Relationship between interleukin 6 and mortality in patients with unstablecoronary artery disease - Effects of an early invasive or noninvasive strategy

Context Inflammatory activity is associated with high rates of long-term mo rtality in unstable coronary artery disease (CAD). Interleukin 6 (IL-6) ind uces C-reactive protein and fibrinogen, systemic markers of inflammation. Objectives To determine whether plasma levels of IL-6 are predictive of mor tality and to evaluate the interaction of IL-6 levels with the effects of i nvasive 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, c onducted among 3489 patients, 3269 of whom had plasma samples analyzed for IL-6 levels, with diagnosed unstable CAD (67% male, median age, 67 years) a t 58 Scandinavian hospitals between June 1996 and August 1998. Interventions Patients were randomly assigned to receive either an early in vasive (n = 1222) or a noninvasive treatment strategy (n = 1235). The fatte r group, as well as 666 patients with contraindications to invasive therapy , were further randomized to 90-day treatment with low-molecular-weight hep arin (dalteparin, 5000-7500 IU twice per day, n = 1140) or placebo (n = 112 7). Main Outcome Measure Mortality at 6 and 12 months in the medically and inte rventionally 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 level s 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%; R R, 3.19; 95% CI, 1.77-5.74). The association remained significant after adj ustment for most established risk indicators. An early invasive treatment s trategy 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 daltepari n 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 mo rtality in unstable CAD and identifies patients who benefit most from a str ategy of early invasive management.