Bempedoic Acid And Cardiovascular Outcomes In Statin Intolerant Patients At High Cardiovascular Risk

Presented at the ACC.23 by: Prof. Steven Nissen, MD - Cleveland, OH, USA

Introduction and methods

Background

Management of patients who are unable or unwilling to take statins is challenging as statin intolerance limits patients to achieve guideline recommended LDL-c levels. Bempedoic acid is an ATP citrate lyase inhibitor which inhibits hepatic cholesterol synthesis upstream of HMG-CoA reductase. This pro-drug is activated in the liver, but not skeletal muscle, which lowers the risk of muscle-related adverse events.

Aim of the study

The CLEAR Outcomes study aimed to investigate the effects of bempedoic acid on cardiovascular outcomes in statin-intolerant patients in primary or secondary prevention.

-

Methods

CLEAR Outcomes was a double-blind, randomized, placebo-controlled trial which was conducted at 1250 sites in 32 countries.

The study enrolled primary and secondary prevention patients with LDL-c ≥ 100 mg/dL and who were statin-intolerant. Patients had to provide informed consent that they were unable or unwilling to take statins due to an adverse effect that had started or increased during statin therapy and resolved or improved after statin therapy was stopped. They also confirmed that they were aware of the benefits of statin therapy to reduce CV events and that many patients who experience adverse events while taking a statin are able use a different statin or dose. The site investigators also confirmed that the patient is unable to tolerate statin therapy. Use of very low dose statin (below the lowest approved dose) was permitted during the trial. Other lipid-lowering therapies, such as ezetimibe and PCSK9i, were allowed as well.

A total of 13.970 patients (mean age 65.5 years, 48,2% female) were randomized (1:1) to receive either bempedoic acid (180 mg/day) or placebo. Median follow up was 40.6 months.

Outcomes

The primary endpoint was 4-component MACE, defined as nonfatal MI, nonfatal stroke, coronary revascularization or CV death. The following key secondary endpoints were tested in hierarchical order: 1) 3-component MACE, defined as nonfatal MI, nonfatal stroke or CV death, 2) fatal or nonfatal MI, 3) coronary revascularization, 4) fatal or nonfatal stroke, 5) CV death, and 6) all cause death.

Main results

• At 6 months, bempedoic acid reduced LDL-c by 21.7% and hsCRP by 22.2%. In comparison, a 0.6% reduction in LDL-c and an increase of 2.2% in hsCRP was observed in the placebogroup at 6 months.
• Bempedoic acid reduced the primary endpoint of 4-component MACE by 13% (HR 0.87, 95%CI 0.79-0.96, P=0.004, ARR 1.6%, NNT 63).
• The first 3 secondary endpoints were reduced as well by bempedoic acid: a 15% reduction in 3-component MACE (HR 0.85, 95%CI 0.76-0.96, P=0.006, ARR 1.3%), a 23% reduction in fatal or nonfatal MI (HR 0.77, 95%CI 0.66-0.91, P=0.002, ARR 1.1%) , and a 19% reduction in coronary revascularization (HR 0.81, 95%CI 0.72-0.92, P=0.001, ARR 1.4%).
• There was no significant difference between the bempedoic acid group and the placebo group for the secondary endpoints of fatal or nonfatal stroke, CV death, and all cause death.
• There were no meaningful differences in overall incidences of adverse events, serious adverse events and adverse events leading to drug discontinuation between groups.
• The incidences of gout (3.1% vs. 2.1%), cholelithiasis (2.2% vs 1.2%), renal impairment (11.5% vs. 8.6%), elevated hepatic-enzyme level (4.5% vs. 3.0%) and hyperuricemia (10.9% vs. 5.6%) were higher in the bempedoic acid group compared to the placebo group.

Conclusion

The CLEAR Outcomes study showed that among statin-intolerant primary and secondary prevention patients, bempedoic acid reduced the risk of the primary composite endpoint of nonfatal MI, nonfatal stroke, coronary revascularization or CV death.

-Our reporting is based on the information provided at the ACC.23/WCC-

This study was simultaneously published in N. Engl. J. Med. Watch a video on the CLEAR Outcomes trial