Antiplatelet Effects of Evolocumab in Patients With Peripheral Arterial Disease

This investigation will be conducted in subjects \>18 years of age with PAD. Platelet activation and aggregation, and biomarkers associated with platelet activation, oxidative stress, and inflammation will be assessed prior to initiation of study-HD statin therapy (baseline), after 8 weeks of high-dose statins and 24 hours and 8 weeks after high dose statin + evolocumab therapy

Monoclonal antibodies against PCSK9 are innovative agents that provide very potent LDL reduction when administered on top of statins. PCSK9 antibodies prevent LDL receptor degradation and enhance circulatory LDL cholesterol clearance. High LDL is a major risk factor for PAD and therefore lipid-lowering therapy constitutes another important therapeutic intervention for patients with PAD. Evolocumab is a common PCSK-9 inhibitor that has been shown to reduce plasma LDL. In this study sixty subjects will be treated with high dose statins for 8 weeks followed by 8 weeks of high dose statin + evolocumab (420mg/4 wk) therapy to determine the effect of Repatha on markers of cholesterol, thrombosis, and inflammation.

Eligibility Criteria:
Criteria: Inclusion Criteria:

Symptomatic PAD, as evidenced by either

* intermittent claudication with ABI \<0.90, or
* peripheral arterial revascularization procedure, or
* amputation due to atherosclerotic disease.
* Subject may be of either sex and of any race, and must be \>18 years of age.
* Subject agrees to not participate in any other investigational or invasive clinical study for a period of 4 months during the study period
* Subject must be willing and able to give appropriate informed consent.
* The subject is able to read and has signed and dated the informed consent document including authorization permitting release of personal health information approved by the investigator's Institutional Review Board (IRB).

Exclusion Criteria:

* Prior use of any PCSK9 inhibition treatment Participation in any investigational study within the last 60 days.
* Severe renal dysfunction, defined as an eGFR \<20 mL/min/1.73 m2 at screening
* Active liver disease or hepatic dysfunction, defined as AST or ALT \>3 x ULN as determined by central laboratory analysis at screening
* Recipient of any major organ transplant (e.g., lung, liver, heart, bone marrow, renal)
* Known major active infection or major hematologic, renal, metabolic, gastrointestinal, or endocrine dysfunction in the judgment of the investigator
* Malignancy (except non-melanoma skin cancers, cervical in situ carcinoma, breast ductal carcinoma in situ, or stage 1 prostate carcinoma) within the last 10 years
* Subject has received drugs via a systemic route that have known major interactions with background statin therapy within 1 month before randomization or is likely to require such treatment during the study period (e.g. cyclosporine, clarithromycin, HIV protease inhibitors, gemfibrozil)
* Female subject who is unwilling to use at least 2 effective birth control methods for at least 1 month before screening and 15 weeks after the end of treatment with investigational products, unless the subject is sterilized or postmenopausal.
* Subject is pregnant or breast feeding, or planning to become pregnant or to breastfeed during receipt of investigational products and within 15 weeks after the end of study treatment
* Known previous hypersensitivity reaction/s to the investigational products' active components and excipients.
* Subjects treated with any antithrombotic agents except aspirin.
* Subject likely to not be available to complete all protocol-required study visits or procedures, to the best of the subject's and investigator's knowledge
* History or evidence of any other clinically significant disorder, condition, or disease other than those outlined above that, in the opinion of the investigator, may compromise the ability of the subject to give written informed consent, would pose a risk to subject safety or interfere with the study evaluation, procedures, or completion.