Rationale and design of the CLEAR-outcomes trial: Evaluating the effect of bempedoic acid on cardiovascular events in patients with statin intolerance

Nicholls, S.; Lincoff, A. Michael; Bays, Harold; Cho, Leslie; Grobbee, Diederick E.; Kastelein, John J.P.; Libby, Peter; Moriarty, Patrick M.; Plutzky, Jorge; Ray, Kausik K.; Thompson, Paul D.; Sasiela, William J.; Mason, Denise; McCluskey, Jaclyn; Davey, Deborah; Wolski, Kathy; Nissen, Steven E.

doi:10.1016/j.ahj.2020.10.060

Cited by 84 publications

(58 citation statements)

References 39 publications

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“…This ongoing trial randomized more than 14,000 patients with a history of possible statin-associated side effects, and who have established CVD or are at high risk for CVD, to receive either bempedoic acid or placebo. The CLEAR Outcomes trial will evaluate the incidence of major cardiovascular events in both groups [54], and results are expected to be reported in 2023.…”

Section: Discussionmentioning

confidence: 99%

“…The cost-effectiveness of bempedoic acid in different countries will depend on the different healthcare systems, drug pricing, and populations within each country. Results of the CLEAR Outcomes clinical endpoint study [54] will be required to establish the true cost-effectiveness of bempedoic acid. The only cost-effectiveness analysis for bempedoic acid conducted to date was based on an Australian healthcare model [55]; however, the Institute for Clinical Economic Review (ICER) has announced that a cost-effectiveness analysis for bempedoic acid in the USA is ongoing and should be available in early 2021.…”

Section: Cost-effectivenessmentioning

confidence: 99%

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Role of Bempedoic Acid in Clinical Practice

Ballantyne

Bays

Catapano

et al. 2021

Cardiovasc Drugs Ther

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Many patients do not achieve optimal low-density lipoprotein cholesterol (LDL-C) levels with statins alone; others are unable to tolerate statin therapy. Additional non-statin treatment options including ezetimibe, proprotein convertase subtilisin/kexin type 9 inhibitors, and bile acid sequestrants are often necessary to further reduce the risk of atherosclerotic cardiovascular disease. This review provides practical guidance as to the use of bempedoic acid to lower LDL-C and includes direction as to which patients may benefit and advice for safety monitoring during treatment. Bempedoic acid, a new class of agent, is a prodrug converted to bempedoyl-CoA by very long-chain acyl-CoA synthetase 1, an enzyme with high expression in the liver but that is undetectable in the skeletal muscle. Bempedoic acid inhibits the enzyme adenosine triphosphate (ATP)-citrate lyase, which lies two steps upstream from β-hydroxy β-methylglutaryl-CoA reductase in the cholesterol biosynthesis pathway. In clinical trials conducted in patients with or at risk for atherosclerotic cardiovascular disease or familial heterozygous hypercholesterolemia, bempedoic acid in combination with statins and/or ezetimibe significantly reduced LDL-C, apolipoprotein B, and high-sensitivity C-reactive protein compared with placebo. Bempedoic acid is generally well tolerated with no clinically meaningful increase in muscle-related symptoms relative to placebo, even in patients taking maximally tolerated statins. A small increase in serum uric acid (mean increase 0.8 mg/dL) is the most noteworthy adverse effect. Bempedoic acid provides an effective and generally well-tolerated medication to further reduce LDL-C in patients taking maximally tolerated statins or manage LDL-C levels in those who are unable to take statins. The potential for a reduced incidence of major cardiovascular events with bempedoic acid is being investigated in the CLEAR Outcomes trial, with results expected in 2023.

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Section: Discussionmentioning

confidence: 99%

Section: Cost-effectivenessmentioning

confidence: 99%

Role of Bempedoic Acid in Clinical Practice

Ballantyne

Bays

Catapano

et al. 2021

Cardiovasc Drugs Ther

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“…The trial will continue until 1620 patients will experience a primary endpoint and minimum treatment duration of 36 months with a projected median treatment exposure of 42 months. 9 …”

Section: Bempedoic Acidmentioning

confidence: 99%

New players in the treatment of hypercholesterolaemia: focus on bempedoic acid and inclisiran

Ruscica

Sirtori

Ferri

et al. 2021

European Heart Journal Supplements

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Dyslipidaemias and in particular elevated plasma low-density lipoprotein cholesterol (LDL-C) levels are major risk factors for atherosclerotic cardiovascular disease (ASCVD). Indeed, the more LDL-C is reduced the larger will be the ASCVD risk reduction. Although statins represent the first-line intervention to reduce the atherosclerotic burden driven by raised levels of LDL-C, adherence is not optimal and most patients do not follow guidelines and recommended doses. Thus, to achieve optimal LDL-C goals, especially in very high-risk patients, there is a need for new and safe agents, more tolerable than statins with low risk of myalgia. Thus, the present review will address the most recent clinical trials with bempedoic acid and inclisiran. Bempedoic acid is an oral drug acting at a biochemical step preceding hydroxymethylglutaryl-CoA reductase and not associated with muscular side effects. Inclisiran, the first-in-class small interfering RNA-based approach, has the ability to effectively reduce LDL-C by inhibiting the hepatic synthesis of proprotein convertase subtilisin/kexin type 9, with the advantage of requiring subcutaneous of a single dose on Day 1, Day 90, and every 6 months thereafter.

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“…While it is notable that adjudicated major adverse cardiovascular event rates were lower in the bempedoic acid treatment arms in both trials, these were trends that did not reach statistical significance. CLEAR Outcomes, a large phase 3 clinical outcomes trial with bempedoic acid, is ongoing with results anticipated in 2022-23 (discussed below) 72 .…”

Section: Introductionmentioning

confidence: 99%

“…CLEAR Outcomes (NCT02993406), the first phase 3 clinical outcomes trial studying bempedoic acid, has randomized 14,014 patients with statin intolerance, LDL-C ≥2.6 mmol/L (100 mg/dL), and high risk for ASCVD to either bempedoic acid 180 mg daily or matching placebo 72 . The primary endpoint is a composite of cardiovascular death, non-fatal MI, non-fatal stroke, or coronary revascularization and the estimated average treatment duration is 3.75 years.…”

Section: Introductionmentioning

confidence: 99%

Low-density lipoprotein cholesterol lowering therapy for the secondary prevention of atherosclerotic cardiovascular disease

Patel

Giugliano

2020

gcsp

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Atherosclerotic cardiovascular disease (ASCVD) is highly prevalent and a major contributor to morbidity and mortality worldwide. Elevated blood cholesterol is a key driver of risk for atherosclerotic events, and patients with established ASCVD comprise a specific high-risk population in which low-density lipoprotein cholesterol (LDL-C) lowering therapy is strongly endorsed by multiple guidelines. An increasing number of medications across several pharmacologic classes are available today in clinical practice. Therefore, guidance on the appropriate use of these interventions is necessary for cost-effective solutions to managing residual atherothrombotic risk. In this review we summarize the key evidence supporting LDL-C lowering as described in the most recent 2018 multi-society Blood Cholesterol Guidelines, and provide a framework for optimizing LDL-C lowering therapy in secondary prevention populations.

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Rationale and design of the CLEAR-outcomes trial: Evaluating the effect of bempedoic acid on cardiovascular events in patients with statin intolerance

Cited by 84 publications

References 39 publications

Role of Bempedoic Acid in Clinical Practice

Role of Bempedoic Acid in Clinical Practice

New players in the treatment of hypercholesterolaemia: focus on bempedoic acid and inclisiran

Low-density lipoprotein cholesterol lowering therapy for the secondary prevention of atherosclerotic cardiovascular disease

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