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Gout is a chronic inflammatory disorder characterized by hyperuricemia, arthropathy, tophus development, and urolithiasis.
In
patients with gout and major cardiovascular coexisting conditions, febuxostat
was non-inferior to allopurinol with respect to rates of adverse cardiovascular
events.
Gout is a chronic inflammatory disorder characterized by
hyperuricemia, arthropathy, tophus development, and urolithiasis. Gout is
reported to be associated with an increased risk of cardiovascular and chronic
kidney disease. Previous studies have reported that the gout patients are at
higher risk of cardiovascular events than the patients without gout.
Febuxostat, nonpurine inhibitor of xanthine oxidase is recommended for the
management of gout as it inhibits both the oxidized and reduced forms of
xanthine oxidase and decreases the formation of uric acid. It provides potent
inhibition of xanthine oxidase and greater hypouricemic activity than
allopurinol. The clinical trials of Febuxostat have suggested a higher rate of
cardiovascular events as compared to placebo and allopurinol involving more
than 5000 gout patients.
Rationale behind research:
Although xanthine oxidase inhibitors are in widespread
clinical use for the treatment of patients with gout, the data on the
cardiovascular safety of these drugs from large, randomized clinical trials are
limited.
This trial was therefore conducted as an FDA requirement to
determine the cardiovascular safety of Febuxostat and allopurinol in patients
with gout and and cardiovascular disease.
Objective:
To compare the cardiovascular
outcomes associated with febuxostat and allopurinol in patients with gout and
cardiovascular disease.
Study outcomes:
Time period: Outpatient visits were scheduled
at screening and randomization and at 2, 4, 6, 8, 10, 12, and 24 weeks after
randomization and every 6 months during subsequent years of the trial.
Outcomes:
Biochemical
Effects: The proportion of patients with a serum urate level of
less than 6.0 mg per deciliter was higher in the febuxostat group than in the
allopurinol group at week 2. After that, at the most points, higher proportions
of patients in the febuxostat group had maintenance of serum urate levels at
less than 6.0 mg per deciliter. Also, a more substantial percentage of patients
in the febuxostat group than in the allopurinol group had serum urate levels of
less than 5.0 mg per deciliter for the entire trial. Overall, the rates of gout
flares were similar in the two treatment groups. There were no significant
differences in serum levels of electrolytes, glucose, or lipids or blood pressure
between the groups during the trial nor were their differences in
cardiovascular medication use.
Safety:
Analyses
of Events That Occurred during Treatment: A primary
end-point event occurred in 7.8% of patients in the febuxostat group and 7.7%
of patients in the allopurinol group. In this analysis, the rate of
cardiovascular death was higher in the febuxostat group than in the allopurinol
group.
Febuxostat
resulted in major cardiovascular events than associated with allopurinol
treatment among patients with gout who had the coexisting cardiovascular
disease. However, cardiovascular death and deaths from any cause were more
frequent in the febuxostat group than in the allopurinol group.
During a development program involving more than 5000 patients, the rate of cardiovascular events was higher among patients treated with febuxostat (0.74 per 100 patient-years; 95% CI, 0.36 to 1.37) than among those treated with allopurinol (0.60 per 100 patient- years; 95% CI, 0.16 to 1.53).
The population in our trial included patients who were at considerably higher cardiovascular risk than those involved in other previous assessments. The safety outcomes in this trial were more reliable than data based on conventional adverse-event reporting. Surprisingly, because of higher cardiovascular deaths, the cause of mortality was higher in the febuxostat group than in the allopurinol group. Findings were similar in the modified intention-to-treat analysis and the prespecified analysis that included events that occurred during treatment and within 30 days after treatment discontinuation.
The pre-clinical cardiovascular studies of febuxostat have shown no toxic effects related to cardiac rhythm, function, or metabolism. In addition, the rates of adjudicated nonfatal events, including myocardial infarction, coronary revascularization, arrhythmias, and hospitalization for heart failure, were similar in the febuxostat group and the allopurinol group.
The only
heterogeneity in the analyses of cardiovascular mortality occurred in two
subgroups-patients with concomitant administration of aspirin or NSAIDs. These
drugs may be associated with more persistent gout flares, which, results in
increases in cardiovascular events. However, we did not find a vast difference
in the reduction in urate level and flare rates between the treatment groups.
Finally, these findings may have been due to chance, given a large number of
tests performed and the small numbers of events in each subgroup.
The biggest limitation of the study was that the large
number of participants discontinued the trial treatment and a large number of
participants did not complete follow-up.
Febuxostat is associated with greater adverse cardiovascular events and is therefore non-inferior to Allopurinol.
N Engl J Med 2018; 378:1200-1210
Cardiovascular Safety of Febuxostat or Allopurinol in Patients with Gout
William B. White et al.
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