Primary objectives1A. To evaluate the effect of maximal LDL-C reduction by Evolocumab on top of high intensity lipid-lowering therapy , initiated immediately after invasive ACS treatment on functional impairment of non-infarct related artery (non-…
ID
Source
Brief title
Condition
- Coronary artery disorders
Synonym
Research involving
Sponsors and support
Intervention
Outcome measures
Primary outcome
1A. The primary physiological study endpoint is the change in FFR from baseline
to follow-up
in non-IRA lesions.
1B. The primary invasive imaging endpoint is the change in lipid core burden
index at the
4mm maximal segment (MaxLCBI4mm) from baseline to follow-up of the non-IRA as
performed in sites capable of Near-InfraRed Spectroscopy (NIRS).
Secondary outcome
Secondary endpoints:
1. The change in percent atheroma volume (PAV, mm3)
2. The change in normalized total atheroma volume (TAV, mm3)
3. The change in maximum plaque burden (%)
4. The change in minimum luminal area (MLA, mm2)
Exploratory endpoints
1. The correlation between achieved on-treatment LDL-C and the change in FFR,
the change
in LCBI, and the change in PAV.
2. The correlation between baseline NIRS derived MaxLCBI4mm and change in FFR
of the non-IRA.
3. The correlation between change in IVUS-derived plaque characteristics and
change in
FFR of the non-IRA
4. Change of microvascular resistance as measured by CFR and IMR
The immunological side study will investigate the relation between LDL-C
reduction and
reduction of pro-inflammatory monocyte phenotypes.
Clinical endpoints will be tabulated and listed in the final study report;
among which
percentage of lesions with a FFR >0.80 at follow-up and patient-oriented
composite endpoint
(POCE): composite of all-cause death, any stroke, any MI and any
revascularization,
unplanned ischemia driven PCI of the target lesion, any unplanned ischemia
driven PCI in
the total study population.
Background summary
In a large number of patients presenting with acute coronary syndrome (ACS)
multivessel disease is identified. Optimal treatment approach for bystander
lesions in non-infarct related arteries (non-IRA*s) has not been well
established. Some RCT*s favor preventive complete revascularization over
deferred PCI. Background medical treatment wasn*t optimal in these studies,
however, which could have caused bias. Revascularization of lesions in the
non-IRA can be guided by fractional flow reserve (FFR). In this study we want
to investigate the effect of maximal LDL-C reduction by Evolocumab and HIST
compared to placebo on functional impairment of non-IRA lesions, measured by
FFR, and we want to evaluate the change in Near-InfraRed Spectroscopy (NIRS)
derived lipid core burden index at the 4mm maximal segment (MaxLCBI4mm) from
baseline to follow-up in the non-IRA. Secondly, we want to evaluate the change
in plaque characteristics, measured by IVUS, and change in microvascular
circulation. We will investigate correlations between on treatment LDL-C, LCBI,
and plaque characteristics, with non-culprit FFR. Finally the study will
investigate the relation between LDL-C reduction and change in pro-inflammatory
monocyte phenotypes.
Study objective
Primary objectives
1A. To evaluate the effect of maximal LDL-C reduction by Evolocumab on top of
high
intensity lipid-lowering therapy , initiated immediately after invasive ACS
treatment on
functional impairment of non-infarct related artery (non-IRA) lesions, measured
by FFR, in
patients presenting with MVD-ACS.
1B. To evaluate the effect of maximal LDL-C reduction by Evolocumab on top of
high
intensity lipid-lowering therapy, initiated immediately after invasive ACS
treatment on the lipid
core burden of non-infarct related artery (non-IRA) lesions, measured by NIRS,
in patients
presenting with MVD-ACS.
Secondary objectives
2A. To evaluate the effect of maximal LDL-C reduction by Evolocumab on top of
high intensity
lipid-lowering therapy, initiated immediately after invasive ACS treatment on
plaque
characteristics of non-infarct related artery (non-IRA) lesions, measured by
IVUS, in patients
presenting with MVD-ACS.
2B. To evaluate the relation between baseline lipid core burden and changes in
functional
impairment of non-IRA lesions during treatment by Evolocumab on top of high
intensity lipid-lowering therapy.
2C. To evaluate the effect of maximal LDL-C reduction by Evolocumab on top of
high intensity
lipid-lowering therapy, initiated immediately after invasive ACS treatment on
microvascular
circulation in patients presenting with MVD-ACS.
2D. To investigate the relationship between LDL-C reduction post-ACS and change
in pro-inflammatory monocyte phenotypes.
Hypotheses
1A. Addition of PCSK-9 inhibitors to treatment post-ACS will lead to
significant reduction of
functional impairment of a non-IRA lesion in patients with MVD-ACS.
1B. Addition of PCSK-9 inhibitors to treatment post-ACS will lead to
significant reduction of
lipid core burden of a non-IRA lesion in patients with MVD-ACS.
2A. Addition of PCSK-9 inhibitors to treatment post-ACS will lead to
significant plaque
reduction in a non-IRA lesion in patients with MVD-ACS.
2B. Change in functional impairment will be more pronounced in patients with
higher
baseline lipid core burden
2C: Addition of PCSK-9 inhibitors to treatment post-ACS will lead to
significant amelioration
of the microvascular circulation in patients with MVD-ACS.
2D. LDL-C lowering attenuates the pro-inflammatory myeloid cell reprogramming
by ACS.
Study design
This is a multi-center, randomized, double blind, placebo controlled clinical
trial.
Intervention
The patients will be randomised 1:1 to (A), one group will recieve 140mg
Evolocumab every two weeks (Q2W) for 12 weeks, using personal injectors; (B)
the other group will receive placebo. All participants will receive high
intensity statin therapy (HIST) as background therapy (Atorvastatin 40mg or
equivalent).
Study burden and risks
After inclusion, all patiënts have to undergo staged FFR + NIRS, meaning they
will undergo invasive strategy for a second time, and if needed additional
stenting of significant lesions, with the asocciated periprocedural risks (eg.
death, stroke, MI, vascular complications), however these risks are quite small
(<2% major complications).
Geert Grooteplein Zuid 10
Nijmegen 6525 GA
NL
Geert Grooteplein Zuid 10
Nijmegen 6525 GA
NL
Listed location countries
Age
Inclusion criteria
- ACS with PCI of infarct related artery
- Multivessel Disease (MVD)
- FFR of non-IRA lesion: 0.67 - 0.85
- Age >= 18 years at screening
Exclusion criteria
- Refusal or inability to provide informed consent
- Prior coronary artery bypass graft
- Known left ventricular ejection fraction (LVEF) < 30%
- Untreated functional left main stem stenosis (FFR <= 0.80)
- Contra-indication for antithrombotic therapy according to ESC guidelines
- Non-IRA stenosis not amenable for PCI treatment (operator*s decision)
- Complicated IRA treatment, with one or more of the following:
- Extravasation
- Permanent no re-flow after IRA treatment (TIMI flow 0-1)
- Inability to implant a stent
- Known severe cardiac valve dysfunction that will require surgery in the
follow-up period.
- Severe kidney disease defined as an eGFR < 30 ml/min.
- Known severe liver disease defined as Child-Pugh score of 10-15.
- Female subject is pregnant, breastfeeding or planning to become pregnant or
planning to breastfeed during treatment and for an additional 15 weeks after
the last dose of investigational product. Females of childbearing potential
should only be included in the study after a confirmed menstrual period and a
negative highly sensitive serum pregnancy test.
- Female subjects of childbearing potential unwilling to use 1 acceptable
method of effective contraception during treatment and for an additional 15
weeks after the last dose of investigational product.
- Female subject who has not used an acceptable method(s) of birth control for
at least 1 month prior to screening, unless the female subject is sterilized or
postmenopausal.
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 | EUCTR2019-002578-29-NL |
| ClinicalTrials.gov | NCT04141579 |
| CCMO | NL71538.091.19 |