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Evidence summaries

Febuxostat for Hyperuricaemia in Chronic Gout

Febuxostat may lower and maintain serum urate levels <6.0 mg/dl (357 µmol/l) more effectively than allopurinol in subjects with hyperuricemia and gout. Level of evidence: "C"

The quality of evidence is downgraded by study limitations (unclear allocation concealment and blinding), and by indirectness (differences between the interventions and of interest and those studied: included trials used a standard allopurinol dosage of 100 to 300 mg/day, not dosage titration of allopurinol up to 900 mg daily).

Summary

A Cochrane review [Abstract] 1 included 6 studies with a total of 3 978 subjects (4 RCTs and 2 open label trials). Patients taking febuxostat 120 mg and 240 mg reported more frequent gout flares compared to placebo during the 8 (febuxostat 120 mg) and 28 (febuxostat 240 mg) first weeks of treatment, but no statistically significant differences were observed at 40 mg and 80 mg. Patients on febuxostat were more likely to achieve serum uric acid levels < 6.0 mg/dL (357 µmol/l) compared to placebo (TableT1).

Febuxostat compared with placebo

OutcomeFollow upParticipants (studies)Assumed risk (placebo)Corresponding risk (febuxostat)Relative risk (95% CI)
1 The reported serious adverse events were cardiovascular disorders (chest pain, coronary artery disease, myocardial infarction and atrial fibrillation).
Gout flares
Febuxostat 80 mg4-8 weeks474 (2)238 per 1000314 per 1000 (228 to 431)1.32 (0.96 to 1.8)
Febuxostat 120 mg4-8 weeks479 (2)238 per 1000407 per 1000 (300 to 552)1.7 (1.3 to 2.3)
Serum uric acid <6.0 mg/dL (357 µmol/l) at final visit
Febuxostat 80 mg4-28 weeks332 (2)7 per 1000482 per 1000 (97 to 1000)68.9 (13.8 to 343.9)
Febuxostat 120 mg4-28 weeks356 (2)7 per 1000565 per 1000 (112 to 1000)80.7 (16.0 to 405.5)
Serious adverse events
Febuxostat 80 mg4-28 weeks479 (2)12 per 100032 per 10001 (8 to 125)1 2.8 (0.72 to 10.7)
Febuxostat 120 mg4-28 weeks479 (2)12 per 100031 per 1000 (8 to 19)2.7 (0.70 to 10.2)

When comparing febuxostat to allopurinol, the number of gout flares was not significantly different between the two groups, except for febuxostat 240 mg (RR 2.3, 95% CI 1.7 to 3.0 at 28 weeks). Patients on febuxostat 80 mg and 120 mg were more likely to achieve serum uric acid levels < 6.0 mg/dL (357 µmol/l) (Table T2). Total discontinuation rates were higher for febuxostat 80 mg and 120 mg compared to allopurinol, but discontinuations due to adverse events were similar across groups. Total adverse events were lower for febuxostat 80 mg and 120 mg compared with allopurinol. After 3 years of follow-up there were no statistically significant differences regarding effectiveness and harms between febuxostat 80 mg or 120 mg and allopurinol groups (adverse event rate per 100 patient-years 227, 216, and 246, respectively).

Febuxostat compared with allopurinol

OutcomeFollow upParticipants (studies)Assumed risk (allopurinol)Corresponding risk (febuxostat)Relative risk (95% CI)
Gout flares
Febuxostat 80 mg8, 26 & 52 weeks2325 (3)204 per 1000228 per 1000 (200 to 259)1.1 (0.98 to 1.3)
Febuxostat 120 mg28 & 52 weeks986(2)420 per 1000542 per 1000 (365 to 802)1.3 (0.87 to 1.9)
Serum uric acid <6.0 mg/dL (357 µmol/l) at final visit
Febuxostat 80 mg8, 26 & 52 weeks2193 (3)398 per 1000716 per 1000 (617 to 832)1.8 (1.6 to 2.2)
Febuxostat 120 mg28 & 52 weeks880 (2)384 per 1000829 per 1000 (733 to 941)2.2 (1.9 to 2.5)
Serious adverse events
Febuxostat 80 mg24, 28, & 52 weeks1044 (3)50 per 100045 per 1000 (17 to 122)0.91 (0.34 to 2.4)
Febuxostat 120 mg28 & 52 weeks1041 (2)50 per 100058 per 1000 (35 to 96)1.2 (0.70 to 1.93)

Clinical comments

The incidence of gout flares may be increased in patients taking febuxostat during early treatment; no such increase was observed in the long-term follow-up study compared to allopurinol. Patient-important outcomes such as pain, functional assessment, quality of life, and patient and physician global assessment were not reported. There are potential signals of febuxostat-associated cardiovascular thromboembolic events 2, and the CARES trial 3 will define the cardiovascular (CV) safety profile of febuxostat and allopurinol in gout patients at high risk for CV events.

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    References

    • Tayar JH, Lopez-Olivo MA, Suarez-Almazor ME. Febuxostat for treating chronic gout. Cochrane Database Syst Rev 2012;(11):CD008653. [PubMed]
    • Gandhi PK, Gentry WM, Bottorff MB. Cardiovascular thromboembolic events associated with febuxostat: Investigation of cases from the FDA adverse event reporting system database. Semin Arthritis Rheum 2013 [Epub ahead of print]. [PubMed]
    • White WB, Chohan S, Dabholkar A et al. Cardiovascular safety of febuxostat and allopurinol in patients with gout and cardiovascular comorbidities. Am Heart J 2012;164(1):14-20. [PubMed]

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