Febuxostat for treating chronic gout
Abstract
Background
Gout is the most common inflammatory arthritis in men over 40 years and has an increasing prevalence among postmenopausal women. Lowering serum uric acid levels remains one of the primary goals in the treatment of chronic gout. In clinical trials, febuxostat has been shown to be effective in lowering serum uric acid levels to < 6.0 mg/dL.
Objectives
To evaluate the benefits and harms of febuxostat for chronic gout.
Search methods
We searched The Cochrane Library, MEDLINE, EMBASE, and International Pharmaceutical Abstracts from inception to July 2011. The ClinicalTrials.gov website was searched for references to trials of febuxostat. Our search did not include any restrictions.
Selection criteria
Two authors independently reviewed the search results and disagreements were resolved by discussion. We included any controlled clinical trial or open label trial (OLT) using febuxostat at any dose.
Data collection and analysis
Data and risk of bias were independently extracted by two authors and summarised in a meta‐analysis. Continuous data were expressed as mean difference and dichotomous data as risk ratio (RR).
Main results
Four randomised trials and two OLTs with 3978 patients were included. Risk of bias differed by outcome, ranging from low to high risk of bias. Included studies failed to report on five to six of the nine outcome measures recommended by OMERACT. Patients taking febuxostat 120 mg and 240 mg reported more frequent gout flares than in the placebo group at 4 to 28 weeks (RR 1.7; 95% CI 1.3 to 2.3, and RR 2.6; 95% CI 1.8 to 3.7 respectively). No statistically significant differences were observed at 40 mg and 80 mg. Compared to placebo, patients on febuxostat 40 mg were 40.1 times more likely to achieve serum uric acid levels < 6.0 mg/dL at 4 weeks (95% CI 2.5 to 639), with an absolute treatment benefit of 56% (95% CI 37% to 71%). For febuxostat 80 mg and 120 mg, patients were 68.9 and 80.7 times more likely to achieve serum uric acid levels < 6.0 mg/dL at their final visit compared to placebo (95% CI 13.8 to 343.9, 95% CI 16.0 to 405.5), respectively; with an absolute treatment benefit of 75% and 87% (95% CI 68 to 80% and 81 to 91%), respectively. Total discontinuation rates were significantly higher in the febuxostat 80 mg group compared to placebo (RR 1.4; 95% CI 1.0 to 2.0, absolute risk increase 11%; 95% CI 3 to 19%). No other differences were observed.
When comparing allopurinol to febuxostat at 24 to 52 weeks, 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). Patients on febuxostat 40 mg showed no statistically significant differences in benefits or harms. Patients on febuxostat 80 mg and 120 mg were 1.8 and 2.2 times more likely to achieve serum uric acid levels < 6.0 mg/dL at their final visit (95% CI 1.6 to 2.2, 95% CI 1.9 to 2.5) with an absolute treatment benefit of 29% and 44% (95% CI 25% to 33%, 95% CI 38% to 50%), respectively, at 24 to 52 weeks. Total discontinuation rates were higher for febuxostat 80 mg and 120 mg compared to allopurinol (RR 1.5; 95% CI 1.2 to 1.8, absolute risk increase 11%; 95% CI 6% to 16%; and RR 2.6; 95% CI 2.0 to 3.3, absolute risk increase 20%; 95% CI 3% to 14%, respectively). Discontinuations due to adverse events were similar across groups. Total adverse events were lower for febuxostat 80 mg and 120 mg compared with allopurinol (RR 0.93; 95% CI 0.87 to 0.99, absolute risk increase 6%; 95% CI 0.7% to 11%; and RR 0.90; 95% CI 0.84 to 0.96, absolute risk increase 8%; 95% CI 3% to 13%, respectively). No other relevant differences were noted.
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).
Authors' conclusions
Although the incidence of gout flares requiring treatment may be increased in patients taking febuxostat compared to placebo or allopurinol during early treatment, no such increase in gout flares was observed in the long‐term follow‐up study when compared to allopurinol. Febuxostat at any dose was shown to be beneficial in achieving serum uric acid levels < 6.0 mg/dL and reducing serum uric acid levels in the period from baseline to final visit when compared to placebo and to allopurinol. However, the grade of evidence ranged from low to high, which indicates that further research is needed.
PICOs
Plain language summary
Febuxostat for treating chronic gout
This summary of a Cochrane review represents what we know from research about the effect of febuxostat for treating chronic gout.
From six studies including 3978 people with chronic gout, the review shows that,
In people with chronic gout:
‐ febuxostat probably reduces uric acid levels;
‐ febuxostat probably increases the incidence of gout flares during early treatment (while getting the uric acid levels down). The normalization of serum uric acid leads to mobilization of urate from tissue deposits, which in turn may increase the number of attacks;
‐ febuxostat probably shows similar benefits as allopurinol after three years of use.
We do not have information about febuxostat effects on joint imaging, musculoskeletal function, pain, overall assessment, and quality of life. Also, we do not have precise information about side effects and complications. This is particularly true for rare but serious side effects. Possible side effects may include liver enzyme elevations, high blood pressure and diarrhoea. Rare complications may include certain cardiovascular events (chest pain, coronary artery disease, myocardial infarction, or atrial fibrillation).
What is chronic gout and what is febuxostat?
Uric acid is a product normally present in the blood as a result of the breakdown of certain products called 'purines'. Gout is a disease caused by high uric acid levels in the blood leading to crystal formation in the joints, most commonly joints of the lower limbs such as the big toe, heels, ankles and knees. Gout usually presents as acute attacks causing joint swelling and pain, but also can lead to chronic arthritis. While there is no cure for the disease, treatment can prevent recurrent gout attacks and improve its chronic form.
Research shows that keeping uric acid levels below 6.0 mg/dL can reduce gout attacks over time. However, in the first months of therapy, there could be an increased number of gout attacks, due to the nature of the treatment.
Febuxostat is a new drug that can help lower uric acid levels in the blood in adults with gout.
Best estimate of what happens to people with chronic gout who take febuxostat:
Febuxostat was proven effective in lowering uric acid to less than 6.0 mg/dL.
In short‐term studies (one year or less), when febuxostat was compared with placebo (a sham or fake medication):
‐ 6 patients out of 100 had more gout attacks taking febuxostat 80 mg (6% absolute increase in attacks);
‐ 75 more patients out of 100 taking febuxostat 80 mg reached their goal of uric acid level below 6.0 mg/dL (75% absolute benefit).
When febuxostat was compared with allopurinol, another medicine often used to lower uric acid:
‐ 2 patients out of 100 had more gout attacks taking febuxostat 80 mg (2% absolute increase in attacks);
‐ 29 more patients out of 100 on febuxostat 80 mg reached an acid level below 6.0 mg/dL (29% absolute benefit).
In studies of more than three years:
febuxostat at any dose had the same effect as allopurinol in reaching a uric acid level of less than 6.0 mg/dL, and there was no observed increase in gout attacks.
