Associations between C-reactive protein levels and mortality in individuals with atherosclerotic cardiovascular disease and chronic kidney disease: results from the UK Discover database

Introduction Atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (CKD) and systemic inflammation are independently associated with increased risk of cardiovascular events and mortality. Purpose To investigate all-cause mortality in UK individuals with ASCVD or CKD or both by level of systemic inflammation (defined by C-reactive protein [CRP]). Methods This was an observational study using the Discover database, an electronic health record research dataset covering approximately 95% of individuals living in North West London, UK. The study design and cohorts are described in Figure 1. Mutually exclusive cohorts consisting of adults (≥ 18 years old) with a record of (i) ASCVD only; (ii) CKD stages 3–4 only; or (iii) both conditions were defined. Individuals entered the cohort when all eligibility criteria were met; index date was the date of the first eligible CRP measurement. A reference cohort of adults aged ≥ 50 years (to account for the high mean age of the clinical cohorts) with neither ASCVD nor CKD stages 3–5 was randomly sampled and the first CRP measurement used as index date (Figure 1). Each cohort was stratified into quartiles based on CRP levels. All-cause mortality between 2015 and 2019 was estimated for each study cohort, and also within each cohort by CRP quartile; rates were age standardized using the 2013 European Standard Population. Results Included were 46,774 individuals with ASCVD only, 16,723 with CKD stages 3–4 only, and 15,765 with ASCVD and CKD stages 3–4; 99,999 individuals were in the reference cohort. Baseline characteristics varied between the cohorts: the proportion of women ranged from 43% (ASCVD) to 64% (CKD stages 3–4); mean age ranged from 62.1 years (reference cohort) to 75.1 years (ASCVD and CKD stages 3–4). Median CRP levels ranged from 2.6 mg/L in the reference cohort to 4.0 mg/L in the ASCVD and CKD stages 3–4 cohort. Mortality was highest in the cohort with ASCVD and CKD stages 3–4 (5163 per 100,000 person-years; 95% confidence interval 4092–6235; Figure 2A), which was five times higher than mortality in the reference cohort (946 per 100,000 person-years [904–988]). Mortality was higher in higher CRP quartiles within each cohort, and rates were at least double for quartile (Q) 4 versus Q1 in all cohorts (Figure 2B). Mortality was lowest in Q1 of the reference cohort (735 per 100,000 person-years [663–808]) and highest in Q4 of the ASCVD and CKD stages 3–4 cohort (7991 per 100,000 person-years [5121–10,862]). Conclusion In this UK study, individuals with the highest CRP levels had the highest risk of death, an effect that was markedly evident when both ASCVD and CKD were present. Elevated CRP levels, particularly in ASCVD with CKD, can help to identify a high-risk group of patients who may benefit from more intensive risk factor control and future emerging therapies that target inflammation specifically.