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

BackgroundEvaluation 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 ResultsOverall, 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.

PCSK9 inhibition and inflammation: A narrative review

“…Among patients with clinically manifest vascular disease, more than 20% showed a risk of recurrent events in the excess of 30% over 10 years, including MI, stroke, or vascular death, thus indicating an area of unmet medical need [2]. The persistence of high risk has been increasingly associated with elevated levels of proinflammatory molecules, such as cytokines and acute-phase reactants [3]. Indeed, beyond the well-known role of LDL in atherosclerosis, data from the proof-of-concept CANTOS (Canakinumab Anti-Inflammatory Thrombosis Outcome Study) trial [4] have clearly identified inflammation as one of the key biological processes of atherosclerosis.…”

Lipoprotein‐associated phospholipase A2: The story continues

“…With a series of eligible compounds available at present, scientists would be admired if they exerted more effort in exploring the role of Lp‐PLA2 in diseases other than atherosclerosis, particularly, in microvascular diseases that may be more sensitive to Lp‐PLA2 inhibition. In addition, the large pool of data generated from clinical trials provides numerous opportunities for comprehensive data mining, which may be beneficial to understanding the biological consequences of Lp‐PLA2 inhibition and help us to learn a profound and valuable lesson from the failure of darapladib . To conclude, we anticipate that the story of Lp‐PLA2 will continue.…”

“…In addition, the large pool of data generated from clinical trials provides numerous opportunities for comprehensive data mining, which may be beneficial to understanding the biological consequences of Lp-PLA2 inhibition and help us to learn a profound and valuable lesson from the failure of darapladib. [279][280][281][282][283][284][285][286][287][288] To conclude, we anticipate that the story of Lp-PLA2 will continue.…”

Recent Evidence on the Impact of Ramadan Diurnal Intermittent Fasting, Mealtime, and Circadian Rhythm on Cardiometabolic Risk: A Review

“…There is a strong association between inflammatory biomarkers and increased risk of metabolic and cardiovascular disorders (63)(64)(65). In the past few years, researchers interest was increased toward studying the effects of Ramadan diurnal IF on inflammatory biomarkers.…”