Combined Biomarkers Predict Major Cardiovascular Events Over 20 Years

A recent study has demonstrated that a combined measurement of LDL cholesterol, high-sensitivity C-reactive protein (hsCRP), and lipoprotein(a) (Lp(a)) can effectively predict major adverse cardiovascular events (MACE) in initially healthy individuals over a two-decade period. This finding arises from the EPIC-Norfolk study, which aimed to validate a previous American study that established the predictive capabilities of this biomarker combination.

The initial research in the United States involved nearly 28,000 healthy women over a span of 30 years. It identified a significant link between the combined measurement of hsCRP, LDL, and Lp(a) and the occurrence of cardiovascular events. The researchers aimed to determine whether these results were applicable to a European population, particularly in primary prevention.

Jordan Kraaijenhof, MSc, and his team from the Amsterdam University Medical Centers, conducted the EPIC-Norfolk study with a specific focus on participants aged 40 to 79. They recruited individuals through general practices in Norfolk, UK. Participants completed comprehensive health questionnaires, and trained nurses gathered additional data during clinic visits. Non-fasting blood samples were analyzed, measuring plasma levels of total cholesterol, HDL cholesterol, triglycerides, and calculating LDL cholesterol based on these metrics. hsCRP levels were evaluated from frozen serum samples, while Lp(a) concentrations were measured using an isoform-independent immunoturbidimetric assay.

The primary objective was to assess the relationship between these biomarkers and cardiovascular risk. Each biomarker was analyzed independently before evaluating their combined impact on cardiovascular events. The study defined MACE as a composite of fatal or non-fatal coronary artery disease and fatal or non-fatal ischemic stroke, with occurrences documented during follow-up if participants were hospitalized or died due to these conditions.

Ultimately, the study included 17,087 patients, with a mean age of 59 years. Baseline levels were recorded as follows: LDL cholesterol at 4 ± 1 mmol/L, hsCRP at 1.5 (0.7-3.2) mg/L, and Lp(a) at 11 (6-27) mg/dL. The participants were followed for a median of 20.5 years, resulting in the documentation of 3,249 first MACE, which included 1,755 events in female participants and 1,494 in male participants.

The researchers calculated age- and sex-adjusted hazard ratios (HRs) for MACE by comparing the highest and lowest quintiles of each biomarker. The findings showed HRs of 1.84 (95% CI, 1.64-2.08) for LDL, 1.75 (95% CI, 1.56-1.97) for hsCRP, and 1.28 (95% CI, 1.15-1.42) for Lp(a). Furthermore, for each quintile increase, the multivariable-adjusted HRs were 1.14 (95% CI, 1.11-1.17) for LDL, 1.12 (95% CI, 1.09-1.15) for hsCRP, and 1.05 (95% CI, 1.02-1.08) for Lp(a). The investigation revealed that while high levels of each biomarker independently increased MACE risk, their combined presence in the highest quintile posed the greatest risk.

Kraaijenhof and colleagues emphasized the significance of their findings, stating, “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.” They advocated for the universal screening of these three biomarkers, asserting that commercial assays for hsCRP and Lp(a) are standardized, cost-effective, and widely available, making this an opportune time for implementation in both primary and secondary prevention strategies.