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Relating Lp(a) Concentrations to CV Event Risk After ACS
Quick Takes
- Expert guideline recommendations for clinical use and targeting Lp(a) in clinical trials strongly support molar concentration (nmol/L) and avoidance of mass measured in mg/dL. While optimal, the former is not readily available for clinical use and there is no reliable conversion factor between mass and molar scales.
- After accounting for LDL-C, each type of Lp(a) test provides important incremental information regarding the risk for MACE in patients with recent ACS and risk reduction with alirocumab.
- In terms of choosing a commercially available Lp(a) immunoassay for individual patient prognosis, both can provide comparable clinical utility for risk assessment.
Study Questions:
Lipoprotein(a) [Lp(a)] concentration can be measured with immunoassays reporting mass or molar concentration or a reference measurement system employing mass spectrometry. Does the relationship between Lp(a) concentrations and cardiovascular events in a high-risk cohort differ across Lp(a) methods?
Methods:
The ODYSSEY OUTCOMES trial investigator group compared the prognostic and predictive value of the three types of Lp(a) tests for major adverse cardiovascular events (MACE). The ODYSSEY OUTCOMES trial compared the proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor (i) alirocumab with placebo in patients with recent acute coronary syndrome (ACS). Risk of MACE in the placebo group and MACE risk reduction with alirocumab according to baseline Lp(a) concentration measured by Siemens n-latex nephelometric immunoassay (ia-mass, mg/dL), Roche Tina-quant turbidimetric immunoassay (ia-molar, nmol/L), and a noncommercial mass spectrometry-based test (ms, nmol/L). Lp(a) values were transformed into percentiles for comparative modeling. Natural cubic splines estimated continuous relationships between baseline Lp(a) and outcomes in each treatment group. Event rates were also determined across baseline Lp(a) quartiles defined by each assay.
Results:
Among 11,970 trial participants with results from all three tests, baseline median (q1, q3) Lp(a) concentrations were 21.8 (6.9, 60.0) mg/dL, 45.0 (13.2, 153.8) nmol/L, and 42.2 (14.3, 143.1) nmol/L for ia-mass, ia-molar, and ms, respectively. The strongest correlation was between ia-molar and ms (r = 0.990), with nominally weaker correlations between ia-mass and ms (r = 0.967) and ia-mass and ia-molar (r = 0.972). Relationships of Lp(a) with MACE risk in the placebo group were nearly identical with each test with estimated cumulative incidences differing by ≤0.4% across Lp(a) percentiles, and all were incrementally prognostic after accounting for low-density lipoprotein cholesterol (LDL-C) (all spline p ≤ 0.0003). Predicted alirocumab treatment effects were also nearly identical for each of the three tests, with estimated treatment hazard ratios differing by ≤0.07 between tests across percentiles and nominally less relative risk reduction by alirocumab at lower percentiles for all three tests. Absolute risk reduction with alirocumab increased with increasing Lp(a) measured by each test, with significant linear trends across quartiles.
Conclusions:
In patients with recent ACS, three Lp(a) tests were similarly prognostic for MACE in the placebo group and predictive of MACE reductions with alirocumab at the cohort level.
Perspective:
The findings provide the clinician assurance for using Lp(a) mass for assessing risk in primary prevention, particularly in younger persons with a family history of premature atherosclerotic cardiovascular disease and deciding to target LDL-C to lower levels for primary and secondary prevention. Intensifying lowering of LDL-C decreases the relative risk contribution of Lp(a); however, it is important to realize statins may raise the Lp(a) mass significantly.
Clinical Topics: Acute Coronary Syndromes, Diabetes and Cardiometabolic Disease, Dyslipidemia, Prevention, Advanced Lipid Testing, Lipid Metabolism, Nonstatins
Keywords: Acute Coronary Syndrome, Cholesterol, LDL, Dyslipidemias, ESC Congress, ESC23, Immunoturbidimetry, Lipoprotein(a), PCSK9 protein, human, Primary Prevention, Risk Assessment, Risk Reduction Behavior, Secondary Prevention
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