White WB, Saag KG, Becker MA, et al; CARES Investigators. Cardiovascular Safety of Febuxostat or Allopurinol in Patients with Gout. N Engl J Med. 2018 Mar 12. doi: 10.1056/NEJMoa1710895. [Epub ahead of print]
Pablo Avanzas, Consultant in Interventional Cardiology, Hospital Universitario Central de Asturias
This is 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). 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 were 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.
In this trial, febuxostat, a gout drug that has been in use for nearly a decade, was found to significantly increase the risk of death, even though it did not raise the risk of the trial’s primary endpoint, a combined rate of fatal and nonfatal adverse cardiovascular events.
As the authors recognize, this was an unexpected finding. All-cause mortality was higher in the febuxostat group than in the allopurinol group, because of an excess of cardiovascular deaths. Findings were similar in the modified intention-to-treat analysis and in the prespecified analysis that included events that occurred during treatment and within 30 days after treatment discontinuation. The mechanism underlying this risk of death is unclear.
The results were consistent across many subgroups; there was no evidence of a relationship with age, sex, race or ethnicity, history of cardiovascular disease, or duration or severity of the gout. The only heterogeneity in the analyses of cardiovascular mortality occurred in two subgroups – patients with concomitant administration of aspirin or NSAIDs. It is important to be careful when interpreting these findings; as it doesn’t necessarily indicate there’s an interaction between these drugs and febuxostat. Patients taking these drugs maybe had more active gout.
The findings, which showed an uptick in deaths after patients had been taking febuxostat for two years or longer, call into question the safety of long-term febuxostat use in patients with cardiovascular disease.