Risk of cardiovascular events with febuxostat

Febuxostat (Feburic®, Astellas Pharma Singapore Pte Ltd) has been registered in Singapore since 2016 and is indicated for the treatment of chronic hyperuricaemia in conditions where urate deposition has already occurred. As pre-market studies had suggested its association with serious cardiovascular (CV) events, warnings that febuxostat is not recommended for use in patients with ischaemic heart disease or congestive heart failure were included in its product labelling when it was first approved. Recently, findings from a completed post-market study have further characterised the CV profile of febuxostat by showing that gout patients with a pre-existing major CV disease treated with febuxostat had a statistically significant higher risk of CV death and all-cause mortality compared to those on allopurinol.

Serious cardiovascular events associated with febuxostat1

Concerns about the CV risk of febuxostat first arose during the pre-market phase, where a numerical excess of serious CV events (including CV death, non-fatal myocardial infarction and non-fatal stroke) was observed among febuxostat-treated subjects compared to allopurinol-treated subjects (1.3 vs 0.3 events per 100 patient-years) in the Phase 3 clinical studies, APEX and FACT. As a result, the product labelling for febuxostat had included warnings on possible CV events when it was first approved and the US Food and Drug Administration (FDA) had requested for the conduct of a large post-market clinical trial to further evaluate its CV safety. This study, known as the Cardiovascular Safety of Febuxostat and Allopurinol in Patients with Gout and Cardiovascular Morbidities (CARES) study, was recently completed in 2017.

About the CARES study2

The CARES study was a phase 4, multi-centre, randomised, double-blind CV outcomes study that involved 6,190 patients with gout who were treated with either febuxostat or allopurinol. The patients also had an established major CV disease, including a history of myocardial infarction, hospitalisation for unstable angina or transient ischaemic attack, stroke, peripheral vascular disease, or diabetes mellitus with evidence of microvascular or macrovascular disease. After a median follow-up of 32 months, the study found a statistically significant higher risk of CV-related death and all-cause mortality in the febuxostat group compared to the allopurinol group (Table 1). The primary endpoint, which was a composite of CV death, non-fatal myocardial infarction, non-fatal stroke, or unstable angina with urgent revascularisation, occurred at similar rates between both groups.

Table 1. CARES study findings



(n= 3,098)



Hazard ratio

(95% CI)

No. of patients (%)

Primary composite end point: cardiovascular death, non-fatal myocardial infarction, non-fatal stroke or urgent coronary revascularisation due to unstable angina

335 (10.8)

321 (10.4)

1.03 (0.89-1.21)

Cardiovascular death

134 (4.3)

100 (3.2)


1.34 (1.03-1.73)

Non-fatal myocardial infarction

111 (3.6)

118 (3.8)

0.93 (0.72-1.21)

Non-fatal stroke

71 (2.3)

70 (2.3)

1.01 (0.73-1.41)

Unstable angina with urgent revascularisation

49 (1.6)

56 (1.8)

0.86 (0.59-1.26)

All-cause mortality

243 (7.8)

199 (6.4)

1.22 (1.01-1.47)


International regulatory actions

Following a review of the CARES study, international regulatory agencies, namely the US FDA, the European Medicines Agency and the Australia Therapeutic Goods Administration concluded that the existing warnings on CV risk in the product labelling for febuxostat should be strengthened to reflect the key findings from the study.3-5 In addition, the US FDA restricted the use of febuxostat as a urate-lowering agent to patients who have inadequate response to, or are intolerant to allopurinol.

Local situation

The imbalances in the incidence of serious CV events between febuxostat- and allopurinol-treated patients observed from the pre-market studies are currently highlighted in the local package insert (PI) of Feburic® to warn healthcare professionals about the potential risk of serious CV events, including CV deaths. The PI also included advice that treatment with febuxostat in patients with ischaemic heart disease or congestive heart failure is not recommended. In response to the CARES study, the company has updated the local PI to highlight the study findings and to recommend that caution should be exercised for exacerbation and/or onset of CV disease when administering febuxostat.

HSA’s advisory

Healthcare professionals are advised to take into consideration the above information when prescribing febuxostat, particularly to patients with a history of CV disease. In patients with ischaemic heart disease or congestive heart failure, treatment with febuxostat is not recommended. 


  1. Singapore Feburic® package insert (approved 3 Dec 2019)
  2. N Engl J Med 2018; 378: 1200-10
  3. https://www.fda.gov/media/120418/download
  4. https://www.ema.europa.eu/en/documents/procedural-steps-after/adenuric-epar-procedural-steps-taken-scientific-information-after-authorisation_en.pdf
  5. https://www.tga.gov.au/node/882032
Healthcare professional, Industry member, Therapeutic Products

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