Cardiovascular Safety of Febuxostat or Allopurinol in Patients with Gout

Kaity Bader, Pharm.D., Smiley’s Family Medicine Clinic

Background: Patients with a diagnosis of gout have an increased risk of cardiovascular (CV) events making  CV safety of medications used for gout a concern. Early febuxostat development trials suggested modestly higher CV event rates when compared with allopurinol and placebo.  As an FDA requirement the CARES trial, Cardiovascular Safety of Febuxostat or Allopurinol in Patients with Gout and Cardiovascular Morbidities, was conducted.

Objective: The purpose of this trial was to assess CV safety of febuxostat, a non-purine xanthine oxidase inhibitor, compared to allopurinol, a purine base analogue xanthine oxidase inhibitor, in patients with gout and history of major CV disease.

Study Design: This trial was a multicenter, randomized, double-blind noninferiority trial.  Takeda Pharmaceuticals funded this trial and participated in trial design, conduct and monitoring along with an independent data safety monitoring committee.  Eligible participants were male ≥50 years of age or female ≥55 years of age with history of major CV or cerebrovascular disease defined as at least one of the following: myocardial infarction (MI), hospitalization for unstable angina, coronary or cerebral revascularization procedure, stroke, hospitalized transient ischemic attack (TIA), peripheral vascular disease, or diabetes with evidence of microvascular or macrovascular disease.  Participants had a diagnosis of gout according to the American Rheumatism Association (ARA) definition and met additional criteria including serum uric acid level ≥7.0 mg/dL at screening or ≥6.0 mg/dL at screening plus inadequately controlled gout, as pre-defined by the investigators.

At the screening visit, previous gout therapy was discontinued for a 1 to 3 week washout period.  Participants were initiated on colchicine 0.6 mg daily. This was given as monotherapy during the washout period and continued concomitantly with study drug for a total of 6 months of colchicine therapy. Participants were randomized and stratified by renal function to received either febuxostat or allopurinol once daily as study drug.  Initial allopurinol dose was renal-adjusted and doses for both allopurinol and febuxostat were titrated up based on serum urate levels following a pre-defined protocol.

The primary endpoint was a composite measure including first occurence of CV death, non-fatal MI, nonfatal stroke, and urgent revascularization for unstable angina.  The individual components of the primary composite were measured as secondary endpoints and death from any cause was measured as a safety endpoint. To assess non-inferiority, the CARES trial was designed to accrue a total of 624 primary events. Non-inferiority determination would be made if the upper bound of the hazard ratio (HR) was less than 1.3.

Results: A total of 6190 participants were included in the modified intention-to-treat analysis.  High rates of discontinuation were noted for both febuxostat and allopurinol groups, 57.3% and 55.9%, respectively. The median duration of exposure and duration of follow-up were 728 days and 968 days for febuxostat and 719 days and 942 days for allopurinol, respectively.  The modified intention to treat analysis in this trial included participants who received at least one dose of trial medication. Therefore, patients who discontinued therapy were included in the analysis rates.

The primary composite outcome occurred in 10.8% of patients in the febuxostat group and 10.4% of patients in the allopurinol group. The HR for primary composite outcome was 1.03 [97% CI 0.87 - 1.23] demonstrating non-inferiority of febuxostat.  The secondary endpoint of CV death comparing febuxostat and allopurinol was HR 1.34 [95% CI 1.03 - 1.73] and death from any cause was HR 1.22 [95% CI 1.01 - 1.47]. No other secondary endpoints demonstrated statistical significance. Of note, the serum urate levels and gout flares between arms were similar, although not collected or analyzed for statistical significance.

Conclusions: Participants with a history of CV disease and current uncontrolled gout requiring additional serum urate level lowering therapy had similar outcomes with febuxostat compared to allopurinol in regard to the primary composite endpoint of first occurence of CV death, non-fatal MI, nonfatal stroke, urgent revascularization for unstable angina.  However, statistical significance was found showing increased risk for CV death and death from any cause with febuxostat when compared to allopurinol.

Limitations: A significant limitation of this trial was the large discontinuation and loss to follow-up rate.  Despite rates between arms being similar, the trial did not provide further information regarding these rates.  Discontinuation of treatment may create bias toward the null hypothesis, creating a potential to miss a statistically and clinically significant difference between arms for the primary and other endpoints.  It should also be noted that the manufacturer of febuxostat and colchicine, two medications used in the trial, funded and supported the trial presenting a risk of bias. Although doses of both medications were titrated according to urate levels, neither medication was titrated up to the maximum dose.

Key Point: Participants in the CARES trial with gout and history of CV disease treated with febuxostat has similar outcomes in regard to overall major CV events as those treated with allopurinol.  Outcomes for CV death and all cause mortality were higher in participants receiving febuxostat therapy.

White WB, Saag KG, Becker MA, et al. Cardiovascular safety of febuxostat or allopurinol in patients with gout. N Engl J Med. 2018;378(13):1200-10. doi:10.1056/NEJMoa1710895.