop gout, higher sUA levels have been correlated with increased risk, emphasizing the importance of sUA-lowering therapies. Indeed, goals of long-term therapy in patients with gout strive to lower the sUA levels enough so that any monosodium urate crystals that are present dissolve, and new ones are prevented from forming. A level of less than 6.0 mg/dL was promulgated by the European League Against Rheumatism several years ago as fully recommended, with other evidence-based reviews in accord as to the clinical benefits that accrue using such a cutoff. Rheumatologists and primary care physicians can benefit from up-to-date information on treatment options for this chronic disease. Current long-term drugs for gout include uricosurics, such as probenecid, sulfinpyrazone, and benzbromarone, and the more widely used xanthine oxidase inhibitors, including allopurinol and febuxostat. Applying the latest clinical evidence to choosing the most appropriate sUA-lowering therapies can go a long way toward diminishing the significant morbidity this disease brings. Given that sUA treatment is long term, a thorough understanding of the characteristics of available sUA-lowering therapies can enhance patient compliance, reduce adverse effects, and provide optimal management of sUA levels. By presenting a series of phases 2 and 3 clinical studies examining the safety and efficacy of febuxostat in comparison with placebo and/or allopurinol, as well as a pharmacologic study on febuxostat, this supplement aims to provide critical evidence to aid clinicians in evaluating the appropriate use of this drug in clinical practice. Febuxostat is a nonpurine xanthine oxidase inhibitor approved by the US Food and Drug Administration in 2009 for use in gout at once-daily dosages of 40 or 80 mg. The European Medicines Agency granted approval at the 80and 120-mg daily doses in May 2008. Febuxostat was approved in Japan in January 2011; the usual maintenance dose is 40 mg once daily, and the maximum dose is 60 mg once daily. The introduction of febuxostat to the sUA-lowering armamentarium is thus significant, given that it is the first approved xanthine oxidase inhibitor since allopurinol was approved for use in 1965. Although the effects of allopurinol and febuxostat are similar in that they prevent the final step in purine metabolism (conversion of xanthine to uric acid), thus lowering the sUA levels, their difference in chemical structure results in a number of important pharmacologic and clinical distinctions. Unlike allopurinol, febuxostat has a nonpurine structure and therefore does not inhibit other enzymes in the purine and pyrimidine pathways. It is metabolized by the liver and has been found to be appropriate for use without dose adjustment in patients with mild-to-moderate renal impairment (creatinine clearance, 30Y80 mL/min), in contrast to that used with allopurinol. Indeed, no changes in the urinary excretion rate of febuxostat were found in patients with renal impairment (Hosoya and Ohno, in this supplement). Dose adjustment for febuxostat is also not required in elderly patients. Of note is the allopurinol hypersensitivity syndrome that, although rare at an incidence of 0.4%, carries mortality rates of up to 25%. It is characterized by rash, fever, eosinophilia, and multiple organ failure. An international position paper on febuxostat recommended febuxostat for use in patients with gout who have failed or are intolerant of allopurinol, or for whom contraindications to available uricosuric sUA therapies exist. However, the limitations of allopurinol at its clinically practiced dosage of 300 mgVsuch as required dose adjustments for patients with renal impairment and often ineffective sUA-lowering efficacyVmay require a reevaluation of its role as first-line therapy for patients with gout. For example, a large retrospective claims analysis not only found a low patient compliance with allopurinol but that very few patients received doses greater than 300 mg/d. This is of clinical importance as patients with sUA levels greater than 6.0 mg/dL have been shown to be 59% more likely to have gout flares than those achieving sUA levels less than 6.0 mg/dL. Moreover, roughly half of patients on a 300-mg/d dose do not meet the target sUA of less than 6.0 mg/dL. Dose titration of allopurinol, combinedwith regular assessment of sUA levels, may achieve this goal, however. A number of clinical trials have been published in the past few years that provide a comparison of the safety and efficacy of allopurinol with febuxostat. Three phase 3 studiesVFACT, APEX, and CONFIRMSVhad the largest numbers of patients. FACT was a yearlong study that compared febuxostat 80 and 120 mg/d with allopurinol 300 mg/d in 762 patients with a history of gout. More patients in the febuxostat groups (53% in the 80-mg group, 62% in the 120-mg group; P G 0.001 both vs allopurinol) achieved the primary endpoint of sUA of less than SUPPLEMENT