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 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.

Figure 1

A, Kaplan‐Meier curves for major adverse cardiovascular event (MACE) by interleukin‐6 quartile (Q) groups. B, Kaplan‐Meier curves for MACE by high‐sensitivity C‐reactive protein (hs‐CRP) Q groups.

Figure 2

A, Spline plots for major adverse cardiovascular event (MACE), cardiovascular (CV) death, myocardial infarction (MI), heart failure, and stroke by quartile (Q) groups of interleukin‐6 (IL‐6). B, Spline plots for MACE, CV death, MI, heart failure, and stroke by Q groups of high‐sensitivity C‐reactive protein (hs‐CRP).

Figure 3

A, The impact of interleukin‐6 (IL‐6) by baseline quartile (Q) groups on outcome (unadjusted analyses). B, The impact of IL‐6 by baseline Q groups on outcome. Adjustments were made for randomized treatment, age, systolic blood pressure (BP), body mass index (BMI), sex, history of hypertension, geographic region for final reporting, prior myocardial infarction (MI), prior coronary revascularization (percutaneous coronary intervention [PCI] or coronary artery bypass graft [CABG] surgery), prior multivessel coronary heart disease (CHD), baseline diabetes mellitus, smoking, polyvascular disease, and significant renal dysfunction. C, The impact of IL‐6 by Q groups at baseline on outcome. Adjustments were made for all variables in model B + hemoglobin, white blood cell count, low‐density lipoprotein cholesterol, high‐density lipoprotein cholesterol, triglycerides, estimated glomerular filtration rate (according to the Chronic Kidney Disease Epidemiology Collaboration), high‐sensitivity cardiac troponin‐T, NT‐proBNP (Nterminal pro B‐type natriuretic peptide), high‐sensitivity C‐reactive protein, cystatin C, growth differentiation factor 15, and lipoprotein‐associated phospholipase A2 activity. CI indicates confidence interval; CV, cardiovascular; HR, hazard ratio; MACE, major adverse cardiovascular event; and MCE, major coronary event.

Figure 4

A, The impact of high‐sensitivity C‐reactive protein (hs‐CRP) by baseline quartile (Q) groups on outcome (unadjusted analyses). B, The impact of hs‐CRP by baseline Q groups on outcome. Adjustments were made for randomized treatment, age, systolic blood pressure (BP), body mass index (BMI), sex, history of hypertension, geographic region for final reporting, prior myocardial infarction (MI), prior coronary revascularization (percutaneous coronary intervention [PCI] or coronary artery bypass graft [CABG] surgery), prior multivessel coronary heart disease (CHD), baseline diabetes mellitus, smoking, polyvascular disease, and significant renal dysfunction. C, The impact of hs‐CRP by baseline Q groups on outcome. Adjustments were made for all variables in model B + hemoglobin, white blood cell count, low‐density lipoprotein cholesterol, high‐density lipoprotein cholesterol, triglycerides, estimated glomerular filtration rate (according to the Chronic Kidney Disease Epidemiology Collaboration), high‐sensitivity cardiac troponin‐T, NT‐proBNP (N‐terminal pro B‐type natriuretic peptide), interleukin‐6, cystatin C, growth differentiation factor 15, and lipoprotein‐associated phospholipase A2 activity. CI indicates confidence interval; CV, cardiovascular; HR, hazard ratio; MACE, major adverse cardiovascular event; and MCE, major coronary event.