Bempedoic Acid for Primary Prevention of Cardiovascular Events in Statin-Intolerant Patients

Abstract

Importance: The effects of bempedoic acid on cardiovascular outcomes in statin-intolerant patients without a prior cardiovascular event (primary prevention) have not been fully described.

Objective: To determine the effects of bempedoic acid on cardiovascular outcomes in primary prevention patients.

Design, setting, and participants: This masked, randomized clinical trial enrolled 13 970 statin-intolerant patients (enrollment December 2016 to August 2019 at 1250 centers in 32 countries), including 4206 primary prevention patients.

Interventions: Participants were randomized to oral bempedoic acid, 180 mg daily (n = 2100), or matching placebo (n = 2106).

Main outcome measures: The primary efficacy measure was the time from randomization to the first occurrence of any component of a composite of cardiovascular death, nonfatal myocardial infarction (MI), nonfatal stroke, or coronary revascularization.

Results: Mean participant age was 68 years, 59% were female, and 66% had diabetes. From a mean baseline of 142.2 mg/dL, compared with placebo, bempedoic acid reduced low-density lipoprotein cholesterol levels by 30.2 mg/dL (21.3%) and high-sensitivity C-reactive protein levels by 0.56 mg/L (21.5%), from a median baseline of 2.4 mg/L. Follow-up for a median of 39.9 months was associated with a significant risk reduction for the primary end point (111 events [5.3%] vs 161 events [7.6%]; adjusted hazard ratio [HR], 0.70 [95% CI, 0.55-0.89]; P = .002) and key secondary end points, including the composite of cardiovascular death, MI, or stroke (83 events [4.0%] vs 134 events [6.4%]; HR, 0.64 [95% CI, 0.48-0.84]; P < .001); MI (29 events [1.4%] vs 47 events [2.2%]; HR, 0.61 [95% CI, 0.39-0.98]); cardiovascular death (37 events [1.8%] vs 65 events [3.1%]; HR, 0.61 [95% CI, 0.41-0.92]); and all-cause mortality (75 events [3.6%] vs 109 events [5.2%]; HR, 0.73 [95% CI, 0.54-0.98]). There was no significant effect on stroke or coronary revascularization. Adverse effects with bempedoic acid included a higher incidence of gout (2.6% vs 2.0%), cholelithiasis (2.5% vs 1.1%), and increases in serum creatinine, uric acid, and hepatic enzyme levels.

Conclusions: In a subgroup of high-risk primary prevention patients, bempedoic acid treatment was associated with reduced major cardiovascular events.

Trial registration: ClinicalTrials.gov Identifier: NCT02993406.

Figure 1.. Flow of Patients Through the Trial (Primary Prevention)

^aPremature termination of treatment (the war in Ukraine [45/115 patients]). ^bPremature withdrawal from the trial (patient could not be contacted, but final vital status known; therefore, not counted as lost to follow-up [37/64]).

Figure 2.. Time to First Incidence of Primary End Point, Key Secondary End Point, and End Point Components

Four-component major adverse cardiovascular events (MACE) indicates a composite of death from cardiovascular causes, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization; 3-component MACE, a composite of death from cardiovascular causes, nonfatal myocardial infarction, or nonfatal stroke. P values were calculated using the log-rank test. The median follow-up time was 39.9 months. HR indicates hazard ratio.