Trained Immunity by Dual-pathway Inhibition in Coronary Artery Disease (DUALCAD)

Trained Immunity by Dual-pathway Inhibition (Low-dose Rivaroxaban and Acetylsalicylic Acid) in Coronary Artery Disease'

Coronary artery disease (CAD) is a manifestation of systemic atherosclerosis for which single antiplatelet therapy (SAPT) is indicated if patients are stable. Recently dual pathway inhibition (DPI) by combining a low-dose factor Xa inhibitor (rivaroxaban2.5mg twice daily) with a single platelet inhibitor (ASA) has been demonstrated to be beneficial in treating CAD. The exact mechanisms underlying the benefits of DPI, are not completely understood. CAD is characterised by a state of chronic low-grade inflammation, where monocytes from CAD patients have a higher immune responsiveness to ex vivo stimulation with lipopolysaccharide (LPS) compared to healthy matched controls. Surprisingly, the investigators have recently observed an elevation in ex vivo immune responsiveness to LPS stimulation when switching from ASA monotherapy to DPI of ASA combined with rivaroxaban inpatients with peripheral arterial disease (n=11; unpublished). Remarkably this was associated with no changes in systemic inflammation, as determined by Olink proteomics analysis. These findings suggest that factor Xa inhibitors can enhance immune cell responsiveness despite being clinically beneficial to CAD. The exact mechanisms contributing to the observed increased immune responsiveness remain unexplored.

Study Overview

• Status: Active, not recruiting
• Conditions: Coronary Artery Disease
• Intervention / Treatment: Drug: Rivaroxaban 2.5 Mg Oral Tablet

• Study Type: Interventional
• Enrollment (Actual): 20
• Phase: Phase 4

Contacts and Locations

Study Locations

• Netherlands
  • Gelderland
    • Nijmegen, Gelderland, Netherlands, 6525GA
      • Radboudumc

Participation Criteria

Eligibility Criteria

• Ages Eligible for Study: 16 years and older (Child, Adult, Older Adult)
• Accepts Healthy Volunteers: No
• Genders Eligible for Study: All

Description

Inclusion Criteria:

In order to be eligible to participate in this study, a subject must meet all of the following criteria:

• stable CAD
• with an indication for single antiplatelet therapy according to international (ESC) guidelines,
• high cardiovascular risk based on a SMART risk score [9] of at least 20% and/or the judgement of the cardiologist
• at least 1 year after myocardial infarction or multivessel CAD
• >16 years old
• Written informed consent

Exclusion Criteria:

A potential subject who meets any of the following criteria will be excluded from participation in this study:

• Use of more intensive antithrombotic treatment (dual antiplatelet therapy, DPI, direct oral anticoagulants, vitamin k antagonists)
• Use of immunosuppressant and/or anti-inflammatory therapy, including glucocorticoids, cytostatics, antibodies, immunophilins, interferons, Tumor Necrosis Factor (TNF) binding proteins, mycophenolate and interleukin antagonists

• Contra-indication to rivaroxaban

  • Hypersensitivity to rivaroxaban

  • at significant risk for major bleeding

    • current gastrointestinal ulceration
    • presence of malignant neoplasms, with the exception of non-melanoma skin cancer
    • recent (<2 months) brain or spinal injury
    • recent (<3 months) brain or spinal surgery
    • recent (<3 months) intracranial, gastrointestinal or pulmonary hemorrhage
    • presence of arteriovenous malformations,
    • major intraspinal or intracerebral vascular abnormalities
    • congenital or acquired bleeding disorders
    • uncontrolled severe arterial hypertension (180 mmHg or more systolic, or 110 mmHg or more diastolic)
  • Severe hepatic disease: Child Pugh B or C [10]
  • Severe kidney failure: estimated glomerular filtration rate<15 ml/min or requiring dialysis
  • severe heart failure with known ejection fraction < 30% or New York Heart Association class III or IV symptoms [12]
  • concomitant treatment with medication with a strong pharmacokinetic interaction with rivaroxaban, leading to contra-indication according to the "regionale_NOAC_richtlijn" [12]
• Pregnant or breastfeeding women
• Unable to give informed consent

Study Plan

How is the study designed?

Design Details

• Primary Purpose: Treatment
• Allocation: N/A
• Interventional Model: Single Group Assignment
• Masking: None (Open Label)

Number of Arms

1

Arms and Interventions

Participant Group / Arm	Intervention / Treatment
Experimental: Stable coronary artery disease; Patients with stable coronary artery disease with an indication for single antiplatelet therapy according to international (ESC) guidelines, with a high cardiovascular risk.	Drug: Rivaroxaban 2.5 Mg Oral Tablet; 2.5 mg rivaroxaban twice a day in addition to acetylsalicylic acid (80-00mg once a day, standard care).

What is the study measuring?

Primary Outcome Measures

Outcome Measure	Measure Description	Time Frame
Whole blood immune responsiveness	Change in whole blood immune responsiveness to lipopolysaccharide stimulation when switching from acetylsalicylic acid to dual pathway inhibition (acetylsalicylic acid and low-dose rivaroxaban).	12 weeks

Secondary Outcome Measures

Outcome Measure	Measure Description	Time Frame
White blood cell count and distribution	changes in white blood cell count and distribution when switching from acetylsalicylic acid to dual pathway inhibition (acetylsalicylic acid and low-dose rivaroxaban).	3 months
Monocyte immune responsiveness	Change in monocyte immune responsiveness to LPS stimulation when switching from acetylsalicylic acid to dual pathway inhibition (acetylsalicylic acid and low-dose rivaroxaban).	3 months
Enrichment of epigenetic marks on genes	Enrichment of epigenetic marks on genes when switching from acetylsalicylic acid to dual pathway inhibition (acetylsalicylic acid and low-dose rivaroxaban).	3 months

Collaborators and Investigators

• Sponsor: Radboud University Medical Center
• Investigators: Study Director: Saloua El Messaoudi, MD PhD, Radboud University Medical Center; Principal Investigator: Michiel C Warlé, MD PhD, Radboud University Medical Center

Study record dates

Study Major Dates

• Study Start (Actual): March 1, 2022
• Primary Completion (Actual): April 15, 2022
• Study Completion (Anticipated): July 1, 2022

Study Registration Dates

• First Submitted: January 13, 2022
• First Submitted That Met QC Criteria: January 13, 2022
• First Posted (Actual): January 27, 2022

Study Record Updates

• Last Update Posted (Actual): April 20, 2022
• Last Update Submitted That Met QC Criteria: April 19, 2022
• Last Verified: January 1, 2022

More Information

Terms related to this study

• Additional Relevant MeSH Terms: Heart Diseases; Cardiovascular Diseases; Vascular Diseases; Arteriosclerosis; Arterial Occlusive Diseases; Coronary Artery Disease; Myocardial Ischemia; Coronary Disease; Molecular Mechanisms of Pharmacological Action; Enzyme Inhibitors; Protease Inhibitors; Factor Xa Inhibitors; Antithrombins; Serine Proteinase Inhibitors; Anticoagulants; Rivaroxaban
• Other Study ID Numbers: NL2021-13291

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