Comprehensive Cardiac CT versus Exercise Testing
in Suspected Coronary Artery Disease (CRESCENT II Trial)

BACKGROUND
Angina pectoris is a clinical syndrome characterized by discomfort of the
chest, provoked by exertion or emotional stress and relieved by rest or
nitroglycerin, typically a symptom of oxygen deprivation of the heart muscle
due to atherosclerotic obstruction of the coronary arteries. However, chest
pain is a very common complaint, and may also be caused by numerous other
cardiac and non-cardiac conditions. While the risk of severe complications
appears relatively low for the group as a whole, subgroups with severely
obstructive CAD with a 10-fold higher event rate can be distinguished. It is
important to identify these high-risk individuals as clinical outcome can be
improved through surgical or PCI myocardial revascularization [Yusuf].

USUAL DIAGNOSTIC CARE OF STABLE ANGINA
Patients with chest complaints, referred by their general practitioner, will
undergo a tiered diagnostic workup at the cardiology clinic [Fox]:
1)History, physical exam, ECG, risk profile, blood analysis.
2)Stress test: exercise ECG (X-ECG), and/or stress imaging by myocardial
perfusion scintigraphy (SPECT) or dobutamine stress echocardiography (DSE).
3)Invasive catheter angiography (ICA): selectively used in case of severe
ischemia, refractory complaints or non-conclusive stress test result.

HEALTH CARE EFFICIENCY PROBLEMS
1)Performance of the current diagnostic work-up is insufficient. Many patients
are unable to exercise, and the sensitivity of X-ECG is only 50% (specificity
90%) in unselected populations [Gibbons]. As second option, stress imaging is
more sensitive (84%), but with lower specificity (73%) and it is more expensive
[Jaarsma].
2)Uncertainty about stress tests leads to invasive angiography. A recent US
registry reported that only 37% of ICAs resulted in (mechanical) treatment,
which illustrates how the noninvasive work-up fails as a gatekeeper to ICA
[Patel]. Invasive angiography has a small risk of severe complications, as well
as a more frequent occurrence of less serious complications and discomfort.
3)Since COURAGE [Boden] and FAME [Tonino, DeBruyne] there is growing consensus
that (surgical) revascularization does not benefit every patient with
angiographic CAD, but should be reserved for those with objective myocardial
ischemia. Invasive angiography, without proper ischemia testing, leads to
over-treatment.
4)Persistent symptoms, uncertainty about test results, layered testing, delayed
or inaccurate diagnoses and under-/overtreatment, all have a negative effect on
patient well-being. In addition, inefficient patient care is costly, in terms
of health care related expenses and productivity losses.

The overall aim of the study is to demonstrate that a comprehensive cardiac CT
examination improves the diagnostic workup of stable chest pain in terms of
accuracy, efficiency and costs. In concrete terms, the purpose of this
randomized controlled trial is to answer the following questions:
1) Does a comprehensive cardiac CT exam reduce the number of negative catheter
angiograms? The unnecessary performance of an invasive examination represents
failure of the non-invasive workup.
2) Does the comprehensive cardiac CT lead to a faster (correct) diagnosis?
3) How does the comprehensive cardiac CT approach affect symptoms and quality
of life?
4) How does the cardiac CT approach affect overall costs, and is this new
approach cost-effective?

Randomized multi-center diagnostic intervention study, with 6-months clinical
follow-up:
a) Comprehensive cardiac CT examination
b) Standard care according to international guidelines

COMPREHENSIVE CARDIAC CT (INTERVENTION), to be completed depending on the
results:
[1] CORONARY CALCIUM SCAN (CT-CALCIUM)
[2] CT CORONARY ANGIOGRAPHY (CT-ANGIO)
[3] CT MYOCARDIAL PERFUSION IMAGING (CT-MPI)

Roentgen exposure
The currently standard approach to stable chest pain complaints includes
several investigations involving potentially harmful ionizing radiation, which
is considered acceptable to reach the diagnostic goals of identifying ischemic
heart disease. Also in the investigational arm there is exposure to radiation
by the CT examination.
In the standard care arm a proportion of patients will undergo SPECT (effective
dose 10-12 mSv) and/or invasive angiography (5-10 mSv).
In the investigational arm most patients will undergo calcium scanning (<1
mSv), approximately 60% will undergo CT angiography (3-4 mSv), and
approximately 20% will undergo CT-MPI (8-10 mSv). Also a proportion (which is
hopefully smaller) will undergo conventional angiography as well. We expect the
overall exposure will not be substantially larger in the investigational group.
Nevertheless, advanced techniques (prospectively triggered sequential mode and
high-pitch spiral mode) and other precautions (low-mA/kV protocols, narrow
longitudinal ranges, etc) will be used to minimize the roentgen exposure for
each examination, including the CT scan.
For comparison, the yearly exposure to natural background radiation is 3.6 mSv.
In conclusion, the study protocol is unlikely to substantially increase the
accumulated radiation exposure during the diagnostic workup.

CT contrast medium
Visualization of the coronary lumen and myocardium can only be accomplished by
injection of iodine-containing contrast medium. Based on our registry data
approximately 60% of the patients in the CT arm will undergo contrast-enhanced
CT. Also in the standard of care group, approximately 20% of patients will be
exposed to contrast during the time of cardiac catheterization. The dose
required for 64-128 slice CT is approximately 80 ml, with 50 ml added if CT-MPI
is performed, which is still less than conventional coronary angiography.
Allergic reactions to iodinated contrast media infrequently occur and may cause
skin reactions or in very rare occasions result in breathing difficulty and
hypotension (shock). Renal impairment (estimated creatinine clearance less than
70% of normal) or an established allergy to contrast media will be considered a
contra-indication for study participation. The CT suite and personnel is
equipped and trained to deal with unexpected allergic reactions to contrast
media.

CT pre-medication
Betablockers are used by millions of patients and are generally considered
safe. The side-effects and risks of incidental use of betablockers includes
bradycardia (which is the reason for administration, to improve image quality),
hypotension, and in rare occasions wheezing (bronchospasm) and dyspnea.
Allergic reactions to beta-blocker are rare. Betablockers will only be
considered in patients with a heart rate over 65 beats per minute, without
clinical signs of heart failure, electrical conduction abnormalities, or a
history of bronchial asthma.
Although several precautions are routinely taken, i.e. flushing, detection
electrodes, extravasation of contrast occasionally occurs, which will require
observation, and in very rare instances surgical intervention.
Also nitroglycerine, which is a vasodilator, is safely used by millions of
patients. Side-effects include hypotension, flushing, palpitations and
headache. It cannot be used in hypotensive patients, or those taking
sildenafil, tadalafil en vardenafil (within 24-72 hours before the
examination), as this may cause severe hypotension. Headache and sensations of
flushing will subside within minutes after administration.
Ivabradin is a selective sinus node inhibitor known for its lack of side
effects or severe bradycardia. It will be second choice to betablockers only
for economic reasons.
The type of heart rate modulation will be chosen depending on the patient and
potential contraindications. To put it in perspective, after close to 1000 CT
examinations as part of the fast-track chest pain clinic no adverse events
attributed to premedication have occurred.
Adenosine may precipitate bronchospasm, and should be avoided in asthmatic
individuals, as well as patients with a 2nd or 3rd degree AV block or sinus
node dysfunction (unless a pacemaker is implanted. Adenosine injection may be
experienced as uncomfortable: flushing, palpitations, dizziness, chest pain,
which resolves shortly after infusion.

Exercise electrocardiography
XECG is routinely performed at the department of cardiology and complications
are rare. Death and MI occur in less than 1 in 2500 tests. The test will
performed under careful supervision, with a physician present in the immediate
vicinity. Patients with contra-indications will not perform XECG. During the
test the ECG will be recorded and continuously displayed, with blood pressure
measurements at 2-min intervals. Trained personnel and equipment is available
in case of emergencies.

Pharmacological stress testing
Pharmacological stress test are generally safe with major complications
(including sustained ventricular arrhythmia) occurring 1/1500 tests with
dipyridamole, and 1/300 tests with dobutamine. Trained personnel and equipment
is available to act upon severe complication, should they occur.
Adenosine may precipitate bronchospasm, and should be avoided in asthmatic
individuals, as well as patients with a 2nd or 3rd degree AV block or sinus
node dysfunction (unless a pacemaker is implanted. Adenosine injection may be
experienced as uncomfortable: flushing, palpitations, dizziness, chest pain,
which resolves shortly after infusion. Dipyridamole has similar side-effects,
and both should be avoided in asthmatic patients. Dobutamine infusion can also
be uncomfortable, but generally to a lesser extent. It cannot be used in
patients with a LV outflow obstruction.

Potential adverse events related to the study algorithm
Participation to the study will affect further management, depending on the
diagnostic approach and subsequent findings. Although we consider it unlikely
that long-term outcome will be (negatively) affected by participation to the
study, patients will be asked to immediately report back any major adverse
cardiovascular events (unplanned hospital visits and treatment in relation to
cardiovascular disease). An excess of major adverse events in the
investigational arm will result in early termination of the study.

Patient burden
Patient response to the fast-track chest pain clinic (which combined CT and
XECG in all patients) as it exists now is very good. In general the CT
examination is tolerated equally well or better than XECG or SPECT).
Randomization to the CT arm will not prolong or otherwise burden the patient in
time or effort. As a matter of fact we hope that implementation of CT will
improve logistics and reduce the number of examinations and hospital visits.
Patients participating in the study will be asked for detailed information
concerning their well being and medical expenses at baseline and during
follow-up (questionnaires). The time consumption for the patient is estimated
to be less than 30 minutes.