Diagnostic Performance of Photon Counting Computed Tomography in High-Risk Patients With Acute Coronary Syndrome Without ST-segment Elevation

Each year >20 million patients in Europe and North America present with
(suspected) acute coronary syndrome (ACS). ACS patients are differentiated into
two groups according to ST-segment elevation on electrocardiography, namely
ST-elevation myocardial infarction (STEMI) and non-ST-elevation ACS (NSTE-ACS).
There has been a continuous increase in the occurrence of NSTE-ACS over the
past few decades, also confirmed by data from the Dutch Heart Registry.
Importantly, compared to STEMI patients, NSTE-ACS patients are older, have more
co-morbidity and carry worse long-term prognosis, resulting in a growing burden
for the healthcare system. Underlying coronary pathology in these patients
ranges from structurally normal epicardial vessels to non-obstructive
atherosclerotic plaques and extensive obstructive coronary artery disease
(CAD).
Based on initial risk stratification, most NSTE-ACS patients have an indication
for invasive coronary angiography (ICA) <24-hours after presentation. In case
of significant obstructive CAD amenable to revascularization, either
percutaneous coronary intervention (PCI) or coronary artery bypass grafting
(CABG) is performed. Importantly, ICA is costly and due to its invasive nature,
associated with a low risk of detrimental complications. Moreover, only ~50% of
patients undergo (direct) revascularization.
According to recent UMCG data of NSTE-ACS patients referred for ICA, merely 56%
of the patients were revascularized during the ICA procedure. Thus, in a large
group of NSTE-ACS patients, who turn out to have no indication for coronary
intervention or the intervention is not technically feasible, the ICA may be
considered unnecessary. Moreover, in the Netherlands, the ICA is often
performed twice, first in the regional hospital (non-interventional center),
and in case of relevant findings the patient is referred for a second ICA
procedure to an interventional center. There, PCI is performed, often preceded
by an additional invasive fractional flow reserve (FFRinv) measurement, to
assess the hemodynamical significance of lesions. In addition to being
patient-unfriendly, this approach wastes hospital and emergency-service
resources (length of hospital stay, transfer of patients between hospitals).
Concluding, there is an urgent clinical need for a non-invasive alternative to
ICA, to pre-select patients for invasive management in order to prevent
unnecessary (dual) ICA.
In the last decades, computed tomography (CT) has undergone remarkable
improvements in hardware and software technology, with increase in temporal and
spatial resolution at even reduced radiation exposure. Nowadays, coronary CT
angiography (CTA) is very accurate in ruling out obstructive CAD. Coronary CTA
recently received a class I indication for evaluation in stable chest pain.
Furthermore, coronary CTA is an alternative to ICA to exclude obstructive CAD
in acute patients with low-intermediate risk, normal or inconclusive cardiac
troponins, and/or ECG without ischemic changes.
Our study aims to extend the indication of coronary CTA to the high-risk
NSTE-ACS patient cohort. These high-risk NSTE-ACS patients generally have more
extensive CAD. This has so far limited the application of coronary CTA in this
patient group, as coronary CTA is more often non-conclusive in case of more
extensive CAD, with overestimation of stenosis degree, and low specificity in
case of stents and/or severe calcifications (due to blooming artefacts). Photon
counting CT (PCCT) technology has recently entered the clinical imaging realm.
This novel modality has a better spatial resolution and soft-tissue contrast,
and reduces image noise and artefacts. Consequently, it has better image
quality and diagnostic accuracy at a similar radiation dose compared to
conventional coronary CTA. Initial results show reduction in blooming and
better visualization of the coronary lumen (with less overestimation of
stenosis). PCCT may also have an important additional value in patients with
coronary stents. Another important improvement of PCCT is the potential for
characterization of atherosclerotic plaques. The composition and extent of
coronary plaques was shown to have important prognostic value. The gold
standard for (vulnerable) plaque characterization is invasive coronary imaging
(intravascular ultrasound [IVUS] or optical coherence tomography [OCT]). PPCT
was shown to outperform conventional coronary CTA for plaque evaluation due to
improved spatial resolution.

Primary objective:
- To study the diagnostic accuracy of PCCT (± CT-derived fractional flow
reserve [FFRct]) as compared to the reference standard ICA (± FFRinv) in the
NSTE-ACS population referred to the UMCG.

Secondary objectives:
- To study the agreement of revascularization decision and strategy based on
PCCT (±FFRct) as compared to ICA (±FFRinv);
- To study the practical feasibility of performing PCCT in NSTE-ACS patients;
- To compare safety parameters between PCCT and ICA: radiation exposure, amount
of contrast used, complication rate;
- To assess the preliminary cost effectiveness of PCCT in NSTE-ACS patients;
- To study the accuracy of coronary plaque evaluation with PCCT as compared to
invasive IVUS and/or OCT.

Prospective single-center study.

All consented NSTE-ACS patients will undergo PCCT, followed by ICA. The patient
flow is a reflection of the current situation in our region (HartNet Noord
Nederland). The PCCT will be performed within 20-hours after presentation in
order to comply with the 24-hour time-window recommended for ICA. All efforts
will be made not to delay the ICA in comparison to the patients not
participating in the study. If the PCCT scan cannot be performed within the
20-hour time window, or there are clinical reasons why ICA should be performed
expeditiously, the PCCT scan will be cancelled and the patient will undergo ICA
without further delay.

The PCCT will be performed with a first-generation dual-source PCCT scanner
(NAEOTOM Alpha; Siemens Healthineers). First, a CT scan without intravenous
contrast will be performed for calcium scoring (unless prior in case of
revascularization). Next, a CT angiography of the coronary arteries will be
performed with intravenous contrast, after administration of beta-blockers (if
indicated) and nitroglycerin. A high-density contrast medium followed by
isotonic saline will be injected with personalized concentration and flow rate.
Depending on the scanning protocol used, automatically determined best
systolic, best diastolic, and/or multiphase data will be reconstructed with a
section thickness of 0.2-0.4 mm.

All main vessels and first degree side-branches (>2mm diameter) will be
assessed. Both the operator performing ICA as well as the investigator
assessing PCCT images will be blinded for the findings of the other modality.
FFRct and FFRinv will be calculated or measured, respectively, for every
stenosis of 30-90%. Siemens FFRct software will be used for the analysis. In
grafts/grafted vessels FFRct is not validated and thus will not be measured.
The determination of significant stenosis in these patients would be based on
anatomical assessment (i.e. PCCT and ICA). Hereby the possible results of the
analysis of PCCT scans and ICA:

- Non-significant stenosis/ non-obstructive CAD: This refers to a stenosis of
less than 30%, or a stenosis between 30% and 90% without reduced FFRinv or
FFRct value (if performed).
- Significant stenosis/ obstructive CAD:
- Coronary CTA/ ICA only (in case of already revascularized vessel i.e. after
CABG or PCI): Stenosis of 70% or more, or a stenosis of 50% in the left main.
- Coronary CTA/ICA and FFRct / FFRinv: Stenosis between 30% and 90% with an
FFR value below 0.80.
- Highly significant stenosis/ obstructive CAD: For stenosis of more than
90%, the FFRct/FFRiv analyses are not performed.
- Chronic Total Occlusion (CTO): This is classified and assessed separately.

The revascularization decision based on PCCT±FFRct will be compared to
ICA±FFRinv. There are five potential test results:
- no coronary pathology
- non-significant CAD/ non-obstructive CAD; revascularization is not indicated
- significant CAD/ obstructive CAD; PCI is indicated and feasible
- significant CAD/ obstructive CAD; CABG is indicated and feasible
- significant CAD/ obstructive CAD; revascularization is not feasible

The diagnostic accuracy of stenosis detection with PCCT±FFRct will be compared
against the reference standard i.e. ICA±FFRinv.

Follow-up will be performed according to the post-ACS protocol of the HartNet
network; all major cardiovascular adverse events (MACE: composite outcome of
all-cause mortality, myocardial infarction, stroke, and unplanned
revascularization) during 1-year will be collected.

The benefits of this research endeavor are multifaceted. By reducing the need
for invasive procedures in the future for a significant proportion of patients
with NSTE-ACS, PCCT holds the promise of minimizing patient discomfort,
reducing healthcare costs, and mitigating the risk of procedural complications.
Moreover, the integration of FFRct enhances the diagnostic accuracy of PCCT,
thereby facilitating more precise identification of patients who truly
necessitate revascularization. This not only optimizes resource allocation but
also ensures that interventions are directed towards those who stand to derive
the greatest clinical benefit.

However, the pursuit of these benefits is not without inherent risks. The risks
associated with the non-invasive imaging techniques are minimal and related to
contrast, and radiation exposure. The incidence of side effects due to contrast
is rare and the side effects are almost exclusively mild. Potential side
effects of iodine contrast include flushing, and (mild) skin rash. Patients
with impaired renal function are at risk of contrast induced nephrotoxicity,
however eGFR<30ml/min is an exclusion criterium for study participation.
Additionally, the radiation dose associated with the newest ultrafast low-dose
PCCT scan is maximally about 13mSv. For comparison, the average radiation
exposure from a nuclear scan in cardiology is about 9 mSv, and annual
background radiation is approximately 2.5 mSv. This means the radiation dose
corresponds to 4-5 times the annual background radiation. While the radiation
theoretically carries a slightly increased risk of developing cancer 15-20
years later, this risk is very small and decreases with increasing age,
especially above 60 years. Therefore, this additional radiation exposure for
this study is relatively low and outweighs the potential benefits.