Two of a kind: mass and molar immunoassay-based lipoprotein (a) concentrations are similarly prognostic for MACE risk and predictive of alirocumab benefit in ODYSSEY OUTCOMES
Bibliographic record
Abstract
Abstract Background Lipoprotein (a) (Lp(a)) is a risk factor for incident and recurrent ischemic cardiovascular (CV) events and may modify the benefit of PCSK9 inhibitors (PCSK9i). While Lp(a) concentration can be measured in either mass or molar units, to date there has been no direct, large-scale comparison of the relationships of mass vs. molar Lp(a) with CV risk and response to treatment. Purpose Using samples from ODYSSEY OUTCOMES where 18,924 patients with recent acute coronary syndrome were randomized 1:1 to the PCSK9i alirocumab (ALI) or placebo (PBO), baseline mass vs. molar Lp(a) were compared in terms of prognosis for first major adverse CV event (MACE, consisting of coronary heart disease death, nonfatal myocardial infarction, ischemic stroke, or hospitalization for unstable angina) in the placebo group and associations with ALI risk reduction. Methods Lp(a) mass and molar tests were the Siemens N latex immunonephelometric test and the Roche TinaQuant immunoturbidimetric assay, respectively. Both tests use polyclonal anti-apo(a) antibodies but are designed to be relatively apo(a)-size independent within allowable measurement uncertainty. Absolute risk of MACE at 4 years in the PBO group and treatment risk ratios (RR) by continuous Lp(a) concentrations were estimated by natural cubic splines from Poisson regression models with log follow-up time as an offset and adjustment for baseline LDL-C. For comparative modeling purposes Lp(a) values were transformed into percentiles; due to ties at the lower limits of quantification, minimum percentiles were 8th and 6th for mass and molar, respectively. All analyses were intention-to-treat. Results Baseline mass and molar Lp(a) concentrations, available in 11943 patients, were correlated (r=0.94). ALI MACE reduction in evaluable patients (1324 events; RR [95% CI] = 0.83 [0.74, 0.92]) was similar to the total population (1955 events; RR [95% CI] = 0.85 [0.78, 0.93]). Relationships with risk of MACE in the PBO group were nearly identical for mass (spline p=0.0001) and molar (spline p=0.0002) concentrations (Figure 1). Of note, the confidence boundaries around the splines were nearly superimposable, indicating similar precision of the estimated Lp(a)-associated risk with both measurement techniques. Risk reductions with ALI were similarly related to mass (spline p<0.0001) and molar (spline p<0.0001) concentrations (Figure 2). Conclusion Baseline mass and molar Lp(a) concentrations were similarly prognostic for MACE risk in the PBO group after adjustment for LDL-C. Mass and molar Lp(a) also similarly modified the ALI treatment effect on MACE, with trends towards less treatment benefit at lower concentrations. These results suggest that, at the treatment group level, the prognostic and predictive value of immunoassay-based Lp(a) tests for ischemic CV events in patients with recent acute coronary syndrome is not meaningfully different for the mass or molar concentration essays that were evaluated.Figure 1Figure 2
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How this classification was reachedexpand
Full frame machine prediction
Teacher imitationNot calibrated prevalence, not ground truth. Human validation pending. The Gemma side is a direct model label for every work in the frame, read from the title-only record. The Codex side is a classifier learned from the 10,348 direct Codex labels and calibrated to design-weighted sample rates; fields without enough sample support carry no Codex call. Candidate is the union of the two sides; consensus is their intersection. These outputs are machine_predicted_unvalidated and are not human labels.
Distilled classifier scores by category (both heads)
| Category | Codex | Gemma |
|---|---|---|
| Metaresearch | 0.002 | 0.007 |
| Meta-epidemiology (narrow) | 0.001 | 0.000 |
| Meta-epidemiology (broad) | 0.001 | 0.001 |
| Bibliometrics | 0.001 | 0.001 |
| Science and technology studies | 0.000 | 0.001 |
| Scholarly communication | 0.001 | 0.001 |
| Open science | 0.000 | 0.001 |
| Research integrity | 0.001 | 0.001 |
| Insufficient payload (model declined to judge) | 0.004 | 0.001 |
Machine scores (provisional)
The two teacher heads of the student model, read on this work. A score orders the frame for review; it never asserts a category, and the validation status ships verbatim with every row.
Baseline scores from an immature model (maturity gate not passed, 7 training rounds). Scores rank; they never assert a category.
score_only:v0-immature-baseline · verbatim from the scoring run: score_only means the number may rank works, and no category label ships from itClassification
machine, unvalidatedMachine predicted; a candidate call from one source (direct Gemma or distilled Codex), not a consensus.
How this classification was reached, model by model and score by score, is at the end of the page under "How this classification was reached".