The Impact of Factor Xa Inhibition on Thrombosis, Platelet Activation, and Endothelial Function in Peripheral Artery Disease

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

Detailed Description
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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.

Official Title
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The Impact of Factor Xa Inhibition on Thrombosis, Platelet Activation, and Endothelial Function in Peripheral Artery Disease

Conditions
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Peripheral Arterial Disease

Intervention / Treatment
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* Drug: Rivaroxaban 2.5 Mg Oral Tablet
* Drug: Placebo
* Drug: Aspirin 81Mg Ec Tab


Participation Criteria
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Eligibility Criteria
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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 History of one or more of the following: An ankle/arm blood pressure (BP) ratio < 0.90, or Significant peripheral artery stenosis (≥50%) documented by angiography, or by duplex ultrasound 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 <30% or New York Heart Association (NYHA) class III or IV symptoms Estimated glomerular filtration rate <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

Ages Eligible for Study
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Minimum Age: 40 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: Quadruple


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Placebo Comparator: Control<br>Participants will receive 81mg daily of aspirin + placebo for 30 days. | Drug: Placebo<br>* placebo<br>Drug: Aspirin 81Mg Ec Tab<br>* aspirin 81 milligrams<br>|
| Experimental: Intervention<br>Participants will receive 81mg of aspirin + rivaroxaban 2.5mg twice daily for 30 days. | Drug: Rivaroxaban 2.5 Mg Oral Tablet<br>* rivaroxaban 2.5 milligrams twice daily<br>Drug: Aspirin 81Mg Ec Tab<br>* aspirin 81 milligrams<br>|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Endothelium-dependent, flow-mediated dilation (FMD) of the brachial artery | FMD will be measured by forearm high-resolution ultrasonography after treatment with low-dose rivaroxaban plus aspirin and compared to the baseline value following treatment with aspirin plus placebo. | Baseline to 37 days | 
| Endogenous PAR-1 activation as measured by flow cytometry | Endogenous PAR-1 activation, a novel marker of platelet activation, will be measured by flow cytometry, following treatment with low-dose rivaroxaban plus aspirin and compared to the baseline value following treatment with aspirin plus placebo. The unit of measure will be relative fluorescence. | Baseline to 37 days | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Prothrombin time | Prothrombin time will be measured using turbidimetric assays following treatment with low-dose rivaroxaban plus aspirin and compared to the baseline value following treatment with aspirin plus placebo. The unit of measure will be in seconds. | Baseline to 37 days | 
| Partial thromboplastin time | Partial thromboplastin time will be measured using turbidimetric assays following treatment with low-dose rivaroxaban plus aspirin and compared to the baseline value following treatment with aspirin plus placebo. The unit of measure will be seconds. | Baseline to 37 days | 
| von Willebrand factor (vWF) | Blood levels of von Willebrand factor will be measured following treatment with low-dose rivaroxaban plus aspirin and compared to the baseline value following treatment with aspirin plus placebo. | Baseline to 37 days | 
| D-Dimer | Blood levels of D-dimer will be measured following treatment with low-dose rivaroxaban plus aspirin and compared to the baseline value following treatment with aspirin plus placebo. | Baseline to 37 days | 
| High-sensitivity C-reactive protein. | Blood levels of high-sensitivity C-reactive protein will be measured following treatment with low-dose rivaroxaban plus aspirin and compared to the baseline value following treatment with aspirin plus placebo. The unit of measure will be mg/L. | Baseline to 37 days | 
| Tumor necrosis factor-alpha | Blood levels of tumor necrosis factor-alpha will be measured following treatment with low-dose rivaroxaban plus aspirin and compared to the baseline value following treatment with aspirin plus placebo. | Baseline to 37 days | 
| Interleukin-1beta | Blood levels of interleukin-1beta will be measured following treatment with low-dose rivaroxaban plus aspirin and compared to the baseline value following treatment with aspirin plus placebo. | Baseline to 37 days | 
| Interleukin-6 | Blood levels of interleukin-6 will be measured following treatment with low-dose rivaroxaban plus aspirin and compared to the baseline value following treatment with aspirin plus placebo. | Baseline to 37 days | 
| Soluble intercellular adhesion molecule-1 (slCAM-1) | Blood levels of soluble intercellular adhesion molecule-1 (slCAM-1) will be measured following treatment with low-dose rivaroxaban plus aspirin and compared to the baseline value following treatment with aspirin plus placebo. | Baseline to 37 days | 
| Monocyte chemoattractant protein-1 (MCP-1) | Blood levels of monocyte chemoattractant protein-1 (MCP-1) will be measured following treatment with low-dose rivaroxaban plus aspirin and compared to the baseline value following treatment with aspirin plus placebo. | Baseline to 37 days | 
| Plasminogen activator inhibitor 1 (PAI-1) | Blood levels of plasminogen activator inhibitor 1 (PAI-1) will be measured following treatment with low-dose rivaroxaban plus aspirin and compared to the baseline value following treatment with aspirin plus placebo. | Baseline to 37 days | 
| CD41a (Integrin alpha-II-beta) | CD41a, a marker of platelet activation, will be measured by flow cytometry following treatment with low-dose rivaroxaban plus aspirin and compared to the baseline value following treatment with aspirin plus placebo. | Baseline to 37 days | 
| CD62p (P-Selectin) | CD62p, a marker of platelet activation, will be measured by flow cytometry following treatment with low-dose rivaroxaban plus aspirin and compared to the baseline value following treatment with aspirin plus placebo. | Baseline to 37 days | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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Peripheral Artery Disease, PAD, Thrombosis, Rivaroxaban, Anticoagulant