Lipoprotein(a) measurements identify patients with elevated likelihood of obstructive coronary artery disease despite very low or low clinical likelihood

Abstract Background Elevated Lipoprotein(a) Lp(a) levels are correlated to the extent of coronary artery disease (CAD) and the risk of major adverse cardiovascular events. Despite Lp(a) lowering treatments being underway, no consensus is established on Lp(a) implementation into clinical patient management or integration into risk assessment models. Purpose To study the clinical likelihood reclassification potential of elevated Lp(a) concentration in patients with no known CAD referred for coronary computed tomography (CT) angiography due to symptoms suggestive of new-onset chronic coronary syndrome (CCS). Methods Patients were evaluated for obstructive CAD with coronary CT angiography and, if the CT was abnormal, subsequent invasive coronary angiography with fractional flow reserve measurements. At baseline, risk factor clinical likelihood (RF-CL) of obstructive CAD was calculated according to the European Society of Cardiology 2024 guideline on CCS, and relevant biomarkers, including Lp(a) levels, were measured. Patients were divided into subgroups according to Lp(a) levels (thresholds 20, 125, and 200 nmol/l) and RF-CL (≤5% = very low, 5-15% = low, 15 = moderate RF-CL). An Lp(a)-adjusted RF-CL was developed from RF-CL (RF-CL-LPA): RF-CL-LPA = RF-CL x 1.5 for patients with Lp(a) ≥ 125 nmol/l and RF-CL-LPA = RF-CL for patients with Lp(a) 125 nmol/l. The associations of predictors with obstructive CAD were investigated by logistic regressions, Chi-square tests of independence, and relative risks of obstructive CAD (RR). Finally, model performance of the two CL-models were evaluated with calibration and areas under the curve (AUC). Results 4,312 patients were available for analyses, of whom 11% patients had obstructive CAD. Independently of RF-CL, the prevalence of obstructive CAD increased by 2% (95% CI: 1-3%) for every 10 nmol/l increase in Lp(a) levels, and patients with Lp(a) ≥125 nmol/l had a RR of 1.49 (95% CI: 1.22-1.83) compared to patients with Lp(a) 125 nmol/l. The effect of Lp(a) levels on the prevalence of obstructive CAD was incremental to that of RF-CL across all RF-CL categories (Figure 1, panel A). In total, 199 (4.6%) patients were up-classified with RF-CL-LPA compared to RF-CL. In up-classified patients, the observed proportion of obstructive CAD corresponded to the new category rather than the original RF-CL category (Figure 1, panel C). In patients with Lp(a) ≥ 125 nmol/l, calibration improved from RF-CL to RF-CL-LPA (calibration-in-the-large: 0.51 (95% CI: 0.34-0.79) vs. 0.05 (95% CI: -0.18-0.28) for RF-CL vs. RF-CL-LPA)(Figure 1, panel B). AUC were similar for the two models. Conclusion Elevated Lp(a) levels were associated with increased risk of obstructive CAD independently from and incrementally to the RF-CL associated risk. Multiplying RF-CL by 1.5 in patients with Lp(a) ≥ 125 nmol/l correctly adjusted patients’ clinical likelihood, yielding improved calibration and similar discrimination of obstructive CAD.