Associations of Serum Urate and Cardiovascular Events in a Clinical Trial of Interleukin-1β Blockade.

BACKGROUND

Serum urate (SU) associates with cardiovascular (CV) events, mortality, and gout.

OBJECTIVES

The purpose of this study was to assess whether SU predicts CV risk in a trial of interleukin (IL)-1β inhibition with canakinumab, and whether IL-1β blockade, kidney function, or gout alter these associations.

METHODS

This study is a subanalysis of the Canakinumab Antiinflammatory Thrombosis Outcome Study (CANTOS), which randomized 10,061 patients with prior myocardial infarction and elevated high-sensitivity C-reactive protein to 3 doses of canakinumab or placebo. SU was measured at baseline. Cox proportional hazards models compared major adverse cardiovascular events (MACE), CV death, and all-cause mortality among those with SU ≤6.8 mg/dL (normal), 6.8 to 9.0 mg/dL (elevated), and ≥9.0 mg/dL (markedly elevated). Cox regressions were repeated within subgroups, including canakinumab vs placebo, estimated glomerular filtration rate ≥60 vs <60 mL/min, and gout vs no gout.

RESULTS

Markedly elevated SU associated with MACE (HR: 1.66 [95% CI: 1.38-1.99]; P < 0.0001), CV death (HR: 2.52 [95% CI: 1.98-3.21]; P < 0.0001), and all-cause mortality (HR: 2.43 [95% CI: 2.01-2.94]; P < 0.0001) compared to normal SU. After multivariable adjustment for a minimal set of potential confounders, SU independently predicted all 3 endpoints. Associations were unchanged after IL-1β blockade with canakinumab. For normal estimated glomerular filtration rate, SU associated with CV and all-cause mortality, but not MACE. Participants with gout had higher event rates independent of SU.

CONCLUSIONS

In over 10,000 patients with coronary artery disease, individuals with markedly elevated SU have elevated CV risk despite aggressive treatment. IL-1β blockade did not modify these associations. Baseline kidney function and monosodium urate deposition may function as effect modifiers.