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Cardiovascular safety of Febuxostat or Allopurinol in patients with gout

Cardiovascular safety of Febuxostat or Allopurinol in patients with gout Cardiovascular safety of Febuxostat or Allopurinol in patients with gout
Cardiovascular safety of Febuxostat or Allopurinol in patients with gout Cardiovascular safety of Febuxostat or Allopurinol in patients with gout

Gout is a chronic inflammatory disorder characterized by hyperuricemia, arthropathy, tophus development, and urolithiasis.

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Key take away

In patients with gout and major cardiovascular coexisting conditions, febuxostat was non-inferior to allopurinol with respect to rates of adverse cardiovascular events.

Background

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.

Method


Study outcomes:

  • Primary composite end point: First occurrence of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or urgent revascularization for unstable angina.
  • Secondary safety end points: Composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke as well as the individual components of the primary end point
  • Additional safety end points included death from any cause, urgent cerebrovascular revascularization, transient ischemic attack, hospitalization for heart failure, arrhythmias not associated with ischemia, and venous thromboembolic events


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.

Result

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:

  • Primary Endpoints: In the complete analysis, a primary end-point event occurred at similar rates in the febuxostat group (10.8) and the allopurinol (10.4%) group at a median period of 32 months
  • Secondary Endpoints: In the analysis of the nonfatal secondary endpoints, the hazard ratios were consistent with the overall result. However, the risk of cardiovascular death was higher in the febuxostat group than in the allopurinol group. Among the causes of cardiovascular death, sudden cardiac death was the most common classification, occurring in 83 patients (2.7%) in the febuxostat group and 56 patients (1.8%) in the allopurinol group. Rates of hospitalization for heart failure, hospital admissions for arrhythmias and ischemic attacks, venous thromboembolic events were similar in the two groups.


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.

Conclusion

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.

Limitations

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.

Clinical take-away

Febuxostat is associated with greater adverse cardiovascular events and is therefore non-inferior to Allopurinol.

Source:

N Engl J Med 2018; 378:1200-1210

Article:

Cardiovascular Safety of Febuxostat or Allopurinol in Patients with Gout

Authors:

William B. White et al.

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