CLEAR Outcomes: Evaluation of Major Cardiovascular Events in Patients With, or at High Risk for, Cardiovascular Disease Who Are Statin Intolerant Treated With Bempedoic Acid (ETC-1002) or Placebo

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Macrovascular Residual Risk Studies

26 April 2021

CLEAR Outcomes specifically enrolled high-risk patients with documented statin intolerance and elevated low-density lipoprotein cholesterol (LDL-C) levels who remain at high residual cardiovascular risk.

Nicholls SJ, Lincoff AM, Bays HE et al. Rationale and design of the CLEAR-outcomes trial: Evaluating the effect of bempedoic acid on cardiovascular events in patients with statin intolerance. Am Heart J 2020;235:104-112.

STUDY SUMMARY

Objective:

To investigate whether treatment with bempedoic acid (ETC-1002) versus placebo decreases the risk of cardiovascular events in patients who are statin intolerant.

Study design:

Randomized, double-blind, placebo-controlled clinical trial. Patients were randomly allocated oral bempedoic acid 180 mg daily or matching placebo on a background of guideline-directed medical therapy.

Study population:

14,014 patients with (i) established atherosclerotic cardiovascular disease (ASCVD) or at high risk of developing ASCVD, (ii) documented statin intolerance (inability to tolerate 2 or more statins, one at a low dose), and (iii) an LDL-C ≥2.6 mmol/L) (≥100 mg/dL) on maximally tolerated lipid-lowering therapy.

Study outcome:

The primary outcome is a composite of first cardiovascular death, nonfatal myocardial infarction, nonfatal stroke, or coronary revascularization.

Methods:

The trial will continue until 1620 patients experience a primary endpoint, with a minimum of 810 hard ischemic events (cardiovascular death, nonfatal myocardial infarction or nonfatal stroke) and a minimum treatment duration of 36 months and a projected median treatment exposure of 42 months.

Results:

Patient enrolment was completed in August 2016, and final results are anticipated by December 2022.

Conclusion:

CLEAR Outcomes will determine whether bempedoic acid 180 mg daily reduces the incidence of adverse cardiovascular events in high vascular risk patients with documented statin intolerance and elevated LDL-C levels.

COMMENT

Elevated plasma LDL-C concentration is an established causal factor for ASCVD (1), and therefore the primary priority lipid target for ASCVD prevention. However, for patients with true statin intolerance, estimated to be in the region of 10% (2), attaining guideline-recommended LDL-C goal is a clinical challenge. This is especially particularly relevant for high-risk patients as it places them at higher risk of ASCVD-related events (3).

While non-statin therapies are now available, including ezetimibe and PCSK9 inhibitors, many statin-intolerant patients remain at high residual cardiovascular risk. Bempedoic acid (ETC-1002), an inhibitor of cholesterol synthesis that targets ATP citrate lyase (ACL) (4) may offer potential. Because bempedoic acid is converted into an active form only in the liver, it is not associated with muscle side effects, and therefore represents another option for the management of statin-intolerant patients who fail to attain LDL-C goal on maximally tolerated lipid lowering therapy.

In phase III trials, bempedoic acid was associated with modest and sustained LDL-C lowering, in patients with and without statin intolerance. There were also decreases in non-high-density lipoprotein cholesterol, total cholesterol, apolipoprotein B, and high-sensitivity C-reactive protein levels (5,6). Bempedoic acid also demonstrated an acceptable safety profile, with no increase in muscle-related adverse events compared with placebo (5,6). The key outstanding question is whether bempedoic acid will reduce the high residual cardiovascular risk that persists in patients with statin intolerance who usually struggle to attain LDL-C goal.

References

1. Ference BA, Ginsberg HN, Graham I, et al. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J 2017;38:2459-72.
2. Stroes ES, Thompson PD, Corsini A, et al. Statin-associated muscle symptoms: impact on statin therapy-European Atherosclerosis Society Consensus Panel Statement on Assessment, Aetiology and Management. Eur Heart J 2015;36:1012-22.
3. Serban MC, Colantonio LD, Manthripragada AD, et al. Statin intolerance and risk of coronary heart events and all-cause mortality following myocardial infarction. J Am Coll Cardiol 2017;69:1386-95.
4. Nguyen H, Akamnonu I, Yang T. Bempedoic acid: a cholesterol lowering agent with a novel mechanism of action. Expert Rev Clin Pharmacol 2021; doi: 10.1080/17512433.2021.1901579.
5. Banach M, Duell PB, Gotto AM Jr, et al. Association of bempedoic acid administration with atherogenic lipid levels in Phase 3 randomized clinical trials of patients with hypercholesterolemia.
JAMA Cardiol 2020;5:1-12.
6. Ballantyne CM, Banach M, Mancini GBJ, et al. Efficacy and safety of bempedoic acid added to ezetimibe in statin-intolerant patients with hypercholesterolemia: A randomized, placebo-controlled study. Atherosclerosis 2018;277:195-203.

Key words

bempedoic acid; statin intolerance; residual cardiovascular risk; CLEAR Outcomes