Research Summary

Bempedoic Acid Reduces First Major Adverse Limb Events in Statin-Intolerant Patients With PAD

Anthony Calabro, MA

Key Highlights

  • Bempedoic acid reduced first major adverse limb events (MALE) by 36% versus placebo among patients with peripheral artery disease (PAD).
  • Total MALE, including recurrent events, decreased by 45% with bempedoic acid.
  • The absolute risk reduction for first MALE was 2.5% at a median follow-up of approximately 40 months.
  • The findings support LDL cholesterol lowering to reduce overall vascular risk in patients with PAD, according to the investigators.

Bempedoic acid reduced first and recurrent major adverse limb events (MALE), considered a group of severe, life-altering complications affecting the legs, among statin-intolerant patients with peripheral artery disease (PAD), according to a post hoc analysis of the CLEAR Outcomes trial published in Circulation. The analysis also showed reductions in composite cardiovascular and limb outcomes when total events were considered.

CLEAR Outcomes was a randomized, double-blind, placebo-controlled trial involving 13,970 statin-intolerant adults aged 18 to 85 years with established cardiovascular disease or a high risk of cardiovascular disease. Participants received bempedoic acid 180 mg or placebo. Of the total population, 1624 patients had investigator-reported PAD at baseline, including 794 assigned to bempedoic acid and 830 assigned to placebo.

The primary outcome of the current analysis was time to first MALE among patients with PAD. MALE included worsening PAD symptoms leading to revascularization, chronic limb-threatening ischemia, and acute limb ischemia. Two independent, blinded vascular medicine specialists reviewed potential events. Investigators assessed first events using Cox proportional hazards models and total events, including recurrences, using negative-binomial models.

Study Findings

Over a median follow-up of 40.6 months, first MALE occurred in 46 patients receiving bempedoic acid and 69 receiving placebo, corresponding to event rates of 5.8% and 8.3%, respectively. Bempedoic acid reduced the risk of first MALE by 36% (hazard ratio [HR], 0.64; 95% CI, 0.44-0.93; P=.018), with an absolute risk reduction of 2.5% at approximately 40 months.

Bempedoic acid also reduced total MALE, including recurrent events, by 45% compared with placebo (2.9 vs 4.0 events per 100 patient-years; relative risk [RR], 0.55; 95% CI, 0.35-0.85; P=.007).

Among patients with PAD, total MACE-4 or MALE decreased by 29% with bempedoic acid (RR, 0.71; 95% CI, 0.54-0.95; P=.017). Total MACE-3 or MALE decreased by 35% (RR, 0.65; 95% CI, 0.48-0.88; P=.004). Both composite outcomes were reduced by 1.9 events per 100 patient-years in absolute terms.

Treatment-emergent adverse event rates were similar with bempedoic acid and placebo. Hyperuricemia occurred in 10.7% versus 5.4% of patients, respectively, and gout occurred in 2.9% versus 1.3%.

Clinical Implications

According to the study authors, the findings reinforce the importance of LDL cholesterol lowering to reduce cardiovascular and limb risk among patients with PAD. Evidence of reductions in both MACE and MALE may also support shared decision-making when selecting preventive lipid-lowering strategies for statin-intolerant patients.

The analysis was limited by the lack of universal PAD screening and post hoc ascertainment of MALE from safety data without supplemental source documentation. In addition, patients with PAD represented 12% of the trial population, leaving the subgroup underpowered for significant differences in the original trial’s primary end point.

Expert Commentary

“These findings suggest the use of bempedoic acid to optimize outcomes in patients with PAD,” the researchers concluded.

Reference
Bonaca MP, Canonico ME, Li N, et al. Bempedoic acid and first and recurrent limb outcomes in statin-intolerant patients with peripheral artery disease: insights from the CLEAR Outcomes trial. Circulation. Vol 154, no. 11. doi:10.1161/CIRCULATIONAHA.125.07846