乌鸦传媒

ORLANDO -- The two most common preventive medications for gout -- febuxostat (Uloric) and allopurinol -- came out largely similar for cardiovascular outcomes, except for a worrying and unexplained higher risk of mortality with febuxostat, the CARES trial showed.

Rates for the primary endpoint of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or unstable angina with urgent revascularization were 10.8% on febuxostat and 10.4% on allopurinol (P=0.002 for noninferiority) in the modified intent-to-treat population of 6,190 gout patients.

However, febuxostat raised the risk of all-cause mortality significantly (HR 1.22, 95% CI 1.01-1.47), driven by an excess in cardiovascular death (HR 1.34, 95% CI 1.03-1.73) and particularly sudden cardiac death (2.7% vs 1.8%).

At this point, there is no known explanation for the mortality risk seen with febuxostat, William White, MD, of the University of Connecticut in Farmington, reported here at the American College of Cardiology meeting late-breaking clinical trial session. The findings were simultaneously released online in the New England Journal of Medicine.

Despite the unclear mechanism, the consistency of the finding across the intent-to-treat and on-treatment analysis made the excess mortality risk "relatively robust" such that it "likely should be used to inform policy," said Noel Bairey Merz, MD, of Cedars-Sinai Hospital in Los Angeles and a member of the discussion panel at the session.

The febuxostat development program across more than 5,000 patients showed a higher rate of cardiovascular events -- albeit not with a mortality signal -- than seen with allopurinol, such that the FDA required the long-term CARES study as a condition of approval, focusing specifically on cardiovascular safety.

The FDA issued a safety alert about the cardiovascular death risk with febuxostat in November 2017, based on preliminary analysis of CARES. The agency said at that time that it would conduct a full review of the data and issue an update after the full data was available.

CARES, which had a considerably higher cardiovascular risk population than studied previously, offers perhaps the most reliable yet data on safety, White's group noted.

"The safety outcomes in this trial were prespecified and adjudicated by members of a cardiovascular endpoint committee who were unaware of the treatment assignments; therefore, our safety outcomes may be more reliable than data based on conventional adverse-event reporting," they wrote.

Proatherothrombotic processes aren't likely responsible, given that the nonfatal outcomes were so similar between groups. Likewise, QT interval was not different, White said. Febuxostat had been studied extensively before testing in humans without a signal seen for cardiac rhythm, function, or metabolism problems, White noted.

One potential explanation still being explored is that the small difference seen in gout flares between arms was a factor, White noted. The play of chance is possible but unlikely, he added.

"I also scanned the medical literature for the last four decades I could not find another prospective randomized double-blind trial in which mortality was increased and none of the nonfatal events were," White said. "I do agree the finding is unique."

However, there might still be rationale for using febuxostat for certain groups despite the risk, White suggested. Febuxostat currently is only used for about 8% of gout patients, in part due to the cheap generic availability of allopurinol. "It's typically used in a higher risk population who have chronic kidney disease, who can't tolerate or take allopurinol, or those who have a history of hypersensitivity to allopurinol," he told 乌鸦传媒.

"So I think for those two high risk groups, it still could be useful in consideration. In fact, in our subgroup who did have chronic kidney disease in the trial, the rates of mortality were not significantly increased for febuxostat versus allopurinol. It was actually more of a hazard if you had normal kidney function."

The findings with febuxostat come on the heels of another cardiovascular safety study of gout medications, comparing allopurinol with probenecid (Probalan) in a retrospective Medicare sample. That analysis found a 20% lower overall event risk and a 13% lower risk of all-cause mortality with probenecid.

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