Bempedoic acid associated with reduced MACE and mortality in primary prevention
Bempedoic Acid for Primary Prevention of Cardiovascular Events in Statin-Intolerant PatientsLiterature - Nissen SE, Menon V, Nicholls SJ, et al. - JAMA. 2023 Jun 24 [Online ahead of print]. doi: 10.1001/jama.2023.9696
Introduction and methods
The recently published CLEAR Outcomes (Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen) trial showed treatment with bempedoic acid reduced the risk of MACE in statin-intolerant patients compared with placebo . In this mixed population of primary and secondary prevention patients, a considerable proportion exhibited characteristics associated with a high CVD risk but with no a prior CV event.
Aim of the study
In a prespecified subgroup analysis of the CLEAR Outcomes trial, the authors examined the effects of bempedoic acid on the occurrence of MACE in primary prevention.
The CLEAR Outcomes trial was an international, double-blind, placebo-controlled, phase 3 RCT in which 13,970 statin-intolerant patients with (current or previous) high CVD risk were enrolled, of whom 4206 (30%) were in the primary prevention group. Participants were randomized to oral bempedoic acid 180 mg once daily or matching placebo. Median follow-up time for the primary prevention group was 39.9 months.
The primary efficacy endpoint was time to the first occurrence of a composite outcome of CV death, nonfatal MI, nonfatal stroke, or coronary revascularization (4-component MACE). Key secondary endpoints included: (1) time to first occurrence of a composite outcome of CV death, nonfatal stroke, or nonfatal MI (3-component MACE); (2) fatal or nonfatal MI; (3) coronary revascularization; (4) fatal or nonfatal stroke; (5) CV death; and(6) all-cause mortality.
- Mean baseline LDL-c level was 142.5 mg/dL. After 6 months of treatment with bempedoic acid (n=2100) the least-squares (LS) mean reduction compared with placebo (n=2106) was 30.2 mg/dL (95%CI: –32.1 to –28.3), which was an LS mean difference of 21.3%.
- Bempedoic acid treatment also resulted in a placebo-adjusted reduction in hs-CRP concentration (using Hodges-Lehmann estimate of location shift) of 0.56 mg/L (21.5%) at 12 months, coming from a median baseline level of 2.4 mg/L.
- The primary 4-component MACE endpoint occurred in 111 patients (5.3%) in the bempedoic acid group and 161 patients (7.6%) in the placebo group (adjusted HR (aHR): 0.70; 95%CI: 0.55–0.89; P=0.002; number needed to treat: 43).
- In addition, bempedoic acid versus placebo reduced the risk of the 3-component MACE endpoint (4.0% vs. 6.4%; aHR: 0.64; 95%CI: 0.48–0.84; P<0.001); fatal or nonfatal MI (1.4% vs. 2.2%; aHR: 0.61; 95%CI: 0.39–0.98); CV death (1.8% vs. 3.1%; aHR: 0.61; 95%CI: 0.41–0.92); and all-cause mortality (3.6% vs. 5.2%; aHR: 0.73; 95%CI: 0.54–0.98).
- Bempedoic acid had no significant treatment effect on coronary revascularization or stroke.
- Bempedoic acid was associated with a higher incidence of elevated hepatic enzyme levels compared with placebo (4.5% vs. 2.6%), frequent kidney adverse events (10.3% vs. 8.1%), hyperuricemia (12.1% vs. 6.3%), gout (2.6% vs. 2.0%), and cholelithiasis (2.5% vs. 1.1%).
- The numbers of serious adverse events and adverse events leading to drug discontinuation were similar between the 2 treatment groups.
In a secondary subgroup analysis of the CLEAR Outcomes trial comprising 4206 statin-intolerant patients with high CVD risk but no prior CV event, bempedoic acid treatment was associated with a risk reduction of MACE, CV death, and all-cause mortality compared with placebo. “These findings emphasize the potential value of lipid-modulating therapy in patients who have had no prior cardiovascular event but who have a high risk for a first event, a population that is currently undertreated,” according to the authors.