South Korean researchers have questioned the findings and implications of the CARES trial
South Korean researchers have questioned the findings and implications of the CARES trial.
The CARES study, published in 2018, randomised patients with gout and CVD to receive febuxostat or allopurinol.
The trial showed that more patients died when taking (or in the 30 days after stopping) febuxostat than allopurinol.
This finding led the FDA to issue a warning about prescribing febuxostat to patients with CVD.
In a letter to the editor of Rheumatology, a South Korean team has re-analysed the CARES trial and raised concerns about the risks of stopping febuxostat or allopurinol in patients who were already taking the medication.
The team found that stopping febuxostat was associated with a spike in mortality over the following 30 days.
Discontinuing allopurinol was also linked to a mortality spike over the subsequent 30 days.
In the re-analysis, there were slightly fewer deaths among the group that discontinued allopurinol than among the patients who discontinued febuxostat (46 compared with 58 deaths).
The authors speculated that stopping these drugs led to a sharp increase in free urate crystal formation in the cardiovascular system and increased inflammation.
“This might lead to plaque rupture and cardiovascular events,” the authors said.
However, the lead author of the CARES study, cardiologist Dr William White from the University of Connecticut, told Rheumatology Republic that there was a risk of “over-interpreting” the mortality data in the CARES trial.
The reason the CARES trial followed patients for 30 days after they stopped the medications was because they were tracking CVD events that were possibly triggered while still taking the medication.
“For example, there might have been an admission to the hospital for heart failure, the study drug was stopped, and the person died 10 days later off study drug,” said Dr White.
“It is clinically appropriate to have this 30-day period in which to count events as if they were on drug or from a legacy effect of the drug.”
In the 30 days after stopping the trial study drug, the patients could have been started on other gout therapy.
“There are no data regarding whether some other gout therapy was started,” said Dr White.
“It is likely that many patients discontinuing from blinded study drug (i.e. febuxostat or allopurinol) were, in fact, treated with a xanthine oxidase inhibitor – however that is speculation and no one knows as these data were not collected (unfortunately in hindsight).
“Thus, we could only analyse the data by randomised treatment group when deaths were reported and we had enough clinical information to adjudicate the event. The amount of time that study participants were followed off study drug in CARES was much longer than when they were on drug – hence more events occurred during that period of observation.”
The TGA updated its advice regarding febuxostat prescribing in October, warning that patients with pre-existing CVD and gout should not be treated with the drug because of the increased mortality risk.
