DUAL Pathway Inhibition to Improve Endothelial Function in Peripheral Artery Disease (DUAL-PAD)

January 13, 2022 updated by: Radboud University Medical Center

DUAL Pathway Inhibition (Low-dose Rivaroxaban and Aspirin) as Compared to Aspirin Only to Improve Endothelial Function in Peripheral Artery Disease.

Peripheral artery disease (PAD) is a manifestation of systemic atherosclerosis, causing patients to be at high risk of major adverse cardiovascular and limb events. Therefore, single antiplatelet therapy is recommended when patients are symptomatic or have undergone revascularization. Rivaroxaban (2.5 mg twice a day) in addition to Aspirin (100 mg once a day) has shown to be effective in reducing morbidity and mortality from major cardiovascular and limb events in patients with stable peripheral or carotid artery disease compared to Aspirin alone. Although a higher rate of major bleeding was detected, the incidence of fatal or critical organ bleedings was not increased.

Endothelial dysfunction is one of the first signs of atherosclerosis and is related to major cardiovascular events. The level of vascular endothelial dysfunction can be measured using the carotid artery reactivity (CAR) test. The investigators hypothesized that a combination of low-dose rivaroxaban and antiplatelet therapy would improve endothelial function in PAD patients.

The investigators aim to study the effectiveness of this combination therapy in improving vascular endothelial function in patients with stable or symptomatic PAD.

Therefore the investigators will study two clinical cohorts of lower extremity PAD patients (n=159) with intermittent claudication (group A: Fontaine stages 1-2) or critical limb ischemia with pain at rest and/or foot ulcers (group B: Fontaine stages 3-4) who have an indication for single antiplatelet therapy.

Aspirin 100mg once a day + 2.5 mg rivaroxaban twice a day will be given during 3 months, preceded by a run-in period of Aspirin alone (100 mg once a day) as reference.

The change in proportion of patients with CAR-constriction from baseline (Aspirin alone) to 3 months after adding low dose rivaroxaban will be compared for both study groups (A and B).

Study Overview

Status

Completed

Conditions

Intervention / Treatment

Detailed Description

Rationale: Peripheral artery disease (PAD) is a manifestation of systemic atherosclerosis, causing patients to be at high risk of major adverse cardiovascular events and major adverse limb events, including amputation. Therefore, clopidogrel or Aspirin depending on national guidelines, is recommended as single antiplatelet therapy when patients are symptomatic or have undergone revascularization. Anticoagulant therapies have not shown to be superior in PAD patients and have high rates of major bleedings. However, rivaroxaban (2.5 mg twice a day), an oral factor Xa inhibitor, in addition to Aspirin (100 mg once a day) has shown to be effective in reducing morbidity and mortality from coronary artery disease and major cardiovascular and limb events in patients with stable peripheral or carotid artery disease compared to Aspirin alone. Although a higher rate of major bleeding was detected, the incidence of fatal or critical organ bleedings was not increased.

Endothelial dysfunction is one of the first signs of atherosclerosis and is present before clinical symptoms appear. Endothelial dysfunction contributes to the progression of atherosclerosis and is related to major cardiovascular events. The level of vascular endothelial dysfunction can be measured using the carotid artery reactivity (CAR) test. This test measures the CAR in response to sympathic stimulation and can also be used to measure endothelial dysfunction in PAD patients and how a combination of rivaroxaban and Aspirin affects it. The investigators hypothesized that a combination of low-dose rivaroxaban and antiplatelet therapy would improve endothelial function in PAD patients.

Objective: To study the effectiveness of low-dose rivaroxaban with Aspirin in improving endothelial function in patients with stable or symptomatic PAD.

Study design: Two clinical cohort studies will be performed. Study population: Lower extremity PAD patients (n=159) with intermittent claudication (group A: Fontaine stages 1-2) or critical limb ischemia with pain at rest and/or foot ulcers (group B: Fontaine stages 3-4) who have an indication for single antiplatelet therapy are eligible for this study.

Intervention (if applicable): Aspirin 100mg once a day + 2.5 mg rivaroxaban twice a day (combination therapy). The use of Aspirin alone (100 mg once a day) during the run-in period is used as reference.

Main study parameters/endpoints: The primary outcome measure is the CAR after 3 months combination treatment. The change in proportion of patients with CAR-constriction from baseline (Aspirin alone) to 3 months after adding low dose rivaroxaban will be compared for both study groups (A and B). Serum endothelin-1 levels will be quantified as a marker for cardiovascular disease at baseline and 3 months after adding low dose rivaroxaban.

Study Type

Interventional

Enrollment (Actual)

159

Phase

  • Phase 4

Contacts and Locations

This section provides the contact details for those conducting the study, and information on where this study is being conducted.

Study Locations

  • Netherlands
      • Arnhem, Netherlands, 6815 AD
        • Rijnstate Hospital
      • Nijmegen, Netherlands, 6525 GA
        • Radboudumc

Participation Criteria

Researchers look for people who fit a certain description, called eligibility criteria. Some examples of these criteria are a person's general health condition or prior treatments.

Eligibility Criteria

Ages Eligible for Study

16 years and older (ADULT, OLDER_ADULT, CHILD)

Accepts Healthy Volunteers

No

Genders Eligible for Study

All

Description

Inclusion Criteria:

  • Symptomatic or stable lower extremity PAD patients (Fontaine stages 2-4) with an indication for single antiplatelet therapy according to international (ESC) guidelines
  • >16 years old
  • Written informed consent

Exclusion Criteria:

  • Patients having or at risk of major bleeding:

    • Gastrointestinal ulceration
    • Current malignant neoplasms
    • Brain or spinal injury
    • Brain, spinal or ophthalmic surgery
    • Intracranial hemorrhage
    • Known or suspected esophageal varices
    • Arteriovenous malformations
    • Major intraspinal or intracerebral vascular abnormalities
    • Hepatic disease associated with coagulopathy and clinically relevant bleeding risk, including cirrhotic patients with Child Pugh B and C
    • Use of selective serotonin reuptake inhibitors or serotonin-norepinephrine reuptake inhibitors
  • Patients with prosthetic valves
  • Patients with a history of asthma attacks caused by salicylates
  • Severe renal impairment (creatinine clearance <30 ml/min)
  • Systemic treatment with strong CYP3A4 and/or P-glycoprotein inhibitors (i.e. azole-antimyotics, HIV protease inhibitors)
  • Concomitant treatment with other anticoagulants
  • Concomitant treatment with methotrexate at a weekly dosage of >15 mg
  • Pregnant or lactating
  • Known hypersensitivity to Aspirin or rivaroxaban

Study Plan

This section provides details of the study plan, including how the study is designed and what the study is measuring.

How is the study designed?

Design Details

  • Primary Purpose: TREATMENT
  • Allocation: NON_RANDOMIZED
  • Interventional Model: PARALLEL
  • Masking: NONE

Arms and Interventions

Participant Group / Arm
Intervention / Treatment
EXPERIMENTAL: Group A
111 patients with intermittent claudication
Drug: Rivaroxaban 2.5 Mg Oral Tablet
2.5 mg rivaroxaban twice a day in addition to Aspirin 100mg once a day (standard care).
Other Names:
  • Xarelto
EXPERIMENTAL: Group B
48 patients with critical limb ischemia with pain at rest and/or foot ulcers
Drug: Rivaroxaban 2.5 Mg Oral Tablet
2.5 mg rivaroxaban twice a day in addition to Aspirin 100mg once a day (standard care).
Other Names:
  • Xarelto

What is the study measuring?

Primary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Carotid artery reactivity
Time Frame: 3 months
The change in proportion of patients with carotid artery reactivity constriction from baseline (Aspirin alone) to 3 months after adding low dose rivaroxaban
3 months

Secondary Outcome Measures

Outcome Measure
Measure Description
Time Frame
Plasma endothelin-1 levels
Time Frame: 3 months
The change in plasma endothelin-1 level as quantified by Enzyme-Linked Immuno Sorbent Assay from baseline (Aspirin alone) to 3 months after adding low-dose rivaroxaban
3 months

Collaborators and Investigators

This is where you will find people and organizations involved with this study.

Sponsor

Radboud University Medical Center

Investigators

  • Principal Investigator: Michel MPJ Reijnen, Professor, Rijnstate

Publications and helpful links

The person responsible for entering information about the study voluntarily provides these publications. These may be about anything related to the study.

General Publications

Study record dates

These dates track the progress of study record and summary results submissions to ClinicalTrials.gov. Study records and reported results are reviewed by the National Library of Medicine (NLM) to make sure they meet specific quality control standards before being posted on the public website.

Study Major Dates

Study Start (ACTUAL)

June 8, 2020

Primary Completion (ACTUAL)

December 31, 2021

Study Completion (ACTUAL)

December 31, 2021

Study Registration Dates

First Submitted

December 23, 2019

First Submitted That Met QC Criteria

January 2, 2020

First Posted (ACTUAL)

January 6, 2020

Study Record Updates

Last Update Posted (ACTUAL)

January 14, 2022

Last Update Submitted That Met QC Criteria

January 13, 2022

Last Verified

February 1, 2021

More Information

Terms related to this study

Additional Relevant MeSH Terms

Other Study ID Numbers

  • NL2019-6036

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

product manufactured in and exported from the U.S.

No

This information was retrieved directly from the website clinicaltrials.gov without any changes. If you have any requests to change, remove or update your study details, please contact register@clinicaltrials.gov. As soon as a change is implemented on clinicaltrials.gov, this will be updated automatically on our website as well.

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