Variability in lipoprotein(a) measurements in ODYSSEY OUTCOMES: is one-and-done testing sufficient?

Introduction Repeated testing of lipoprotein(a) (Lp(a)) levels is generally viewed as unnecessary for most individuals since concentrations are largely genetically determined. Given that Lp(a)-targeting therapeutics under development are focused on concentrations above certain thresholds, there is a need to determine whether there are characteristics associated with greater variability in Lp(a) measurements over time, which might impact eligibility for these emerging treatments and therefore warrant repeated testing. Purpose To document predictors of variability in Lp(a) measurements in a cohort of high-risk participants on optimized statin therapy following an acute coronary syndrome (ACS). Methods The analysis cohort comprised participants from the placebo arm of the ODYSSEY OUTCOMES study with measurements of Lp(a) mass concentration at randomization, month 4, and month 12. Participants were randomized 1-12 (median 2.6) months after qualifying ACS; accordingly, baseline values were not expected to be influenced by an acute phase response resulting from ACS. A plot of the per-participant mean versus the maximum difference of the three measurements relative to the mean was generated to summarize variability in the measurements. The range of measurements was related to participant characteristics in linear regression models, overall and for subsets above the LLQ and with averages above clinically relevant thresholds. Results Among 9462 participants, 9212 (97.3%) had baseline, month 4, and month 12 Lp(a) assessments; none initiated PCSK9i therapy prior to 12 months, and median (IQR) was 21.6 (6.6, 60.1), 20.0 (6.1, 58.4), and 20.3 (6.1, 59.4) mg/dL, respectively. The measurements were strongly correlated (all pairwise Spearman r>0.95); absolute but not relative variability increased with average concentration (Figure). Of 27,636 Lp(a) measurements, 7286 (26.4%) deviated from the per-participant means by more than ±20%, and 1180 (4.3%) deviated from the per-participant means by more than ±20 mg/dL. Furthermore, 8.6% of 1181 participants with baseline Lp(a) 30 to <50 mg/dL had at least one subsequent measurement >=70mg/dL, whereas 5.8% of 1923 participants with baseline Lp(a) >=70mg/dL had at least one subsequent measurement <50 mg/dL. While several characteristics were related to range, only baseline and average Lp(a) explained a meaningful proportion of the variance in this outcome (Table). Conclusion Over 12 months, material fractions of individuals at high risk for cardiovascular events but unselected for Lp(a) shifted in and out of ranges studied in Lp(a)-targeting outcomes studies. Baseline and average concentration explained a meaningful proportion of variability, suggesting repeated testing of those with relatively high Lp(a) may be warranted to determine eligibility for treatment if these therapeutics are ultimately indicated for individuals with elevated levels.