Interleukin-6 inclusion adds value to the SMART risk score for prediction of cardiovascular death in patients with established ASCVD

Abstract Background Interleukin-6 (IL-6) participates causally in the development of atherosclerotic cardiovascular disease (ASCVD). Large cardiovascular outcome trials targeting the IL-6 pathway are ongoing. IL-6 can identify patients with residual inflammatory risk. To seek more information on clinical relevance we analyzed whether addition of IL-6 to the SMART (Second Manifestations of Arterial Disease) risk score provides incremental prognostic value in the prediction of cardiovascular death in patients with established ASCVD. Methods We included 1,814 UK Biobank participants with established ASCVD and available circulating IL-6 levels (proteomics subset). The UK Biobank is a population-based cohort study that was conducted in the UK from 2006 to 2010. As a validation cohort, IL-6 was measured in 2,999 patients with ASCVD (coronary artery disease) who underwent coronary angiography at baseline (1997–2000) and are part of the Ludwigshafen Risk and Cardiovascular Health Study (LURIC). The primary end point was cardiovascular death. Results Mean age of the UK Biobank participants at baseline was 56.6 years and 46% were male. 214 cardiovascular death events occurred during the median follow-up of 13.4 years. Increasing baseline levels of IL-6 predicted cardiovascular death. This association remained significant after adjustment for age, sex, body mass index, diabetes, smoking, systolic blood pressure, total cholesterol and creatinine (Chi2: 98.8; p 0.001). Furthermore, the sequential addition of IL-6 to the multivariable model already containing high sensitivity c-reactive protein (hsCRP) further enhanced risk prediction (Model + hsCRP + IL-6: delta Chi2: 9.96; p = 0.002). Adjustment of the SMART risk score by IL-6 significantly improved prediction of 10-year risk of cardiovascular death (SMART risk score: Chi2: 69.34; SMART risk score + IL-6: Chi2: 74.54; delta Chi2: 5.2; p = 0.02). We validated our findings in the LURIC study (559 cardiovascular death events; SMART risk score: Chi2: 383.11; SMART risk score + IL-6: Chi2: 394.08; delta Chi2: 10.97; p 0.001). Similar results were found for all-cause death in both cohorts. Conclusion The addition of IL-6 to models containing hsCRP and to the SMART score improves risk prediction of cardiovascular- and all-cause death in patients with established ASCVD in two independent cohorts. IL-6 might serve as a useful biomarker to identify patients with residual inflammatory risk for cardiovascular risk stratification and guiding of anti-inflammatory therapies for secondary prevention of cardiovascular disease.