Effects of Rivaroxaban on Vascular FMD in Patients With Stable Atherosclerotic Vascular Diseases

NCT ID: NCT06986369

Last Updated: 2025-05-23

Basic Information

• Recruitment Status: COMPLETED
• Clinical Phase: PHASE4
• Total Enrollment: 140 participants
• Study Classification: INTERVENTIONAL
• Study Start Date: 2021-05-04
• Study Completion Date: 2024-03-01

Brief Summary

The specific mechanistic benefit of rivaroxaban versus other FXa inhibitors on atherothrombotic events remain unclear. Therefore plan to initiate a prospective, randomized study to investigate the effect of rivaroxaban and aspirin versus aspirin alone on changes of number circulating endothelial cells and endothelial function, and alteration in systemic inflammation, platelet and coagulation activation in patients with stable atherosclerotic vascular diseases.

The working hypothesis of this trial is that rivaroxaban and aspirin is superior to aspirin alone improvement in the number of circulating endothelial cells and endothelial function, assessed by flow-mediated vasodilatation, and reduction in systemic inflammation, platelet and coagulation activation in patients with stable atherosclerotic vascular diseases at 3 months follow-up.

Detailed Description

Factor Xa (FXa) and thrombin are well-known components of the coagulation cascade and other biological and pathophysiological processes that are linked to atherothrombotic as well as thromboembolic events. As a result, novel oral anticoagulants that are direct inhibitors of factor Xa (e.g., rivaroxaban) and thrombin (e.g.,dabigatran) have been developed for the prevention of thromboembolic recurrences in patients with venous thromboembolism and atrial fibrillation (AF) . Moreover, FXa inhibitors have also been investigated as an adjunct antithrombotic therapy in addition to dual antiplatelet therapy in selected patients with acute coronary syndrome. While APPRAISE-2 trial (apixaban), which was prematurely terminated because of an excess of bleeding and showed no evidence of benefit, ATLAS ACS 2 TIMI 51 trial (rivaroxaban) demonstrated a significant reduction in clinical events compared with placebo. These differences in clinical outcomes cannot be accounted by the discrepancy in the rates of bleeding, which was increased to a fairly similar extent in both trials. Moreover, recent clinical trials (COMPASS trial) in patients with stable atherosclerotic vascular diseases, either in patients with stable coronary artery disease (CAD) or peripheral artery disease (PAD), rivaroxaban plus aspirin reduced cardiovascular (CV) events but increased major bleeding compared with aspirin alone. Rivaroxaban alone did not differ from aspirin alone for CV events and increased major bleeding. Nevertheless, the specific mechanistic benefit of rivaroxaban versus other FXa inhibitors on atherothrombotic events remain unclear. During the development of atherosclerosis, vascular endothelial cells, platelets, pro-inflammatory cytokines and several serine proteases, such as thrombin, Xa and tissue factor can promote vascular inflammation and leukocyte infiltration via the activation of protease-activated receptor (PAR) signalling pathway. Indeed, FXa and thrombin mediated PAR activation contributes to the linking between coagulation and inflammatory pathways on the endothelium. In experimental studies, rivaroxaban showed a concentration-dependent positive effect on cell viability and growth of vascular endothelial cells verses controls. Furthermore, preclinical studies demonstrated that direct Xa inhibition can have anti-inflammatory and protective activities in atherosclerotic plaque development beyond anticoagulation.

Here, investigators hypothesize that the vascular protective effects of rivaroxaban are mediated via increasing endothelial progenitor cells and improvement of vascular endothelial function to reduce vascular inflammation and coagulation activation in patients with stable atherosclerotic vascular diseases.

Conditions

Atherosclerosis, Coronary

Study Design

• Allocation Method: RANDOMIZED
• Intervention Model: PARALLEL
• Primary Study Purpose: TREATMENT
• Blinding Strategy: DOUBLE

Study Groups

rivaroxaban 2.5mg twice daily and aspirin 100mg once daily

Rivaroxaban 2.5mg twice daily Oral Tablet novel oral anticoagulants , 2.5mg twice daily for 3 months and Aspirin 100 MG Oral Tablet, Enteric Coated antiplatelet agent, 100mg once daily for 3 months

Group Type: ACTIVE_COMPARATOR

Rivaroxaban 2.5 MG Oral Tablet [Xarelto]

Intervention Type: DRUG

prospective, randomized, 3 months study to clarify the efficacy of rivaroxaban and aspirin versus aspirin in the alone the changes on the number of circulating endothelial cells and endothelial function, and systemic inflammation, platelet and coagulation activation in patients with stable atherosclerotic vascular diseases.

Aspirin 100mg daily for 3 months

Aspirin 100 MG Oral Tablet, Enteric Coated antiplatelet agent, 100mg once daily for 3 months

Group Type: NO_INTERVENTION

No interventions assigned to this group

Interventions

Rivaroxaban 2.5 MG Oral Tablet [Xarelto]

prospective, randomized, 3 months study to clarify the efficacy of rivaroxaban and aspirin versus aspirin in the alone the changes on the number of circulating endothelial cells and endothelial function, and systemic inflammation, platelet and coagulation activation in patients with stable atherosclerotic vascular diseases.

Intervention Type: DRUG

Other Intervention Names

Xarelto

Eligibility Criteria

Inclusion Criteria

patients must fulfill the following criteria.

• Willing and able to provide written informed consent
• CAD and/or PAD
• Subjects with CAD must also meet at least 1 of the following criteria:

Age 65 years or older, or Age younger than 65 years and documented atherosclerosis or revascularization involving at least 2 vascular beds or at least 2 additional risk factors:

• Current smoker (within 1 year of randomization)
• Diabetes mellitus
• Renal dysfunction with estimated glomerular filtration rate < 60 mL/min
• Heart failure
• Non-lacunar ischemic stroke >/= 1 month ago

Exclusion Criteria

• High risk of bleeding
• Stroke within 1 month or any history of hemorrhagic or lacunar stroke
• Severe heart failure with known ejection fraction < 30% or New York Heart Association class III or IV symptoms
• Estimated glomerular filtration rate < 15 mL/min
• Need for dual antiplatelet therapy, other non-aspirin antiplatelet therapy, or oral anticoagulant therapy
• Known non-cardiovascular disease that is associated with poor prognosis (eg, metastatic cancer) or that increases the risk of an adverse reaction to study interventions
• History of hypersensitivity or known contraindication for rivaroxaban, aspirin, pantoprazole, or excipients, if applicable
• Systemic treatment with strong inhibitors of CYP3A4 as well as p-glycoprotein (eg, systemic azole antimycotics, such as ketoconazole, and HIV-protease inhibitors, such as ritonavir), or strong inducers of CYP 3A4 (ie, 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 (eg, surgically sterile, prescription oral contraceptives, contraceptive injections, intrauterine device, double- barrier method, contraceptive patch, male partner sterilization)
• Previous assignment to treatment during this study
• Concomitant participation in another study with investigational drug
• Known contraindication to any study-related procedures

• Minimum Eligible Age: 65 Years
• Eligible Sex: ALL
• Accepts Healthy Volunteers: No

Sponsors

Bayer

INDUSTRY

Sponsor Role: collaborator

The University of Hong Kong

OTHER

Sponsor Role: lead

Responsible Party

Tse Hung Fat

Professor

Responsibility Role: PRINCIPAL_INVESTIGATOR

Principal Investigators

Hung Fat Tse

Role: PRINCIPAL_INVESTIGATOR

Queen Mary Hospital, Hong Kong

Locations

Queen Mary Hospital, the University of Hong Kong

Hong Kong, , China

Countries

China

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Other Identifiers

UW 20-312

Identifier Type: -

Identifier Source: org_study_id