When febuxostat—the generic name for Uloric—was being developed by Takeda Pharmaceuticals, initial clinical trials revealed an overall increase in Uloric cardiovascular events of a non-fatal nature.

This data was gathered in comparison to a competing medication for gout—an arthritis characterized by elevated levels of uric acid in the blood—known as allopurinol.

The slight elevation in non-fatal Uloric cardiovascular events over allopurinol spurred the U.S. Food and Drug Administration (FDA) to only approve Uloric with the stipulation that an extensive post-market cardiovascular study be undertaken.

This study was expected to be long-term and the results were just published in the New England Journal of Medicine in March 2018. Febuxostat, or Uloric, was approved in 2009.

The data from the study, according to an article by P&T Community, pointed to a surprising conclusion—Uloric cardiovascular events tended to have a fatal outcome in patients already diagnosed with prior heart disease.

The two gout medications produced statistically similar data when measuring the number of cardiac arrests, strokes, and emergent surgeries for heart angina without fatal consequences. Also, statistics were likewise similar when it came to death from cardiac events without a prior heart disease diagnosis among the two drugs.

The principal investigator of the study, William B. White, M.D., indicates in the study’s journal review that the results were unexpected.

As mentioned in the P&T Community article, he controlled for all variables such as race and ethnicity, gender, age, and length of time with gout diagnosis and symptom severity. Across the board, Uloric cardiovascular events had more fatal consequences in those with heart disease.

Heart disease itself is associated with gout, as high blood uric acid levels have been known to contribute to heart problems such as high blood pressure, angina, and heart attack. Purportedly, febuxostat was developed to provide a choice to gout patients that might be safer.

Allopurinol, approved in 1966, had been known to cause issues with the kidneys and, in those of African-American descent, sometimes produced a severe allergic reaction.

Both allopurinol and Uloric are xanthine-oxidase inhibitors which work in conjunction with lifestyle incorporating regular exercise and dietary changes to keep the build-up of uric acid at bay.

Details of the 2010 CARES Trial

The clinical study, known as the CARES trial, started in 2010 and eventually involved over 6,000 patients. The enrollees for the trial all had a primary diagnosis of gout and symptoms of heart disease. These symptoms varied from a history of cardiac arrest to random chest pain, stroke, and peripheral artery disease.

Each patient’s health status and events were tracked from two and a half to six and a half years. Three-thousand enrollees were taking allopurinol and the other half took febuxostat or Uloric—participants were blinded as to the identity of the drug they were taking.

Not every participant in the CARES trial completed the study. Of those that dropped out, it is not known if they continued to take Uloric or allopurinol by prescription.