Systemic inflammation and risk of death in patients with atherosclerotic cardiovascular disease and chronic kidney disease

Abstract Background Atherosclerotic cardiovascular disease (ASCVD) and chronic kidney disease stage 3 - 4 (CKD) affects 7% and 10% of the Danish population, respectively. Systemic inflammation (SI) contributes to destabilisation of atherosclerotic plaques and is characterized by elevated levels of C-reactive protein (CRP) in the blood. CKD is associated with SI and is independently associated with an increased risk of ASCVD. CRP levels ≥2 mg/L have been identified as a risk factor for mortality and major adverse cardiovascular events (MACE). Purpose To provide real-world evidence on the clinical burden of SI in patients diagnosed with ASCVD and CKD, using national health registers. Method Data from the Danish National Patient Registry from 1994-2022 was used to identify ASCVD patients by ICD-10 codes. CKD was identified by eGFR test results in the range [15 -59mL/min/1.73m2], in the Register of Laboratory Results for Research (RLRR). The latter diagnosis of ASCVD and CKD was set as index date. CRP-test results were extracted from RLRR and only individuals with at least two CRP tests were included. If two CRP-test results ≥2mg/L to < 20mg/L were observed less than six month apart, and within two years of index date, the individual was classified to have SI. The eGFR data from RLRR was available from 2011 onwards, with some regional differences in reporting. Individuals observed with CKD or ASCVD in the first year of eGFR availability were excluded to ensure a study of incident individuals. Individuals using select medications or diagnosed with selected chronic conditions thought to influence CRP levels were excluded. Additional population characteristics were extracted from corresponding national health and administrative registers. Hazard of all-cause mortality and MACE was analysed in a Cox proportional risk regression. Results From 2012 to 2022, a total of 19,162 individuals were eligible for the study population (SI: 13,039, No SI: 6,123). Median follow-up time was 4.1 and 8.2 years for individuals with or without SI, respectively. Median CRP two years before and after index date in the two groups was 7mg/L and 1mg/L. No clinically significant differences were found for demographic or socioeconomic characteristics. Patients with SI had more frequent history of hypertension, atrial fibrillation, COPD, heart failure and Type 2 diabetes before index, and higher risk of hypertension, atrial fibrillation, stroke, heart failure and type 2 diabetes after index. SI population had significantly increased hazard of mortality in a crude model (HR: 2.35, 95% CI: [2.22 – 2.50]), and in adjusted analysis HR: 2.06 ([1.92 - 2.21]). The corresponding hazard ratios for MACE were 1.9 ([1.81 – 2.01]) and 1.66 ([1.57 – 1.77]). The results were consistent across different model specifications and subgroups. Conclusion SI is associated with a significantly higher clinical burden of disease and a higher risk of all-cause mortality.Flowchart of inclusion/exclusionHazard ratio, overall and by subgroup