Bempedoic acid 180 mg reduces risk of nonfatal myocardial infarction and revascularization; NNT = 42 in primary prevention group (CLEAR)

Reference

Nissen SE, Lincoff AM, Brennan D, et al, CLEAR Outcomes Investigators. Bempedoic acid and cardiovascular outcomes in statin-intolerant patients. N Engl J Med 2023;388(15):1353-1364.

Synopsis

Bempedoic acid is a prodrug that when activated in the liver reduces cholesterol synthesis and has been shown to reduce low-density lipoprotein (LDL) cholesterol levels by 17% to 28% in previous studies. In this study, patients with a previous cardiovascular event (n = 9764) or who were at elevated risk for cardiovascular events (n = 4206) at one of 1250 sites in 32 countries were randomized to receive bempedoic acid 180 mg daily or placebo. All patients had to confirm that they were statin-intolerant before randomization; other lipid-lowering drugs, such as ezetimibe, niacin, or PCSK9 inhibitors, could be continued. Prior to randomization, each patient had to confirm at least 80% adherence to and tolerance of a placebo in a 30-day run-in period, biasing the results in favor of the drug. After 6 months, patients whose LDL cholesterol level had increased at least 25% were counseled regarding diet, and, if the increase persisted, their other cholesterol-lowering drugs could be adjusted. Groups were balanced at baseline with a mean age of 65 years, 48% were women, the mean LDL level was 139 mg/dL, 70% had a prior myocardial infarction (MI), and 46% had diabetes (including 20% with uncontrolled diabetes). Patients who tolerated a very low daily dose of statin were allowed in the trial and constituted 22% of each group; 11.5% were taking ezetimibe. The primary outcome was a composite of cardiovascular death, nonfatal stroke, nonfatal MI, or coronary revascularization and was assessed after a median follow-up of 41 months. This composite was less likely in the bempedoic acid group (11.7% vs 13.3%; P = .004; number needed to treat = 62 for 41 months). This was driven primarily by significant reductions in fatal or nonfatal MI (3.7% vs 4.8%) and coronary revascularization (6.2% vs 7.6%). There was no difference in cardiovascular (3.8% vs 3.7%) or all-cause (6.2% vs 6.0%) mortality. Of particular relevance for primary care clinicians, the hazard ratio (HR) for the primary composite endpoint was actually a bit more favorable for the primary prevention patients (HR 0.68; 95% CI 0.53 - 0.87) than for the secondary prevention patients (HR 0.91; 0.82 - 1.01). Myalgias occurred at similar rates in the treatment and placebo groups (6.8% vs 5.6%). Premature discontinuation was approximately 30% in both groups, which seems high and may be because this population is generally intolerant of medications.