Impact of LDL-cholesterol Lowering on Platelet Activation

Study Overview
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Brief Summary
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The primary goal is to assess the impact of Evolocumab therapy on platelet function of familial hypercholesterolemia (FH) patients in a randomized, double blind study. Evolocumab is a humanized monoclonal antibody that targets circulating PCSK9, increases hepatic LDL receptor, decreases plasma LDL cholesterol and reduces risk of cardiovascular events. Evolocumab (brand name Rapatha) has been approved by FDA along with diet and maximally tolerated statin therapy in adults with FH or atherosclerotic heart or blood vessel problems, who need additional lowering of LDL cholesterol. The secondary goal is to determine if platelet activation or the response to Evolocumab therapy is modified by rs3184504 polymorphism. The investigators believe that these investigations will complement ongoing studies to demonstrate that Evolocumab reduces athero-thrombotic risk and aid the decision-making as to whether Evolocumab can reduce the atherothrombotic risk in acute coronary syndrome (ACS) patients.

Detailed Description
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Hyperlipidemia as exemplified by familial hypercholesterolemia is associated with increased platelet activation and an underlying pro-coagulant state. Hyperlipidemia primes platelets and increases platelet activation in response to various agonists. Plasma cholesterol levels appear to have a critical role in modulating platelet activity as hypercholesterolemia increases platelet activation more potently than hypertriglyceridemia. Increased platelet reactivity may contribute to the increased risk of atherothrombosis associated with hypercholesterolemia. Plasma levels of platelet activation markers such as thrombin-antithrombin complex (TAT), soluble P-selectin (sP-selectin), soluble CD40L (sCD40L) or P-selectin exposure at surface of platelets are increased in hypercholesterolemic patients. Increased levels of the platelet activation markers are associated with increased platelet membrane cholesterol content in hypercholesterolemia.Statins may show antithrombotic properties.

Official Title
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Impact of LDL-cholesterol Lowering on Platelet Activation

Conditions
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Familial Hypercholesterolemia

Intervention / Treatment
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* Drug: Evolocumab


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Subjects who have a clinical diagnosis of familial hypercholesterolemia (FH) Subjects who are referred to Dr. Ginsberg's Lipid Practice for treatment with PCSK9 inhibitor Subjects with LDL cholesterol levels >100 mg/dl on baseline treatment with statins and/or ezetimibe Exclusion Criteria: Children under 18 years of age

Ages Eligible for Study
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Minimum Age: 18 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Prevention
Allocation: Randomized
Intervention Model: Crossover Assignment
Masking: Double


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Active Comparator: Evolocumab<br>Subjects will start with placebo and will receive Evolocumab 140 mg every 14 days starting Day 14 until Day 196. | Drug: Evolocumab<br>* 140 mg every 14 days A monoclonal antibody designed for the treatment of hyperlipidemia<br>* Other names: REPATHA;|
| Placebo Comparator: Placebo<br>Subjects will start with placebo and will receive Evolocumab 140 mg every 14 days starting Day 28 until Day 196. | Drug: Evolocumab<br>* 140 mg every 14 days A monoclonal antibody designed for the treatment of hyperlipidemia<br>* Other names: REPATHA;|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Adenosine Di-phosphate (ADP) Induced, P2Y12 Dependent and Arachidonic Acid Induced Platelet Activation (P2Y12 Reaction Units (PRU)) | ADP- or arachidonic acid-stimulated platelet aggregation as assessed by the commercially-available VerifyNow P2Y12 (VerifyNow PRUTest) will be performed. Unit: PRU | Day 7, Day 14, Day 21, Day 28, Day 84 | 
| Adenosine Di-phosphate (ADP) Induced, P2Y12 Dependent and Arachidonic Acid Induced Platelet Activation (Aspirin Reaction Unit (ARU)) | ADP- or arachidonic acid-stimulated platelet aggregation as assessed by the commercially-available VerifyNow Aspirin assay (Accriva Diagnostics) will be performed. Unit: Aspirin Reaction Unit (ARU) | Day 7, Day 14, Day 21, Day 28, Day 84 | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Hyperlipidemia, Hypercholesterolemia, atherothrombosis