Cardiovascular safety warnings for the gout drug febuxostat should be reconsidered in light of new findings showing no increased risk of cardiovascular adverse events or mortality, researchers say.

Professor Nicola Dalbeth, a rheumatologist at Auckland University is one of several co-authors of a new paper that calls for reassessment of the cardiovascular safety of febuxostat based on results of the FAST study published in the Lancet in November 2020.

In 2019 the TGA followed the example of other regulators in requiring additional safety warnings for febuxostat for patients with a history of cardiovascular disease. The update was based on US-based CARES study, involving more than 6000 patients with gout and pre-existing major cardiovascular disease. It found that patients taking febuxostat had a higher risk of death, and specifically heart-related death, compared to patients who took the other medicine.

However the new results from the European-based FAST study found that febuxostat was non-inferior to allopurinol therapy with respect to the primary cardiovascular endpoint, and its long-term use was not associated with an increased risk of death or serious adverse events compared with allopurinol.

The study conducted between 2011 and 2018 randomised 6128 patients  to receive allopurinol or febuxostat. After follow up of almost four years the incidence of the primary endpoint (a composite of hospitalisation for non-fatal myocardial infarction or acute coronary syndrome; non-fatal stroke; or cardiovascular death), was similar for febuxostat  and allopurinol (1·72 vs 2.05 events per 100 patient-years, adjusted HR 0·85 [95% CI 0·70–1·03].

The study also found that there were fewer deaths in the febuxostat group than in the allopurinol group and that in contrast to CARES, treatment with febuxostat was not associated with an increase in cardiovascular death or all-cause death.

The FAST study authors noted that patients in their trial had lower cardiovascular risk than those in the CARES study (33% with previous cardiovascular disease), but also noted that they were exposed to higher doses of febuxostat.

In their article, published in Arthritis and Rheumatology, Professor Dalbeth and co-authors said they believed the FAST study results had more validity because there were far fewer losses to follow up (6% vs 45%) than the CARES study. They also believed that the FAST study had better acscertainment of cardiovascular events and more accurately reflected real world use of got therapy as it was based in primary care.

“Thus, based on the current evidence, it is our view that the collective verdict on the cardiovascular safety of febuxostat should rely more on FAST’s results than CARES,” they wrote.

“To that end, we support the FAST authors’ suggestion for regulatory agencies to update their guidance on the CV risk of febuxostat,” they added

However they acknowledged there were still uncertainties remaining about the cardiovascular safety profile of febuxostat, such as the associations between serum urate levels and risk and the potential role of gout flares in cardiovascular risk.

Disclosure: One of the co- authors, Profesoor Hyon Choi of Massachusetts General Hospital, US,  declared interests including consulting fees from Takeda, manufacturer of febuxostat.