Febuxostat (Uloric) emerged as noninferior to allopurinol regarding risk of cardiovascular death among people 60 years and older with gout and at least one additional cardiovascular risk factor, results of the Febuxostat versus Allopurinol Streamlined Trial (FAST) suggest.
Dr. Thomas MacDonald
This primary outcome of the FAST trial stands in contrast to results of the CARES trial in 2018. The CARES researchers previously reported a 4.3% increased risk of cardiovascular death associated with febuxostat, compared with a 3.2% rate with allopurinol, a statistically significant 34% increase in the relative risk.
“In contrast to previous studies, there was no evidence of increased mortality with febuxostat, and we believe the regulators should review febuxostat licensing restrictions,” senior author Thomas MacDonald, MD, of the University of Dundee (Scotland), said during a late-breaking abstract session at the virtual annual meeting of the American College of Rheumatology.
The results of the FAST trial were simultaneously published online in The Lancet.
Both febuxostat and allopurinol treat gout by lowering urate levels. Concerns about the cardiovascular safety of febuxostat led to two post-licensing studies: the Cardiovascular Safety of Febuxostat and Allopurinol in Participants with Gout and Cardiovascular Comorbidities (CARES) study, mandated by the U.S. Food and Drug Administration, and FAST, requested by the European Medicines Agency. In February 2019, the FDA added a warning about elevated cardiovascular death and death risk associated with febuxostat.
“When CARES was published, it was somewhat of a threat to our study,” Dr. MacDonald said. “After hearing from our data-monitoring committee, we were told we could continue the trial.”
Some switched from allopurinol to febuxostat
So Dr. MacDonald, lead author Isla Mackenzie, MBChB, and their colleagues enrolled 6,128 people with gout in the United Kingdom, Sweden, and Denmark between December 2011 and January 2018. They followed patients for a median of 4 years. Participants had a mean age of 71 years, 85% were men, and 33% had a history of cardiovascular disease. The investigators excluded anyone with a stroke or myocardial infarction in the previous 6 months.
All participants were being treated with allopurinol. The investigators titrated those not at target up to an ideal dose that achieved a serum urate concentration of less than 0.357 mmol/L (< 6 mg/dL). Next, they randomly assigned 3,065 people to continue allopurinol and another 3,063 to switch to 80-120 mg of febuxostat.
The primary outcome of the multicenter, prospective, randomized, open-label FAST trial was a composite of hospitalization for nonfatal MI or biomarker positive for acute coronary syndrome, nonfatal stroke, or cardiovascular death.
Key findings
“There was definitely a noninferior primary outcome,” Dr. MacDonald said. In the on-treatment analysis, 172 patients in the febuxostat group reached the composite endpoint versus 241 patients in the allopurinol group. There were 1.72 events per 100 patient-years in the febuxostat group versus 2.05 events in the allopurinol group (adjusted hazard ratio, 0.85; 95% confidence interval, 0.70-1.03). An intent-to-treat analysis also found that febuxostat was noninferior to allopurinol on this measure.
Urate levels were approximately 80 micromoles lower in the febuxostat group versus the allopurinol group each year of the study, Dr. MacDonald said.
At least one gout flare was experienced by 1,017 patients in the febuxostat group and by 1,044 participants in the allopurinol group. “However, there was no placebo group, so we don’t know the effectiveness of either of these agents at preventing flares” based on this research, he said.
Both the on-treatment and intention-to-treat (ITT) secondary analyses demonstrated the noninferiority of febuxostat, compared with allopurinol, for all-cause death, each individual component of the composite primary outcome – cardiovascular death, hospitalization for heart failure, and hospitalization for new, unstable, or worsening angina.
In contrast, the ITT analysis revealed a “nominally significant increase” in hospitalization for arrhythmia with no evidence of ischemia in the febuxostat group. The 0.583 events per 100 patient-years in this group versus 0.385 events in the allopurinol cohort generated an adjusted HR of 1.51 (95% CI, 1.05-2.17).
In terms of all-cause mortality, 222 participants (7.2%) in the febuxostat group died, compared with 263 people (8.6%) in the allopurinol group.
Adverse events and withdrawals
A total 1,720 participants (57.3%) in the febuxostat group experienced at least one serious adverse event, as did 1,812 participants (59.4%) in the allopurinol group. Less than 1% of serious adverse events in each group were considered treatment-related.
Dr. MacDonald said that 6.2% of the febuxostat patients and 5.5% of the allopurinol group withdrew from the study. “We had pretty good follow-up [94%],” Dr. MacDonald said. “I don’t want to criticize CARES, but 47% did drop out of that study, and they could not follow them anymore.”
Limitations of FAST include its open-label design and lack of a placebo group, although Dr. MacDonald pointed out that a placebo group would have been unethical. Strengths included its large randomized trial design and good external validity, he added. “This is what will happen in clinical practice if you switch people from allopurinol to febuxostat.”
When asked how he would treat people with gout now given the FAST findings, Dr. MacDonald said, “I’m not a rheumatologist, I’m a cardiovascular physician. But I would say from the evidence from the FAST trial, it appears to be safe to give patients febuxostat whether or not they have cardiovascular risk factors or prior cardiovascular disease.”
“The FAST study indicates that febuxostat is similar to allopurinol in terms of cardiovascular events during the treatment period. The strengths of this study are its large sample size, excellent follow-up rate, and the relatively long follow-up time,” session moderator Shervin Assassi, MD, said when asked for comment. Dr. Assassi, director of the division of rheumatology at the University of Texas Health Science Center at Houston, was not involved in the research.
Menarini, Ipsen, and Teijin Pharma funded the study. The University of Dundee receives research funds from Menarini. Dr. MacDonald disclosed that he received speaker or consultant fees from Menarini. Dr. Assassi had no relevant disclosures.
SOURCE: MacDonald T et al. Arthritis Rheumatol. 2020;72(suppl 10). ACR 2020, Abstract L08.