Cardiovascular Safety of Febuxostat or Allopurinol in Patients with Gout

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SCIENCE
Cardiovascular Safety of Febuxostat or Allopurinol in Patients with Gout
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.

Gout is a chronic inflammatory disorder characterised by hyperuricemia, arthropathy, tophus development, and urolithiasis. Gout is reported to be associated with an increased risk of cardiovascular and chronic kidney disease. 

ABSTRACT: 
Background: 

Gout is a chronic inflammatory disorder characterised 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 the oxidised as well as the 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 cardiovascular disease.

Objective

To compare the cardiovascular outcomes associated with febuxostat and allopurinol in patients with gout and cardiovascular disease.

Methods: 

 

Study outcomes:

  • Primary Outcomes: The first occurrence of cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or urgent revascularization for unstable angina.
  • Secondary outcomes: The composite of cardiovascular death, nonfatal myocardial infarction, or nonfatal stroke as well as the individual components of the primary endpoint.
  • Additional safety endpoints: Death from any cause, urgent cerebrovascular revascularisation, transient ischemic attack, hospitalisation for heart failure, arrhythmias not associated with ischemia, and venous thromboembolic events.
  • Time Period: Outpatient were scheduled for visits at screening and randomization and at 2, 4, 6, 8, 10, 12, and 24 weeks after randomization and also every 6 months during subsequent years of the trial.
Results: 

Study outcomes

  • Biochemical Effects:

The patients in the febuxostat group showed the more significant decrease in serum urate level than in the allopurinol group at week 2. Even after the 2 weeks, febuxostat group showed the consistent level of serum urate, i.e. 6mg/dl. Also, a more substantial percentage of patients in the febuxostat group than in the allopurinol group had serum urate levels less than 5.0 mg per deciliter for the entire trial. Overall, the rates of gout flares were similar in the two treatment groups. During the trial, no significant difference was shown in serum levels of electrolytes, glucose, or lipids or blood pressure between the groups.

  • Safety:
  • Primary Endpoints: In the complete analysis, a primary end-point event occurred at a median period of 32 months was similar in both febuxostat (10.8%) and allopurinol group (10.4%) (hazard ratio, 1.03; upper bound of one-sided 98.5% with confidence interval [CI], 1.23; P = 0.002 for noninferiority).
  • Secondary Endpoints: In the investigation of the nonfatal endpoints such as the hazard ratios were consistent within the overall study. However, the hazard of cardiovascular death was raised in the febuxostat group than in the allopurinol group. Sudden cardiac death was occurred in  83 (2.7%) and 56 (1.8%) patients in febuxostat and allopurinol group respectively. Incidences of hospitalisation for heart failure, arrhythmias, ischemic attacks and venous thromboembolic events were similar in the two groups.
  • Analyses of Events That Occurred during Treatment:

A primary end-point event occurred in febuxostat and allopurinol group was 7.8% and 7.7% respectively. In the present study, febuxostat group showed the higher rate of cardiovascular death than in the allopurinol group. Results of the post hoc analysis also showed similar primary end-point event in both the group. Febuxostat group have a higher mortality rate due to heart failure or due to any other cause 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 which involved more than 5000 patients, the rate of cardiovascular events reported was higher, i.e. 0.74 per 100 patient-years; 95% CI, 0.36 to 1.37 among patients treated with febuxostat 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 pre-specified analysis that included events that occurred during treatment and within 30 days after treatment discontinuation.

The results of the number of pre-clinical cardiovascular studies on febuxostat demonstrated no lethal effects associated with heart rhythm, function, or metabolism. Also, the incidences of nonfatal events, such as myocardial infarction, coronary revascularisation, arrhythmias, and heart failure, were similar in both the 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.

N Engl J Med. 2018 Mar 29;378(13):1200-1210

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