The Addition of Cardiac CT to Exercise Treadmill Testing in the Evaluation of Angina
The Addition of Cardiac CT to Exercise Treadmill Testing in the Evaluation of Angina
The current outpatient evaluation for angina in low and intermediate risk patients typically
 starts with a functional assessment for coronary ischemia. Exercise treadmill testing is
 often selected as the initial diagnostic modality for coronary artery function. However,
 exercise treadmill testing is limited by its moderate sensitivity and specificity, often
 resulting in further cardiac resource utilization for patient risk stratification and
 reassurance. With the advent of coronary multislice computed tomography (MSCT) angiography,
 coronary artery anatomy can now be evaluated noninvasively. Despite its impressive
 performance characteristics, the role of coronary MSCT angiography in the outpatient
 evaluation of angina remains undefined.

 CT-EXTRA compares the impact on patient safety and downstream resource utilization of a novel
 initial diagnostic strategy employing the addition of coronary MSCT angiography to exercise
 treadmill testing with a standard diagnostic strategy of exercise treadmill testing for the
 ambulatory evaluation of low-intermediate risk patients with possible angina. The study is a
 single center, prospective, non-blinded, randomized clinical trial. Men and women, age 18-70,
 with a low to intermediate pretest probability of coronary artery disease who are referred
 for an exercise treadmill test for angina are eligible. Subjects are randomized either to an
 initial diagnostic strategy of exercise treadmill testing or exercise treadmill testing with
 coronary MSCT angiography. Subsequent diagnostic testing and treatment are the discretion of
 the referring physician. Subjects will be clinically followed for 24 months.

 The clinical impact on patient safety and downstream clinical resource utilization of this
 novel diagnostic strategy in which both coronary artery anatomy and function are initially
 evaluated will be determined. The primary outcome is a composite endpoint consisting of
 freedom from adverse cardiac events, further cardiac diagnostic testing, and future cardiac
 clinical encounters. Secondary outcomes include the impact on the indiscriminate use of
 coronary angiography, subject anxiety, depression, motivation for healthy behavioral change,
 and satisfaction with diagnostic evaluation and use of antiplatelet and antilipid therapy.
 Lastly, the cost effectiveness of the routine addition of coronary MSCT angiography in the
 outpatient evaluation of possible angina will be determined.
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.