Gout Drug Febuxostat Linked to More CV Deaths Without Uptick in CV Events: CARES Trial

ORLANDO, FL—Patients with gout and coexisting cardiovascular disease saw no increase in major cardiovascular events while taking febuxostat versus allopurinol in the CARES trial, but investigators and outside experts are struggling to understand the significantly higher risk of death—both all-cause and cardiovascular—among patients taking febuxostat.

Lack of a clear mechanism “has been the biggest challenge from the perspective of looking at a trial in which the nonfatal events didn’t go in the same direction as the fatal events,” said lead author William B. White, MD (University of Connecticut School of Medicine, Farmington), in a late-breaking session at the American College of Cardiology 2018 Scientific Session.

The drugs each have a lengthy history, with allopurinol earning approval from the US Food and Drug Administration (FDA) in 1966 and febuxostat (Uloric, Takeda) in 2009.

CARES, a noninferiority trial, was conducted at the behest of the FDA as a postmarketing requirement to address the “imbalance in cardiovascular events without a known mechanism [that were] observed during clinical development of febuxostat,” White said.

Last November, the agency issued a safety communication based on preliminary results from CARES.

Asked by TCTMD how much the CV mortality signal would rattle clinicians, White pointed out that it’s not cardiologists prescribing these gout drugs but rather rheumatologists and primary care physicians. They’re likely to be concerned by this finding, he predicted. “Rheumatologists, however, take care of very ill patients where there’s morbidity with all the drugs that they use. So if they’re having substantial efficacy and the person’s been on it 8 years, I suspect they’re just going to continue giving that drug to them. It’s like anything else.”

Analyses are ongoing, White added, so there is not yet a final answer on what’s driving these perplexing results.

Difference Driven by CV Mortality

Published simultaneously online in the New England Journal of Medicine, the CARES trial randomized 6,190 patients (median age of 64-65 years; 84% men) with gout plus coronary, cerebrovascular, or peripheral artery disease or diabetes with small-vessel disease to receive either febuxostat (Uloric; Takeda Pharmaceuticals) or allopurinol. More than half of patients (56.6%) discontinued their trial regimen while taking part in the study, and 45.0% discontinued follow-up; median follow-up duration was 32 months.

“No differences were observed between treatment groups throughout the trial for renal function, blood pressure, electrolytes, or lipids,” White said. Nor were there differences in cardiovascular medication use. While gout flare rates also were similar between groups, urate lowering was greater with febuxostat.

In a modified intention-to-treat analysis that included all patients apart from 8 who never received either drug, the primary endpoint (a composite of CV death, nonfatal MI, nonfatal stroke, or unstable angina with urgent revascularization) was no higher in the febuxostat group than in the allopurinol group (10.8% vs 10.4%; P for noninferiority = 0.002). However, there were significant increases in the risks of all-cause and cardiovascular mortality with febuxostat.

Mortality Risk With Febuxostat vs Allopurinol: Modified Intention-to-Treat

 

Outcomes followed a similar pattern when calculations were restricted to the times patients were on treatment.

While most subgroup analyses were unrevealing, certain medications appeared to influence the risk of cardiovascular mortality.

Patients on NSAIDs had a significant 232% increase in CV death risk with febuxostat versus allopurinol, whereas those not taking NSAIDS had similar risk with both drugs (P for interaction = 0.036). Compared with patients taking aspirin, those not on aspirin appeared to be slightly more vulnerable to CV mortality while on febuxostat (P for interaction = 0.019). Additionally, those taking colchicine saw a significant 217% rise in risk with febuxostat, while those not on that drug fared similarly with either gout medication (P for interaction = 0.062).

“All-cause mortality was greater on febuxostat versus allopurinol due to an imbalance in CV deaths, particularly sudden cardiac death,” White said, adding: “safety analyses from the trial are ongoing to evaluate the unexpected mortality findings in CARES.”

Is It the Drug or Something Else Entirely?

Following the presentation, Athena Poppas, MD (Rhode Island Hospital, Providence), a panelist in the session, pointed out that some of the deaths occurred after patients were no longer on their gout medication and that not all were on guideline-directed medical therapy for cardiovascular disease. Given these complexities, she asked, “how much of [the difference] may or may not be the drug?”

There are some clues to explore that could possibly explain the contradictory findings, White continued. “My rheumatology colleagues feel very strongly that we need to really sensibly look at gout flares, even though the rates weren’t that different between the two treatment groups—it’s known to increase oxidative stress, perhaps cause temporary increases in endothelial dysfunction, and possibly lend itself towards vasomotor abnormalities.”

Another possibility is that there’s an arrhythmogenic effect of febuxostat, though “we simply didn’t find that,” White noted.

Panelist C. Noel Bairey Merz, MD (Cedars-Sinai Heart Institute, Los Angeles, CA), asked for more detail on the aspirin and NSAID interactions, specifically whether the biological mechanism might relate to atherosclerotic plaque composition.

“Certainly, that’s crossed our minds,” White replied, noting that in vivo experiments showed no signs of enhanced thrombotic effect with febuxostat. The rate of urgent revascularization for ACS actually was numerically lower among patients receiving febuxostat versus allopurinol, he added. “And I would’ve thought if gout flares and some proatherogenic phenomenon was occurring, we would’ve seen [the opposite].”

Bairey Merz said that, taken as a whole, the consistency of the various analyses showing an uptick in mortality is “relatively robust and probably should be used to inform policy.”

White, when asked about next steps during the ACC press briefing, emphasized that it was data from CARES that sparked the FDA’s November 2017 safety alert. “They will be doing their typical due diligence investigation of the clinical report over the course of the next several months,” he said, noting that he and the sponsor haven’t “heard anything definitive from them as of yet.”

A press release issued by Takeda said the company is “committed to the scientific exchange of this data to inform the medical community.”

“Patient safety is Takeda’s top priority, and CARES provides physicians with important safety information about Uloric that is useful when evaluating treatment options for patients with hyperuricemia and gout,” Darryl Sleep, MD, head of Takeda Pharmaceuticals’ US Medical Office, notes in the statement. “We are actively working with regulators and medical experts to ensure physicians have comprehensive and accurate information to make educated treatment decisions.”