Trained Immunity by Dual-pathway Inhibition 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from ASA monotherapy to DPI of ASA combined with rivaroxaban inpatients with peripheral arterial disease (n=11; unpublished).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.


Eligibility Criteria:
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