FDA Advisers Back Febuxostat for Gout Despite Possible CV Risk

Troy Brown, RN

January 14, 2019

The US Food and Drug Administration's (FDA's) Arthritis Advisory Committee (AAC) and Drug Safety and Risk Management (DSaRM) Advisory Committee voted by a large margin (19 yes, 2 no, 1 abstention) to still recommend febuxostat (Uloric, Takeda) for some patients with gout-related hyperuricemia after a discussion of a postmarketing study showing possible cardiovascular risk.

Treatment and prevention of gout include use of anti-inflammatories during acute attacks and urate-lowering medications to manage hyperuricemia. Medications used to manage hyperuricemia include xanthine oxidase inhibitors (XOIs), which lower uric acid production (allopurinol and febuxostat); uricosuric therapies (probenecid, sulfinpyrazone, and lesinurad), which increase uric acid excretion; and uricase products (pegloticase). Xanthine oxidase inhibitors, uricosuric therapies, and uricase products are first-line, second-line, and third-line treatments, respectively, for gout.

Allopurinol is currently the only other XOI approved in the United States for gout. Therapies for gout are in general limited, and there is an unmet need for gout treatments.

"I do think there is a need for this drug in a certain patient population that has been intolerant to allopurinol or where the drug has had no efficacy," voting AAC member Alyce M. Oliver, MD, PhD, professor of medicine, Medical College of Georgia at Augusta University, said of her yes vote.

Postmarketing Safety Study: CARES Trial

The FDA approved febuxostat for the treatment of gout on February 13, 2009, after declining to approve it twice for concerns about cardiovascular safety and death. As part of the approval, the FDA required the company to conduct a postmarketing safety study to determine whether febuxostat is linked to a moderately increased risk for serious adverse cardiovascular outcomes compared with allopurinol.

The vote follows consideration of results from the postmarketing study — the Cardiovascular Safety of Febuxostat and Allopurinol in Patients With Gout and Cardiovascular Morbidities (CARES) trial — published online March 12, 2018, in the New England Journal of Medicine and reported by Medscape Medical News.

CARES was a multicenter, double-blind, noninferiority trial that randomly assigned 6190 patients with gout and cardiovascular disease (CVD) to receive febuxostat or allopurinol. Doses were adjusted on the basis of kidney function. The study's primary composite endpoint was the first occurrence of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or unstable angina with urgent revascularization. Secondary endpoints included the individual components of the major cardiovascular event (MACE) composite as well as any-cause mortality.

Patients were followed for a median of 32 months and a maximum of 85 months. More than half (56.6%) of patients discontinued the treatment regimen, and 45% discontinued follow-up.

Time and again during the meeting, the discussion returned to the high number of treatment and follow-up discontinuations, with members disagreeing at times about the importance of, and possible reasons for, these discontinuations.

In the modified intention-to-treat analysis, 335 patients (10.8%) in the febuxostat group and 321 patients (10.4%) in the allopurinol group experienced a primary endpoint event (hazard ratio [HR], 1.03; upper limit of the one-sided 98.5% confidence interval [CI], 1.23; P = .002 for noninferiority).

Those in the febuxostat group had higher all-cause and cardiovascular mortality compared with those in the allopurinol group (HR for death from any cause, 1.22; 95% CI, 1.01 - 1.47; HR for cardiovascular death, 1.34; 95% CI, 1.03 - 1.73).

"In the CARES trial, treatment with febuxostat resulted in overall rates of major cardiovascular events that were similar to those associated with allopurinol treatment among patients with gout who had coexisting cardiovascular disease. However, cardiovascular death and deaths from any cause were more frequent in the febuxostat group than in the allopurinol group," the researchers write in the journal article.

"The study was designed to accrue 624 MACE events and have 90% power to rule out a hazard ratio risk margin for MACE (febuxostat vs. allopurinol) greater than 1.3 at one-sided 2.5% alpha level, assuming a true hazard ratio of 1.0," the FDA stated in a briefing document.

One panel member was unconvinced by the CARES trial and voted no. "I do not believe that the trial met the regulatory standard for noninferiority for the primary MACE endpoint, in spite of the fact that the upper confidence interval was below 1.3," temporary voting member Steven E. Nissen, MD, chair, Department of Cardiovascular Medicine, Cleveland Clinic, and professor, Cleveland Clinic Lerner College of Medicine, Ohio, said.

"The trial conduct was so poor that it so biased the trial toward the null hypothesis that if you do any imputation of the data, it doesn't take very much data to get the upper confidence interval to be 1.3 or greater. I don't think we want to set the regulatory precedent that you can do a trial, lose 45% of the patients, have a whole bunch of people off a study drug, and then come in under 1.3 and say that's good enough," Nissen continued.

Panel members discussed Friday's vote with respect to the current recommendations of the American College of Rheumatology (ACR) and the European League Against Rheumatism (EULAR).

"[R]ecommendations for pharmacologic urate-lowering therapy (ULT)...included recommendation of XOI therapy with either allopurinol or febuxostat as the first-line pharmacologic approach (evidence A). The panel did not preferentially recommend either XOI over the other XOI drug," according to the ACR's 2012 guidelines for the management of gout.

"Allopurinol is recommended as first-line ULT and its dosage should be adjusted according to renal function. If the SUA [serum uric acid] target cannot be achieved with allopurinol, then febuxostat, a uricosuric or combining a xanthine oxidase inhibitor with a uricosuric should be considered. For patients with refractory gout, pegloticase is recommended," the EULAR recommends in its 2016 guidelines on the management of gout.

"The drug is favorable in a very limited population, and that is patients who need uric acid reduction, who can't tolerate — with adverse effects to — allopurinol, and [in] whom those adverse effects would not translate to this particular drug," voting DSaRM advisory committee member Steven B. Meisel, PharmD, system director of medication safety, Fairview Health Services/Healtheast Care System, Minneapolis, Minnesota, said of his yes vote.

Meisel and several other panel members said patients need to be fully informed about the potential for adverse events and suggested that a risk evaluation and mitigation strategy might be one way to accomplish this.

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