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Trial registered on ANZCTR


Registration number
ACTRN12618001058268
Ethics application status
Approved
Date submitted
13/06/2018
Date registered
25/06/2018
Date last updated
22/02/2019
Date data sharing statement initially provided
22/02/2019
Type of registration
Retrospectively registered

Titles & IDs
Public title
Detecting coronary artery inflammation by imaging the surrounding fat, and its association with coronary artery disease
Scientific title
Association between pericoronary adipose tissue attenuation and coronary artery disease presence, progression and vulnerability
Secondary ID [1] 295038 0
None
Universal Trial Number (UTN)
U1111-1214-8657
Trial acronym
INFLAME: Inflammation of pericoroNary Fat and its association with coronary atheroscLerosis Assessed by coMputEd tomography coronary angiography

Linked study record
None

Health condition
Health condition(s) or problem(s) studied:
Coronary heart disease 308077 0
Vascular inflammation 308078 0
Condition category
Condition code
Cardiovascular 307125 307125 0 0
Coronary heart disease

Intervention/exposure
Study type
Observational
Patient registry
False
Target follow-up duration
Target follow-up type
Description of intervention(s) / exposure
We aim to evaluate the association between pericoronary fat attenuation (PFa) and coronary plaque characteristics assessed by computed tomography angiography (CTCA) in patients with myocardial infarction, compared to matched controls with stable coronary artery disease (CAD) and asymptomatic patients.
We will also evaluate the natural history of PFa in patients with myocardial infarction and its association with plaque progression and vulnerability, by comparing their baseline CTCA (performed within 24 hours of hospital admission) to their follow-up CTCA at 12-months.
Intervention code [1] 301374 0
Not applicable
Comparator / control treatment
Comparator group 1: patients with stable coronary artery disease. A propensity matched cohort from the historical MonashHeart CTCA database (>21,000 patients from January 2008 - December 2017 with complete data quantification).
Comparator group 2: asymptomatic patients. A cohort of patients (recruited February 2015 - Febuary 2018) from the CAUGHT-CAD study, a NHMRC funded multi-centre prospective interventional trial (ACTRN12614001294640) based at the Baker Heart & Diabetes Institute.
Control group
Historical

Outcomes
Primary outcome [1] 306078 0
Comparison of pericoronary fat attenuation (PFa) in culprit lesions in myocardial infarction (MI) patients to that of the highest grade stenosis lesion in patients with stable CAD and in asymptomatic patients.

PFa will be measured on CTCA using Autoplaque software, in the complete vessel and at segmental and lesion-specific sites. PFa will be considered the mean density (Hounsfield units) in the 1-mm-layer of adipose tissue immediately adjacent to the outer coronary artery wall.

Stable CAD patients are those who: i) are having stable angina or other symptoms felt to be related to coronary artery disease; ii) were previously symptomatic with known CAD who have become asymptomatic with treatment and need regular follow-up; iii) those who report symptoms for the first time and are judged to already be in a chronic stable condition.

Asymptomatic patients are those without known CAD who are symptom free and may have one or more risk factors for CAD.
Timepoint [1] 306078 0
CTCA at baseline and 12 months
Primary outcome [2] 306079 0
Association of the change in pericoronary fat attenuation (delta PFa) in culprit lesions with plaque quantification change (low attenuation plaque and calcified plaque volumes).

PFa will be measured on CTCA using Autoplaque software in the complete vessel and at segmental and lesion-specific sites. PFa will be considered the mean density (Hounsfield units) in the 1-mm-thick layer of adipose tissue immediately adjacent to the outer coronary artery wall.

Quantitative plaque analysis will be performed with Autoplaque with manual adjustment of vessel lumen and wall contouring.
Timepoint [2] 306079 0
12 months post baseline CTCA
Primary outcome [3] 306080 0
Comparison of PFa in high-risk plaque patients with future MI versus those without MI at 1-year follow-up.

A cohort of stable CAD patients with a single high-risk plaque and subsequent MI will be age and sex-matched to HRP patients without MI. Data will be obtained from hospital cardiac databases, medical records and patient self-reports.

PFa will be measured on CTCA using Autoplaque software, in the complete vessel and at segmental and lesion-specific sites. PFa will be considered the mean density (Hounsfield units) in the 1-mm-thick layer of adipose tissue immediately adjacent to the outer coronary artery wall.
Timepoint [3] 306080 0
12-months post baseline CTCA
Secondary outcome [1] 347484 0
Comparison of full vessel PFa between patients with MI vs. stable CAD vs. asymptomatic cohorts.

PFa will be measured on CTCA using Autoplaque software in the complete vessel and at segmental and lesion-specific sites. PFa will be considered the mean density (Hounsfield units) in the 1-mm-thick layer of adipose tissue immediately adjacent to the outer coronary artery wall.

Stable CAD patients are those who: i) are having stable angina or other symptoms felt to be related to coronary artery disease; ii) were previously symptomatic with known CAD who have become asymptomatic with treatment and need regular follow-up; iii) those who report symptoms for the first time and are judged to already be in a chronic stable condition.

Asymptomatic patients are those without known CAD who are symptom free and may have one or more risk factors for CAD.
Timepoint [1] 347484 0
Baseline comparison

Eligibility
Key inclusion criteria
1. Admitting diagnosis of first myocardial infarction
2. Not on statin therapy
3. Must agree to undergo serial CTCA imaging at baseline and at 12 months
4. If willing, agree to collection of blood for storage
Minimum age
18 Years
Maximum age
80 Years
Gender
Both males and females
Can healthy volunteers participate?
No
Key exclusion criteria
1. Inability to provide informed consent or willingness to be followed for outcome over the course of the study
2. Under 18 years or greater than 80 years of age or unable to give informed consent.
3. Previous allergic reaction to contrast media
4. Impaired renal function (eGFR <50mL/min)
5. Asthma or Chronic Respiratory Disease in patients who may need beta-blockade to lower heart rate
6. Women who may be pregnant (premenopausal women will undergo pregnancy testing)

Study design
Purpose
Natural history
Duration
Longitudinal
Selection
Defined population
Timing
Prospective
Statistical methods / analysis
T-test or ANOVA, and chi-square tests will be used for between-group comparisons of PFa as appropriate. Logistic regression will be used for propensity score matching with nearest neighbour algorithm.

Linear regression will be used to assess the association of delta PFa with delta plaque measure. Generalised estimating equations will be used to correct for repeated measures.

Cox proportional hazards multivariable modelling between groups will be used to assess the effect of PFa on future MI. The incremental benefit of using PFa over traditional factors - stenosis severity, plaque burden, HRP presence - will be tested.

Recruitment
Recruitment status
Recruiting
Date of first participant enrolment
Anticipated
Actual
Date of last participant enrolment
Anticipated
Actual
Date of last data collection
Anticipated
Actual
Sample size
Target
Accrual to date
Final
Recruitment in Australia
Recruitment state(s)
VIC
Recruitment hospital [1] 11032 0
Monash Medical Centre - Clayton campus - Clayton
Recruitment postcode(s) [1] 22826 0
3168 - Clayton

Funding & Sponsors
Funding source category [1] 299621 0
Hospital
Name [1] 299621 0
Monash Cardiovascular Research Centre, Monash Medical Centre
Address [1] 299621 0
246 Clayton Road, Clayton VIC 3168
Country [1] 299621 0
Australia
Primary sponsor type
Hospital
Name
Monash Cardiovascular Research Centre, Monash Medical Centre
Address
246 Clayton Road, Clayton VIC 3168
Country
Australia
Secondary sponsor category [1] 298946 0
None
Name [1] 298946 0
Address [1] 298946 0
Country [1] 298946 0

Ethics approval
Ethics application status
Approved
Ethics committee name [1] 300521 0
Monash Health Human Research Ethics Committee
Ethics committee address [1] 300521 0
Research Support Services
Level 2, i Block
Monash Medical Centre
246 Clayton Road
CLAYTON VIC 3168
Ethics committee country [1] 300521 0
Australia
Date submitted for ethics approval [1] 300521 0
08/02/2016
Approval date [1] 300521 0
04/04/2016
Ethics approval number [1] 300521 0

Summary
Brief summary
Atherosclerosis is the build-up of cholesterol deposits (plaque) within the walls of the coronary arteries which are the blood vessels supplying heart muscle. If the plaque ruptures, it can cause a reaction and block off the vessel causing a heart attack. Vessel inflammation is a major contributor to both plaque formation and rupture. The fat (adipose tissue) surrounding the coronary arteries is a rich source of inflammatory chemical messengers, many of which are the same as those found in plaques, and in particular plaques considered to be vulnerable to rupture, called high risk plaques (HRP).

Computed tomography coronary angiography (CTCA) is a widely used investigation for the assessment of plaque as well as HRP. Inflammation of the coronary arteries, however, is not as easily assessed. Specialised imaging methods are limited by cost, availability and image resolution. Circulating blood markers of inflammation do not reflect what happens at the level of the vessel. Therefore, the ability to measure a regional marker of inflammation is highly desirable and may improve risk prediction beyond the current measures that CTCA provides.

Pericoronary adipose tissue (PCAT) is the layer of fat immediately adjacent to the coronary artery wall. It has been demonstrated that inflammatory chemical messengers cross between the vessel and adjacent fat in both directions. Therefore, PCAT may act as a signal for vessel inflammation, as well as a driver of plaque formation.

A recent seminal scientific study showed that exposure to inflammatory chemical messengers stops fat cells from maturing. The density (attenuation) of PCAT can be accurately assessed on CTCA, and has been validated as a marker of inflammation. A more negative fat attenuation represents less inflammation (fat-rich tissue) whereas higher values suggest greater inflammation (less fat maturation).

With increasing evidence of the benefits of anti-inflammatory medications to reduce cardiovascular events, the use of CTCA to detect vascular inflammation as well as its established role in plaque analysis represent an ideal tool for a single, non-invasive imaging test to guide future research into coronary plaque formation and vulnerability.

Our hypotheses are:
1. Patients with heart attacks will demonstrate lower PFa than stable and asymptomatic patients.
2. Persisting low PFa predicts plaque progression and vulnerability.
3. The baseline PFa at sites of HRP predicts future heart attacks.

This study aims to demonstrate that PFa is a surrogate for coronary inflammation. It is expected that PFa will exhibit a gradient of increasing inflammation from normal vessel to HRP. We will aim to define a threshold at which PFa predicts HRP presence and progression, to then guide future studies using anti-inflammatory medications. The long-term goal is the ability to detect inflammation in normal vessels free of plaque and therefore are at risk of accelerated plaque progression.
Trial website
Trial related presentations / publications
Public notes

Contacts
Principal investigator
Name 83930 0
A/Prof Dennis Wong
Address 83930 0
Monash Cardiovascular Research Centre
MonashHeart, Monash Health
Monash Medical Centre
246 Clayton Rd, Clayton VIC 3168
Country 83930 0
Australia
Phone 83930 0
+61 3 95946666
Fax 83930 0
Email 83930 0
drdenniswong@yahoo.com
Contact person for public queries
Name 83931 0
Dr Andrew Lin
Address 83931 0
Monash Cardiovascular Research Centre
MonashHeart, Monash Health
Monash Medical Centre
246 Clayton Rd, Clayton VIC 3168
Country 83931 0
Australia
Phone 83931 0
+61 3 95946666
Fax 83931 0
Email 83931 0
andrewklin@gmail.com
Contact person for scientific queries
Name 83932 0
Dr Andrew Lin
Address 83932 0
Monash Cardiovascular Research Centre
MonashHeart, Monash Health
Monash Medical Centre
246 Clayton Rd, Clayton VIC 3168
Country 83932 0
Australia
Phone 83932 0
+61 3 95946666
Fax 83932 0
Email 83932 0
andrewklin@gmail.com

Data sharing statement
Will individual participant data (IPD) for this trial be available (including data dictionaries)?
No
No/undecided IPD sharing reason/comment
What supporting documents are/will be available?
Study protocol
Summary results
No Results