The warning klaxon sounded when investigators scrutinized the individual components of the primary endpoint. They found that the 4.3% cardiovascular death rate in the febuxostat group was significantly higher than the 3.2% rate in the allopurinol group, representing a statistically significant 34% increase in relative risk. The event curves began to separate roughly 30 months into the trial. Moreover, all-cause mortality was also significantly increased in the febuxostat group, by a margin of 7.8% to 6.4%, for a 22% increase in risk.
The increased cardiovascular mortality in the febuxostat group was driven by a higher adjudicated sudden cardiac death rate: 2.7%, compared with 1.8% in the allopurinol group.
In a prespecified per protocol analysis of cardiovascular events occurring while patients were actually on treatment or within 1 month after discontinuation, the key findings remained unchanged: no between-group difference in the primary composite endpoint, but a 49% increase in the relative risk of cardiovascular death in the febuxostat-treated patients.
A hefty 45% of participants stopped taking their assigned drug early. Dr. White said this isn’t unusual; high dropout rates are common in clinical trials of patients with painful conditions. Because of the high lost-to-follow-up rate, however, the investigators hired a private investigator to scour the country looking for missed deaths among enrollees. This turned up an extra 199 deaths. When those were added to the total, all-cause mortality in the febuxostat group was no longer significantly higher than for allopurinol.