Medicines Healthcare Products Regulatory Agency
This article replaces advice issued in Drug Safety Update published in July 2019.
Advice for healthcare professionals:
- in patients with pre-existing major cardiovascular diseases, febuxostat therapy should be used cautiously, particularly in those with evidence of high urate crystal and tophi burden or those initiating urate-lowering therapy
- following initiation of febuxostat, prescribers should titrate the febuxostat dose to minimise gout flares and inflammation
- note that clinical guidelines for gout (see, for example, NICE guideline 219 Gout: diagnosis and management) recommend that allopurinol should be offered as first-line treatment for people with gout who have major cardiovascular disease
- report suspected adverse drug reactions associated with febuxostat to the Yellow Card scheme
Advice for healthcare professionals to give to patients:
- febuxostat is used to treat gout by reducing an excess of a chemical called uric acid (urate) in the body, which prevents attacks of gout in the long term; it can also be used to treat and prevent high blood levels of uric acid that may occur when you start to receive chemotherapy for blood cancer
- there are new recommendations to healthcare professionals about use of febuxostat in patients with previous heart problems
- if you currently have or have previously had heart failure, heart problems or stroke, it is recommended to talk to your doctor before taking febuxostat
- no action is needed from patients already on febuxostat, but talk to a healthcare professional if you are concerned
About febuxostat and treatment of gout
Febuxostat, at doses of 80 milligrams (mg) and 120mg, is indicated for treatment of chronic hyperuricaemia in conditions where urate deposition has already occurred (including a history, or presence, of tophus or gouty arthritis). Febuxostat at a dose of 120mg is indicated for the prevention and treatment of hyperuricaemia in adult patients undergoing chemotherapy for haematologic malignancies at intermediate to high risk of tumour lysis syndrome. The advice in this article relates to treatment of chronic hyperuricaemia (gout).
Gout is a type of inflammatory arthritis caused by monosodium urate crystals forming inside and around joints, causing sudden flares of severe pain, heat, and swelling. Gout has been associated with an increased risk of cardiovascular disease and cardiovascular mortality. Gout flares may occur during initiation of urate-lowering treatment due to changing serum uric acid levels resulting in mobilisation of urate from tissue deposits. Management of gout flares may require use of non-steroidal anti-inflammatory drugs, colchicine, or oral corticosteroids.
Warnings regarding cardiovascular disease
In July 2019, we advised healthcare professionals to avoid febuxostat treatment in patients with pre-existing major cardiovascular disease (for example, myocardial infarction, stroke, or unstable angina), unless no other therapy options were appropriate. This followed a review of the findings from a phase 4 clinical trial (the CARES study1) in patients with gout and a history of major cardiovascular disease. The CARES study showed a higher risk for cardiovascular-related death and for all-cause mortality in patients assigned to febuxostat than in those assigned to allopurinol.
A further trial has now been concluded on the cardiovascular safety of febuxostat, the FAST study.2 The FAST study was conducted in patients in the UK, Denmark, and Sweden who had at least one cardiovascular risk factor and had already been treated with allopurinol for a median duration of 6 years; additionally, serum urate levels were controlled with dose-optimised allopurinol before randomisation. The FAST study concluded that febuxostat was non-inferior to allopurinol therapy with respect to the primary cardiovascular endpoint, and, unlike the CARES study results, that long-term use was not associated with an increased risk of death or cardiovascular death compared to allopurinol.
Following a review of the FAST study findings and advice from the Pharmacovigilance Expert Advisory Group of the Commission on Human Medicines, the product information for febuxostat has been updated to include the results. The product information retains the warning for cardiovascular disorders and now advises that treatment of patients with pre-existing major cardiovascular diseases with febuxostat should be exercised cautiously.
In particular, treatment should be exercised cautiously in patients with pre-existing major cardiovascular diseases with evidence of high urate crystal and tophi burden or those initiating urate lowering therapy. Prescribing clinicians should titrate febuxostat appropriately to minimise gout flares following initiation, thus minimising additional inflammation.
We also note that clinical guidelines for gout (for example, NICE guideline 219 Gout: diagnosis and management which has been updated since the time of the FAST study publication), state that allopurinol should be offered as first-line treatment to people with gout who have major cardiovascular disease (for example, previous myocardial infarction or stroke, or unstable angina).
Detailed study findings
The CARES study
Further information on the design and findings of the CARES study can be found in the Drug Safety Update issued July 2019 and in the published findings. [footnote 1] In summary, the CARES study was a phase 4, randomised, double-blind, non-inferiority trial in which patients with gout and a history of major cardiovascular disease from the USA, Canada and Mexico. A total of 6,190 patients were randomised to receive febuxostat or allopurinol and were followed for a median of 32 months.
The primary major adverse cardiovascular events (MACE) endpoint occurred at similar rates in the febuxostat and allopurinol treatment groups (10.8% versus 10.4% of patients, respectively; hazard ratio (HR) 1.03, 95% confidence interval (CI) 0.87 to 1.23). In secondary analysis, the incidence of cardiovascular deaths was higher in the group assigned to febuxostat than in the group assigned to allopurinol (4.3% versus 3.2%, respectively; HR 1.34, 95% CI 1.03 to 1.73). The incidence of all-cause mortality was also higher in patients assigned to febuxostat than in those assigned to allopurinol (7.8% versus 6.4% respectively; HR 1.22, 95% CI 1.01 to 1.47), which was mainly driven by the higher rate of cardiovascular deaths in the febuxostat group.
The FAST study
The FAST study was a prospective, randomised, open label, blinded-endpoint, non-inferiority trial that evaluated the risk of cardiovascular events with febuxostat versus allopurinol in 6128 patients with gout in the UK, Denmark, and Sweden who had at least one cardiovascular risk factor. [footnote 2]
Patients had been receiving urate-lowering therapy with allopurinol at inclusion for a median duration of 6 years. Prior to randomisation they had received dose-optimised allopurinol to lower urate concentration to European Alliance of Associations for Rheumatology (EULAR) target level of below 0357 mmol/L (below 6 mg/dL).
The FAST study results showed that febuxostat was non-inferior to allopurinol therapy with respect to the primary cardiovascular endpoint (composite of hospitalisation for non-fatal myocardial infarction or biomarker-positive acute coronary syndrome; non-fatal stroke; or cardiovascular death), with an on-treatment incidence of 5.6% for febuxostat vs 7.9% for allopurinol (HR 0.85, 95% CI 0.70 to 1.03, p<0.0001, non-inferior). Secondary endpoints for febuxostat versus allopurinol on-treatment included cardiovascular death 2% vs 2.7% respectively, HR 0.91 (066127), and all cause death 3.5% vs 5.7% respectively, HR 0.75 (059095) p<0.0001, non-inferior. [footnote 2]
There were differences between the FAST and CARES study populations and protocols, which need to be considered when comparing and contrasting the results of these trials, including:
- febuxostat-treated patients were older in FAST than in CARE