Residual inflammation, cholesterol risks and rates of major cardiovascular events in routinely cared patients with atherosclerotic cardiovascular disease

Background Hyperlipidaemia and systemic inflammation contribute to atherosclerotic cardiovascular disease (ASCVD). In trials of statin-treated ASCVD patients, residual inflammation risk outweighed residual cholesterol risk. Whether this pattern holds in routine care, including patients not on lipid-lowering therapy (LLT), and whether it differs by chronic kidney disease (CKD) status, where inflammation is a key driver of cardiovascular morbidity and mortality, remains unclear. Purpose To assess the contributions of inflammation and cholesterol on recurrent ASCVD risk in routine clinical practice. Methods This observational study included 39,368 adults with ASCVD undergoing low-density lipoprotein cholesterol (LDL-C) and high-sensitivity C-reactive protein (hsCRP) testing in Swedish healthcare system during 2007–2021. Patients were categorized by cross-classifying LDL-C (≥1.8 vs. <1.8 mmol/L) and hsCRP (≥2 vs. <2 mg/L): no residual risk (n=5,351); cholesterol risk (n=13,636); inflammation risk (n=4,751); and combined risk (n=15,900). The primary outcome was major adverse cardiovascular events (MACE), a composite of myocardial infarction, stroke and death attributed to cardiovascular diseases. The secondary outcome was all-cause death. Outcomes were assessed using Cox regression overall and stratified by LLT use and CKD status (eGFR <60 ml/min/1.73 m²). Results The mean age was 69 years, 61% were men, 19.4% had CKD and 61% were receiving LLT. Median hsCRP and LDL-C were 2 mg/L and 2.30 mmol/L, respectively. Over a median (Q1–Q3) follow-up of 4.5 (2.0–7.7) years, 5,349 MACE and 7,955 deaths occurred. In crude analyses, patients with elevated hsCRP had a higher cumulative incidence of both MACE and all-cause death, regardless of LDL-C levels (FIGURE). In multivariable Cox regression, compared with patients without residual risk, those with combined residual cholesterol and inflammation risks showed the highest hazard for MACE (hazard ratio [HR] 1.39; 95% confidence interval [CI] 1.26–1.54), followed by residual inflammation risk alone (HR 1.18; 95% CI 1.05–1.33) and residual cholesterol risk alone (HR 1.12; 95% CI 1.01–1.24). For all-cause death, both categories with elevated hsCRP were at higher risk (HR 1.47; 95% CI 1.34–1.62 for inflammation risk alone; HR 1.27; 95% CI 1.16–1.38 for combined risk), whereas those with only elevated LDL-C were not (HR 0.99; 95% CI 0.91–1.09). Findings were consistent regardless of CKD status or LLT use, although the magnitude of the HRs was somewhat larger among those receiving LLT and those without CKD (p for interaction <0.05). Conclusions In this large cohort of adults with ASCVD, patients with combined residual inflammation and cholesterol risk exhibited the highest rate of MACE recurrence. However, residual inflammation risks, regardless of LDL-C levels, was a stronger predictor of death. Addressing inflammatory risk in secondary prevention strategies for ASCVD may improve patient outcomes.