The purpose of this study is to understand how the drug rivaroxaban improves symptoms associated with peripheral artery disease.

The Primary Investigator's central hypothesis is that activation of thrombotic pathways and downstream effectors of factor Xa signaling contribute to the development of PAD and its complications.

Aim 1: To assess the impact of rivaroxaban on macrovascular endothelial function in a randomized, double-blind, placebo-controlled crossover intervention in humans with PAD.

Aim 2: To assess the impact of rivaroxaban on PAR-1-mediated platelet activation in addition to its pleiotropic effects on thrombosis, thrombolysis, and inflammation in a randomized, double-blind, placebo-controlled crossover intervention in humans with PAD.

Inclusion criteria:

History of peripheral artery disease (PAD) defined as:

• Previous aorto-femoral bypass surgery, limb bypass surgery, or percutaneous transluminal angioplasty revascularization of the iliac or infra-inguinal arteries, or
• Previous limb or foot amputation for arterial vascular disease, or
• An ankle/arm blood pressure (BP) ratio less than 0.90, or
• Significant peripheral artery stenosis (≥50%) documented by angiography, or by duplex ultrasound, or
• An ankle-brachial index (ABI) greater than 1.4 with a toe-brachial index (TBI) less than 0.7 AND
• Willing and able to provide written informed consent
• Receiving aspirin therapy prior to enrollment

Exclusion Criteria:

• High risk of bleeding
• Stroke within 1 month of any history of hemorrhagic or lacunar stroke
• Severe heart failure with known ejection fraction less than 30% or New York Heart Association (NYHA) class III or IV symptoms
• Estimated glomerular filtration rate less than 15 mL/min/1.73m2
• Need for dual-antiplatelet therapy, other non-aspirin antiplatelet therapy, or oral anticoagulant therapy
• Known non-cardiovascular disease that is associated with poor prognosis (e.g. metastatic cancer) or that increases the risk of an adverse reaction to study interventions
• History of hypersensitivity or known contraindication to rivaroxaban or aspirin
• Systemic treatment with strong inhibitors of both CYP 3A4 and p-glycoprotein (e.g. systemic azole antimycotics, such as ketoconazole, and human immunodeficiency virus [HIV]-protease inhibitors, such as ritonavir), or strong inducers of CYP 3A4, i.e. rifampicin, rifabutin, phenobarbital, phenytoin, and carbamazepine
• Any known hepatic disease associated with coagulopathy
• Subjects who are pregnant, breastfeeding, or are of childbearing potential, and sexually active and not practicing an effective method of birth control (e.g. surgically sterile, prescription oral contraceptives, contraceptive injections, intrauterine device, double- barrier method, contraceptive patch, male partner sterilization)
• Concomitant participation in another study with investigational drug
• Upcoming invasive procedure within 3 months
• Invasive procedure within the prior 1 month
• Being treated for an active infection
• Acute or chronic limb-threatening ischemia
• Known contraindication to any study related procedures