The Addition of Cardiac CT to Exercise Treadmill Testing in the Evaluation of Angina

CT-EXTRA is a randomized clinical trial that will compare a novel diagnostic strategy
employing the addition of coronary MSCT angiography to exercise treadmill testing with a
standard diagnostic strategy of exercise treadmill testing for the outpatient evaluation of
low-intermediate risk patients with possible angina. This is the first randomized clinical
trial that evaluates a diagnostic strategy for outpatient chest pain that incorporates a
noninvasive assessment of both coronary artery function and anatomy. CT- EXTRA will
determine whether coronary MSCT angiography adds any incremental prognostic value over
exercise treadmill testing alone for predicting future adverse cardiac events and reduces
downstream clinical resource utilization. This study will also evaluate the impact of this
strategy on the avoidance of unnecessary invasive coronary angiography, statin and aspirin
prescription, patient anxiety, satisfaction with the diagnostic approach, and motivation for
healthy behavioral change. Finally, an economic analysis will be performed to assess the
differences in overall healthcare costs between the diagnostic approaches. In today’s
managed care-dominated paradigm, it is paramount that a new diagnostic modality such as
coronary MSCT angiography is not only clinically effective but cost effective as well. CT
EXTRA will provide critical information to clinicians and health care administrators on the
clinical and cost effectiveness of an initial diagnostic strategy employing routine coronary
MSCT angiography in the evaluation of patients for possible angina.

300 male and female military health care beneficiaries between the ages of 18-70, who are
low to intermediate risk for symptomatic coronary artery disease and are referred to the
Walter Reed Cardiology Clinic for an exercise treadmill test for the evaluation of possible
angina (chest pain or angina-equivalent).

This study is a randomized, non-blinded, prospective trial to be conducted in the Cardiology
clinic at Walter Reed Army Medical Center. Patients, age 18-70 years, referred to the
Cardiology clinic for an exercise treadmill test for an outpatient evaluation of possible
angina and are low-intermediate risk for symptomatic coronary artery disease, will be
eligible. All patients who meet the aforementioned inclusion/exclusion criteria will be
consented by an investigator and randomized from sealed envelopes to either “mandatory
coronary MSCT angiography” or “no coronary MSCT angiography” before initiation of exercise
treadmill testing. The randomization sequence will be generated using a sequence of
computer-generated random numbers. All consented subjects will complete surveys assessing
baseline depression using the Beck Depression Inventory, anxiety using the State and Trait
Anxiety Inventory, and motivation healthy behavioral change using the ladder scale
questionnaire. Completion of these three questionnaires are for research purposes and will
take approximately 15 minutes.

Exercise Treadmill Testing

All subjects will undergo exercise treadmill testing as initially ordered by the referring
physician. All exercise treadmill testing will be conducted at the Cardiology clinic at
Walter Reed Army Medical Center according to standard clinic protocol. Testing will be
conducted by a health care professional (staff physician, fellow, or nurse practitioner) not
associated with the protocol. A Cardiology staff physician not affiliated with the protocol
will officially interpret each exercise treadmill test. Subjects will perform a graded
exercise treadmill test according to a Full Bruce protocol aimed at reaching 85% of the
maximal predicted heart rate for age. According to standard clinical practice, an exercise
treadmill test is considered positive if 0.1 mV of new horizontal or downsloping ST segment
depression or ST segment elevation 0.80 ms beyond the J point occurs during exercise or
recovery in two or more contiguous lead. A nondiagnostic test is defined as the absence of
ischemic electrical changes in the setting of reproduction of chest pain symptoms or when
peak heart rate is ≤85 % of the age-predicted maximal heart rate. An exercise treadmill test
is considered negative when > 85% of the age-predicted maximal heart rate is achieved and
reproduction of anginal symptoms and development of electrocardiographic ischemic changes
are absent. In accordance with standard clinical practice, exercise treadmill testing will
be prematurely terminated in the event of lightheadedness, severe ST depression (>2mm) or
elevation (>1mm), ventricular or supraventricular arrhythmias, exaggerated blood pressure
increase (>250 mm Hg systolic or >120mm Hg diastolic) and a >10mm Hg decrease in diastolic
blood pressure. Upon completion of exercise treadmill testing, the subject will be provided
a copy of the results and official interpretation of the exercise treadmill test for
inclusion in their medical records. A copy of the exercise treadmill test results will be
kept in the subject’s file for the investigational team. Completion of an exercise treadmill
test generally takes about 25 minutes.

Immediately Following Exercise Treadmill Testing

All consented subjects following exercise treadmill testing will undergo initial laboratory
assessment to include fasting lipid panel (LDL-C, HDL-C, and triglycerides), C-reactive
protein, fasting blood glucose, creatinine, thyroid stimulating hormone (TSH) and urine
pregnancy test (for females). Approximately 15 mL (3 teaspoons) of blood will be drawn by
the central laboratory, the clinical laboratory at Walter Reed Army Medical Center. Excess
blood will be discarded by the central laboratory according to their standard protocol. All
laboratory values will be processed through this central laboratory.

Subjects assigned to the “no coronary MSCT angiography” arm will follow up with their
referring physician for further evaluation. Additional selection of testing, consultation,
and choice of therapy is at the discretion of the referring physician. Coronary CT
angiography will not be available to this group of subjects. Otherwise, the protocol will
not predetermine the clinical diagnostic or treatment course for the subject. This approach
will simulate the previous standard of care for the evaluation of possible angina (prior to
the availability of coronary CT angiography in clinical practice). By excluding the option
of coronary CT angiography in this group, any possible incremental value of the test can
more accurately be assessed.

In the event of a “high risk” exercise treadmill test, subjects will be offered inpatient
admission. High risk tests will include any of the following: the occurrence of sustained
ventricular tachycardia, syncope, a high risk Duke treadmill score (>-10), limiting angina
in stage 1 of the Full Bruce protocol, > 2 mm ST depression in 3 or more leads in stage 1 of
the Full Bruce protocol. Subjects with such high risk tests who are assigned to the “no
coronary MSCT angiography” arm will be encouraged to undergo invasive coronary angiography.
Subjects assigned to the “mandatory coronary MSCT angiography” arm will undergo coronary
MSCT angiography in an expedited manner. This will be followed by invasive coronary
angiography, if warranted, 48 hours later. Because the protocol excludes subjects deemed as
having a high pretest probability of obstructive coronary artery disease, the potential for
this occurrence should be minimized.

Patients assigned to the “mandatory coronary MSCT angiography” arm will be scheduled for
coronary MSCT angiography on an outpatient basis. The procedure for coronary MSCT
angiography is described below. After completion of coronary MSCT angiography, the results
will be provided to the referring physician. Additional selection of testing, consultation,
or therapy is at the discretion of the referring physician. The protocol will not
predetermine the clinical course for the subject following coronary MSCT angiography.

Coronary MSCT angiography

Pre-procedural Medications: In order to obtain high quality computed tomographic images with
minimal motion artifacts, the goal heart rate is ≤ 65 beats per minute. This usually
requires administration of beta-blocker medications before image acquisition. In addition,
subjects with baseline low rates (> 65bpm) generally need a reduced dose of beta-blockers to
blunt increases in rate during the MSCT scan due to anxiety and or reflex responses to
contrast. The dose of initial oral beta-blocker will be determined based on resting heart
rate at the time of exercise treadmill testing. For subjects with a baseline heart rate
above 65bpm and blood pressure above 100/50, 100-150mg of short acting metoprolol will be
prescribed by the investigator. Subjects will be instructed to ingest this medication
approximately one hour before the scheduled outpatient MSCT scan. For subjects with heart
rates above 50bpm and less than 65bpm and blood pressure above 100/50, 25-50 mg of oral
short acting metoprolol will be prescribed by the investigator. Subjects will be instructed
to ingest this medication approximately one hour before the scheduled outpatient MSCT scan.
For subjects with a baseline heart rate < 50bpm, no metoprolol will be prescribed.

On the day of the MSCT scan and upon arrival to the Radiology Department, the subject will
receive a peripheral upper extremity intravenous catheter, placed by a certified nurse in
the Radiology Department. The subject’s baseline blood pressure and heart rate will be
recorded. For subjects whose heart rate remains ≥ 65 beats per minute and blood pressure ≥
100/50, intravenous metoprolol (5 mg aliquots every 2-5 minutes under close observation and
continuous telemetric monitoring, up to 40 mg total) will be administered by a cardiology
staff or fellow. Once satisfactory heart rate and blood pressure stability are established,
subjects will undergo MSCT testing as listed below. However, if target heart rate is not
achievable by this protocol, this is not cause for exclusion from the study, since
feasibility and accuracy studies have shown that diagnostic scans can be obtained in many
patients with higher heart rates with advanced scanners. Nitroglycerin, a coronary
vasodilator, will be administered to all subjects (0.8 mg sublingually) approximately 1
minute before initiation of the MSCT scan to optimize image quality. Subjects will be
queried regarding the recent use (within the previous 72 hours) of medications for erectile
dysfunction (Cialis, Levitra and Viagra) on the day of the MCST scan since these drugs can
interact with nitroglycerin to cause a potential life-threatening hypotensive effect. On the
day of the scheduled MSCT scan, subjects who admit to have taken Cialis within the past 72
hours or Levitra / Viagra within the past 48 hours will not be allowed to undergo coronary
MSCT angiography and will be rescheduled. Subjects will be instructed to withhold these
medications for at least 3 days before the scheduled scan.

All female subjects who are randomized to the MSCT arm will be required to wear a
radioprotective bismuth shield during the actual MSCT scan. This radioprotective brassiere
(Cone Instruments Inc, Solen, Ohio) composed of neoprene and bismuth trioxide has been
studied in 16 slice CT scans and has been shown to reduce breast radiation exposure by
approximately 40%.25 The bra will be placed directly over both breasts of the female
subjects by either a female nurse or technician in the Radiology Department. The adhesive
strips on the undersurface of these radioprotective bras will prevent any slippage during
the actual scan. Depending on the bust size of the subject, either a medium or large bra
will be employed for best fit. Each bra is intended for single patient use only and will be
discarded after each study. The effect of these bismuth shields on image interpretation is
unknown. If images of the coronary arteries are deemed to be unevaluable, women 40 years and
younger will be excluded from participation in the study. In this event, only women greater
than the age of 40 years will be enrolled and radioprotective shields will not be used.

Subject follow-up

After completion of initial testing (exercise treadmill test +/- MSCT angiography), subjects
will be returned to the referring physicians who will dictate further clinical management.
The results of the exercise treadmill testing and coronary MSCT angiography (if applicable)
will be provided to the referring physician. Additional selection of testing, consultation,
and choice of therapy is at the discretion of the referring physician. For subjects assigned
to the “no coronary MSCT angiography” arm, the referring provider will be instructed not to
make MSCT an available option for these subjects if further testing is deemed appropriate.
Otherwise, the protocol will not predetermine the clinical diagnostic or treatment course
for the subject. This approach should simulate actual clinical practice and the previous
standard of care (prior to availability of MSCT) and will allow assessment of downstream
clinical resource utilization in an unbiased fashion.

Subjects will be followed for a total of two years. During that time, the following factors
will be evaluated:

- Status of the presenting syndrome including final diagnosis

- Number of cardiac visits to an outpatient physician or emergency department (ED)
because of chest pain/anginal equivalent

- Cardiac hospitalizations for chest pain syndrome/angina equivalent

- Requirement for additional cardiac diagnostic testing, namely further stress testing
(nuclear, MRI, echocardiography) and/or cardiac catheterization

- Need for additional radiographic testing for incidental findings found on coronary MSCT

- Need for coronary revascularization procedures

- Unstable angina, myocardial infarction or cardiac death. Myocardial infarction is
defined as a cardiac event requiring admission to the hospital with the development of
cardiac enzyme level elevation. Unstable angina is defined by accelerating anginal
symptoms with or without ischemic electrocardiographic changes requiring hospital
admission and coronary revascularization. Death will be attributed to a cardiac origin
in the case of documented significant arrhythmia and/or cardiac arrest, congestive
heart failure, or myocardial infarction. Moreover, any unexplained death that occurs
suddenly out of the hospital will be ascribed a cardiac cause.

- Prescription of antilipid and antiplatelet therapy

These factors will be determined by electronic medical record review (CHCS-II) and
telephonic interview with the subjects every 6 months for a total of 2 years. Any visit to
an outpatient clinic or ED and any inpatient admission will be categorized as “cardiac” if
the presenting complaint is chest pain or identical to the original complaint which prompted
the initial exercise treadmill test referral.

Subjects will return to the clinic at 12 months to complete questionnaires to assess changes
in depression, anxiety and motivation for healthy behavioral change using the Beck
Depression Inventory(BDI), State and Trait Anxiety Inventory (STAI) and ladder scale
respectively. Subjects will also be surveyed about their current perception of chest pain as
cardiac or noncardiac and the utility of their index cardiovascular evaluation, to provide
insight into the etiology of their symptoms.

Endpoints Primary The primary outcome will be a composite endpoint consisting of adverse
cardiac events and cardiac resource utilization. Specifically, this will include the
occurrence of adverse cardiac events (cardiac death, myocardial infarction, unstable angina,
coronary revascularization), utilization of additional diagnostic testing for initial
complaint, and the occurrence of future clinical outpatient/inpatient/ED encounters for the
initial cardiac complaint.

Secondary

Secondary endpoints will include:

1. Occurrence of adverse cardiac events (cardiac death, myocardial infarction, unstable
angina, coronary revascularization)

. 2. Need for subsequent cardiac diagnostic testing for the initial complaint of
angina/angina equivalent 3. Occurrence of future clinical outpatient/inpatient/ED encounters
for the initial cardiac complaint 4. Avoidance of unnecessary cardiac catheterizations 5.
Change in motivation for healthy behavioral change, as assessed by the ladder motivational
scale 6. Change in subject anxiety, as assessed by the State and Trait Anxiety Inventory.

7. Change in subject depression, as assessed by the Beck Depression Inventory. 8.
Satisfaction with diagnostic evaluation for initial complaint

Predefined Analyses

In addition to the primary and secondary outcomes, there will be two predefined analyses
related to these outcomes.

1. Cost Efficiency Analysis, measured as total direct per-patient cost incurred for each
diagnostic strategy as related to the primary outcome. The direct per -patient cost in the
evaluation of outpatient angina will be calculated by adding the following components and
dividing by the number of patients tested:

1. cost of all initial tests of each diagnostic arm (exercise treadmill testing +/-
coronary MSCT angiography

2. cost of any additional cardiac diagnostic tests deemed necessary by the referring
provider after the completion of the initial diagnostic strategy arms for evaluation of
the initial complaint

3. cost of any subsequent inpatient/outpatient/ED evaluations for the initial cardiac
complaint over the following 24 months

4. cost of any subsequent radiographic testing needed for incidental findings found on
MSCT over the following 24 months The cost of the different diagnostic tests utilized
(coronary MSCT angiography, exercise treadmill testing, myocardial perfusion testing,
exercise echocardiography, coronary angiography, and other radiographic tests) and
clinical encounters (inpatient admissions, ED evaluations, outpatient evaluations) will
be estimated from current Medicare reimbursement rates.

2. Statin and aspirin use, measured as the change in the prevalence of statin and aspirin
use among subjects in each diagnostic arm.

Inclusion Criteria:

1. Chest pain or anginal equivalent symptoms possibly suggestive of symptomatic coronary
artery disease.

2. Low-intermediate risk (<75% pretest probability) for symptomatic coronary artery
disease on basis of age, sex, and quality of reported symptom as classified by the
Diamond and Forrester scheme6

3. Referred to Walter Reed Cardiology clinic for an exercise treadmill test as the
initial diagnostic test of choice

4. Age equal to or greater than 18 years and less than 70 years

5. Ability to provide informed consent

Exclusion Criteria:

1. Abnormal baseline electrographic changes that would preclude proper diagnosis of
ischemia including preexcitation (Wolff-Parkinson-White) syndrome, a paced
ventricular rhythm, more than 1 mm of ST depression at rest, complete left bundle
branch block, or criteria for left ventricular hypertrophy, even if they have less
than 1 mm of baseline ST depression

2. Presence of known pre-existing coronary artery disease (known prior myocardial
infarction, EKG evidence of prior infarction, prior angiographic evidence of
significant coronary artery disease, history of prior coronary revascularization).

3. Previous outpatient or inpatient evaluation for coronary artery disease to include
exercise treadmill testing, stress echocardiography or nuclear myocardial perfusion
studies within the last three years.

4. Presence of signs or symptoms that are clearly compatible with non-cardiac chest
pain, including musculoskeletal, gastrointestinal or neuropathic causes.

5. Renal insufficiency (creatinine >1.5mg/dl) or renal failure requiring dialysis.

6. Baseline heart rate > 100bpm, atrial fibrillation or other markedly irregular rhythm
(frequent ectopy, multifocal atrial tachycardia) on baseline ECG.

7. Pregnancy or unknown pregnancy status.

8. Known allergy to iodinated contrast.

9. Inability to tolerate beta-blocking drugs, including patients with reactive airways
disease requiring maintenance inhaled bronchodilators or steroids, complete heart
block or second-degree atrioventricular block.

10. Patients with hyperthyroidism including Grave’s disease and toxic multinodular goiter

11. Computed tomography imaging, or iodinated contrast administration over 50 ml, within
the past 48 hours.

12. Unwillingness to withhold ingestion of metformin or commonly used erectile
dysfunction medications (Viagra, Cialis, Levitra) for 48 hours prior to MSCT scan.

13. Previous history of radiation therapy to the thorax.