Evaluation of the Relationship Between Serum Urate Levels, Clinical Manifestations of Gout, and Death From Cardiovascular Causes in Patients Receiving Febuxostat or Allopurinol in an Outcomes Trial

Abstract

Objective: To investigate whether serum urate levels, number of gout flares, and tophi burden are related to death from cardiovascular (CV) causes after treatment with febuxostat or allopurinol in patients with gout from the Cardiovascular Safety of Febuxostat or Allopurinol in Patients With Gout and Cardiovascular Comorbidities (CARES) trial.

Methods: Patients were randomly assigned to receive febuxostat (40 mg or 80 mg once daily, according to serum urate levels at week 2) or allopurinol titrated in 100-mg increments from 200-400 mg or 300-600 mg (with dose determined according to kidney function). Changes from baseline in serum urate level, gout flares, and tophus resolution were key exploratory efficacy parameters in the overall population and in subgroups of patients who died and those who did not die from a CV-related cause. The latter subgroup included patients who died due to non-CV causes and those who did not die due to any cause.

Results: Patients received treatment with febuxostat (n = 3,098) or allopurinol (n = 3,092) for a median follow-up period of 32 months (for a maximum of 85 months). In the overall population, mean serum urate levels were lower in those receiving febuxostat compared with those receiving allopurinol at most study visits. There were no associations between serum urate levels and death from CV causes with febuxostat. The number of gout flares requiring treatment was higher within 1 year of treatment with febuxostat compared with allopurinol (mean incidence of gout flares per patient-years of exposure 1.33 versus 1.20), but was comparable thereafter and decreased overall throughout the study period (mean incidence of gout flares per patient-years of exposure 0.35 versus 0.34 after 1 year of treatment; overall mean incidence 0.68 versus 0.63) irrespective of whether the patient died from a CV-related cause. Overall, 20.8% of patients had ≥1 tophus at baseline; tophus resolution rates were similar between treatment groups, with cumulative resolution rates of >50%.

Conclusion: In the CARES trial, febuxostat and allopurinol (≤600 mg doses) had comparable efficacy in patients with gout and CV disease, and there was no evidence of a relationship between death from CV causes and serum urate levels, number of gout flares, or tophus resolution among the patients receiving febuxostat.

Trial registration: ClinicalTrials.gov NCT01101035.

© 2022 The Authors. Arthritis & Rheumatology published by Wiley Periodicals LLC on behalf of American College of Rheumatology.

Figures

Figure 1

Change in mean serum urate (sUA) levels in patients receiving febuxostat and those receiving allopurinol in the overall modified intent‐to‐treat (ITT) population (A) and in the subgroup of patients who died from a cardiovascular (CV)–related cause compared with patients who did not die from a CV‐related cause (B). The modified ITT population comprised patients randomized to a treatment group who received ≥1 dose of study drug. Bars show the mean ± SD. Patient numbers are summarized in Supplementary Table 2 (available on the Arthritis & Rheumatology website at http://onlinelibrary.wiley.com/doi/10.1002/art.42160). The number of patients in each subgroup who had serum urate (sUA) data at months 60 and 72 was too low (n ≤ 5) to allow for meaningful interpretation of serum urate levels at these time points.

Figure 2

Gout flares requiring treatment among patients receiving febuxostat or allopurinol in the overall modified ITT population (A) and in the subgroup of patients who died from a CV‐related cause compared with patients who did not die from a CV‐related cause (B). The modified ITT population comprised patients who were randomized to a treatment group and received ≥1 dose of study drug. Symbols represent the mean number of gout flares per patient‐years of exposure, with numbers of patient‐years shown in the tables below the graphs. See Figure 1 for definitions.