Replacement of invasive diagnostic coronary procedures by innovative noninvasive Imaging Technologies

Coronary artery disease (CAD) is caused by the accumulation of plaque in the
coronary arteries, which can cause stenosis of the vessel and consequently
cause inadequate oxygen and nutrient supply to the downstream myocardial
tissue. CAD is the most common cause of death in the EU with 1.8 million people
dying each year (European Heart Network data) and is expected to remain the
leading cause of death for the next 20 year (1). The management for CAD
patients forms a major burden for society with healthcare costs around ¤ 23
billion and a total burden of over ¤ 40 billion per annum for EU society
(European Heart Network 2009 data).

Patients with angina and suspected flow limiting CAD are classified based on
their risk profile. Low-risk patients (<15%) generally receive no additional
diagnostic testing, intermediate risk patients undergo one or more stress test
for further stratification, while high-risk patients (>85%) are referred to
invasive coronary angiography (ICA).
ICA is an invasive, contrast-enhanced x-ray method to visualize coronary
arteries, localize stenoses and assess their severity. Many coronary stenoses
of intermediate and sometimes even higher grade (50-70% or 70-90% diameter
stenosis) do not significantly reduce blood flow, and thus, are not suspected
to cause myocardial ischemia. Especially in case of intermediate grade
stenosis, visual analysis of the degree of diameter stenosis frequently fails
to provide an accurate measure of the functional significance of a stenosis and
thus, falls short in identifying which coronary lesion requires invasive
treatment (2).
Quantification of the *downstream* blood supply is essential. The invasive
reference method (gold standard) to determine the effect of a stenosis on blood
flow, is fractional flow reserve (FFR) across the stenosis measured by a
dedicated pressure wire in the coronary artery during ICA. Here, the pressure
under (adenosine) hyperemia behind the coronary stenosis is compared to the
aortic pressure, to give an estimate of the functional consequence of a
stenosis on the coronary blood flow. The FAME trial (n=1005) showed the
significant improvements that ICA-FFR guided therapy provides as compared to a
angiography-guided intervention alone. In this study guidance of stent
placement by FFR resulted in a third less stent placements(2). Furthermore, the
FAME II study showed strong evidence that the combination of optimal medical
treatment and FFR-guided revascularization was superior compared to optimal
medical treatment alone. The study was even prematurely stopped due to highly
significant differences of the composite endpoint between the two groups. The
guidelines recommend FFR measurement during ICA in CAD of intermediate grade to
guide therapy (3). The COURAGE and BARI 2D trials showed that, in the absence
of myocardial ischemia, there is no benefit of revascularization on
cardiovascular events or mortality (4,5). Thus, information about the
functional consequences of a stenosis on downstream flow is essential for a
cost-effectively and patient safe strategy of selecting patients who should
undergo revascularization.

An advantage of ICA, in theory, is the ability to not only diagnose relevant
CAD but also to determine its functional significance by FFR and the
possibility to treat stenoses by percutaneous coronary intervention (PCI) in
the same session. Unfortunately, in practice, the majority of ICAs are being
performed in centers without the option to perform ad-hoc PCI or FFR. A
considerable proportion of patients will undergo a second ICA for additional
diagnostics (FFR) and/or treatment by PCI or CABG. In addition, the diagnostic
yield of ICA for flow limiting CAD is not very high. In the elective setting
only 38% of patients had flow limiting CAD (6). Even the setting of *typical
angina* which defines the highest a-priori chance, only in about ~40% of
patients flow limiting CAD is present (6,7).

Another disadvantage of ICA is the inherent risk of complications of an
invasive procedure. Serious complications associated with ICA are major
bleeding (~1.4%), myocardial infarction (~2.4%), stroke (~0.3%) and death
(~1.4%) (8,9). In addition, ICA subjects a patient to a substantial radiation
dose of up to ~7 mSv with an additional exposure of up to ~15 mSv if PCI is
performed.(10) Next to the patient related disadvantages of ICA, the costs
related to ICA and invasive FFR measurements are considerable. In 2009/2010,
nearly 2.7 million ICA procedures took place in Europe, with about 750.000 ad
hoc PCI procedures (European Society of Cardiology data). ICA is expensive with
an estimated ¤ 1600 per patient including day-stay (NL data 2012). The
frequently required FFR assessment is costly due to the expensive pressure wire
(additional >700¤), and increases the procedural time and radiation dose
involved in the procedure (11,12). The ESC guidelines for revascularization of
214 state that ICA-FFR should be used (Ia recommendation) to identify
haemodynamically relevant coronary lesion(s) in stable patients when evidence
of ischemia is not available (13). The use of ICA-FFR is at the operators
discretion and will especially be performed in the setting of intermediate
stenoses based on visual interpretation of ICA images.
The emerging role of noninvasive imaging techniques in CAD

The most recent European Society of Cardiology (ESC) guideline considers
noninvasive imaging as preferable to exercise ECG in case of intermediate
pre-test probability patients (3). Coronary CTA is a noninvasive,
contrast-enhanced x-ray method to visualize the coronary arteries. The
radiation dose associated with coronary CTA is decreased with the newest CT
scanners to 1-4 mSv (14). In patients with low-intermediate likelihood of CAD,
coronary CTA safely rules out coronary stenoses with negative predictive value
of 99% (15). CTA is an accurate method to detect the presence and extent of
coronary plaques and stenosis, with sensitivity for >50% stenosis of 98% (14).
However, in up to 14% of patients (14), the degree of stenosis is overestimated
by CTA compared to ICA, mainly due to artifacts related to calcified plaques or
motion.
The anatomical degree of stenosis on CTA (or ICA) has only limited value for
determining flow-limiting lesions, especially at stenosis grade of 50-70% (16).
The low specificity en negative predictive value of CTA have triggered the
search for other imaging techniques that can more accurately determine flow- or
perfusion limiting CAD by providing both anatomical and functional
characteristics. One promising noninvasive imaging technique that has emerged
in recent years is the CT fractional flow reserve (CT FFR)
quantification(17,18) This technique uses computational fluid dynamics to
determine a CT-based calculation of the FFR (17,19) and correlates with
ICA-FFR(17,20,21). The Transluminal Attenuation Gradient (TAG) method can
determine the linear regression coefficient between luminal contrast
opacification and distance from the coronary ostium, and reflects the rate of
fall-off of contrast opacification along a vessel and can be used as an
estimation of coronary blood flow(22)(23).

Adenosine MR perfusion is another imaging modality which has great potential in
the evaluation of CAD. The main advantage of MR perfusion as compared to other
imaging modalities (such as SPECT, PET, and CTA) is the absence of radiation as
it uses magnetic resonance for image acquisition. Furthermore, the high spatial
resolution makes it possible to assess (sub-)endocardial perfusion defects
(24). Late enhancement acquisition can be used to detect myocardial infarction.

Primary objective: To study whether we can replace ICA with noninvasive imaging
(ultra low-dose CTA and MR-perfusion) to determine obstructing CAD, in patients
scheduled for ICA.

Secondary objectives:
To establish a CTA and MR perfusion dataset to develop and/or validate
quantitative image biomarkers measures aimed at (1.) improve evaluation of
functional severity of CAD and/or identify subjects who will benefit from
coronary revascularization (2.) improving risk stratification and prediction of
events.

The study is a prospective single-center observational study performed at the
department of Cardiology of the UMCG. In total 400 patients, at high risk of
CAD will be included. All patients will undergo CT and CMR perfusionI imaging
to assess potential flow- or perfusion limiting CAD in addition to the
scheduled Invase Coronary angiogram. The study will take place at the
University Medical Center of Groningen. Total study duration is 48 months.

Non-contrast and contrast (iodine) enhanced coronary CTA will be performed.
Total study related radiation dose will be less than 6 mSv. Potential side
effects of iodine contrast include flushing, and (mild) skin rash. Patients
with impaired renal function are at risk of contrast induced nephrotoxicity.

Vasodilator stress myocardial MR-perfusion, including gadolinium (Dotarem 0.2
mmol/kg) enhancement will be performed. Hyperemia is induced with either
adenosine or regadenoson. Potential side effects of the vasodilator agents
during infusion include flushing, angina, and dyspnea. Potential side effects
of gadolinium include brief headache, nausea (feeling sick) and dizziness for a
brief time following the injection. Allergic reactions are rare. Furthermore,
patient will be asked to fill out questionnaires. Patients will be followed by
telephone interview for clinical endpoints for two years.