Inflammation and cholesterol as predictors of cardiovascular events among patients receiving statin therapy: a collaborative analysis of three randomised trials

Background Inflammation and hyperlipidaemia jointly contribute to atherothrombotic disease. However, when people are treated with intensive statin therapy, the relative contributions of inflammation and hyperlipidaemia to the risk of future cardiovascular events might change, which has implications for the choice of adjunctive cardiovascular therapeutics. We aimed to evaluate the relative importance of high-sensitivity C-reactive protein (CRP) and low -density lipoprotein cholesterol (LDLC) as determinants of risk for major adverse cardiovascular events, cardiovascular death, and all-cause-death among patients receiving statins.Methods We did a collaborative analysis of patients with-or at high risk of-atherosclerotic disease, who were receiving contemporary statins and were participants in the multinational PROMINENT (NCT03071692), REDUCE -IT (NCT01492361), or STRENGTH (NCT02104817) trials. Quartiles of increasing baseline high-sensitivity CRP (a biomarker of residual inflammatory risk) and of increasing baseline LDLC (a biomarker of residual cholesterol risk) were assessed as predictors of future major adverse cardiovascular events, cardiovascular death, and all-cause death. Hazard ratios (HRs) for cardiovascular events and deaths were calculated across quartiles of high-sensitivity CRP and LDLC in analyses adjusted for age, gender, BMI, smoking status, blood pressure, previous history of cardiovascular disease, and randomised treatment group assignment.Findings 31 245 patients were included in the analysis from the PROMINENT (n=9988), REDUCE-IT (n=8179), and STRENGTH (n=13 078) trials. The observed ranges for baseline high-sensitivity CRP and LDLC, and the relationships of each biomarker to subsequent cardiovascular event rates, were almost identical in the three trials. Residual inflammatory risk was significantly associated with incident major adverse cardiovascular events (highest high -sensitivity CRP quartile vs lowest high-sensitivity CRP quartile, adjusted HR 1 center dot 31, 95% CI 1 center dot 20-1 center dot 43; p<0 center dot 0001), cardiovascular mortality (2 center dot 68, 2 center dot 22-3 center dot 23; p<0 center dot 0001), and all-cause mortality (2 center dot 42, 2 center dot 12-2 center dot 77; p<0 center dot 0001). By contrast, the relationship of residual cholesterol risk was neutral for major adverse cardiovascular events (highest LDLC quartile vs lowest LDLC quartile, adjusted HR 1 center dot 07, 95% CI 0 center dot 98-1 center dot 17; p=0 center dot 11), and of low magnitude for cardiovascular death (1 center dot 27, 1 center dot 07-1 center dot 50; p=0 center dot 0086) and all-cause death (1 center dot 16, 1 center dot 03-1 center dot 32; p=0 center dot 025).Interpretation Among patients receiving contemporary statins, inflammation assessed by high-sensitivity CRP was a stronger predictor for risk of future cardiovascular events and death than cholesterol assessed by LDLC. These data have implications for the selection of adjunctive treatments beyond statin therapy and suggest that combined use of aggressive lipid-lowering and inflammation-inhibiting therapies might be needed to further reduce atherosclerotic risk.Funding Kowa Research Institute, Amarin, AstraZeneca.Copyright (c) 2023 Published by Elsevier Ltd. All rights reserved.