Febuxostat does not increase the risk of major cardiovascular outcomes compared with allopurinol in selected gout patients, according to new European study findings published online ahead of print in the Lancet.

“In contrast to a previous large study, we found no signal of increased all-cause or cardiovascular deaths with febuxostat. In light of these findings, regulatory advice to avoid the use of febuxostat in patients with cardiovascular disease should be reconsidered and modified,” investigators concluded.

In the Febuxostat versus Allopurinol Streamlined Trial (FAST), which was required by the European Medicines Agency, 6128 patients (mean age 71 years; 85.3% men; 99.1% White) were randomly assigned to receive allopurinol or febuxostat (both xanthine oxidase inhibitors) following a lead-in phase in which their existing allopurinol dose was optimized towards achieving a serum urate concentration of less than 6 mg/dL. The primary cardiovascular safety endpoint was a composite of hospitalization for nonfatal myocardial infarction or biomarker-positive acute coronary syndrome, nonfatal stroke, or cardiovascular death.

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Over a median on-treatment follow-up period of 1324 days, 1.72 events per 100 patient-years occurred in the febuxostat group compared with 2.05 events per 100 patient-years in the allopurinol group, which is within the noninferiority margin selected for the study, Thomas M. MacDonald, BSC, MBCHB, MD, of the University of Dundee in Dundee, United Kingdom, reported on behalf of the FAST Study Group. Furthermore, long-term use of febuxostat displayed 9% and 25% statistically lower risks for cardiovascular and all-cause death, respectively, compared with allopurinol, proving noninferiority.

The 2018 US FDA-required Cardiovascular Safety of Febuxostat and Allopurinol in Patients with Gout and Cardiovascular Morbidities (CARES) trial found that the primary endpoint – a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or unstable angina with urgent revascularization — occurred in similar proportions of the febuxostat and allopurinol group: 10.8% vs 10.4%, respectively. The trial also found 22% and 34% increased risks of all-cause and cardiovascular death, respectively, with febuxostat compared with allopurinol. But the excess deaths became nonsignificant when non-adjudicated deaths were counted.

The FAST Study Group highlighted some key differences in study populations and doses of urate-lowering therapy between FAST and CARES. All patients in CARES had established cardiovascular disease, whereas 33% of patients in FAST had cardiovascular disease at baseline. CARES included patients with severe heart failure, whereas FAST excluded patients with New York Heart Association III or IV heart failure. The prevalence of tophi was greater in the CARES population, suggesting more severe gout at baseline. Additionally, CARES included newly treated patients, whereas FAST only recruited patients established on allopurinol therapy. By design, FAST excluded patients with an estimated glomerular filtration rate of less than 30 mL/min/1.73 m2 and CARES excluded patients with an estimated creatinine clearance of less than 30 mL/min.

CARES tested 40 to 80 mg/d of febuxostat, whereas FAST tested higher doses of 80 to 120 mg/d used in Europe. Allopurinol doses ranged from 200 to 600 mg/d in CARES compared with 100 to 900 mg/d in FAST. Treatment discontinuation rates were also much lower in FAST. Additionally, colchicine use was higher in the febuxostat than the allopurinol group in FAST.

“To what extent the results of FAST are generalisable to patients with gout who have not previously been treated with urate-lowering therapy or to patients with severe heart failure is not clear,” Dr MacDonald’s team stated.

In an accompanying editorial, Thomas Bardin, MD, and Pascal Richette, MD, PhD, of Lariboisière Hospital APHP Paris Nord and University of Paris, INSERM, in Paris, France, commented:

“The FAST results appear to be robust and reassuring with regard to cardiovascular tolerance to febuxostat in the vast majority of white male patients with gout, although it does not allow firm conclusions to be drawn about patients with severe cardiovascular disease. These new data should prompt updates from regulatory agencies on the cardiovascular risk of febuxostat.”

Disclosure: This clinical trial was supported by Menarini, Ipsen, and Teijin Pharma Ltd. Please see the original references for a full list of authors’ and reviewers’ disclosures.


Mackenzie IS, Ford I, Nuki G, et al; FAST Study Group. Long-term cardiovascular safety of febuxostat compared with allopurinol in patients with gout (FAST): a multicentre, prospective, randomised, open-label, non-inferiority trial. Lancet. Published online November 9, 2020. doi:10.1016/S0140-6736(20)32234-0

Bardin T, Richette P. FAST: new look at the febuxostat safety profile. Lancet. Published online November 9, 2020. doi:10.1016/S0140-6736(20)32343-6