Combined Biomarkers Predict Adverse Cardiovascular Events Over 20 Years

Researchers from the EPIC-Norfolk study have found that a combined measurement of LDL cholesterol, high-sensitivity C-reactive protein (hsCRP), and lipoprotein(a) [Lp(a)] can accurately predict major adverse cardiovascular events (MACE) in initially healthy individuals over a span of 20 years. This finding supports the validity of a universal screening model for primary prevention of cardiovascular diseases.

The study aimed to replicate the results of a previous American trial that assessed nearly 28,000 healthy women over a 30-year period. The earlier research established a significant correlation between the combined levels of hsCRP, LDL, and Lp(a) and the occurrence of cardiovascular events. In light of these findings, Jordan Kraaijenhof, MSc, from the Amsterdam University Medical Centers, emphasized the necessity for universal one-time screening for these biomarkers in primary prevention.

Study Design and Patient Cohort

To explore this topic, Kraaijenhof and colleagues recruited participants aged 40 to 79 from general practices in Norfolk, UK. The study gathered extensive health and lifestyle data through questionnaires and assessments conducted by trained nurses during clinic visits. Non-fasting blood samples were collected at the start of the study to measure plasma levels of total cholesterol, HDL cholesterol, and triglycerides, from which LDL cholesterol levels were calculated. Additionally, hsCRP levels were analyzed from frozen serum samples, while Lp(a) concentrations were measured using an isoform-independent immunoturbidimetric assay.

The primary objective of the study was to evaluate the relationship between LDL cholesterol, hsCRP, and Lp(a) in terms of cardiovascular risk. Each biomarker was analyzed individually before assessing their combined effect on cardiovascular events, specifically the occurrence of first MACE, which includes fatal or non-fatal coronary artery disease and ischemic stroke.

The study involved a total of 17,087 patients, with a mean age of 59 years. Baseline levels recorded were 4 +/- 1 mmol/L for LDL cholesterol, 1.5 (0.7-3.2) mg/L for hsCRP, and 11 (6-27) mg/dL for Lp(a). Participants were followed for a median duration of 20.5 years, during which a total of 3,249 MACE events were documented.

Significant Findings and Implications

The analysis revealed that 1,755 of the MACE events occurred in female participants, comprising 18% (n = 9,745) of the cohort, while 1,494 events were noted among male participants, accounting for 20.3% (n = 7,342). Investigators calculated age- and sex-adjusted hazard ratios for MACE, finding substantial increases in risk among individuals in the highest quintiles for each biomarker: HR 1.84 for LDL, HR 1.75 for hsCRP, and HR 1.28 for Lp(a). Moreover, multivariable-adjusted hazard ratios indicated that for each quintile increase, the risks were 1.14 for LDL, 1.12 for hsCRP, and 1.05 for Lp(a).

The research demonstrates that while elevated levels of LDL, hsCRP, and Lp(a) each contribute to an increased risk of MACE, the combination of all three biomarkers in the highest quintile poses the greatest risk. Kraaijenhof and colleagues noted, “These data both replicate and extend very recent American evidence that a simple biomarker panel can detect unique patterns of risk for many patients that would otherwise be missed using traditional global risk algorithms or commonly used imaging tests.”

The findings suggest that with the availability of standardized and cost-effective commercial assays for hsCRP and Lp(a), there is a strong case for implementing universal screening of these biomarkers in both primary and secondary prevention initiatives.