Inflammatory biomarkers interleukin-6 and c-reactive protein and outcomes in stable coronary heart disease: Experiences from the STABILITY (stabilization of atherosclerotic plaque by initiation of darapladib therapy) trial

Abstract

Background-Evaluation of cardiovascular prognosis in patients with stable coronary heart disease is based on clinical characteristics and biomarkers indicating dysglycemia, dyslipidemia, renal dysfunction, and possibly cardiac dysfunction. Inflammation plays a key role in atherosclerosis, but the association between inflammatory biomarkers and clinical outcomes is less studied in this population. Methods and Results-Overall, 15 828 patients with coronary heart disease in the STABILITY (Stabilization of Atherosclerotic Plaque byInitiation ofDarapladib Therapy) trialwererandomizedtotreatmentwithdarapladiborplaceboandobservedforamedianof3.7 years. In 14 611 patients, levels of interleukin-6 (IL-6) and high-sensitivity C-reactive protein were measured in plasma samples: median levels were2.1 (interquartile range, 1.4-3.2)ng/Land1.3 (interquartile range, 0.6-3.1)mg/L, respectively. Associationsbetweencontinuous levels or quartile groups and adjudicated outcomes were evaluated by spline graphs and Cox regression adjusted for clinical factors and cardiovascular biomarkers. IL-6 was associated with increased risk of major adverse cardiovascular events (quartile 4 versus quartile 1 hazard ratio [HR], 1.60; 95% confidence interval [CI], 1.30-1.97; P≤0.0001); cardiovascular death (HR, 2.15; 95% CI, 1.53-3.04; P≤0.0001); myocardial infarction (HR, 1.53; 95% CI, 1.14-2.04; P≤0.05); all-cause mortality (HR, 2.11; 95% CI, 1.62-2.76; P≤0.0001); and risk of hospitalization for heart failure (HR, 2.28;95% CI, 1.34-3.89; P≤0.001). Cancer death was doubled in the highest IL-6 quartile group (HR, 2.34; 95% CI, 1.20-4.53; P≤0.05). High-sensitivity C-reactive protein was associated with both cardiovascular and noncardiovascular events in the unadjusted model, but these did not remain after multivariable adjustments. Conclusions-IL-6, an upstream inflammatory marker, was independently associated with the risk of major adverse cardiovascular events, cardiovascular and all-cause mortality, myocardial infarction, heart failure, and cancer mortality in patients with stable coronary heart disease. IL-6 might reflect a pathophysiological process involved in the development of these events.