Lipoprotein(a) and the risk of major adverse limb events in patients with stable atherosclerotic vascular disease

Abstract

Abstract Background/Introduction Patients with atherosclerotic vascular disease are at heightened risk of ischemic events, including adverse limb events. The pathobiology of adverse limb events ranges from events that are predominantly thrombotic such as acute limb ischemia (ALI) to those that are due primarily to progressive atherosclerosis such as worsening functional imitation requiring elective peripheral revascularization and development of critical limb ischemia (CLI). Evolving data suggest that lipoprotein(a) [Lp(a)] may be associated with the risk of adverse limb events; however, which type of events are related to Lp(a) has not been well described. Purpose To evaluate the association between Lp(a) and specific limb outcomes in patients with stable atherosclerotic vascular disease. Methods Data from two randomized clinical trials including patients with stable atherosclerotic vascular disease were combined: TRA2P-TIMI 50 and FOURIER. We measured Lp(a) in baseline samples in the TIMI Clinical Trials Laboratory. Major adverse cardiovascular events (CV death, myocardial infarction (MI), or stroke) were the primary or key secondary outcomes of the trials. Peripheral revascularization procedures occurring during follow up were investigator reported. Adverse limb events, including CLI and ALI, were categorized through the review of safety data by two blinded vascular specialists. MALE was defined as the composite of peripheral revascularization, CLI, or ALI. The association of Lp(a) as a continuous variable and MALE was assessed and adjusted for randomized therapy in each trial, age, sex, race, region, prior MI, prior stroke, peripheral artery disease, hypertension, diabetes mellitus, smoking status, and statin use. Results A total of 28,892 patients were included in the combined analysis population. The median Lp(a) was 36 nmol/L (IQR 12 – 159). A total of 1336 MALE events occurred during follow-up, including 1307 peripheral revascularizations (1237 elective, 173 urgent), 259 CLI events, and 148 ALI events. Lp(a) was associated with an increased risk of MALE (Adj HR 1.07 per SD, 95% CI 1.02 – 1.13, p=0.007, Figure Panel A) with the risk of a similar magnitude for that of MACE (Adj HR 1.05 per SD, 95% CI 1.01 – 1.10, p=0.020). The association of Lp(a) and MALE was driven by peripheral revascularizations including elective revascularization (Adj. HR 1.07, 95% CI 1.02 – 1.13, p=0.010) with a consistent trend for CLI; however, a relationship with ALI was unclear (Figure Panel B). Conclusion In patients with stable atherosclerotic vascular disease, Lp(a) is associated with MALE with the relationship driven by peripheral revascularization and a consistent trend for CLI. Any relationship with ALI, a primarily thrombotic event, is less clear. Overall, these data support the relationship of Lp(a) and progression of lower extremity atherosclerosis.Figure Panel AFigure Panel B