Lipoprotein apheresis for lowering Lp(a): the conceptual confusion between ‘acute removal’ and ‘chronic control’ may mislead clinical interpretation

Dear editor, We read with great interest the systematic review and meta-analysis conducted by Razi et al.1 (published online 24 February 2026), which provides a timely and comprehensive synthesis of evidence on lipoprotein apheresis for lowering lipoprotein(a) [Lp(a)] levels. By aggregating data from 67 studies encompassing 2466 participants, the authors compellingly demonstrate that lipoprotein apheresis significantly reduces serum Lp(a) concentrations, with a pooled standardized mean difference (SMD) of −1.52 (95% confidence interval: −1.76 to −1.29). We commend the authors for their valuable contribution to the field. Nevertheless, we harbour a fundamental concern regarding the clinical interpretation of their core findings, specifically that the analysis may conflate the ‘acute removal effect’ of apheresis with patients’ ‘chronic exposure levels’. A particularly striking finding of this meta-analysis is the near-identical effect sizes reported for single-session and long-term treatments (SMD of −1.51 and −1.52, respectively). The authors interpret this congruence as mutually reinforcing evidence for the efficacy of apheresis. However, we contend that this pattern of findings instead underscores a fundamental limitation in study design and methodological interpretation: what precisely do the ‘post-treatment’ Lp(a) values reported in the included studies represent? Do they reflect acute trough levels measured immediately following apheresis, or do they correspond to the more clinically meaningful interval mean concentration—that is, the average lipoprotein exposure over the course of the inter-treatment period? This distinction carries not only methodological weight but also profound implications for clinical translation. From a pharmacokinetic standpoint, the plasma half-life of Lp(a) is approximately 3 to 5 days.2 Accordingly, the assessment of long-term therapeutic efficacy in apheresis should rely on metrics that capture average exposure throughout the entire treatment cycle, such as ‘pre-treatment trough values’ or ‘time-averaged concentrations’, rather than instantaneous values obtained immediately post-procedure.3–5 This principle is indirectly validated by the design of the Pro(a)LiFe study, which evaluated the efficacy of apheresis using the incidence of cardiovascular events over a 5-year follow-up period as its primary endpoint, rather than the acute reduction in Lp(a) following a single session.6 Although a single apheresis session reduced Lp(a) by an average of 68.1%, the tangible clinical benefit manifested as a sustained reduction in event rates,6 indicating that the therapeutic effect derives from the cumulative reduction in average Lp(a) exposure achieved through repeated, long-term treatment, rather than transient improvements in instantaneous biochemical values.