Perspective from Joep Perk, MD, PhD, FESC
August 31, 2018
3 min read

FREED: Febuxostat shows renoprotective effect; cardioprotection unclear

Perspective from Joep Perk, MD, PhD, FESC
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Kunihiko Matsui
Kunihiko Matsui

MUNICH — A study evaluating the occurrence of CV, cerebrovascular and renal events in elderly patients with hyperuricemia showed that lowering serum uric acid levels with febuxostat had a greater renoprotective effect than conventional therapy with lifestyle modification.

“Febuxostat has a greater renoprotective effect. However, cardiovascular protection may not be expected compared with renal protection,” Kunihiko Matsui, MD, from Kumamoto University Hospital in Japan, said during a press conference at the European Society of Cardiology Congress.

The FREED study enrolled 1,070 patients aged 65 years and older with serum uric acid > 7 mg/dL to 9 mg/dL and risk for CV, cerebral or renal disease, including a history of type 2 diabetes, hypertension, cerebrovascular disease or renal disorder before enrollment. Patients underwent random assignment to treatment with febuxostat (Uloric, Takeda; n = 537; mean age, 75 years; 69% men) or conventional treatment (n = 533; mean age, 76 years; 69% men), in addition to lifestyle modification. Febuxostat dose could be increased from 10 mg to 40 mg per day, if tolerated. The mean dose at the end of the study was 29 mg. In the conventional-treatment group, allopurinol 100 mg was considered if serum uric acid was elevated. Overall, 27% of patients in the non-febuxostat group received allopurinol. In both groups, doses of febuxostat or allopurinol were adjusted to avoid a serum uric acid level less than 2 mg/dL. Mean serum uric acid was 4.4 mg/dL in the febuxostat group vs. 6.7 mg/dL in the control group.

The primary composite endpoint was death from cerebral or cardiorenal vascular disease, new or recurring nonfatal CAD, new or recurring cerebrovascular disease, arteriosclerotic disease requiring treatment, cardiac failure requiring hospitalization, new atrial fibrillation, renal impairment and death from other causes. During a median follow-up of 36 months, the primary endpoint occurred in 28.7% of the control group vs. 23.3% of the febuxostat group (HR = 0.75; 95% CI, 0.592-0.95).

When the researchers analyzed individual components of the primary endpoint, renal impairment was the most frequent event, and the only significantly different event, at 16.2% in the febuxostat group vs. 20.5% in the control group (HR = 0.745; 95% CI, 0.562-0.987). Among patients with renal impairment, microalbuminuria or mild proteinuria was common in both treatment groups, according to the press release.

However, results showed no difference in CV clinical outcomes examined separately with febuxostat vs. control treatment.

Matsui noted that “febuxostat treatment did not decrease hard endpoint events during the study period.” The trial’s hard endpoint of all-cause mortality, cerebrovascular disease or nonfatal CAD occurred in 4.3% of the febuxostat group vs. 4.9% of the conventional treatment group (HR = 0.861; 95% CI, 0.492-1.506).

In addition, excessive lowering of uric acid levels by febuxostat might be avoided, Matsui said. More than a 7-mg/dL reduction in serum acid level at 12 weeks after treatment was a stronger risk factor for the primary composite endpoint compared with lesser reductions, Matsui said.

Adverse events were similar with either treatment, at 24.6% in the febuxostat group vs. 25.3% in the control group (P = .83). Two patients in the febuxostat group died during follow-up.

A major limitation of the study was sample size, Matsui said.

Febuxostat, a xanthine oxidase inhibitor, was approved by the FDA in 2009 for chronic management of hyperuricemia in patients with gout.

In June, Public Citizen, a nonprofit consumer advocacy organization, petitioned the FDA to remove febuxostat due to what it called “unique, serious – some fatal” CV risks, as reported by

The FREED trial comes on the heels of results from the CARES study presented at the American College of Cardiology Scientific Session in March. As Cardiology Today previously reported, febuxostat was noninferior to allopurinol for adverse CV events in patients with gout and major CV conditions; however, those assigned febuxostat had higher rates of all-cause and CV mortality. Matsui noted that “it remains to be elucidated” whether the mortality results of the CARES trial are due to beneficial effects of allopurinol or deleterious effects of febuxostat.” – by Darlene Dobkowski


Kojima S, et al. Hot Line Session 4. Presented at: European Society of Cardiology Congress; Aug. 25-29, 2018; Munich.

Disclosures: The study was funded by Teijin Pharma. The authors report no relevant financial disclosures.