Targeting high-sensitivity C-reactive protein levels in acute coronary syndrome patients undergoing contemporary lipid-lowering therapy: a sub-analysis of the HIJ-PROPER trial.

Background: The effects of high-sensitivity C-reactive protein (hs-CRP) levels on clinical outcomes in chronic-phase acute coronary syndrome (ACS) patients undergoing aggressive lipid-lowering therapy remain unclear. We examined the effects of hs-CRP levels on the prognosis of ACS patients who underwent aggressive lipid-lowering therapy and determined treatment targets for hs-CRP value.

Methods: This post-hoc sub-analysis of a prospective randomized control trial (HIJ-PROPER) included 1734 ACS patients with dyslipidemia, who were divided into hs-CRP quartiles after 3 months of treatment. Primary endpoints were combined all-cause death, non-fatal myocardial infarction, non-fatal stroke, unstable angina, and ischemia-driven coronary revascularization. Secondary endpoint was all-cause death.

Results: The median follow-up period was 3.7 years. Overall, 1415 patients were evaluated retrospectively. No significant among-group differences were noted in low-density lipoprotein cholesterol (LDL-C) levels over time (p = 0.44). Kaplan-Meier analyses revealed that the incidence of the primary and secondary endpoints was significantly higher in the highest hs-CRP group than in the other groups [hazard ratio (HR) = 1.52, 95% confidence interval (CI) = 1.16-2.00, p < 0.01; HR = 5.30, 95% CI = 2.47-11.32, p < 0.01, respectively]. The cut-off hs-CRP level to predict all-cause death was 0.74 mg/L (receiver operating characteristic curve: sensitivity: 68%, specificity: 62%). Multivariate analyses revealed that hs-CRP ≥0.74 mg/L　at 3 months was correlated with an increased risk of all-cause death (adjusted HR = 3.68, 95% CI = 2.22-6.10, p < 0.01).

Conclusion: Elevated hs-CRP levels independently predicted a worse prognosis, regardless of LDL-C levels, suggesting that interventions against elevated inflammatory responses plus intensive lipid-lowering therapy and coronary revascularization are encouraging options for secondary prevention in ACS patients.

Trial Registration: This trial is registered with the UMIN Clinical Trials Registry number UMIN000002742. Trial name: Proper level of lipid lowering with pitavastatin and ezetimibe in acute coronary syndrome (HIJ-PROPER) URL: https://upload.umin.ac.jp/cgi-open-bin/ctr/ctr-view.cgi?recptno=R000003334.