Patient-Oriented Evidence That Matters

Febuxostat Increases All-Cause and Cardiovascular Mortality Compared with Allopurinol


Am Fam Physician. 2018 Sep 15;98(6):385.

Clinical Question

Do febuxostat (Uloric) and allopurinol differ with regard to cardiovascular safety?

Bottom Line

For patients with gout who require treatment to lower their uric acid level, allopurinol is a safer option than febuxostat. (Level of Evidence = 1b–)


Because gout is an independent risk factor for cardiovascular events, manufacturers of medications for gout, such as febuxostat, have been asked to perform safety trials. The authors of this trial recruited 6,190 patients with known cardiovascular disease and gout with a serum uric acid level greater than 7.0 mg per dL (420 μmol per L), or greater than 6.0 mg per dL (360 μmol per L) if the gout was poorly controlled. The uric acid level was measured after a one- to three-week washout period. The mean age of participants was 64 years, 84% were men, and 70% were white. This was a noninferiority study comparing febuxostat with allopurinol, with noninferior defined as a less than 30% increase in the risk of a combined cardiovascular end point. The dose was titrated using an investigator-masked computer system based on renal function and the amount of drug needed to achieve a serum uric acid level of less than 6.0 mg per dL. Although the data safety monitoring board saw noninferiority with regard to the composite outcome, they saw a trend toward an increase in mortality rates, so the study ran until its conclusion. The mean duration of treatment was approximately two years, and the mean duration of follow-up was just less than three years. Notably, more than one-half of the patients discontinued the study drug, with similar rates between the study groups. Near five years, the mortality curves separated, with higher cardiovascular and all-cause mortality in the febuxostat group. Specifically, cardiovascular mortality was 3.2% in the allopurinol group and 4.3% in the febuxostat group (P = .03; number needed to treat to harm [NNTH] over 2.7 years = 90), while the all-cause mortality was also higher in the febuxostat group compared with the allopurinol group (7.8% vs. 6.4%; P = .04; NNTH over 2.7 years = 71). The overall dropout risk was 56%, which is a concern. Notably, febuxostat was not any better for symptom control, with episodes of flare-ups similar between the groups (0.68 episodes per year for febuxostat vs. 0.63 for allopurinol).

Study design: Randomized controlled trial (double-blinded)

Funding source: Industry

Allocation: Uncertain

Setting: Outpatient (any)

Reference: White WB, Saag KG, Becker MA, et al.; CARES Investigators. Cardiovascular safety of febuxostat or allopurinol in patients with gout. N Engl J Med. 2018;378(13):1200–1210.

POEMs (patient-oriented evidence that matters) are provided by Essential Evidence Plus, a point-of-care clinical decision support system published by Wiley-Blackwell. For more information, see http://www.essentialevidenceplus.com. Copyright Wiley-Blackwell. Used with permission.

For definitions of levels of evidence used in POEMs, see http://www.essentialevidenceplus.com/product/ebm_loe.cfm?show=oxford.

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This series is coordinated by Sumi Sexton, MD, Editor-in-Chief.

A collection of POEMs published in AFP is available at https://www.aafp.org/afp/poems.



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