Key Points:
- Patients with peripheral artery disease (PAD) at an increased risk of both major adverse cardiovascular events (MACEs) and major adverse limb events (MALEs)
- Bempedoic acid is thought to reduce MACEs in primary and secondary prevention patients, but it is unknown whether the same can be said for MALEs
- The CLEAR Outcomes trial randomized patients to either bempedoic acid versus placebo to determine rates of MALEs, and some rates of MACEs, among at risk patients and patients diagnosed with PAD
- The study showed significant reduction in MALEs for all patients and patients with diagnosed PAD, as well as reduction in composite MACEs and MALEs, suggesting a possible role for bempedoic acid in PAD treatment and prevention
Patients with peripheral artery disease (PAD) at are high risk of both major adverse cardiovascular events (MACEs) and major adverse limb events (MALEs). Unfortunately, they are also at high risk of recurrence of these health events. Recent data suggests that bempedoic acid may reduce MACE in primary and secondary prevention of cardiovascular disease (CVD). However, it is unknown whether the same can be said for reduction of MALEs.
CLEAR Outcomes was a double-blind, randomized, placebo-controlled trial involving patients who were unable or unwilling to take statins owing to unacceptable adverse effects (“statin-intolerant” patients) and had, or were at high risk for, cardiovascular disease. The patients were assigned to receive oral bempedoic acid, 180 mg daily, or placebo. The primary end point was a four-component composite of major adverse cardiovascular events, defined as death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization. The main study showed that among statin-intolerant patients, treatment with bempedoic acid was associated with a lower risk of major adverse cardiovascular events (death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization)
A pre -specified analysis of the CLEAR Outcomes trial sought to determine if bempedoic acid could reduce MALEs in patients with PAD. This trial randomized 13,970 patients to bempedoic acid 180mg versus placebo. MALEs were defined as a composite outcome that included worsening PAD symptoms leading to revascularization, chronic limb threatening ischemia (CLI), or acute limb ischemia (ALI). These outcomes were assessed as time to first event in addition to total events, including recurrent.
Of the enrolled patients, 1624 had PAD at baseline. Over a median of approximately 41 months, the rate of first MALEs among PAD patients in the placebo group was 8.3%, and the rate of total MALEs among this same population was 13.7%. Bempedoic acid was found to reduce first MALEs by 36% (HR 0.64, 95% CI: 0.44-0.93); compared to placebo, Absolute risk reduction (ARR) was 2.5% with number needed to treat (NNT) of 40. Bempedoic acid was also found to reduce total MALEs by 45% (RR 0.55, 95% CI 0.35 – 0.85). Among all patients, bempedoic acid also reduced two distinct composite outcomes of MACEs and MALEs. First, bempedoid acid reduced a composite outcome of death from cardiovascular causes, nonfatal stroke, nonfatal myocardial infarction (MI), or MALEs by 18% among all patients (p<0.001). For those with PAD, this composite outcome was reduced by 35% (p=0.004). In addition, bempedoic acid reduced a composite outcome of death from cardiovascular causes, nonfatal MI, nonfatal stroke, coronary revascularization, or MALEs by 19% (p<0.001). For those with PAD, this composite outcome was reduced by 29% (p=0.017).
Ultimately, the study authors conclude that bempedoic acid significantly reduces MALEs, in addition to MACEs. Based on these results, the benefits may be greater when taking into a total/recurrent events. Furthermore, these benefits appear more pronounced in those with established PAD. The study results support the importance of LDL lowering in PAD patients with an agent like bempedoic acid. They also suggest that bempedoic acid may have a role in the early prevention of MALEs to improve PAD outcomes.