The Therapeutic Goods Administration (TGA) has added a boxed warning to febuxostat tablets advising of an increased risk of death in patients with established cardiovascular disease. The addition of this warning follows the publication of the CARES (Cardiovascular Safety of Febuxostat or Allopurinol in Patients with Gout) trial.

This double-blind non-inferiority study followed over 6,000 patients with coexisting gout and cardiovascular disease. Patients were randomly assigned to receive either febuxostat or allopurinol. A primary end point event (cardiovascular death, non-fatal myocardial infarction, non-fatal stroke, or unstable angina with urgent revascularisation) occurred at similar rates in the febuxostat group and allopurinol group (7.8% and 7.7% respectively). However, the rate of cardiovascular death was higher in the febuxostat group compared to the allopurinol group (4.3% vs 3.2%), as was the rate of death from any cause (7.8% vs 6.4%). While there is currently no proposed mechanism for this apparent increase in all-cause mortality, the manufacturer advises against using febuxostat in patients with pre-existing major cardiovascular disease. Limitations of this study include high overall rates of premature discontinuation (56.6%) and loss to follow-up (45.0%).

While gout is associated with an increased risk of cardiovascular disease, some evidence suggests that allopurinol may offer cardiovascular benefits. The ongoing ALL-HEART (Allopurinol and Cardiovascular Outcomes in Patients With Ischemic Heart Disease) study is investigating whether allopurinol is associated with improved cardiovascular outcomes in patients with ischaemic heart disease. The results of this trial are expected after 2019.


  1. Adenuric® (febuxostat) Australian approved product information. Chatswood: Menarini Australia. Approved October 2019.
  2. Mackenzie I, Ford I, Walker A, Hawkey C, Begg A, Avery A, et al. Multicentre, prospective, randomised, open-label, blinded end point trial of the efficacy of allopurinol therapy in improving cardiovascular outcomes in patients with ischaemic heart disease: protocol of the ALL-HEART study. BMJ Open. 2016; 6: e013774.
  3. Thanassoulis G, Brophy JM, Richard H, Pilote L. Gout, allopurinol use, and heart failure outcomes. Arch Intern Med. 2010; 170(15): 1358-64.
  4. White WB, Saag KG, Becker MA, Borer JS, Gorelick PB, Whelton A, et al. Cardiovascular safety of febuxostat or allopurinol in patients with gout. N Engl J Med. 2018; 378: 1200-10.

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