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Febuxostat increases all-cause and CV mortality compared with allopurinol
Clinical Question
Do febuxostat 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 (Uloric). 1b-
Reference
Study design: Randomized controlled trial (double-blinded)
Funding: Industry
Setting: Outpatient (any)
Synopsis
Because gout is an independent risk factor for cardiovascular (CV) events, manufacturers of medications for gout, such as febuxostat, have been asked to perform safety trials. The authors recruited 6190 patients with known cardiovascular disease and gout with a serum uric acid level greater than 7.0 mg/dL (420 mmol/L), or greater than 6.0 mg/dL (360 mmol/L) if the gout was poorly controlled. The uric acid level was measured after a 1-week to 3-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 CV 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/dL. Although the data safety monitoring board saw noninferiority with regard to the composite outcome, they saw a tened toward an increase in mortality rates, so the study ran until its conclusion. The mean duration of treatment was approximately 2 years, and the mean duration of follow-up just less than 3 years. Notably, more than half the patients discontinued the study drug, with similar rates between the study groups. Near 5 years, the mortality curves separated, with higher CV 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. Note that febuxostat also wasn't any better with symptom control, with episodes of flares similar between the groups (0.68 episodes/year for febuxostat vs 0.63 for allopurinol).
Reviewer
Mark H. Ebell, MD, MS
Professor
University of Georgia
Athens, GA
Comments
I am concerned about the tendency to go to uric acid lowering drugs. I have seen other practitioners start with only elevated uric acid or one attack of gout the trigger. One patient after one attack had a most severe exfoliative dermatitis.
I do prefer amore conservative approach; xyloprim after 3 attacks
What about the zero comparison? The effect of Zyloprim on CAD compared to no treatmrent
Uliric is often marketed as dropping Utica acid level more than allopurinol, could it be that those on this drug are less healthy than those on allopurinol?
good poem
I did not prescribe yet this new medication for gout and after this information, I will not prescribe this med.
Il est important de réaliser que febuxostat a un impact sur la mortalité cardiovasculaire. Il aurait été intéressant de voir avec quelle fréquence les gens arrêtent l’allopurinol. Mais en gros je vais favoriser l’allopurinol.
very informative . I always prescribed Allupurinol for Gout pts to control high uric acid
I wonder how the cardiovascular mortality rate even with allopurinol compares with placebo in patients with gout. Too bad they didn’t have a placebo arm
Noninferiority, another word for "it is pretty close, not as good, but close enough to justify the use of this new markedly more expensive drug".