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).
A Cochrane review 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 (Table).
| Outcome | Follow up | Participants (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 mg | 4-8 weeks | 474 (2) | 238 per 1000 | 314 per 1000 (228 to 431) | 1.32 (0.96 to 1.8) |
| Febuxostat 120 mg | 4-8 weeks | 479 (2) | 238 per 1000 | 407 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 mg | 4-28 weeks | 332 (2) | 7 per 1000 | 482 per 1000 (97 to 1000) | 68.9 (13.8 to 343.9) |
| Febuxostat 120 mg | 4-28 weeks | 356 (2) | 7 per 1000 | 565 per 1000 (112 to 1000) | 80.7 (16.0 to 405.5) |
| Serious adverse events | |||||
| Febuxostat 80 mg | 4-28 weeks | 479 (2) | 12 per 1000 | 32 per 10001 (8 to 125)1 | 2.8 (0.72 to 10.7) |
| Febuxostat 120 mg | 4-28 weeks | 479 (2) | 12 per 1000 | 31 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 ). 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).
| Outcome | Follow up | Participants (studies) | Assumed risk (allopurinol) | Corresponding risk (febuxostat) | Relative risk (95% CI) |
|---|---|---|---|---|---|
| Gout flares | |||||
| Febuxostat 80 mg | 8, 26 & 52 weeks | 2325 (3) | 204 per 1000 | 228 per 1000 (200 to 259) | 1.1 (0.98 to 1.3) |
| Febuxostat 120 mg | 28 & 52 weeks | 986 (2) | 420 per 1000 | 542 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 mg | 8, 26 & 52 weeks | 2193 (3) | 398 per 1000 | 716 per 1000 (617 to 832) | 1.8 (1.6 to 2.2) |
| Febuxostat 120 mg | 28 & 52 weeks | 880 (2) | 384 per 1000 | 829 per 1000 (733 to 941) | 2.2 (1.9 to 2.5) |
| Serious adverse events | |||||
| Febuxostat 80 mg | 24, 28, & 52 weeks | 1044 (3) | 50 per 1000 | 45 per 1000 (17 to 122) | 0.91 (0.34 to 2.4) |
| Febuxostat 120 mg | 28 & 52 weeks | 1041 (2) | 50 per 1000 | 58 per 1000 (35 to 96) | 1.2 (0.70 to 1.93) |
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 , and the CARES trial will define the cardiovascular (CV) safety profile of febuxostat and allopurinol in gout patients at high risk for CV events.
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