Relationship between interleukin 6 and mortality in patients with unstable coronary artery disease: effects of an early invasive or noninvasive strategy

Abstract

Context: Inflammatory activity is associated with high rates of long-term mortality in unstable coronary artery disease (CAD). Interleukin 6 (IL-6) induces C-reactive protein and fibrinogen, systemic markers of inflammation.

Objectives: To determine whether plasma levels of IL-6 are predictive of mortality and to evaluate the interaction of IL-6 levels with the effects of invasive vs noninvasive treatment strategies in unstable CAD patients.

Design, setting, and patients: The prospective, randomized Fragmin and Fast Revascularisation During Instability in Coronary Artery Disease II trial, conducted among 3489 patients, 3269 of whom had plasma samples analyzed for IL-6 levels, with diagnosed unstable CAD (67% male; median age, 67 years) at 58 Scandinavian hospitals between June 1996 and August 1998.

Interventions: Patients were randomly assigned to receive either an early invasive (n = 1222) or a noninvasive treatment strategy (n = 1235). The latter group, as well as 666 patients with contraindications to invasive therapy, were further randomized to 90-day treatment with low-molecular-weight heparin (dalteparin, 5000-7500 IU twice per day; n = 1140) or placebo (n = 1127).

Main outcome measure: Mortality at 6 and 12 months in the medically and interventionally randomized cohorts, respectively, in relation to IL-6 levels, measured at randomization.

Results: Plasma levels of IL-6 that were at least 5 ng/L compared with levels lower than 5 ng/L were associated with greatly increased mortality in the noninvasive group (7.9% vs 2.3%; relative risk [RR], 3.47; 95% confidence interval [CI], 1.94-6.21) and in the placebo-treated group (7.9% vs 2.5%; RR, 3.19; 95% CI, 1.77-5.74). The association remained significant after adjustment for most established risk indicators. An early invasive treatment strategy strongly reduced 12-month mortality among those with elevated IL-6 levels (5.1% absolute reduction; P =.004) whereas mortality was not reduced among patients without elevated IL-6 concentrations. Those taking dalteparin with elevated IL-6 levels experienced lower 6-month mortality than those who did not take dalteparin (3.5% absolute reduction; P =.08).

Conclusions: Circulating IL-6 is a strong independent marker of increased mortality in unstable CAD and identifies patients who benefit most from a strategy of early invasive management.