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Cardiovascular Safety of Febuxostat or Allopurinol in Patients with Gout
William B White1, Kenneth G Saag1, Michael A Becker1
1From the University of Connecticut School of Medicine, Farmington (W.B.W.); the University of Alabama, Birmingham (K.G.S.); University of Chicago Medicine, Chicago (M.A.B.), and Takeda Development Center Americas, Deerfield (B.H., M.C., L.G.) - both in Illinois; the State University of New York, Downstate Medical Center, Brooklyn (J.S.B.); Michigan State University College of Human Medicine, Grand Rapids (P.B.G.); and Johns Hopkins University School of Medicine, Baltimore (A.W.).
Insights
Febuxostat was noninferior to allopurinol for cardiovascular events in gout patients. However, febuxostat showed higher all-cause and cardiovascular mortality rates compared to allopurinol.
Area of Science:
- Cardiology
- Rheumatology
- Pharmacology
Background:
- Cardiovascular risk is elevated in patients diagnosed with gout.
- Gout patients often have coexisting cardiovascular conditions.
- Xanthine oxidase inhibitors are commonly prescribed for gout management.
Purpose of the Study:
- To compare cardiovascular outcomes between febuxostat and allopurinol in gout patients with cardiovascular disease.
- To evaluate the noninferiority of febuxostat against allopurinol regarding major adverse cardiovascular events.
- To assess the safety profiles of febuxostat and allopurinol in this patient population.
Main Methods:
- A multicenter, double-blind, noninferiority trial was conducted.
- Patients with gout and cardiovascular disease were randomized to receive either febuxostat or allopurinol.
- Stratification by kidney function and a composite primary endpoint (cardiovascular death, myocardial infarction, stroke, unstable angina) were utilized.
Main Results:
- Febuxostat demonstrated noninferiority to allopurinol for the primary composite cardiovascular endpoint (HR, 1.03; 95% CI, 0.90 to 1.18).
- All-cause mortality was higher in the febuxostat group (HR, 1.22; 95% CI, 1.01 to 1.47).
- Cardiovascular mortality was also significantly higher with febuxostat compared to allopurinol (HR, 1.34; 95% CI, 1.03 to 1.73).
Conclusions:
- Febuxostat is noninferior to allopurinol in preventing major adverse cardiovascular events in gout patients with established cardiovascular disease.
- Physicians should be aware of the increased risk of all-cause and cardiovascular mortality associated with febuxostat compared to allopurinol in this high-risk group.
- The findings suggest a need for careful consideration of febuxostat use in gout patients with comorbid cardiovascular conditions.
Background:
Cardiovascular risk is increased in patients with gout. We compared cardiovascular outcomes associated with febuxostat, a nonpurine xanthine oxidase inhibitor, with those associated with allopurinol, a purine base analogue xanthine oxidase inhibitor, in patients with gout and cardiovascular disease.
Methods:
We conducted a multicenter, double-blind, noninferiority trial involving patients with gout and cardiovascular disease; patients were randomly assigned to receive febuxostat or allopurinol and were stratified according to kidney function. The trial had a prespecified noninferiority margin of 1.3 for the hazard ratio for the primary end point (a composite of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or unstable angina with urgent revascularization).
Results:
In total, 6190 patients underwent randomization, received febuxostat or allopurinol, and were followed for a median of 32 months (maximum, 85 months). The trial regimen was discontinued in 56.6% of patients, and 45.0% discontinued follow-up. In the modified intention-to-treat analysis, a primary end-point event occurred in 335 patients (10.8%) in the febuxostat group and in 321 patients (10.4%) in the allopurinol group (hazard ratio, 1.03; upper limit of the one-sided 98.5% confidence interval [CI], 1.23; P=0.002 for noninferiority). All-cause and cardiovascular mortality were higher in the febuxostat group than in the allopurinol group (hazard ratio for death from any cause, 1.22 [95% CI, 1.01 to 1.47]; hazard ratio for cardiovascular death, 1.34 [95% CI, 1.03 to 1.73]). The results with regard to the primary end point and all-cause and cardiovascular mortality in the analysis of events that occurred while patients were being treated were similar to the results in the modified intention-to-treat analysis.
Conclusions:
In patients with gout and major cardiovascular coexisting conditions, febuxostat was noninferior to allopurinol with respect to rates of adverse cardiovascular events. All-cause mortality and cardiovascular mortality were higher with febuxostat than with allopurinol. (Funded by Takeda Development Center Americas; CARES ClinicalTrials.gov number, NCT01101035 .).
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