Effects of aSPIrin Versus Aspirin Plus Low-dose RIvaroxaban on Carotid aTherosclerotic Plaque Inflammation (SPIRIT)

Primary Study Objective : To compare the effects of low-dose rivaroxaban plus aspirin versus aspirin on atherosclerotic plaque inflammation using serial FDG Positron Emission Tomography/Computed Tomography(PET-CT) imaging of carotid artery and ascending aorta.

Secondary Study Objective : To compare the effects of low-dose rivaroxaban plus aspirin versus aspirin on biomarkers including high-sensitivity C-Reactive Protein(CRP) and lipid profiles.

Study Overview

• Status: Completed
• Conditions: Coronary Artery Disease; Peripheral Arterial Disease; Carotid Stenosis; Atherosclerosis of Artery
• Intervention / Treatment: Drug: Rivaroxaban 2.5mg

Detailed Description

Cardiovascular disease is a major health problem across the world. The age-adjusted death rate for cardiovascular disease has significantly decreased during recent decades, and this decline is related to the widespread use of evidence-based medicines. However, even upon optimal medical therapies, patients remains at a substantial residual risk for acute coronary syndrome (ACS) or acute ischemic stroke(AIS), requiring new therapeutic approaches. Plaque rupture and subsequent thrombus formation is the most common cause of ACS and AIS. Atherosclerosis is a chronic immune-inflammatory disorder. Inflammation is believed to be critically important to plaque rupture by destroying the fibrous cap, thereby predisposing to ACS and AIS. Cross-talk between coagulation and inflammatory pathway via protease-activated receptor (PAR) activation has been recognized . Factor Xa is responsible for promoting inflammation, which participate in the atherosclerotic process and plaque destabilization either directly via activation of PARs or indirectly through the generation of thrombin .

In the Cardiovascular Outcomes for People Using Anticoagulation Strategies (COMPASS) trial, the rate of a composite of cardiovascular death, stroke, or myocardial infarction was lower by 24% with low-dose rivaroxaban (2.5 mg twice daily) plus aspirin than with aspirin alone among patients with stable atherosclerotic vascular disease, but the rate of major bleeding was higher by 70%. Interestingly, the rate of stroke was remarkably lower by 42% with rivaroxaban plus aspirin than with aspirin alone. The substantial net clinical benefits seen with rivaroxaban plus aspirin may not be fully explained by their anti-thrombotic effect alone, suggesting pleiotropic effects coupled with factor Xa antagonism. Besides its role in hemostasis and thrombosis, low-dose rivaroxaban may inhibit atherosclerotic plaque inflammation and decrease plaque destabilization. To test this hypothesis, the investigators will compare the effects of aspirin versus aspirin plus low-dose rivaroxaban on carotid atherosclerotic plaque inflammation using serial 18F-fluorodeoxyglucose (FDG) Positron Emission Tomography/Computed Tomography(PET-CT) imaging of carotid artery and ascending aorta.

• Study Type: Interventional
• Enrollment (Actual): 92
• Phase: Phase 4

Contacts and Locations

Study Locations

• Korea, Republic of
  • Seoul, Korea, Republic of, 05505
    • Asan Medical Center

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 18 years and older (Adult, Older Adult)
• Accepts Healthy Volunteers: No

Description

Inclusion Criteria:

• Men or women at least 18 years of age inclusive
• Asymptomatic Carotid Artery Disease (diameter stenosis, 20-80%)
• Inclusion criteria for the COMPASS trial (stable Peripheral Artery Disease(PAD); or stable Coronary Artery Disease(CAD) with 1 of age over 65 years, or age <65 years plus atherosclerosis less than 2 vascular beds or less than 2 additional risk factors)
• FDG Postron Emission Tomography(PET)/Computed tomogrphy(CT) shows hot uptakes at carotid artery (with or without hot uptake at ascending aorta)
• The patient or guardian agrees to the study protocol and the schedule of clinical and FDG Postron Emission Tomography(PET)/Computed tomogrphy(CT) follow-up, and provides informed, written consent, as approved by the Institutional Review Board/Ethical Committee.

Exclusion Criteria:

• Patients treated with carotid endarterectomy or stent placement
• Contraindications to rivaroxaban or aspirin.
• Stroke in 1 month or any hemorrhagic or lacuna stroke
• Need for dual antiplatelet therapy or oral anticoagulant therapy
• Severe left ventricular dysfunction (ejection fraction < 30%)
• Any clinically significant abnormality identified at the screening visit, physical examination, laboratory tests, or electrocardiogram which, in the judgment of the Investigator, would preclude safe completion of the study.
• Hepatic disease or biliary tract obstruction, or significant hepatic enzyme elevation (alanine aminotransferase(ALT) or aspartate aminotransferase(AST) > 3 times upper limit of normal).
• Unwillingness or inability to comply with the procedures described in this protocol.
• Patient's pregnant or breast-feeding or child-bearing potential.
• Insulin requiring diabetes
• Patients who have experienced critical organ bleeding within 1 year

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Prevention
• Allocation: Randomized
• Interventional Model: Parallel Assignment
• Masking: None (Open Label)

Number of Arms

2

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Rivaroxaban + Aspirin group; patients are prescribed aspirin at a daily dose of 100mg and Rivaroxaban (2.5 mg twice a day)	Drug: Rivaroxaban 2.5mg; patients are prescribed aspirin at a daily dose of 100mg and Rivaroxaban (2.5 mg twice a day); Other Names: Xarelto 2.5mg
No Intervention: Aspirin group; patients are prescribed aspirin at a daily dose of 100mg

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
The percent change (%) in Most Diseased segment(MDS) Target-to-Background Ratio(TBR) of the index vessel	The percent change (%) in Most Diseased segment(MDS) Target-to-Background Ratio(TBR) of the index vessel defined as (Most Diseased segment(MDS) Target-to-Background Ratio(TBR) at 12 months - Most Diseased segment(MDS) Target-to-Background Ratio(TBR) at baseline)/(Most Diseased segment(MDS) Target-to-Background Ratio(TBR) at baseline)*100. * Index vessel: carotid artery with the highest 18-FDG uptake at baseline	12 months

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Change from baseline in whole vessel Target-to-Background Ratio(TBR)	Change from baseline in whole vessel Target-to-Background Ratio(TBR) within the index vessel, Most Diseased segment(MDS) Target-to-Background Ratio(TBR), & whole vessel Target-to-Background Ratio(TBR) of the aorta.	12 months
Change from baseline in hs-C-Ractive Protein(CRP) and lipid profiles	Change from baseline in hs-C Ractive Protein(CRP) in mg/dL and lipid profiles(total cholesterol in mg/dL, Triglyceride(TG) in mg/dL, High Density Lipoprotein(HDL) in mg/dL, Low Density Lipoprotein(LDL) in mg/dL)	12 months

Collaborators and Investigators

• Sponsor: Asan Medical Center
• Collaborators: Bayer

Study record dates

Study Major Dates

• Study Start (Actual): August 24, 2021
• Primary Completion (Actual): November 12, 2024
• Study Completion (Actual): December 5, 2024

Study Registration Dates

• First Submitted: March 9, 2023
• First Submitted That Met QC Criteria: April 2, 2023
• First Posted (Actual): April 4, 2023

Study Record Updates

• Last Update Posted (Actual): March 25, 2025
• Last Update Submitted That Met QC Criteria: December 23, 2024
• Last Verified: December 1, 2024

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Cerebrovascular Disorders; Brain Diseases; Central Nervous System Diseases; Nervous System Diseases; Vascular Diseases; Cardiovascular Diseases; Pathologic Processes; Pathological Conditions, Anatomical; Heart Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Coronary Disease; Myocardial Ischemia; Carotid Artery Diseases; Inflammation; Peripheral Arterial Disease; Coronary Artery Disease; Plaque, Atherosclerotic; Atherosclerosis; Peripheral Vascular Diseases; Carotid Stenosis; Molecular Mechanisms of Pharmacological Action; Protease Inhibitors; Enzyme Inhibitors; Anticoagulants; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Rivaroxaban
• Other Study ID Numbers: 2020-1322

Plan for Individual participant data (IPD)

• Plan to Share Individual Participant Data (IPD)?: NO

Drug and device information, study documents

• Studies a U.S. FDA-regulated drug product: No
• Studies a U.S. FDA-regulated device product: No