Effect of age and glycaemic control on the association between fibrinogen and risk of acute coronary events after transient ischaemic attack or stroke.

BACKGROUND: Fibrinogen is an independent risk factor for acute vascular events, but there is uncertainty as to whether it is causal. One potential causal mechanism is the formation of low permeability fibrin clot in association with raised fibrinogen. We hypothesised that if this effect of fibrinogen were causally related to risk of vascular events, the risk relationship would be affected by the two other factors that affect fibrin clot permeability - age and glycaemic control. METHODS: We studied the relationship between fibrinogen and risk of incident coronary events by age and baseline glucose levels in pooled data from three cohorts of patients with known cerebrovascular disease (UK-TIA Aspirin trial; Dutch TIA trial; Oxford TIA Study) during 23,272 patient-years of follow-up. RESULTS: Risk of coronary events increased linearly with fibrinogen, but there was a significant interaction with age (p = 0.01 across tertiles of age), with the association being strongest for individuals aged <60 years (upper fibrinogen quintile hazard ratio = 3.95, 95% CI = 2.67-5.85, p < 0.0001). The risk relation was diminished in individuals with impaired glucose tolerance or diabetes. The effects of age and glycaemic control were independent, such that there was an almost fivefold increase in risk across quintiles of fibrinogen in patients aged <60 years with below median normal glucose levels (upper quintile hazard ratio = 4.90, 95% CI = 2.79-8.58, p < 0.0001). CONCLUSIONS: The effect of age and glycaemic control on the relationship between fibrinogen and risk of acute coronary events supports the hypothesis of a causal effect of fibrinogen mediated via the permeability of fibrin clot.