medwireNews: Febuxostat, used for the treatment of chronic hyperuricemia in patients with gout, has been approved in the USA and Europe for more than 10 years. However, the cardiovascular (CV) safety profile of the xanthine oxidase inhibitor remains controversial, with two studies mandated by the regulatory authorities reaching different conclusions.
In the CARES trial, required by the US FDA and published in 2018, patients treated with febuxostat were found to have a significantly higher risk for all-cause and CV mortality than those given allopurinol. These findings led the FDA to add a boxed warning to the prescribing information advising of an increased risk for death with febuxostat. However, in 2020 the European FAST trial found no increased risk for CV events, mortality, or serious adverse events among patients treated with febuxostat compared with allopurinol. The FAST investigators concluded that regulatory guidance to avoid febuxostat in patients with CV disease should be reconsidered.
So why did these trials have apparently contradictory findings, how will the latest results impact regulatory guidance, and what does this all mean for managing CV risk in patients with gout? To explore these questions further, we speak to rheumatologist Jasvinder Singh, from the University of Alabama at Birmingham, USA, and cardiologist Steven Nissen, from the Cleveland Clinic in Ohio, USA.
Similar primary outcomes
Singh says that the findings from the CARES and FAST trials “differ slightly [but] not too much.”
He explains that in CARES, rates of the primary outcome – a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, and unstable angina with urgent revascularization – were not significantly different among participants treated with febuxostat versus allopurinol, but rates of the secondary outcome of CV mortality were significantly higher in the febuxostat compared with the allopurinol arm (4.3 vs 3.2%).
Singh says that the primary outcome of the FAST trial was also neutral, with comparable rates of CV death, hospitalization for nonfatal myocardial infarction or biomarker-positive acute coronary syndrome, and nonfatal stroke in the febuxostat and allopurinol groups. In contrast to CARES, rates of CV death in FAST were not significantly different in the febuxostat and allopurinol groups, at 2.0% and 2.7%, respectively.
Different study populations in CARES and FAST
Singh notes that “[t]he populations differ a lot between the two trials,” which can “easily explain differences in primary and secondary outcomes between the two trials.” These differences are outlined in the table.
Number of participants
Patients with inadequately controlled gout and pre-existing cardiovascular disease
Patients with gout and at least one additional CV risk factor
Median 64.0 years (febuxostat group), 65.0 years (allopurinol group)
Average 71.0 years
Proportion of patients with history of CV disease
1–3 week washout from previous gout therapies
Stable dose of allopurinol prior to study entry
Febuxostat 40–80 mg/day or allopurinol (dosed according to kidney function)
Febuxostat 80–120 mg/day or allopurinol at the optimized dose established prior to study entry
57.3% in the febuxostat arm, 55.9% in the allopurinol arm
32.4% in the febuxostat arm, 16.5% in the allopurinol arm
Table: Summary of the study populations and treatment groups in the CARES and FAST trials
Whereas the FAST trial included gout patients aged 60 years and older with at least one additional CV risk factor and excluded those with severe congestive heart failure or renal impairment, “it was a much higher risk population in the CARES trial,” he says, with all participants having a history of major CV disease prior to enrollment.
Another major difference was that the FAST participants were already receiving a stable dose of allopurinol before study entry, with a median treatment duration of 6 years, whereas CARES “gave you data on people getting really started on one versus another,” notes Singh. The inclusion criteria for CARES specified that patients should have serum urate levels of at least 7 mg/dL (0.38 mmol/L), or at least 6 mg/dL (0.33 mmol/L) with inadequately controlled gout after a 1- to 3-week washout period from previous therapies.
Following CARES, the FAST study of CV safety with febuxostat provides “additional evidence in a different patient population”, and we now have “two very large studies, two very well done studies” providing data on CV risk, summarizes Singh.
‘Continued uncertainty’ about febuxostat safety
Steven Nissen, on the other hand, views the FAST results less favorably, and believes that the trial has a number of limitations that “leave great uncertainty about the safety of febuxostat.”
He notes that FAST was not a blinded study and that it was underpowered, with fewer CV events than anticipated. Moreover, because only approximately a third of participants had pre-existing CV disease, the trial was “not studying the population for which the concern existed,” he adds.
“You're much less likely to have a cardiovascular adverse event including death if you're healthier.”
Nissen also notes that “twice as many patients stopped randomized therapy in the febuxostat group as in the allopurinol group,” which may have influenced the results. In all, 32.4% of febuxostat-treated patients discontinued treatment, compared with 16.5% of those in the allopurinol group, and the FAST investigators speculate that this difference may have been due to higher rates of colchicine use in the febuxostat arm (3.6 vs 3.1%), or an increased likelihood of discontinuation due to switching from established allopurinol therapy.
“I don't think [the FAST trial] answers the question, and we're left with continued uncertainty,” says Nissen.
Nissen believes that “what we really need here is probably a third trial, larger, in patients with cardiovascular disease,” which is blinded and not open-label, to evaluate CV safety in an at-risk population.
regulatory agencies should reconsider the limitations imposed for the use of febuxostat in patients with CV risk”
Singh agrees that “there are still some pieces of the puzzle missing” that were not addressed by the CARES and FAST studies, and recommends that future studies should evaluate:
- the CV risk associated with febuxostat in gout patients with concomitant diabetes and known CV disease;
- whether this risk varies by sex; and
- the CV risk of febuxostat in patients with tophaceous gout.
Will the regulatory advice change?
In light of the FAST results, Fernando Pérez-Ruiz, Editorial Board Member for Medicine Matters rheumatology and FAST co-investigator, says that “regulatory agencies should reconsider the limitations imposed for the use of febuxostat in patients with CV risk.”
He also notes that among patients achieving serum urate levels below 5 mg/dL (0.3 mmol/L) in the study, febuxostat was associated with a lower risk for the primary endpoint than allopurinol.
“While EULAR recommended to avoid very low serum urate levels while on therapy, FAST has not shown any danger signal for such patients,” and guidance “discouraging a lower serum urate target” should be re-evaluated, Pérez-Ruiz says.
Conversely, Nissen believes that the FAST trial “does not entirely address the problem” of febuxostat safety due to the limitations of the study.
“I don't know what the regulators will do,” but “I don't think it [will] change recommendations,” he says.
How should the trial results inform rheumatology practice?
Although it is currently unknown whether the regulatory advice will change, Singh believes that “any additional data like those from the FAST trial do help providers,” and rheumatologists “can [now] have a more informed discussion with their patients, given the new data.”
He thinks that “different patients and providers, depending on their risk averseness, will look at the data differently.” For instance, “for a more conservative patient–provider dyad, these data [might provide] some additional comfort in the ability to use febuxostat,” whereas “those that value efficacy a little more may be comforted even more with additional data about cardiovascular risk with febuxostat,” he says.
Singh also notes that patients’ own CV risk factors, including family history of CV disease, lifestyle factors, age, and sex, should influence “their comfort in choosing febuxostat.”
He stresses that “in all these instances, febuxostat is a second-line drug, so by the time you’re getting to it, you either have not responded to, or cannot tolerate [allopurinol].”
And Nissen believes that patients who are “doing well on allopurinol [should] stay on it,” but if people are at high risk for Stevens–Johnson syndrome or have had an adverse reaction to allopurinol, “then it’s probably not unreasonable” to take febuxostat.
Better CV risk management is needed
Both Nissen and Singh emphasize the importance of better management of CV risk in people with gout.
Nissen points out that “only a modest fraction” of participants in the FAST trial were taking statins or other cardioprotective therapies, highlighting that healthcare providers should do a “better job of treating cardiovascular risk factors” in people with gout.
Singh agrees, noting that “[r]egardless of the drug they’re choosing, [gout] is a huge risk factor for cardiovascular morbidity and mortality,” and so all patients “should get early screening, regular screening, and appropriate management of cardiovascular risk.”
He adds: “That applies to 100% of our patients, 100% of the time, but is something we still, as a provider community, need to do a much, much better job at.”
Singh points out that people with diabetes “tend to get cardiovascular risk screening and detection a decade earlier and much more aggressively” than those with gout, and stresses that “the same set of algorithms have to come into gout.”
As to whether patients considering or taking febuxostat should undergo additional CV monitoring, Singh thinks “the jury is still out” and notes that the cost-effectiveness of such an approach would need to be investigated.
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