Clinical Trial Details
— Status: Not yet recruiting
Administrative data
| NCT number |
NCT06113510 |
| Other study ID # |
AC23119 |
| Secondary ID |
|
| Status |
Not yet recruiting |
| Phase |
|
| First received |
|
| Last updated |
|
| Start date |
January 2025 |
| Est. completion date |
August 2027 |
Study information
| Verified date |
June 2024 |
| Source |
University of Edinburgh |
| Contact |
n/a |
| Is FDA regulated |
No |
| Health authority |
|
| Study type |
Observational
|
Clinical Trial Summary
We now have very sensitive blood tests that can pick up damage to the heart and find patients
who have had a heart attack. However, whilst this is welcome, it does not identify what
causes the heart attack and can sometimes pick up other conditions that cause a strain on the
heart.
The classic cause of a heart attack is when a blood clot forms on fatty deposits within the
heart arteries. This leads to treating patients with blood thinning medication, and this is
very effective and saves lives. However, many apparent heart attacks are not caused by blood
clots and some may be caused by blood clots but pass unrecognised.
In this proposal, we will test an exciting new imaging test that can 'see' from outside the
body whether there is a blood clot in the heart arteries. This could provide a major new way
of assessing patients to ensure they get the right diagnosis and the right treatment. This
could ultimately improve the outcomes of or patients with heart attacks.
We will recruit 80 patients in total who have recently been diagnosed with a heart attack
from the cardiology department at the Royal Infirmary of Edinburgh. The research team will
review patient's medical records to determine eligibility for the study.
The research study involves participants undertaking the following research procedures and
assessments:
1. A combined Positron Emission Tomography and Computed Tomography (PET-CT) scan of the
heart
2. Ultrasound scan of the heart (Echocardiogram)
3. MRI scan of the heart
4. A blood test - a total of up to four tablespoons (60 mL) of blood will be taken for
immediate testing and the remaining blood will be stored for future ethically approved
studies
5. A follow up questionnaire 6 -12 months following the heart attack
Description:
1.1 BACKGROUND
1.1.1 Background of coronary artery disease and acute myocardial infarction
Coronary artery disease remains the leading cause of death worldwide, with more than 23
million annual deaths estimated to occur by 2030. The introduction of high-sensitivity
cardiac troponin measurement has revolutionised the identification and management of patients
presenting with acute chest pain and myocardial infarction. However, elevated cardiac
troponin concentrations can result from both ischaemic (myocardial infarction) or
non-ischaemic (myocardial injury) causes. Moreover, the further subclassification of
myocardial infarction relies on the underlying aetiology of infarction which is often not
readily apparent and remains a diagnostic challenge.
1.1.2 Universal definition of myocardial infarction
Acute myocardial infarction is defined as cardiomyocyte injury and necrosis in a clinical
setting consistent with acute myocardial ischaemia. The fourth universal definition of
myocardial infarction describes five subtypes of acute infarction. Type 1 myocardial
infarction is characterised by underlying atherosclerotic plaque disruption (rupture,
ulceration, fissuring, erosion, or calcific nodules) resulting in intraluminal thrombosis,
distal coronary embolisation and intraplaque haemorrhage that ultimately cause myocyte
necrosis. In contrast, type 2 myocardial infarction is classified as an ischaemic myocardial
injury secondary to oxygen supply and demand mismatch, and importantly is not a consequence
of atherosclerotic plaque rupture and coronary atherothrombosis. However, some causes of type
2 myocardial infarction do involve intracoronary thrombus including coronary thromboembolism
and spontaneous coronary artery dissection. Currently, invasive coronary angiography remains
the primary modality to identify patients presenting with plaque related disruption and
coronary thrombosis, ultimately providing the distinction between type 1 and type 2
myocardial infarction. However, it is not always definitive and only 10-20% of patients
presenting with type 2 myocardial infarction undergo further investigations to identify the
presence of underlying coronary artery disease or to exclude coronary atherothrombosis.
Indeed, we recently demonstrated comprehensive cardiac imaging and coronary angiography that
identified two thirds of patients had previously unrecognised underlying coronary artery
disease, and this resulted in diagnostic reclassification of many patients. These standard
techniques were however unable to determine whether this plaque was implicated in the
presentation or simply a bystander finding. A non-invasive imaging technique to reliably
detect intracoronary thrombus and facilitate this distinction would therefore be of major
clinical value.
1.1.3 Imaging intracoronary thrombosis
At present, invasive coronary angiography is the primary modality used to detect the presence
of intracoronary thrombus in patients presenting with acute myocardial infarction, through an
abrupt occlusion of the coronary artery or a filling defect in partially occluded vessels.
This approach has high specificity but low sensitivity for detection of intracoronary
thrombus, necessitating the introduction of adjunctive invasive coronary intravascular
imaging including angioscopy, intravascular ultrasound and optical coherence tomography to
improve rates of identification of coronary thrombosis and atherothrombosis. Intravascular
ultrasound-based studies have indicated an incidence of plaque disruption of 30-40% in
patients with myocardial infarction and non-obstructive coronary arteries, although this
imaging technique cannot differentiate between echo-lucent plaques and acute thrombus.
Optical coherence tomography has replaced intravascular ultrasound as the gold standard in
high-resolution cross-sectional imaging of the arterial intima, providing a more detailed
assessment of coronary artery dissection and thrombus formation. However, these invasive
techniques are not always available, have limitations in respect to assessing smaller or
stenosed vessels, and only provide circumstantial evidence of the presence of a thrombus
based on the characteristic appearances of the images. As such, atherothrombotic events may
be missed, resulting in misdiagnosis and, importantly, a missed opportunity to establish
patients on appropriate treatment and secondary prevention.
1.1.4 Uncertain role of coronary thrombosis in myocardial infarction
An accurate diagnosis is imperative for establishing subsequent appropriate therapeutic
intervention in patients with myocardial infarction. Patients presenting with type 1
myocardial infarction require short-term anticoagulation as well as medium-term dual
antiplatelet therapy, in conjunction with other secondary prevention therapies. For most
patients with type 2 myocardial infarction, the above strategy would be both ineffective and
potentially harmful, such as in patients with bleeding associated anaemia. However,
intracoronary thrombus formation underpins certain causes of type 2 myocardial infarction
including coronary thromboembolism and spontaneous coronary artery dissection. Accurate
identification of intracoronary thrombus is a central tenet in both the diagnosis of type 1
myocardial infarction, and in the differentiation of the various aetiologies underlying type
2 myocardial infarction.
1.1.4.1 Myocardial infarction with non-obstructive coronary arteries
Co-existing coronary artery disease is common in patients with myocardial infarction and
non-obstructive coronary arteries, with plaque disruption being the key trigger of acute
myocardial infarction in many cases. Myocardial infarction and non-obstructive coronary
arteries was first documented over 75 years ago when pathological studies reported evidence
of myocardial necrosis in the absence of coronary atherosclerosis. Its recognition in
clinical practice remains more recent, and it comprises a heterogenous group of vascular or
myocardial disorders, occurring in 5-15% of patients presenting with acute myocardial
infarction. Compared to patients with obstructive coronary artery disease, patients with
myocardial infarction and non-obstructive coronary arteries are younger, more likely to be
female, and have specific genetic and ethnic predispositions. Interestingly, the prevalence
of traditional coronary artery risk factors including dyslipidaemia, hypertension and
diabetes mellitus is lower in patients with myocardial infarction and non-obstructive
coronary arteries.
Myocardial infarction and non-obstructive coronary arteries has defined criteria as outlined
by the European Society of Cardiology in 2017 and the American Heart Association/American
College of Cardiology in 2019. To fulfil the diagnosis, patients must present with (i) acute
myocardial infarction as defined by the fourth universal definition of myocardial infarction,
(ii) non-obstructive coronary arteries on angiography (no coronary artery stenosis ≥ 50%),
and (iii) no specific alternative diagnosis for the clinical presentation. Only ischaemic
causes of acute myocardial infarction are now included in the underlying aetiology of
myocardial infarction and non-obstructive coronary arteries. This includes patients
presenting with either type 1 or type 2 myocardial infarction but excludes those with
takotsubo cardiomyopathy and myocarditis. Although this has simplified the diagnostic work-up
of this patient cohort, there remains a high degree of variability in the way patients with
suspected myocardial infarction and non-obstructive coronary arteries are investigated and
treated, because it is a diagnosis of exclusion. The identification and management of these
patients will depend on local practice and resources, where there may be limited access to
more advanced diagnostic testing. This is likely one of the contributory factors underlying a
recent analysis demonstrating that patients with myocardial infarction and non-obstructive
coronary arteries had a higher one-year adjusted mortality than patients with myocardial
infarction and obstructive coronary artery disease. As such, there is a clinical need to
improve the accuracy in the identification, investigation, and management of this patient
population.
1.1.4.2 Coronary thromboembolism
Coronary thromboembolism results in myocardial infarction and non-obstructive coronary
arteries if it involves the microcirculation or if the epicardial coronary thrombus is not
associated with atherosclerotic coronary artery disease. Underlying aetiologies can range
from atrial fibrillation, hypercoagulable states, inherited thrombophilia, paradoxical
embolism, valvular vegetations, valvular calcifications and cardiac tumours. As this subtype
of event typically involves smaller calibre coronary vessels, their identification using
catheter-based techniques is limited by the inability to access smaller vessels due to the
size and physical limitations of the intravascular probes. A more sensitive novel and
non-invasive imaging modality that can more accurately assess small calibre coronary vessel
thrombosis would be of great clinical value to identify coronary thrombosis events resulting
in type 2 myocardial infarction.
1.1.4.3 Spontaneous coronary artery dissection
Spontaneous coronary artery dissection is an uncommon cause of acute myocardial infarction,
with a predominance in younger (<50 years) women. Myocardial ischaemia is driven by
obstruction to coronary blood flow, secondary to separation of medial and adventitial
coronary vascular walls, with associated intramural haematoma resulting in protrusion into
the coronary arterial lumen. The coronary arteries can appear normal or near normal on
coronary angiography, due to gradual tapering of the vessel, and this is commonly a missed
diagnosis. Moreover, the prevalence of iatrogenic catheter-induced coronary artery dissection
is reported to be increased in patients with spontaneous coronary artery dissection, meaning
that many clinicians are reluctant to perform intravascular imaging in patients with this
suspected diagnosis. Consequently, the true incidence of spontaneous coronary artery
dissection is likely to be underestimated.
1.1.5 Non-invasive imaging of coronary thrombus - Pilot data
We have recently used positron emission tomography (PET) with computed tomography (CT)
coronary angiography to identify intracoronary thrombus using a novel radiotracer, 18F-GP1.
This radiotracer is highly selective and specific for the activated glycoprotein IIb/IIIa
receptor on activated platelets. As part of a previous BHF-funded Clinical Research Training
Fellowship (Dr Evangelos Tzolos; FS/CRTF/20/24086) and Project Grant (PG/19/40/34422), we
have demonstrated that 18F-GP1 has specificity for the detection of intravascular thrombosis
in a range of cardiovascular conditions. We have recently undertaken studies in patients with
coronary atherothrombosis in acute type 1 myocardial infarction. This was the first
demonstration that non-invasive imaging can identify in vivo intracoronary thrombus in
patients presenting with acute myocardial infarction, and for this work, Dr Tzolos was
awarded the European Society of Cardiology Young Investigator Award in 2021. We have
confirmed the high selectivity and specificity of 18F-GP1 binding to activated platelets
within fresh human thrombus and coronary thrombectomy specimens, and importantly we have
observed 18F-GP1 uptake only occurs within the culprit coronary arteries of those with acute
myocardial infarction. For example, in patients with triple vessel disease, coronary 18F-GP1
uptake was only seen at the site of the culprit lesion. We have also demonstrated preliminary
findings of focal 18F-GP1 uptake at the site of spontaneous coronary artery dissection,
coronary thromboembolism and extra-coronary thrombus including unrecognized left ventricular
and atrial thrombus, as well as infarct-related intramyocardial 18F-GP1 uptake. This changed
both the diagnosis (type 1 reclassified as type 2 myocardial infarction) and the treatment
(initiation of anticoagulation) of patients presenting with acute myocardial infarction.
These data demonstrate the feasibility of identifying patients with intracoronary thrombus
and type 1 myocardial infarction, and those with type 2 myocardial infarction caused by
spontaneous coronary artery dissection and coronary thromboembolism. Importantly the pattern
of 18F-GP1 distribution differs among these three conditions, allowing their differentiation.
This technique holds major promise in aiding the classification of myocardial infarction,
especially in patients with myocardial infarction and non-obstructive coronary arteries or
where the presence of coronary thrombosis is unclear.
1.2 RATIONALE FOR STUDY
With the evolving complexity in modern diagnostic criteria and treatments, it has become
increasingly important to determine the aetiology of acute myocardial infarction and
specifically determine the presence of intracoronary thrombosis. This has major implications
for treatment decisions and patient outcome. However, there are currently no techniques that
can reliably determine the presence of intracoronary thrombus throughout the coronary
circulation. Here, we will assess a promising highly sensitive and accurate technique to
determine the contribution of coronary thrombosis in patients presenting with uncertain or
difficult to diagnose causes of myocardial infarction. This will potentially provide a
completely novel approach that could provide major insights into the diagnosis, investigation
and treatment of these patients.
2 STUDY OBJECTIVES
2.1 OBJECTIVES
2.1.1 Primary Objective The primary objective of this study is to establish the origin,
frequency and distribution of activated platelets and thus thrombotic causes of myocardial
infarction in patients presenting with myocardial infarction with non-obstructive coronary
arteries 2.1.2 Secondary Objectives To inform the pathophysiology and understanding of acute
myocardial subtypes, by providing additional mechanistic information regarding the presence
of intracoronary activated platelets and thrombosis.
2.2 ENDPOINTS
2.2.1 Primary Endpoint
The primary endpoint will be the degree and location of platelet activation as determined by
the target to background ratio of 18F-GP1.
2.2.2 Secondary Endpoints
The secondary endpoints will include measuring the presence of platelet activation in acute
myocardial infarction with non-obstructive coronary arteries and identifying the presence and
site of platelet activation in thrombosis-related coronary causes of type 2 myocardial
infarction.
3 STUDY DESIGN
This will be a prospective observational case-control cohort study
4 STUDY POPULATION
4.1 NUMBER OF PARTICIPANTS
We will recruit two patient populations after invasive coronary angiography has been
completed. We have established comparator control populations including 50 patients with
stable coronary artery disease (no angina or recent myocardial infarction) and valvular heart
disease who underwent 18F-GP1 cardiac PET-CT as part of a concurrent study (NCT04073875)
(34).
4.1.1 Cohort 1: Patients with myocardial infarction with non-obstructive coronary arteries
We will recruit 50 patients with myocardial infarction and non-obstructive coronary arteries
on coronary angiography
4.1.2 Cohort 2: Patients with coronary causes of type 2 myocardial infarction
We will recruit 10 patients with coronary artery thromboembolism and 10 patients with
spontaneous coronary artery dissection. Finally, we will include 10 subjects who have had
iatrogenic coronary artery dissection or intramural haematoma as a complication of their
percutaneous coronary intervention.
4.2 INCLUSION CRITERIA
- Males and females ≥ 18 years of age
- Clinical presentation of chest pain, ST-segment deviation within a coronary artery
territory on the electrocardiogram, raised cardiac troponin and non-obstructive coronary
arteries on invasive coronary angiography as per international societal diagnostic
criteria (19, 26).
4.3 EXCLUSION CRITERIA
- <18 years of age
- Takatsubo cardiomyopathy
- Myocarditis
- Renal failure (estimated glomerular filtration rate <30 mL/min/1.73 m2)
- Woman of child-bearing potential who are pregnant or breastfeeding
- Known allergy or contraindication to iodinated contrast or radiotracer
- Patients unable to tolerate the supine position
- Patients unable to provide informed consent
