The use of bempedoic acid to lower low-density lipoprotein cholesterol (LDL-C) is similar to that of statin use, as a new prespecified analysis outlines the therapy’s role in reducing the risk of major adverse cardiovascular events (MACE). After normalizing hazard ratio (HRs) for a major vascular event, researchers found that for every 1 mmol/L difference in LDL-C levels, there was a 25% risk reduction with bempedoic acid use and a 22% risk reduction with statin use. The CLEAR Outcomes trial’s main findings showed that among patient unable or unwilling to take statins, bempedoic acid was associated with a lower risk of MACE compared to placebo. The findings from this Cholesterol Lowering via Bempedoic Acid, an ACL-Inhibiting Regimen (CLEAR) Outcomes trial compare favorably with a meta-regression analysis from 2010. Findings from the Cholesterol Treatment Trialists’ Collaboration (CTTC) showed that every 1 mmol/L (38.7 mg/dL) reduction in LDL-C over 1 year was associated with a 22% reduction in major vascular events. “The findings of the CLEAR Outcomes trial and the CTTC meta-analysis support a hypothesis that patients who are earlier in the course of their atherosclerotic disease process may experience enhanced treatment effect from LDL-C reduction by bempedoic acid or statins,” said the authors of the new CLEAR OUTCOMES analysis paper, which was published Monday online. Major vascular event Led by A. Michael Lincoff, MD, from the Cleveland Clinic, the team noted a first major vascular event occurring in 703 (10.1%) patients in the bempedoic acid group and 816 (11.7%) patients in the placebo group (HR: 0.85; 95% CI: 0.77-0.94). When normalized per 1 mmol/L reduction in LDL-C, the HR was 0.75 (95% CI: 0.63-0.90), which the team said was comparable to the rate ratio of 0.78 reported for statins in the CTTC meta-analysis. Further findings revealed that normalized risk reductions were similar for bempedoic acid and statins for the endpoints of major coronary events, nonfatal myocardial infarction, and coronary revascularization. “The results of this analysis of the CLEAR Outcomes trial reinforce the primary goal of lipid management to achieve optimal LDL-C lowering, rather than focus on the specific class of agents used to do so,” said the authors of the paper, which was also published in the July 9 issue of the Journal of the American College of Cardiology. “While statins remain the first-line therapy in cardiovascular disease prevention, treatment with bempedoic acid can provide significant reductions in cardiovascular risk among patients who cannot achieve desired LDL-C levels with statins.” CLEAR implications The study’s findings were the focus for Maya S. Safarova, MD, PhD, and colleagues. In an editorial comment, the experts homed in on the clinical implications of the CLEAR Outcomes trial, which included 48% women, compared with 27% in the 2010 CTTC meta-analysis of 26 trials. This generated key outcomes data in women who historically had higher reported statin intolerance and for whom there was often therapeutic lag and underrepresentation in clinical trials of atherosclerotic cardiovascular disease. The comment also pointed out that bempedoic acid did not lower cardiovascular mortality, nor did it lower the risk of ischemic stroke. Modified definition In placing the findings into perspective and looking ahead, the experts said that to match the endpoints, the definition of cardiovascular death was modified to include death due to acute myocardial infarction or sudden cardiac death in the CLEAR Outcomes subanalysis. “The CTTC protocol specified deaths as those probably/definitely due to coronary disease and those from extracardiac causes, introducing confounding ‘intervening’ causes of death,” they pointed out. The experts went on to highlight that the primary analysis, but not the subgroup analyses, were adjusted for multiple testing, complicating the process of definitively determining whether the benefit was sex-specific or uniform. As current guidelines identify fewer younger adults eligible for statins and preventive therapies at the time of their myocardial infarction, the comment concluded by emphasizing the need for improved risk assessment. Suggested approaches included the use of early screening and 30-year risk estimates as well as incorporating genetic factors such as polygenic, monogenic, and family history into updated prevention guidelines. The experts added that concomitantly, providers should be “nudged” to achieve LDL-C quality and performance measures. Study methods To compare the treatment effect of bempedoic acid with statins, the methodology of the CTTC was applied to outcomes among the 13,970 patients enrolled in the CLEAR Outcomes trial.) These patients were 18 to 85 years of age, and 48% of the patients were women. The median duration of patient follow-up was 40.6 months (interquartile range: 37.1-46.2 months). The CTTC endpoint of “major vascular event” was a composite of coronary heart disease death, nonfatal myocardial infarction, fatal or nonfatal stroke, or coronary revascularization. HRs for CTTC-defined endpoints were normalized to 1 mmol/L differences in LDL-C levels between the bempedoic acid and placebo groups. Sources: Lincoff AM, Ray KK, Sasiela WJ, et al. Comparative Cardiovascular Benefits of Bempedoic Acid and Statin Drugs. J Am Coll Cardiol. 2024;84:152–162. Safarova MS, Moriarty PM, Kullo IJ, et al. Bempedoic Acid Falls in Line. J Am Coll Cardiol. 2024;84:163–164 Image Credit: Ruslan Batiuk – stock.adobe.com