Lp(a) does not predict limb events after CLTI revascularisation, but predicts all-cause death once kidney function is accounted for, BEST-CLI substudy finds (J Am Heart Assoc 2025)

Original title: Association of Lipoprotein(a) With Major Adverse Limb Events and All-Cause Mortality Following Revascularization for Chronic Limb-Threatening Ischemia: A Substudy of the BEST-CLI Trial

J Am Heart Assoc · 22 May 2025 · 7

Sullivan AE, Huang S, Kundu S, Thomas VE, Clair DG, Aday AW, Menard MT, Farber A, Rosenfield K, Newman JD, Berger JS, Wells QS et al.

This substudy of the BEST-CLI trial, which tested optimal initial revascularisation strategy for chronic limb-threatening ischaemia (CLTI), performed blinded core-laboratory Lp(a) assessment in 189 patients (median age 67.3 years) followed for a median 2.1 years, to test Lp(a)'s prognostic relevance and its modification by renal function. Median Lp(a) was 27.3 mg/dL, and 62 patients (32.8%) had elevated levels (50 mg/dL or above); the 1-year event rate for the primary outcome (major adverse limb event or death) was 33.3 per 100 person-years. Lp(a) was not associated with the primary outcome (HR 1.00, 95% CI 0.99-1.00, P = 0.186), but after controlling for renal function, elevated Lp(a) was associated with increased all-cause death risk (HR 1.03, 95% CI 1.01-1.05, P = 0.009), consistent regardless of revascularisation strategy. The authors conclude Lp(a) is not linked to limb events in CLTI but does predict mortality once kidney function is accounted for, positioning it as a potential therapeutic target in this high-risk population.

Original abstract

Background: The BEST-CLI (Best Endovascular Versus Best Surgical Therapy in Patients With Critical Limb Ischemia) trial tested the optimal initial revascularization strategy in patients with chronic limb-threatening ischemia. Little is known about the prognostic relevance of Lp(a) (lipoprotein[a]) and its modification by renal function in patients with chronic limb-threatening ischemia. We investigated the relationship between Lp(a) and prespecified cardiovascular outcomes.

Methods: A subgroup of patients from the BEST-CLI trial (as part of the TIDE [The Impact of Diabetes on Revascularization] study) underwent blinded, core-laboratory assessment of Lp(a) levels and were included in this analysis. The primary end point was major adverse limb events or death from any cause. Secondary end points were the components of the primary end point, major amputation, major reintervention, and major adverse cardiac events (myocardial infarction, ischemic stroke, or death from any cause). The association of Lp(a) with end points was assessed using Cox proportional hazard models adjusting for traditional risk factors and then also for renal function and statin use, which increase Lp(a) levels.

Results: A total of 189 patients (median [interquartile range] age 67.3 [61.6-74.1] years) were included and followed for a median of 2.1 (1.2-2.9) years. Median Lp(a) for the total study population was 27.3 (10.4-65.8) mg/dL, and 62 (32.8%) patients had elevated values (≥50 mg/dL). The 1-year event rate of the primary outcome was 33.3 (95% CI, 23.7-42.8) per 100 person-years. There was no association between Lp(a) and the primary outcome (hazard ratio [HR], 1.00 [95% CI, 0.99-1.00]; P=0.186). In secondary analyses controlling for renal function, elevated Lp(a) was associated with increased risk for all-cause death (HR, 1.03 [95% CI, 1.01-1.05]; P=0.009). Results were similar regardless of peripheral revascularization strategy.

Conclusions: Elevated Lp(a) level was not associated with major adverse limb events or death but was associated with all-cause death after controlling for renal function. Lp(a) may be an important therapeutic target in the patient population with high-risk chronic limb-threatening ischemia.

Registration: https://clinicaltrials.gov/study/NCT03085524; Unique identifier: NCT03085524.

Summary written by lp-a.org from the published abstract; figures as published. Page updated 17 August 2026. Methods.