EPIC-Norfolk: Combination Measurement of LDL, hsCRP, and Lp(a) Predicts Incident MACE

A single combined measurement of LDL cholesterol, high-sensitivity C-reactive protein (hsCRP), and Lp(a) among initially healthy patients has shown predictive capabilities for incident major adverse cardiovascular events (MACE) during a 20-year period, confirming the generalizability of this universal screening model in primary prevention.1

The EPIC-Norfolk study was conducted in an effort to affirm a prior American trial investigating the efficacy of this combination measurement. The prior trial examined nearly 28,000 healthy American women over 30 years; investigators noted a significant association between the combination measure of hsCRP, LDL, and Lp(a) and incident cardiovascular events.2

“From a policy perspective, moving universal 1-time screening for LDL cholesterol, hsCRP, and Lp(a) into primary prevention as strongly suggested by the WHS requires external replication for consistency, validity, and generalizability,” Jordan Kraaijenhof, MSc, department of vascular medicine, Amsterdam Cardiovascular Sciences, Amsterdam University Medical Centers, University of Amsterdam, and colleagues wrote. “We therefore sought to determine whether the predictive value of LDL cholesterol, hsCRP, and Lp(a), both individually and in combination, extends to a European primary prevention population.”1

Kraaijenhof and colleagues recruited patients aged 40-79 via general practices in Norfolk, UK. Participants completed a detailed health and lifestyle questionnaire and had additional information collected by trained nurses during clinic visits. Non-fasting blood samples were obtained at baseline – plasma levels of total cholesterol, HDL cholesterol, and triglycerides were measured from fresh samples, while LDL cholesterol was calculated based on these measurements. hsCRP levels were analyzed via frozen baseline serum samples, and Lp(a) concentrations were assessed with an isoform-independent immunoturbidimetric assay.1

The study’s primary objective was to assess the relationship between LDL cholesterol, hsCRP, and Lp(a) and cardiovascular risk. Each biomarker was analyzed independently before the combined effect on cardiovascular events was assessed. The cardiovascular outcome was a composite of first MACE, defined as fatal or non-fatal coronary artery disease and fatal or non-fatal ischemic stroke. MACEs were documented during follow-up if participants were hospitalized or died with coronary artery disease or ischemic stroke as the primary cause.1

Ultimately, investigators included 17,087 patients, who had a mean age of 59 years. Baseline levels of LDL cholesterol, hsCRP, and Lp(a) were 4 +/- 1 mmol/L, 1.5 (0.7-3.2) mg/L, and 11 (6-27) mg/dL, respectively. Patients were followed up for a median of 20.5 years (interquartile range [IQR], 19.6-21.5). During this time, investigators noted 3249 first MACEs, including 1755 in the 18% (n = 9745) female participants and 1494 events in the 20.3% (n = 7342) male participants.1

Investigators analyzed the age- and sex-adjusted hazard ratios (HRs) for MACE, comparing the highest and lowest quintiles (HR, 1.84; 95% CI, 1.64-2.08 for LDL; HR, 1.75; 95% CI, 1.56-1.97 for hsCRP; HR, 1.28; 95% CI, 1.15-1.42 for Lp(a)). For each quintile increase, 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). While high levels of LDL, hsCRP, and Lp(a) independently contributed to increased MACE risk, all 3 biomarkers being in the highest quintile caused the greatest risk.1

“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,” wrote Kraaijenhof and colleagues. “As commercial assays for hsCRP and Lp(a) are standardized, inexpensive, and widely available, we believe the time has come for universal screening of these three biomarkers in primary as well as secondary prevention.”1

References

1. Kraaijenhof JM, Nurmohamed NS, Nordestgaard AT, et al. Low-density lipoprotein cholesterol, C-reactive protein, and lipoprotein(a) universal one-time screening in primary prevention: the EPIC-Norfolk study. Eur Heart J. 2025;46(39):3875-3884. doi:10.1093/eurheartj/ehaf209

2. Ridker PM, Moorthy MV, Cook NR, Rifai N, Lee IM, Buring JE. Inflammation, Cholesterol, Lipoprotein(a), and 30-Year Cardiovascular Outcomes in Women. N Engl J Med. 2024;391(22):2087-2097. doi:10.1056/NEJMoa2405182