To demonstrate elevation in immune responsiveness to LPS stimulation when switching from ASA to DPI in patients with CAD, and to further explore whether changes in monocyte function and epigenetic landscape are responsible for the observed…
ID
Source
Brief title
Condition
- Arteriosclerosis, stenosis, vascular insufficiency and necrosis
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
The primary outcome is a change in whole blood immune responsiveness to LPS
stimulation when switching from ASA to DPI.
Secondary outcome
Secondary outcomes are changes in white blood cell count and distribution,
change in monocyte immune responsiveness to LPS stimulation, change in
enrichment of epigenetic marks on genes associated with inflammation in
monocytes, and changes in circulating cytokines when switching from ASA to DPI.
Background summary
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 (rivaroxaban 2.5mg 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, we 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 in patients 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(n=11; unpublished).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 objective
To demonstrate elevation in immune responsiveness to LPS stimulation when
switching from ASA to DPI in patients with CAD, and to further explore whether
changes in monocyte function and epigenetic landscape are responsible for the
observed elevations in immune responsiveness to LPS stimulation when treating
with DPI.
Study design
An explorative clinical cohort study.
Intervention
patients will be prescribed rivaroxaban 2.5mg twice daily in addition to ASA
75-100mg once daily for a period of 12 weeks. Blood samples will be taken at
baseline, and 4 and 12 weeks after switching ASA to DPI. The comparator is ASA
monotherapy (baseline).
Study burden and risks
The use of DPI by low-dose rivaroxaban with ASA has been approved for various
indications, such as coronary artery disease. DPI has shown to reduce ischemic
events at the expense of more non-fatal bleedings, with a net-clinical benefit
for DPI over ASA monotherapy.[5] Investigating the influence of adding
rivaroxaban to ASA monotherapy on changes in immune responsiveness, white blood
cell counts, monocytes and epigenetic landscape will facilitate understanding
the mechanism underlying the benefits of DPI over ASA in CAD. Understanding
this mechanism will facilitate optimizing treatment of future patients and
prevent progression of the disease.
The risks include possible side effects of rivaroxaban (2.5 mg), such as
bleedings, muscle pain, stomach and bowel complaints, dizziness, headache, skin
rash, and malaise. To minimize risk, the research team will evaluate the
subject for any adverse events related to the treatment during the course of
the study.
The total period of DPI treatment has been set on 12 weeks, since an elevation
in immune responsiveness to LPS stimulation when switching ASA to DPI has been
observed after 12 weeks of DPI treatment in patients with peripheral arterial
disease. Therefore, this time frame should be sufficient to answer our research
questions. The additional measurement after 4 weeks will inform us about an
eventually course of rivaroxaban influencing changes in immune responsiveness,
white blood cell counts, monocytes and epigenetic landscape. Additionally, when
similar results are found after 4 and 12 weeks of DPI, there are substantiated
arguments that participants in future studies on comparable topics can be
exposed to a shorter treatment period.
Geert Grooteplein Zuid 10
Nijmegen 6525 GA
NL
Geert Grooteplein Zuid 10
Nijmegen 6525 GA
NL
Listed location countries
Age
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,
- at least16 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,
dual-pathway inhibition, direct oral anticoagulants, vitamin k antagonists)
- Contra-indication to rivaroxaban
o Hypersensitivity to rivaroxaban
o 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)
o Severe hepatic disease: Child Pugh B or C
o Severe kidney failure: estimated glomerular filtration rate <15 ml/min or
requiring dialysis
o severe heart failure with known ejection fraction < 30% or New York Heart
Association class III or IV symptoms
o concomitant treatment with medication with a strong pharmacokinetic
interaction with rivaroxaban, leading to contra-indication according to the
*regionale_NOAC_richtlijn* [11]
- Pregnant or breastfeeding women
- Unable to give informed consent
Design
Recruitment
Medical products/devices used
Followed up by the following (possibly more current) registration
No registrations found.
Other (possibly less up-to-date) registrations in this register
No registrations found.
In other registers
| Register | ID |
|---|---|
| EudraCT | EUCTR2021-006189-19-NL |
| CCMO | NL79727.091.21 |