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 by Initiation of Darapladib Therapy) trial were randomized to treatment with darapladib or placebo and observed for a median of 3.7 years. In 14 611 patients, levels of interleukin-6 (IL-6) and high-sensitivity C-reactive protein were measured in plasma samples: median levels were 2.1 (interquartile range, 1.4-3.2) ng/L and 1.3 (interquartile range, 0.6-3.1) mg/L, respectively. Associations between continuous 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 non-cardiovascular 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.
Clinical trial registration: URL: http://www.clinicaltrials.gov. Unique identifier: NCT00799903.
Keywords: C‐reactive protein; coronary disease; inflammation; interleukin‐6; white blood cells.
© 2017 The Authors and GlaxoSmithKline. Published on behalf of the American Heart Association, Inc., by Wiley.