Interleukin-6 and the Risk of Adverse Outcomes in Patients After an Acute Coronary Syndrome: Observations From the SOLID-TIMI 52 (Stabilization of Plaque Using Darapladib-Thrombolysis in Myocardial Infarction 52) Trial

Abstract

Background: Interleukin-6 (IL-6) is an inflammatory cytokine implicated in plaque instability in acute coronary syndrome (ACS). We aimed to evaluate the prognostic implications of IL-6 post-ACS.

Methods and results: IL-6 concentration was assessed at baseline in 4939 subjects in SOLID-TIMI 52 (Stabilization of Plaque Using Darapladib-Thrombolysis in Myocardial Infarction 52), a randomized trial of darapladib in patients ≤30 days from ACS. Patients were followed for a median of 2.5 years for major adverse cardiovascular events; cardiovascular death, myocardial infarction, or stroke) and cardiovascular death or heart failure hospitalization. Primary analyses were adjusted first for baseline characteristics, days from index ACS, ACS type, and randomized treatment arm. For every SD increase in IL-6, there was a 10% higher risk of major adverse cardiovascular events (adjusted hazard ratio [adj HR] 1.10, 95% confidence interval [CI] 1.01-1.19) and a 22% higher risk of cardiovascular death or heart failure (adj HR 1.22, 95% CI 1.11-1.34). Patients in the highest IL-6 quartile had a higher risk of major adverse cardiovascular events (adj HR Q4:Q1 1.57, 95% CI 1.22-2.03) and cardiovascular death or heart failure (adj HR 2.29, 95% CI 1.6-3.29). After further adjustment for biomarkers (high-sensitivity C-reactive protein, lipoprotein-associated phospholipase A₂ activity, high-sensitivity troponin I, and B-type natriuretic peptide), IL-6 remained significantly associated with the risk of major adverse cardiovascular events (adj HR Q4:Q1 1.43, 95% CI 1.09-1.88) and cardiovascular death or heart failure (adj HR 1.79, 95% CI 1.22-2.63).

Conclusions: In patients after ACS, IL-6 concentration is associated with adverse cardiovascular outcomes independent of established risk predictors and biomarkers. These findings lend support to the concept of IL-6 as a potential therapeutic target in patients with unstable ischemic heart disease.

Keywords: acute coronary syndrome; atherosclerosis; biomarker; inflammation; vascular biology.

Figure 1

Cumulative 3‐year Kaplan‐Meier event rates for major cardiovascular end points by IL‐6 quartile. CV indicates cardiovascular; CVD, cardiovascular death; HF, heart failure; KM, Kaplan‐Meier; MACE, major adverse cardiovascular events; MI, myocardial infarction.

Figure 2

Kaplan‐Meier 30‐day landmark analysis for MACE (A) and for cardiovascular death or HF (B) by IL‐6 quartiles. CV indicates cardiovascular; HF, heart failure; KM, Kaplan‐Meier; MACE, major adverse cardiovascular events including cardiovascular death, MI or stroke; MI, myocardial infarction.

Figure 3

Association of baseline IL‐6 quartile with cardiovascular end points after further adjustment with biomarkers. Adj HR indicates adjusted hazard ratio; CV, cardiovascular; HF, heart failure; KM, Kaplan‐Meier; MACE, major adverse cardiovascular events including cardiovascular death, MI, or stroke. Model adjusted for age, sex, smoking status, body mass index, race (white vs nonwhite), hypertension, diabetes mellitus, peripheral artery disease, estimated glomerular filtration rate <60 mL/min per 1.73 m², hyperlipidemia, prior myocardial infarction, percutaneous coronary intervention, index qualifying event (ST‐elevation ACS vs non‐ST elevation ACS), days from qualifying event, randomized treatment arm, low‐density lipoprotein cholesterol, high‐sensitivity C‐reactive protrin, lipoprotein‐related phospholipase A₂, high‐sensitivity troponin I, and B‐type natriuretic peptide.