Elsevier

The Lancet

Volume 396, Issue 10264, 28 November–4 December 2020, Pages 1745-1757
The Lancet

Articles
Long-term cardiovascular safety of febuxostat compared with allopurinol in patients with gout (FAST): a multicentre, prospective, randomised, open-label, non-inferiority trial

https://doi.org/10.1016/S0140-6736(20)32234-0Get rights and content

Summary

Background

Febuxostat and allopurinol are urate-lowering therapies used to treat patients with gout. Following concerns about the cardiovascular safety of febuxostat, the European Medicines Agency recommended a post-licensing study assessing the cardiovascular safety of febuxostat compared with allopurinol.

Methods

We did a prospective, randomised, open-label, blinded-endpoint, non-inferiority trial of febuxostat versus allopurinol in patients with gout in the UK, Denmark, and Sweden. Eligible patients were 60 years or older, already receiving allopurinol, and had at least one additional cardiovascular risk factor. Those who had myocardial infarction or stroke in the previous 6 months or who had severe congestive heart failure or severe renal impairment were excluded. After a lead-in phase in which allopurinol dose was optimised towards achieving a serum urate concentration of less than 0·357 mmol/L (<6 mg/dL), patients were randomly assigned (1:1, with stratification according to previous cardiovascular events) to continue allopurinol (at the optimised dose) or start febuxostat at 80 mg/day, increasing to 120 mg/day if necessary to achieve the target serum urate concentration. The primary outcome was a composite of hospitalisation for non-fatal myocardial infarction or biomarker-positive acute coronary syndrome; non-fatal stroke; or cardiovascular death. The hazard ratio (HR) for febuxostat versus allopurinol in a Cox proportional hazards model (adjusted for the stratification variable and country) was assessed for non-inferiority (HR limit 1·3) in an on-treatment analysis. This study is registered with the EU Clinical Trials Register (EudraCT 2011-001883-23) and ISRCTN (ISRCTN72443728) and is now closed.

Findings

From Dec 20, 2011, to Jan 26, 2018, 6128 patients (mean age 71·0 years [SD 6·4], 5225 [85·3%] men, 903 [14·7%] women, 2046 [33·4%] with previous cardiovascular disease) were enrolled and randomly allocated to receive allopurinol (n=3065) or febuxostat (n=3063). By the study end date (Dec 31, 2019), 189 (6·2%) patients in the febuxostat group and 169 (5·5%) in the allopurinol group withdrew from all follow-up. Median follow-up time was 1467 days (IQR 1029–2052) and median on-treatment follow-up was 1324 days (IQR 870–1919). For incidence of the primary endpoint, on-treatment, febuxostat (172 patients [1·72 events per 100 patient-years]) was non-inferior to allopurinol (241 patients [2·05 events per 100 patient-years]; adjusted HR 0·85 [95% CI 0·70–1·03], p<0·0001). In the febuxostat group, 222 (7·2%) of 3063 patients died and 1720 (57·3%) of 3001 in the safety analysis set had at least one serious adverse event (with 23 events in 19 [0·6%] patients related to treatment). In the allopurinol group, 263 (8·6%) of 3065 patients died and 1812 (59·4%) of 3050 had one or more serious adverse events (with five events in five [0·2%] patients related to treatment). Randomised therapy was discontinued in 973 (32·4%) patients in the febuxostat group and 503 (16·5%) patients in the allopurinol group.

Interpretation

Febuxostat is non-inferior to allopurinol therapy with respect to the primary cardiovascular endpoint, and its long-term use is not associated with an increased risk of death or serious adverse events compared with allopurinol.

Funding

Menarini, Ipsen, and Teijin Pharma Ltd.

Introduction

Gout is a metabolic disorder in which prolonged elevation of serum urate can lead to the deposition of crystals of monosodium urate, tophus formation, chronic inflammatory arthritis, urolithiasis, and nephropathy, as well as to recurrent flares of acute arthritis and bursitis. Gout is frequently associated with comorbidities such as chronic kidney disease, obesity, diabetes, hypertension, and cardiovascular disease, and with increased mortality.1, 2, 3 In addition to the treatment of acute flares with anti-inflammatory drugs, management of gout requires long-term urate-lowering therapy to persistently reduce serum urate below its crystallisation threshold in order to dissolve crystal deposits and prevent further crystal deposition, recurrent flares of gout, and progressive joint damage. The most widely used urate-lowering medications are the xanthine oxidase inhibitors allopurinol and febuxostat. Prophylaxis against acute flares of gout is recommended when urate-lowering therapy is initiated or following dose increases of a xanthine oxidase inhibitor, typically for a period of up to 6 months.4

Research in context

Evidence before this study

We searched PubMed on Sept 17, 2020, using the search terms “febuxostat”, “allopurinol”, and “cardiovascular outcomes”. We searched, with no date or language restrictions, for reports of any randomised clinical trials comparing febuxostat with allopurinol in terms of cardiovascular outcomes in more than 500 participants. We found one trial, the CARES trial, which involved 6190 randomised patients with gout and coexisting major cardiovascular conditions and reported that febuxostat was non-inferior to allopurinol with respect to rates of adverse cardiovascular events. However, the risks of death from any cause (hazard ratio 1·22 [95% CI 1·01–1·47]) and of cardiovascular death (1·34 [1·03–1·73]) in a modified intention-to-treat analysis were higher in the febuxostat group than in the allopurinol group.

Added value of this study

The Febuxostat versus Allopurinol Streamlined Trial (FAST) was a large, multicentre, prospective, randomised, open-label, blinded-endpoint, non-inferiority trial to compare the cardiovascular safety of febuxostat versus allopurinol in patients with gout, at least one additional cardiovascular risk factor, and who were already being treated with allopurinol. The population studied was generally at lower cardiovascular risk than that in the CARES trial, with only about a third of patients in FAST having previous major cardiovascular comorbidity. Daily doses of febuxostat in FAST were higher (80 mg/day or 120 mg/day) than in CARES (40 mg/day or 80 mg/day), and dose ranges of allopurinol were wider in FAST (100–900 mg/day) than in CARES (200–600 mg/day). Only 5·8% of patients in FAST withdrew from all follow-up, and discontinuation of randomised treatment was less frequent (16·5% in the allopurinol group and 32·4% in the febuxostat group) than in the CARES trial (in which 45·0% of patients did not complete all trial visits and 56·6% of patients discontinued randomised treatment prematurely). FAST used record linkage to national health-care databases to complement other methods of reporting for the detection of hospitalisations and deaths. We found that febuxostat was non-inferior to allopurinol for the primary composite endpoint (hospitalisation for non-fatal myocardial infarction or biomarker-positive acute coronary syndrome; non-fatal stroke; or cardiovascular death) during a median on-treatment period of 1324 days (IQR 870–1919; 3·63 years). In contrast to CARES, FAST found that treatment with febuxostat was not associated with an increase in cardiovascular death or all-cause death. Overall there were fewer deaths in the febuxostat group than in the allopurinol group.

Implications of all the available evidence

Although the CARES study suggested that febuxostat therapy might be associated with higher risks of all-cause death and cardiovascular death than allopurinol, FAST, with better ascertainment of events, found no increase in these risks.

Initial clinical trials comparing febuxostat to allopurinol or placebo identified a numerically higher risk of cardiovascular events in patients taking febuxostat.5, 6, 7, 8 Marketing authorisation for febuxostat was granted after a subsequent 6-month randomised controlled trial of febuxostat compared with allopurinol in 2269 participants (the CONFIRMS trial)9 showed equal frequencies (0·4%) of adjudicated cardiovascular events with febuxostat (80 mg) and allopurinol, and no cardiovascular deaths in febuxostat-treated patients. However, because of lingering concerns about the possibility of increased cardiovascular risk with febuxostat, the European Union Risk Management Plan for febuxostat indicated that a post-authorisation safety study should be done in Europe in patients with gout to evaluate the cardiovascular effects of febuxostat versus standard urate-lowering therapy with allopurinol. The Febuxostat versus Allopurinol Streamlined Trial (FAST) was approved to fulfil this requirement.

Section snippets

Study design and participants

We did a prospective, randomised, open-label, blinded-endpoint multicentre trial in patients with gout at 18 regional centres in the UK (Scotland and England), Denmark, and Sweden.10 The trial was designed to assess the cardiovascular safety of febuxostat in comparison with allopurinol. Allopurinol was chosen as the comparator because it is the long-established, first-line urate-lowering therapy for gout.

Patients were mainly recruited from 850 primary care practices in the UK and Denmark (by a

Results

From Dec 20, 2011, to Oct 17, 2017, 6603 patients consented to be enrolled in the trial and were assessed for eligibility, of whom 475 were excluded before randomisation. Separate from these 6603 patients, data for 14 randomly allocated patients and one non-allocated patient (all recruited at one UK site) were deleted from the study database following instruction by the sponsor because of concerns identified at a monitoring visit regarding the validity of consent and inclusion of these patients

Discussion

In this study of more than 6000 patients with gout, who had been receiving urate-lowering therapy with a xanthine oxidase inhibitor at doses designed to lower urate concentration to EULAR target levels (<0·357 mmol/L) for up to 7 years, febuxostat was non-inferior to allopurinol with regard to the occurrence of major cardiovascular outcomes, including the primary outcome of hospitalisation for non-fatal myocardial infarction or biomarker-positive acute coronary syndrome, non-fatal stroke, or

Data sharing

Once the investigators have been given the opportunity to publish further papers, the steering committee will be happy to consider applications for de-identified information. Requests should be made to the corresponding author.

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