Intraindividual Variability in Serial Lipoprotein(a) Concentrations Among Placebo-Treated Patients in the OCEAN(a)-DOSE Trial

Lipoprotein(a) [Lp(a)] is a presumed risk factor for atherosclerotic cardiovascular disease (ASCVD), and its levels are primarily genetically determined (∼70%-90%). As such, many guidelines and consensus groups recommend measuring Lp(a) levels only once in a person’s lifetime for risk stratification. However, data assessing the intraindividual variability of Lp(a) levels over time are limited. Methods Study design and participants OCEAN(a)-DOSE was a phase 2, randomized, placebo-controlled trial that evaluated the efficacy of the investigational Lp(a)-lowering therapy olpasiran in patients with elevated Lp(a) concentration (>150 nmol/L) and established ASCVD. The trial was approved by all relevant ethics committees. Enrolled individuals were to be clinically stable and to receive optimized lipid-lowering therapy before screening. Serial Lp(a) measurements were conducted using an isoform-independent method (Roche Tina-quant Lipoprotein(a) Gen.2 assay) at a central laboratory with validated interassay coefficients of variation (CV) between 1.5% and 4.4%. Statistical analysis Analyses were conducted in patients randomized to placebo. An individual’s mean Lp(a) was calculated by averaging all available Lp(a) values for a given individual during the 72-week study period. The proportion of individuals with changes in Lp(a) of ≥50 nmol/L at any given study visit and those with a relative percentage change in Lp(a) of ≥25% compared with their individual mean Lp(a) were also examined. The absolute and percentage differences between a patient’s baseline value or visit value compared with the average Lp(a) concentration across subsequent visits were also examined. Intraindividual biological variation (CVi) was calculated as the SD of measurements over time in an individual divided by the mean of those values and was done for Lp(a) as well as LDL-C, triglycerides, and apolipoprotein B (apoB) values. Comparisons were made using the Feltz and Miller asymptotic test for the equality of variation. Results Fifty-three patients were randomized to placebo and had at least 1 postrandomization Lp(a) measurement available. The median number of Lp(a) measurements per subject was 16 (Q1-Q3: 16-16), and the median follow-up time was 1.7 years (Q1-Q3: 1.4-1.7 years). The median baseline Lp(a) concentration in the placebo arm was 248 nmol/L (Q1-Q3: 200-343 nmol/L) and across all follow-up visits was 257 nmol/L (Q1-Q3: 207-343 nmol/L). Each individual’s Lp(a) levels across study visits are shown in Figure 1A. The median of the absolute variability in Lp(a) concentration across study visits, when compared with an individual’s mean Lp(a) value, was 16.4 nmol/L (Q1-Q3: 7.3-30.1 nmol/L), with a maximum absolute difference of 135 nmol/L from an individual patient’s mean (Figure 1B). The median of the absolute values of the percent changes in Lp(a) concentration across study visits when compared with an individual’s mean Lp(a) was 6.2% (Q1-Q3: 2.7%-10.8%), with a maximum percentage difference of 49% (Figure 1C). Twenty-five percent of patients experienced an upward or downward relative change of ≥25% in Lp(a) from their individual mean on ≥1 study visit; 53% of patients saw an upward or downward absolute change of ≥50 nmol/L on ≥1 study visit. For 30% of patients, their first Lp(a) value differed by 5% to 10% from the average of repeated measures, and 19% had a first value that differed by >10% (either upward or downward) from subsequent values. Whereas overall Lp(a) concentration in the placebo arm was constant over time (standard deviation 2.6% of the mean), the intraindividual variation (CVi) was 10.0% ± 3.9% of the mean. This variation was consistent across the range of Lp(a) values (Figure 1D). When 2 outliers were excluded, the CVi was reduced to 9.5% ± 2.6%. The intraindividual CVi was smaller for Lp(a) than for LDL-C (15.6%; P = 0.005) and triglyceride concentration (22%; P < 0.001) but similar to apoB (10.8%; P = 0.60). Discussion Among patients with stable ASCVD and elevated baseline Lp(a) concentrations, there was notable intraindividual variability in Lp(a) levels. Across all visits, the intraindividual variation (CVi) in Lp(a) was 10%. In approximately one-half of the study population, their first Lp(a) value differed by ≥5% when compared with subsequent Lp(a) values, with 19% having an initial value that subsequently differed by >10% from the average of subsequent measures. These findings raise questions about whether Lp(a) should be measured more than once for patients with elevated Lp(a) values, particularly if Lp(a) thresholds are to be used to guide treatment decisions. Studies examining serial values of Lp(a) over time remain sparse. In early-phase clinical studies of novel therapeutics to lower Lp(a) that included a wide range of baseline Lp(a) values, 40% of patients had a >25% rise or fall in Lp(a) at any study visit. In a study from the UK Biobank (96% without prevalent coronary artery disease), correlation was high between the baseline Lp(a) and the follow-up value, and the absolute differences were small. However, this low-risk population had a low median baseline Lp(a) of ∼20 nmol/L, and only 1 follow-up time point was available. The current findings build on earlier observations by examining many more serial values, yielding 819 samples from patients in stable condition with ASCVD and baseline values >150 nmol/L. This population is of key interest if future decisions regarding treatment are based on Lp(a) values if novel therapeutics to lower Lp(a) prove to be effective. The study’s limitations include its relatively modest sample size and its restriction to patients with Lp(a) values >150 nmol/L. Samples were all analyzed at a central laboratory but on different days rather than in batches. These findings should be replicated across populations with a broader range of baseline Lp(a) values because most patients in practice will have concentrations <150 nmol/L, and the need for repeated measurements in those with lower values remains unclear. The optimal frequency of reassessment, if one obtains serial values, is also unknown. Several commercial assays exist in clinical practice, and variability at the higher range of values should be more extensively studied. Conclusions Among patients with ASCVD and elevated baseline Lp(a) concentrations, there was notable intraindividual variability in serial Lp(a) concentration during follow-up. As routine clinical assessment of Lp(a) becomes more widespread, these findings shed light on the reliability of single assessments of Lp(a) when values are high and near thresholds that may ultimately help guide treatment decisions.