Background and Purpose—There are few reports on proinflammatory cytokines and risk of primary or recurrent stroke. We studied the association of interleukin (IL)-6, IL-18, and tumor necrosis factor- (TNF-) with recurrent stroke in a nested case-control study derived from the Perindopril Protection Against Recurrent Stroke Study (PROGRESS).

Methods—We performed a nested case-control study of 591 strokes (472 ischemic, 83 hemorrhagic, 36 unknown subtype) occurring during a randomized, placebo-controlled multicenter trial of perindopril-based therapy in 6105 patients with a history of stroke or transient ischemic attack. Controls were matched for age, treatment group, sex, region, and most recent qualifying event at entry to the parent trial.

Results—IL-6 and TNF-, but not IL-18, were associated with risk of recurrent ischemic stroke independently of conventional risk markers. Adjusted odds ratios comparing the highest to lowest third of their distributions were 1.33 (95% CI, 1.00 to 1.78) for IL-6 and 1.46 (1.02 to 2.10) for TNF-. No inflammatory marker was associated with hemorrhagic stroke risk. In multivariable models, IL-6 and TNF- fully explained observed associations of C-reactive protein and fibrinogen with risk of ischemic stroke, but TNF- retained borderline significance after full adjustment.

Conclusions—Inflammatory markers associated with the acute-phase response (IL-6, TNF-, C-reactive protein, and fibrinogen, but not IL-18) are associated with risk of recurrent stroke. These markers are dependent on each other in multivariable models, and once all were included, only TNF- retained a borderline association. Markers of generalized inflammation of the acute-phase response are associated with recurrent stroke, rather than IL-6, C-reactive protein, or fibrinogen in particular.