The FAST study that pitted febuxostat against allopurinol for patients with gout and CVD risk factors has released its results in a late breaking abstract at ACR.
The TGA and other regulators around the world have been slapping warnings on febuxostat after the CARES trial showed a greater risk of mortality in patients with CVD who were taking febuxostat instead of the more commonly prescribed drug allopurinol.
Now, the prospective FAST study that randomised around 6,000 patients with gout and CVD risk factors to receive either febuxostat or allopurinol is telling a different story.
The results, presented during the ACR Convergence 2020 virtual meeting and published in The Lancet this week, showed that febuxostat was non-inferior to allopurinol in terms of its CVD adverse events (including death, stroke, myocardial infarction or acute coronary syndrome).
In contrast to the CARES study, the FAST study found that febuxostat use was not associated with an increased risk of death or serious cardiovascular adverse events over four years.
The FAST study used hospital record linkage to track the outcome of patients over many years and had a much lower dropout rate than the CARES trial (only 5.8% compared with about 50%).
Thomas MacDonald, the senior author and a professor of medicine at the University of Dundee in the UK, came on the Rheumatology Republic podcast to discuss the study.
“What we found was that, if anything, febuxostat had a lower rate of [CVD] events than allopurinol,” said Professor MacDonald.
“Now, the question is why? Why is there a difference between the two trials?
“I don’t want to criticise CARES. You know, it was a major study. But in that study, 47% of people withdrew from all follow up. That meant that with data protection laws et cetera you just couldn’t be followed up in the trial. And so maybe that might explain what happened.”
There were several other important differences between the studies, including that the population in FAST had a lower CVD risk than the CARES cohort and the daily doses of febuxostat in FAST were higher (80 mg/day or 120 mg/day) than in CARES (40 mg/day or 80 mg/day).
Professor William White, an American cardiologist who led the CARES trial, told Rheumatology Republic that the two trial results were not actually all that different.
“The primary endpoint (composite) for both studies showed non-inferiority,” he said. “Of course, there were imbalances in CV death in CARES whereas there were less deaths on febuxostat vs allopurinol in FAST. The reason for this finding is not crystal clear at this time but there were differences in the studies.”
Only a third of patients in FAST had CVD, whereas all the patients in CARES had CVD. “Hence the CV risk in FAST was definitely lower than CARES,” said Professor White.
“There was a problem with patient drop-out in CARES – nearly half of the patients ‘left’ the trial before it was over – over half stopped study medication before the study was over,” he said.
“As for prescribers, I would say that in patients with low-moderate CV risk, there should be no restrictions for prescribing febuxostat in patients with gout,” said Professor White.
“However, in the US I do have to point out that the label of febuxostat carries a black box warning and its use is limited to patients not able to tolerate allopurinol and/or those who do not achieve goal uric acid on allopurinol.”
FAST #ACR20 L08
Clinically-relevant study showing that Febuxostat did NOT lead to more adverse CVS events in gout patients >60yo with at least 1 CVS risk factors vs Allopurinol
Does seem to overturn the findings of the CARES study pic.twitter.com/L8qCTMqzod
— Dr Irwin Lim (@_connectedcare) November 11, 2020
“There’s a lot of poring over the data, I think, to happen,” said Professor MacDonald. “I would hope that at least physicians will take the view that if you’re a patient who’s having trouble with allopurinol that it’s not unreasonable to change you to febuxostat.”
That doesn’t mean febuxostat will work for all patients, he said. Some patients withdrew from the FAST trial early because they had been stable on allopurinol for many years and didn’t like the effects of febuxostat, said Professor MacDonald.
Professor MacDonald expected the regulators would move slowly to remove any warnings on febuxostat and that any changes would be made after much consideration of the data.
“I suspect that the regulators will look closely at this,” he said. “We’re preparing the full trial report, which is an enormous document of everything that happened.”
This mirrored the response from a spokeswoman for the TGA, who told Rheumatology Republic, “At present, the TGA is not planning to update the safety advisory for febuxostat (Adenuric) published on 1 October 2019”.
The spokeswoman said that the updated warnings on the febuxostat product information sheets about use in patients with pre-existing major cardiovascular disease would remain until the TGA had the chance to evaluate the FAST study and any other studies that were submitted by the sponsor in relation to the safety of febuxostat.