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The authors do not present a statistical analysis comparing the rates of discontinuation in the 80-mg febuxostat group with those in the allopurinol group. On the basis of the data they present, there was a significantly higher rate of discontinuation in the group receiving 80 mg per day of febuxostat (P=0.04 by Fisher's exact test).
This result affects the conclusions of the authors. A higher discontinuation rate in the group receiving 80 mg per day of febuxostat implies that febuxostat was not as well tolerated as allopurinol. Febuxostat may be an advance in the treatment of gout, but we need to be clear and precise in interpreting the trial data regarding its use.
Mark E. Lustberg, M.D., Ph.D.
York Hospital
York, PA 17405
mlustberg{at}wellspan.org
References
As such, the arrival of febuxostat is greatly anticipated. Its superior efficacy as compared with allopurinol in the reduction of serum urate concentrations, even to optimally low levels, is heralded in the Journal. Caution, however, needs to be exercised inasmuch as the reported frequency of adverse events leading to discontinuation of the drug occurred two and three times as often in the low-dose and high-dose febuxostat groups, respectively, as in the allopurinol group. Moreover, the occurrence of four deaths in the febuxostat groups, as compared with none in the allopurinol group, is further reason for pause. A compelling recent lesson regarding new arthritis medication is to be watchful as new agents are introduced into practice.4 Vigilance and post-marketing pharmacoepidemiology can be particularly enlightening in this regard.
Allan C. Gelber, M.D.
Johns Hopkins University School of Medicine
Baltimore, MD 21239
agelber{at}jhmi.edu
References
We reviewed the basis of these differences. Results reported in the article for comparisons of groups that were relevant to premature discontinuation were those determined with the use of a continuity-adjusted chi-square test (P=0.053 for comparison of the allopurinol group with the 80-mg febuxostat group, and P=0.003 for comparison of the allopurinol group with the 120-mg febuxostat group), rather than those determined with a Fisher's exact test, as intended.
All other analyses in the article have been rechecked, and an additional point for correction has been identified. In Table 1 of the article, data about renal impairment are based on calculated creatinine clearance, and the P value should be 0.26, not 0.90. The P value of 0.90 was based on renal impairment as defined in the ineligibility criteria that were outlined in the Methods section. We believe that these changes do not affect the overall conclusion of the article, which is that febuxostat at a dose of 80 mg or 120 mg daily is more effective than allopurinol at a dose of 300 mg daily in lowering serum urate in patients with gout.
We thank Dr. Gelber for calling attention to the data in Figure 1 of the original article showing increased rates of premature discontinuation among patients treated with febuxostat. Although rashes and abnormal results of liver-function tests — the major adverse reactions leading to withdrawal — were mild to moderate in severity and reversible after discontinuation of febuxostat, we agree that roles for vigilance and post-marketing pharmacoepidemiology are essential in establishing the ultimate safety profile for febuxostat and, indeed, any new drug.
Michael A. Becker, M.D.
University of Chicago Pritzker School of Medicine
Chicago, IL 60637
mbecker{at}medicine.bsd.uchicago.edu
William A. Palo, M.S.
Nancy Joseph-Ridge, M.D.
TAP Pharmaceutical Products
Lake Forest, IL 60045
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