Patients with peripheral artery disease (PAD) face elevated risk for both major adverse limb events (MALE) and major adverse cardiovascular events (MACE). Prior results from CLEAR Outcomes showed that bempedoic acid lowers cardiovascular event risk in statin‑intolerant populations, but whether it reduces limb events in patients with PAD was previously unknown. This analysis examined limb‑related outcomes, including first and recurrent MALE, in the CLEAR Outcomes trial cohort and assessed combined limb and cardiovascular event effects.
CLEAR Outcomes (Cholesterol Lowering via Bempedoic Acid [ETC1002], an ACL‑Inhibiting Regimen) randomized 13,970 statin‑intolerant patients to bempedoic acid 180 mg daily or placebo between December 22, 2016, and August 14, 2019. The trial's primary endpoint was MACE‑4, defined as cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization. Investigators recorded a clinical history of PAD at baseline; 1,624 participants (mean±SD age 63.9±9.9 years; 56.3% female) were reported to have PAD and form the subgroup of interest for limb outcomes.
Two vascular medicine specialists, blinded to treatment assignment, independently adjudicated MALE. Adjudicated MALE encompassed adverse events indicative of worsening PAD that led to peripheral revascularization, chronic limb‑threatening ischemia, and acute limb ischemia. Both time‑to‑first event and total (including recurrent) events were evaluated to capture the burden of limb complications.
Time‑to‑first events were analyzed using hazard ratios (HRs) with corresponding 95% confidence intervals (CIs) and P values for hypothesis testing. Recurrent and total event counts were analyzed using a negative binomial approach, yielding relative risks (RRs) and 95% CIs for total events. Interaction testing assessed consistency of treatment effects in participants with and without PAD.
Among the 1,624 patients identified with PAD at baseline, the mean age was 63.9 years and 56.3% were female. The report provides these aggregate demographics; additional baseline risk factor distributions and concomitant therapies were not detailed in the abstract.
In the placebo group with baseline PAD, 69 patients (8.3%) experienced a first adjudicated MALE over a median follow‑up of 40.6 months, with a recurrent event rate reported as 4.0% per year. Allocation to bempedoic acid was associated with a 36% relative reduction in risk of first MALE (HR 0.64; 95% CI 0.44–0.93; P = 0.018). When recurrent events were included, bempedoic acid reduced total MALE by 45% (RR 0.55; 95% CI 0.35–0.85; P = 0.007). These results indicate both a lower incidence of initial limb events and a reduced burden of recurrent limb events in the PAD subgroup assigned to bempedoic acid.
When considering the composite of first events of MACE‑4 or MALE, the overall trial population experienced a 13% reduction with bempedoic acid (HR 0.87; 95% CI 0.80–0.95). In subgroup analyses, the direction of effect was consistent in participants with PAD (HR 0.82; 95% CI 0.64–1.04) and those without PAD (HR 0.87; 95% CI 0.79–0.86), although the within‑PAD first‑event reduction did not reach statistical significance and the interaction test was not significant.
For total (including recurrent) MACE‑4 or MALE events, bempedoic acid reduced event counts overall (RR 0.81; 95% CI 0.73–0.90). The effect was consistent in the PAD subgroup (RR 0.71; 95% CI 0.54–0.95) and in patients without PAD (RR 0.82; 95% CI 0.73–0.92), with no significant interaction between PAD status and treatment effect.
This prespecified analysis of CLEAR Outcomes shows that in statin‑intolerant patients with a history of PAD, bempedoic acid reduced both first and recurrent major adverse limb events and lowered total combined limb and cardiovascular events. The findings support the concept that lowering LDL‑cholesterol with bempedoic acid can reduce both limb‑related and cardiovascular risk among patients with atherosclerotic vascular disease, with notable absolute benefits among those with PAD. These data may inform lipid‑lowering strategies in statin‑intolerant patients with PAD, emphasizing the importance of addressing LDL reduction to mitigate both MALE and MACE burdens.
The abstract reports aggregate subgroup results for the PAD cohort but does not provide detailed baseline covariate distributions or event subtype breakdowns within this summary. The PAD subgroup first‑event composite reduction did not achieve statistical significance despite directionally consistent effects, and precise absolute risk reductions and number‑needed‑to‑treat calculations are not presented in the abstract.
The authors disclose multiple potential conflicts of interest. Several investigators receive research support, have consultancy relationships, or, in some cases, employment or stock ownership related to Esperion Therapeutics and other companies. Specific financial relationships and institutional funding are detailed in the source document and should be consulted when interpreting results.
In the CLEAR Outcomes randomized trial, bempedoic acid 180 mg reduced the incidence of first MALE by 36% and total MALE by 45% among statin‑intolerant patients with investigator‑reported PAD, and reduced total combined MACE‑4 or MALE events overall and within the PAD subgroup. These results reinforce the role of LDL lowering to reduce both cardiovascular and limb complications in patients with PAD. Clinicians should consider these findings alongside individual patient characteristics, concomitant therapies, and the detailed disclosures provided by the study authors.