Two experimental urate lowering drugs, febuxostat (an oral xanthine oxidase inhibitor) and pegloticase (a parenteral urate oxidase), have advanced to late-stage clinical development in the US (1, 2). If approved, these drugs will be the first new urate lowering therapies in over 40 years. In this issue of Arthritis Care & Research, Schumacher and colleagues report results from a pivotal trial of febuxostat versus allopurinol and placebo in subjects with gout (3). Rheumatologists have long awaited the arrival of new urate lowering therapies, but as we approach this new era it is important that we learn from the past and establish a sound body of evidence that will ensure high-quality gout management in the future.
Forty years ago, Dr. R. Wayne Rundles, lead author of the landmark allopurinol treatment trial (4), remarked that the introduction of allopurinol was likely to set the field of gout back by 20 years (Silberman H: personal communication). Dr. Rundles was concerned that knowledge gaps regarding allopurinol and the treatment of gout would persist amidst the enthusiasm for a new treatment. As prophetic as his comment was, 20 years turned out to be an underestimate.
It was not until 2005 that the first randomized, controlled, comparative trial of allopurinol in patients with gout was published (5). We now know that the most widely prescribed dosage of allopurinol, 300 mg/day, is not effective in controlling serum urate levels in most patients (5, 6). Recent studies indicate that many patients starting urate lowering therapies never have followup laboratory studies to confirm that serum urate levels have been reduced to appropriate levels (6, 7). Even when urate levels are measured, the allopurinol dose is often not titrated to achieve the accepted target serum urate concentration of <6 mg/dl (6, 7). Our literature places physicians in a double bind, recommending reduced doses of allopurinol in patients with chronic kidney disease while simultaneously demonstrating that dose reduction fails to achieve therapeutic targets for serum urate levels (8, 9). Compliance with urate lowering therapy is notoriously low, perhaps related to gaps in patient education. Finally, it is all too common for rheumatologists to evaluate patients with advanced gout who have never been offered urate lowering therapy.
It is disappointing that gout, a disease affecting up to 5 million Americans (10), with well understood pathophysiology and generally safe and effective therapy remains such a challenge to manage. Potential causes of this situation have been well chronicled by Becker and Chohan (11), and include: 1) difficulty in obtaining an accurate diagnosis; 2) absence of evidence-based disease management guidelines; 3) inadequate patient education on treatment goals; 4) poor adherence to therapy; 5) comorbid illness and drug interactions that limit optimal therapy; and 6) lack of alternative urate lowering therapies. Unfortunately, these problems are made more difficult to solve because of the rising prevalence and incidence of gout (12–14), a shrinking rheumatology workforce, and pressures on the financial viability of rheumatology teaching programs.
We in the medical education and research establishment bear the responsibility for deficiencies in current gout management. The field of gout has been unfettered by any significant industry influence for decades. In fact, the entry of the pharmaceutical industry into the field of gout has helped accelerate efforts to raise disease awareness, characterize the burden of disease, define important clinical outcome measures, and advance new therapies. Amid the recent calls to markedly limit the relationship of the medical profession with industry, one wonders what will replace such industry sponsorship and who will pay for it.
Clearly we need to make up for lost time, and the introduction of new urate lowering therapies presents an important opportunity to accomplish this. In this context, attention turns to febuxostat and the article in this issue by Schumacher et al (3). Febuxostat is an oral, once-daily, selective inhibitor of xanthine oxidase (1). Pharmacologic properties of febuxostat that may have advantages over those of allopurinol include greater selectivity for xanthine oxidase and the ability to inhibit both the oxidized and reduced forms of xanthine oxidase (1, 15). Febuxostat is metabolized in the liver and eliminated predominantly in the stool. Therefore, it is possible that febuxostat may be used in patients with mild to moderate kidney disease without dose reduction, a decided advantage given concerns about allopurinol use in this setting (1).
Febuxostat was recently approved by the European Medicines Evaluation Agency (EMEA) for the treatment of hyperuricemia in gout, in part on the basis of 2 pivotal phase III trials known as the Febuxostat Versus Allopurinol Controlled Trial (FACT) and the Allopurinol- and Placebo-Controlled Efficacy Study of Febuxostat (APEX) trial, the latter of which is reported in this issue (3, 5, 16). Key features of each trial and the corresponding response rates are shown in Table 1. Allopurinol was the active comparator in both trials, and was administered in a fixed dosage of 300 mg daily. Patients with chronic kidney disease (serum creatinine level >1.5 mg/dl and ≤2.5 mg/dl) were eligible for enrollment in the APEX trial, and they received allopurinol, 100 mg/day. The primary endpoint of both studies was a reduction in serum urate below 6 mg/dl at the final 3 monthly measurements.
|Followup period, weeks||52||28|
|Primary outcome response rate, %|
|Febuxostat 80 mg/day||53||48|
|Febuxostat 120 mg/day||62||65|
|Febuxostat 240 mg/day||N/D||69|
|Allopurinol 300 mg/day†||21||22|
In both studies, all dosage levels of febuxostat were more effective than a fixed dosage of allopurinol in achieving the primary endpoint. Febuxostat was also superior to allopurinol in the secondary outcome measures of the proportion of subjects with serum urate <6 mg/dl at each visit and the percent reduction in serum urate level. As would be expected, the response rate to febuxostat and allopurinol was diminished in subjects with higher baseline serum urate levels.
Gout flares during the first 8 weeks of the trial were common in all dosing groups including placebo (20–46%), but were significantly more common in subjects taking the highest dosages of febuxostat. The flare rate correlated with the magnitude of reduction in serum urate and therefore may be viewed as a sign of therapeutic success. Beyond 8 weeks, after gout flare prophylaxis was discontinued, there were no significant differences between groups in flare frequency, owing possibly to the short time frame of the study.
There were no other important differences in adverse event rates between treatment groups, and overall withdrawal rates were similar in the APEX trial. This is in contrast to the FACT trial, in which there were significantly more withdrawals in subjects taking febuxostat compared with allopurinol, mainly due to rash and abnormal liver function studies (5). There were no deaths in the APEX trial. In the FACT trial there were 4 deaths in subjects taking febuxostat versus none in subjects taking allopurinol, although the difference was not statistically significant. The adverse event data from the APEX trial are reassuring, but long-term observational studies will be helpful in identifying any important low-frequency adverse events. In fact, current EMEA labeling of febuxostat states that the drug is not recommended in patients with ischemic heart disease or congestive heart failure (16).
Another important objective of the APEX study was to determine the safety and efficacy of febuxostat in the setting of chronic kidney disease. Unfortunately, only 4% of the subjects enrolled had chronic kidney disease. Among this small number of subjects, febuxostat was superior to allopurinol, 100 mg day. In fact, none of the chronic kidney disease subjects who took allopurinol were responders. These data are encouraging, but more studies are needed to be able to fully assess the safety and efficacy of standard dosages of febuxostat in chronic kidney disease. It is also important to note that subjects with serum creatinine levels ≥2.5 mg/dl were not permitted in this trial, yet this is a patient population with a significant unmet need.
Results from the FACT and APEX trials also provided new information on allopurinol. Among 522 subjects treated with allopurinol for 6–12 months, there were no cases of allopurinol hypersensitivity syndrome or drug-related serious adverse events. This should provide some reassurance to physicians and patients. Perhaps the most striking finding is the consistently small percentage of subjects taking 300 mg of allopurinol daily who had well-controlled serum urate levels (Table 1). Most rheumatologists appreciate the necessity of titrating the allopurinol dosage to attain therapeutic goals. However, studies suggest that the majority of gout patients in the US receive ≤300 mg of allopurinol per day, potentially leaving many patients inadequately treated (6).
Febuxostat will be a welcome addition to urate lowering therapies, but is febuxostat superior to allopurinol? Based on available data, there is no evident safety advantage of febuxostat over allopurinol, and in the FACT trial allopurinol was slightly better tolerated. With respect to reducing serum urate levels, febuxostat is clearly superior to allopurinol when given at a fixed dosage of 300 mg/day. However, it is possible that the response rate to appropriately titrated dosages of allopurinol would be equivalent to or even superior to that of febuxostat. Therefore, based on current data, it is unlikely that febuxostat will be the drug of first choice for patients starting a xanthine oxidase inhibitor. Patients who develop intolerance to allopurinol or have inadequate reduction in serum urate levels with an appropriate dosage of allopurinol would be good candidates for therapy with febuxostat. In patients with chronic kidney disease there is more uncertainty. It would be reasonable to use allopurinol starting with doses adjusted based on creatinine clearance levels. However, it is important to keep in mind that dose reduction may not protect against allopurinol hypersensitivity syndrome, and likely will not control serum urate levels adequately (8, 17). Febuxostat would be a reasonable next step towards controlling serum urate levels in these patients.
More important than speculating on the use of new urate lowering therapies is the task of developing research and educational programs that will definitively improve the management of gout. Educational programs that will change the way practicing physicians prescribe and monitor urate lowering therapies are needed. Medical students and residents should also be targeted by initiatives that will establish appropriate diagnostic and treatment habits. New guidelines on gout management should be helpful in this regard (18, 19). Many of the recommendations in current guidelines are based upon expert opinion rather than evidence derived from well-designed clinical trials. Therefore, as a starting point we need clinical trials that compare the safety and efficacy of urate lowering therapies titrated to optimal doses, determine optimal levels of serum urate reduction, and better define the safety of urate lowering therapies in patients with chronic kidney disease. These and many other questions need to be answered in order for us to get it right this time. We must not let the field of gout be set back another 20 years.