A systematic review and meta-analysis of elevated lipoprotein(a) and adverse limb outcomes in peripheral artery disease after revascularization

Objective Lipoprotein(a) [Lp(a)] is an atherogenic and prothrombotic lipoprotein with a well-established role in cardiovascular disease. However, its association with peripheral artery disease (PAD) prevalence and limb-related outcomes following lower-extremity revascularization remains incompletely defined. We conducted a systematic review and meta-analysis to evaluate the relationship between elevated Lp(a), PAD prevalence, and post-revascularization limb outcomes. Methods A systematic review was performed in accordance with PRISMA guidelines. MEDLINE, Embase, CINAHL, and Web of Science were searched from January 1990 through August 2024 to identify observational studies reporting associations between Lp(a) levels and PAD prevalence and/or outcomes following lower-extremity revascularization. Risk of bias was assessed using ROBINS-E and ROB-2, and certainty of evidence was graded using the GRADE framework. Pooled odds ratios (ORs) and mean differences were estimated using random-effects models. Between-study heterogeneity was quantified using the I 2 statistic and prespecified sensitivity and subgroup analyses were performed. Results Ten observational studies comprising 5,794 participants met inclusion criteria. Elevated Lp(a) was associated with a significantly higher prevalence of PAD (pooled OR, 1.81; 95% confidence interval [CI], 1.37–2.39; P < .001), with low heterogeneity (I 2 = 26%). This association remained consistent in prospective cohort studies (OR, 1.60; 95% CI, 1.24–2.07; I 2 = 0%). Patients with PAD also had higher circulating Lp(a) concentrations than non-PAD control participants (mean difference, 21.8 mg/dL; 95% CI, −5.5 to 49.1), although heterogeneity was substantial (I 2 = 85%). Among patients undergoing lower-extremity revascularization, only two observational cohort studies contributed to pooled limb-outcome analyses. Within this limited evidence base, elevated Lp(a) was strongly associated with adverse limb outcomes, including repeat target-lesion revascularization (TLR) (OR, 3.22; 95% CI, 2.36–4.40), major adverse limb events (OR, 5.09; 95% CI, 3.89–6.67), and major amputation (OR, 2.62; 95% CI, 1.36–5.03), with no detectable heterogeneity across these endpoints (I 2 = 0%). Several included studies reported estimates adjusted for established vascular risk factors, including diabetes mellitus, smoking, hypertension, and lipid-lowering therapy; however, harmonized adjusted estimates were not available for all pooled analyses. Conclusions Elevated lipoprotein(a) is consistently associated with increased PAD prevalence and adverse limb-related outcomes following lower-extremity revascularization. These findings better define Lp(a) as a marker of limb-related risk and postprocedural prognosis in PAD. However, the current evidence remains insufficient to conclude that Lp(a)-directed treatment improves PAD-specific outcomes.