Online link: https://sci-hub.tw/10.1056/NEJMoa1710895

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 was 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.

–          This is a double-blinded randomized controlled trial with a total population of 6190 patients. During this RCT, some pts had to discontinue treatment prematurely in both the febuxostat group and in the allopurinol group (57.3% and 55.9%, respectively) and this was due to non-compliance, intolerable side effects and other personal reasons.

–          Enrolled patients were from North-American clinical sites from April of 2010 through May 2017.

–          Every single pts included in this study had a history of gout and major cardiovascular disease (history of myocardial infarction, hospitalization for unstable angina, transient ischemic attack, stroke, peripheral vascular disease, or diabetes mellitus).

–          Patients were randomly assigned to receive either febuxostat or allopurinol once daily and were followed for a median of 32 months after the initiation of treatment with either febuxostat or allopurinol.

–          At 2 weeks checkup for serum urate levels, pts who received allopurinol reported lower levels of serum urate than those who received febuxostat. This trend continued for the remaining of the weeks of this study. Even though the difference between in serum urate levels was not significantly that large, its important to note it.

–          The gout flares were similar in both treatments (0.68 and 0.63 flares per patient-year in the febuxostat group and allopurinol group, respectively).

–          Risk of death from a cardiovascular event and the overall mortality rate was higher in those pts who were treated with febuxostat than those treated with allopurinol. Among the cardiovascular deaths, sudden cardiac death had the highest prevalence which was seen in 2.7% in the febuxostat group while in the allopurinol group only 1.8% experienced sudden cardiac death. However, the rate of hospitalization for HF, arrythmias, TIAs and VTEs were similar in both groups. To clarify this, treatment with febuxostat resulted in overall similar cardiovascular events as those who received allopurinol, however cardiovascular death and deaths from any cause were more frequent in the febuxostat group than in the allopurinol group.