Similar Cardiovascular Risk Reported in Patients Initiating Febuxostat vs Allopurinol

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The risk for cardiovascular events and all-cause mortality was similar between febuxostat and allopurinol initiators.
The risk for cardiovascular events and all-cause mortality was similar between febuxostat and allopurinol initiators.

A comparison of older patients with gout with and without existing cardiovascular disease (CVD) starting febuxostat vs allopurinol found no significant differences in risk for CV events or all-cause mortality, according to data published in Circulation. In febuxostat initiators, the risk for all-cause mortality was slightly higher after long-term use and the risk for heart failure (HF) exacerbation was slightly decreased.

A retrospective cohort study used Medicare data from 2008 to 2013 to examine the association between initiation of xanthine oxidase inhibitor therapy and subsequent CVD risk, assessing medical records of patients with gout who were ≥65 years and who had recently begun febuxostat (n=24,936) or allopurinol (n=74,808) therapy. Participants were propensity score matched in a 1:3 fixed ratio to control for possible confounders and had similar baseline characteristics (median age, 76 years; 52.3% men; 12% with existing CVD).

A composite measure of hospitalization for myocardial infarction (MI) or stroke was the primary outcome. Secondary outcomes included individual measures of hospitalization for stroke, MI, new or recurrent HF, and coronary revascularization, as well as all-cause mortality.

For the primary outcome, febuxostat initiators demonstrated an incidence rate of 3.43 (95% CI, 3.22-3.66), and those beginning allopurinol had an incidence rate of 3.36 (95% CI, 3.25-3.49). When researchers compared febuxostat with allopurinol, the hazard ratio (HR) for the primary outcome was 1.01 (95% CI, 0.94-1.08; log-rank test P =.83).

For the secondary outcomes, researchers found similar CV risk profiles for both groups in most categories, including all-cause mortality (log-rank test P =.15). Analyses of subgroups (CVD vs no CVD at baseline and high vs low CVD risk) and sensitivities (equipotent dosing of ≥40 mg and ≥300 mg of febuxostat and allopurinol, respectively) also yielded equivocal findings between groups.

Researchers observed a slightly reduced HF exacerbation risk (HR, 0.94; 95% CI, 0.91-0.99) for febuxostat initiators and a mildly elevated risk for all-cause mortality (HR, 1.25, 95% CI 0.56-2.80) for those taking febuxostat >3 years, but neither was statistically significant.

Study strengths included an active comparator design minimizing unmeasured confounding, a large sample size enhancing generalizability, use of propensity score matching to adjust for covariates, use of validated outcome measurements, and inclusion of a representative Medicare population regardless of CVD at baseline.

Study limitations included potential misclassification bias, possible confounding secondary to lack of Medicare information on cause-specific mortality and other clinical measures, a low proportion of men, less clear effect of long-term febuxostat use, lack of comparison with untreated patients with gout, and possible underdosing and inadequate therapy secondary to not having patient uric acid levels available.

The effect on CV safety, CVD development, and mortality appeared to be similar for allopurinol and febuxostat in patients starting new therapy regimens. However, the authors also observed that, "there is a suggestion for an increased risk of all-cause mortality associated with long-term use of febuxostat versus allopurinol."

Disclosures: SCK has received research grants to the Brigham and Women's Hospital from Roche/Genentech, Pfizer, Bristol-Myers Squibb, Merck, and AstraZeneca for unrelated studies. RJD has received research grants to the Brigham and Women's Hospital from Merck. TN, EHK, JL and MZ have nothing to disclose. DHS has received research grants to the Brigham and Women's Hospital from Lilly, Pfizer, AstraZeneca, Genentech, Amgen and CORRONA. DHS serves in an unpaid role on a trial sponsored by Pfizer unrelated to the current study.

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Reference

Zhang M, Solomon DH, Desai RJ, et al. Assessment of cardiovascular risk in older patients with gout initiating febuxostat versus allopurinol: a population-based cohort study [published online June 13, 2018]. Circulation. doi:10.1161/circulationaha.118.033992

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