Detection of Ischemia

• Indication Overview
• Methods
• Search Results
• Summary Table
• References
• Appendix 1
• Appendix 2
• Appendix 3
• Appendix 4
• Appendix 5

Indication Overview

Ischemia results from the inadequate supply of blood to an organ or tissue caused by blockage of the blood vessels to the area. Within the heart, this blockage is most often due to coronary atherosclerosis-related stenosis (narrowings). Myocardial ischemia (lack of blood flow to the heart) is the most common cause of symptoms of coronary heart disease — also referred to as coronary artery disease (CAD).¹ Prolonged or significant ischemic conditions in the heart may result in a myocardial infarction (MI) — that is, a heart attack — or sudden death. MIs contribute to heart failure. Therefore, diagnosis of CAD prior to a heart attack or other event is important. Symptoms of myocardial ischemia may include chest pain, shortness of breath, nausea and vomiting, palpitations, and sweating. In some cases, myocardial ischemia is not associated with any symptoms (silent ischemia).

In addition to clinical symptoms and laboratory testing, cardiac imaging is often used in patients suspected to have CAD. Imaging can assist not only in detecting ischemia and diagnosing CAD, but also in stratifying patients according to their risk of having an ischemic event — low, intermediate, or high. Risk stratification can assist physicians in planning patient management. Imaging in patients with known CAD is also performed to assess the extent of damage to the myocardium, or heart tissue. Patients with viable myocardium may benefit from revascularization,² a treatment that involves restoring the flow of blood to damaged areas of the myocardium.

Population: Patients with suspected CAD (for diagnosis and immediate treatment) or patients with known CAD undergoing risk stratification and subsequent treatment planning.

Intervention: Stress single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) with technetium-99m (^99mTc)

During cardiac nuclear imaging, the relative amount of the radioisotope that collects in the cardiac muscle is reflective of the areas of reduced blood flow and therefore areas of ischemia.³ This information can be used to help inform disease management and to determine risk for short- or long-term future cardiac events.³ The basic principle of radionuclide MPI is to administer a tracer labelled with a radioisotope (often thallium-201 [²⁰¹TI] or technetium-99m [^99mTc] sestamibi or tetrafosmin) intravenously and image blood flow to the heart muscle (myocardial perfusion), both at rest and under stress conditions. Stress is induced by either exercise or a pharmaceutical agent (e.g., dobutamine, dipyridamole, or adenosine), which increases coronary blood flow to the myocardium.⁴ Viable myocardial cells take up the radionuclide tracer in proportion to blood flow.^4,5 Through sequential image acquisition, the gamma camera works with a computer to evaluate perfusion of the cardiac muscle.⁶

Comparators: For this report, the following diagnostic tests are considered as alternatives to MPI using ^99mTc:

• Computed tomography (CT) angiography (CTA): In a CT scan, a rotating X-ray device moves around the patient and takes detailed multiple images of organs and body parts⁷ and reconstructs them into a three-dimensional (3-D) image. This series of X-rays images are often referred to as "slices," and are taken from varying angles in order to reconstruct a 3-D image of the heart's anatomy. A contrast agent is administered intravenously before images are taken, to better visualize the body part being examined;⁷ a sedative may also be administered if the patient is uncomfortable.⁸
• Stress echocardiogram (Echo, ECG; also called stress test): During stress Echo, adhesive electrodes are placed onto the bare chest of the patient and a sonographer takes several ultrasound (U/S) images of the heart while the patient is at rest. Blood pressure and Echo recordings are also measured at rest. The exercise-induced phase involves the patient engaging in physical activity (e.g., walking or running on the treadmill, pedalling a stationary bike) and the recording of blood pressure. In some cases when exercise is not an option for the patient, a pharmacological stressor may be used to simulate the stress of exercise. Following the stress phase, the patient is instructed to lie down again, and U/S images of the heart are taken a second time, as are blood pressure and Echo measurements.⁹
• Stress MPI using ²⁰¹Tl: The procedure for ²⁰¹Tl-SPECT is the same as ^99mTc-SPECT, except the isotope ²⁰¹Tl is used in place of ^99mTc.
• Stress magnetic resonance imaging (MRI): A cardiac MRI uses magnets and a computer to reproduce images of the organs and tissues while the heart is beating.¹⁰ As with other cardiac imaging approaches, patients are assessed under rest and stress conditions. During an MRI examination, a patient is required to lie down on a table that glides into the scanner's cavity. The patient is required to lie still for the duration of the examination, which ranges from 15 minutes to over an hour.¹¹
• Stress positron emission tomography (PET): PET perfusion studies use radiopharmaceuticals (Rubidium-82 chloride, ¹⁵O-labelled water, and ¹³N-labelled ammonia [¹³NH₃]) to visualize how well blood flows to the heart. The radiopharmaceutical is administered intravenously while the patient lies under the camera. Images are then taken for 10 to 20 minutes. To induce stress-related symptoms, a drug (e.g., dobutamine, dipyridamole, or adenosine) is administered. The patient lies still again for 10 to 20 minutes while additional images are taken. A second drug (aminophylline) is given at the end of the test to reverse the effects of the pharmacological stressor. The total duration of the test is approximately one hour.¹²

It is recognized that treadmill alone may be sufficient to diagnose ischemia, in some cases. For the purpose of this report, however, we have assumed that the need for imaging has been pre-determined. Treadmill testing, therefore, is not included as a comparator in this report.

Outcomes: Eleven outcomes (referred to as criteria) are considered in this report:

• Criterion 1: Size of the affected population
• Criterion 2 : Timeliness and urgency of test results in planning patient management
• Criterion 3: Impact of not performing a diagnostic imaging test on mortality related to the underlying condition
• Criterion 4: Impact of not performing a diagnostic imaging test on morbidity or quality of life related to the underlying condition
• Criterion 5: Relative impact on health disparities
• Criterion 6: Relative acceptability of the test to patients
• Criterion 7: Relative diagnostic accuracy of the test
• Criterion 8: Relative risks associated with the test
• Criterion 9: Relative availability of personnel with expertise and experience required for the test
• Criterion 10: Accessibility of alternative tests (equipment and wait times)
• Criterion 11: Relative cost of the test.

Definitions of the criteria are in Appendix 1.

Methods

The literature search was performed by an information specialist using a peer-reviewed search strategy.

Published literature was identified by searching the following bibliographic databases: MEDLINE with In-Process records & daily updates via Ovid; The Cochrane Library (2011, Issue 3) via Wiley; and PubMed. The search strategy consisted of both controlled vocabulary, such as the National Library of Medicine's MeSH (Medical Subject Headings), and keywords. The main search concepts were radionuclide imaging and myocardial ischemia.

Methodological filters were applied to limit retrieval to health technology assessments (HTA), systematic reviews (SR), meta-analyses (MA), and diagnostic accuracy studies (primary studies of randomized and non-randomized design). Where possible, retrieval was limited to the human population. The search was also limited to the English language. No date limits were applied for the systematic review search. The primary studies search was limited to the human population and to documents published between January 1, 2006 and March 29, 2011. Regular alerts were established to update the search until October 2011. Detailed search strategies are located in Appendix 2.

Grey literature (literature that is not commercially published) was identified by searching relevant sections of the CADTH Grey Matters checklist. Google was used to search for additional web-based materials. The searches were supplemented by reviewing the bibliographies of key papers. See Appendix 2 for more information on the grey literature search strategy.

Targeted searches were done as required for the criteria, using the aforementioned databases and Internet search engines. When no literature was identified that addressed specific criteria, experts were consulted.

Search Results

The literature search identified 131 health technology assessments/systematic reviews/meta-analyses and 1,107 primary studies. Forty-one of the 131 health technology assessments/systematic reviews/meta-analyses (HTA/SR/MA) articles identified underwent full-text screening. These included a series of seven reports published in 2010 from the Ontario Ministry of Health and Long-Term Care Medical Advisory Secretariat (MAS)^13-19 to assist the Ministry in providing an evidentiary platform for the effectiveness and cost-effectiveness of non-invasive cardiac imaging technologies. These reports were reviewed and summarized, as each consisted of a meta-analysis of research from over the past six to seven years (2004 to 2009).

One-hundred and thirty-eight of the 1,107 primary studies identified in the search underwent full-text screening. A total of 17 studies related to the criterion of diagnostic accuracy were included in the final report.^20-36 For the detection of ischemia, primary studies were excluded if they were published before the search date for the MAS reports (i.e., eligible for inclusion in the MAS report), with the exception of: primary studies comparing ^99mTc-based imaging to PET imaging, as this was not an eligible comparison in the MAS reports; if sensitivity and specificity outcomes were not reported; if the purpose of the study was to evaluate the accuracy of SPECT using ^99mTc alone and in combination with another imaging modality (e.g., ^99mTc-SPECT versus ^99mTc-SPECT/CT), if both ^99mTc-SPECT and ²⁰¹TI-SPECT were used in a study and separate analyses for the isotopes were not provided; or, if the primary study was already evaluated in one of the five MAS reports. For the evaluation of myocardial viability, inclusion was limited to studies in which ^99mTc-based imaging was compared directly with another cardiac imaging modality. Studies that were included in the MAS reports on myocardial viability on MRI and PET were not assessed separately in the current report.

Summary table

Table 1: Summary of Criterion Evidence

Domain 1: Criteria Related to the Underlying Health Condition
Criterion		Synthesized Information
1	Size of the affected population	No precise estimates were found as to the size of the patient population which may potentially undergo cardiac imaging for the diagnosis of ischemia. According to the CIHI Hospital Morbidity Database, in 2005/06, there were 160,323 hospitalizations with ischemic heart disease, corresponding to a crude rate hospitalization rate of 494.5 per 100,000 population (age-standardized rate = approximately 400 hospitalizations per 100,000 Canadians).37 The 2007 CCHS found that 4.8% of the Canadian population aged 12 years and older reported having heart disease (including heart attack, angina, and congestive heart failure) diagnosed by a health professional.37 Based on the limited evidence available, the size of the affected population is more than 1 in 1,000 (0.1%) and less than 1 in 100 (1%).
2	Timeliness and urgency of test results in planning patient management	The Wait Time Alliance has published benchmarks for cardiac nuclear imaging — immediate to 24 hours for emergent cases, within three days for urgent cases, and within 14 days for scheduled cases.38 According to urgency classifications developed by the Saskatchewan Ministry of Health, MPI for detection of CAD in cases of acute chest pain without ST-elevation and negative enzymes should be conducted within two to seven days of the request for imaging (Patrick Au, Acute & Emergency Services Branch, Saskatchewan Ministry of Health: unpublished data, 2011). MPI for other indications should be conducted within eight to 30 days of the request for imaging (Patrick Au, Acute & Emergency Services Branch, Saskatchewan Ministry of Health: unpublished data, 2011). Imaging results have a moderate impact on patient management.
3	Impact of not performing a diagnostic imaging test on mortality related to the underlying condition	Limited information was available to directly inform this criterion. Not performing a diagnostic imaging test to diagnose a suspected case of CAD in a person deemed to be at high risk of an ischemic event could result in the patient not receiving the appropriate treatment in a timely manner. However, the impact on not performing a diagnostic imaging test on a low-risk individual would likely be low. On average, diagnostic imaging results can have a moderate impact on mortality
4	Impact of not performing a diagnostic imaging test on morbidity or quality of life related to the underlying condition	Overall, limited information was available to directly inform this criterion. The impact of not performing a diagnostic imaging test to diagnose a suspected case of CAD in a person deemed to be at high risk of an ischemic event would likely be significant. However, the impact on not performing a diagnostic imaging test on low-risk individuals would likely be low. Patients with known CAD who did not receive a diagnostic imaging test to assist in risk stratification for treatment planning purposes might not receive the appropriate treatment in a timely manner. If a diagnostic imaging test to assess myocardial viability is not performed, patients with viable myocardium would not benefit from revascularization procedures. If the revascularization procedure was performed without diagnostic imaging information (i.e., with the assumption there was viable myocardium), some patients who did not have viable myocardial tissue would undergo the invasive procedure unnecessarily. It is assumed that diagnostic imaging test results can have a moderate impact on morbidity or quality of life.

 

Domain 2: Criteria Comparing 99mTc with an Alternative or Comparing Between Clinical Uses
Criterion		Synthesized Information
5	Relative impact on health disparities	To be scored locally.
6	Relative acceptability of the test to patients	A 2004 British study compared patient satisfaction and preference toward SPECT versus MRI adenosine stress myocardial perfusion scans and found little difference.39 The only statistically significant finding was that the SPECT scan was preferred in terms of space on the scanner.39 Three participants (9%) stated that they would not have an MRI again, while two patients (6%) said they would not repeat a SPECT.39 The study authors recognized that the relatively small sample size may have affected their ability to demonstrate a statistically significant preference for one scan over the other.39 Exercise or pharmacological agents used to induce stress conditions may be unpleasant for some patients. Patients undergoing a CT scan may have concerns about radiation exposure and may also feel claustrophobic while in the scanner. Patients may also need to take heart rate–lowering medication in order to undergo the test. Stress Echo may preferred by some patients, as there is no radiation exposure with it. Exercise or pharmacological agents used to induce stress conditions may be unpleasant for some patients. Because of the closed space of an MRI, patients may experience feelings of claustrophobia, as well as being bothered by the noise. It has been reported that up to 30% of patients experience apprehension and 5% to 10% endure some severe psychological distress, panic, or claustrophobia.40,41 Some patients may have difficulty remaining still during the scan. Patients are not exposed to radiation during an MRI scan, which may be more acceptable to some. Exercise or pharmacological agents used to induce stress conditions may be unpleasant for some patients. With PET, patients may have concerns about radiation exposure and the intravenous injection of a radiopharmaceutical agent. Exercise or pharmacological agents used to induce stress conditions may be unpleasant for some patients. The stress PET exam is shorter than the SPECT exam. SPECT stress MPI with 99mTc-labelled radiotracers: is minimally less acceptable than CTCA is minimally less acceptable than stress Echo has similar acceptability as stress MRI is minimally less acceptable than stress PET has similar acceptability as stress 201TI-SPECT.
7	Relative diagnostic accuracy of the test	The MAS of the Ontario MOHLTC conducted an evidence-based review of the literature surrounding cardiac imaging modalities.13-1999mTc-SPECT, 201Tl-SPECT, stress Echo, contrast Echo, CTA, and stress MRI were compared relative to CA, on the basis of their ability to diagnose CAD.13-17 Diagnostic Accuracy: Diagnosis of CAD Test No. of Trials (Patients) Pooled Sensitivity (%) Pooled Specificity (%) 99mTc -SPECT17 39 (3,488) 88 70 201Tl-SPECT17 24 (3,338) 84 71 Stress Echo14 127* (13,035) 80 84 Contrast Echo13 11 (patients with suspected CAD) 87.3 86.0 12 (patients with known or suspected CAD) (6 MPA and 6 WMA) MPA: 87.8 MPA: 64.9 WMA: 69.2 WMA: 79.4 64-slice CTA14 8 trials 97.7 78.8 OMCAS trial (117 patients) 81.2 95.8 8 studies + OMCAS trial 96.1 81.5 Stress MRI15 One MA + 11 studies MPA: 91 MPA: 81 WMA: 83 WMA: 86 CA = coronary angiography; CAD = coronary artery disease; CTA = computed tomography angiography; Echo = echocardiogram; MA = myocardial angiography; MPA = myocardial perfusion angiography; MRI = magnetic resonance imaging; OMCAS = Ontario Multidetector Coronary Angiography Study; 99mTc = Technitium-99m; 201Tl =Thallium-201; SPECT = single-photon emission computed tomography; WMA = wall motion analysis. * A study was counted twice if data were reported on different stress agents. Our search for studies published after August 2009 identified five studies on the relative diagnostic accuracy of 99mTc-SPECT, for diagnosis of ischemia.20-22,27,28 In addition, four studies23-26 reported the diagnostic accuracy of one or more comparators in the diagnosis of ischemia, using 99mTc–SPECT as the gold standard. Primary Studies: Diagnostic Accuracy: Diagnosis of CAD Author, Date n Gold Standard Intervention Sens (%) Spec (%) PPV (%) NPV (%) 99mTc-SPECT/CTA versus CA Kong et al., 201120 104 ICA 99mTc sestamibi SPECT/CTA 3-D fusion 100 80.8 94 100 Weustink et al., 201121 61 ICA 99mTc sestamibi SPECT/CTCA 89 77 91 72 CTCA 98 82 93 93 Lu et al., 201022 76 ICA 99mTc sestamibi SPECT 90 53 57 89 Dipyridamole Echo 61 91 83 77 Dobutamine Echo 87 82 77 90 CTCA versus 99mTc-SPECT Cheng et al., 201023 55 99mTc tetrofosmin SPECT Dual source CTCA 59 89 NR NR Bauer et al., 200924 72 99mTc tetrofosmin SPECT 64-MDCT (> 50% stenosis) 46 83 58 75 Ruzsics et al., 200925 36 99mTc tetrofosmin SPECT Dual source CTCA 97 67 93 80 Stress Echo versus 99mTc-SPECT Abdelmoneim et al., 201026 88 99mTc sestamibi SPECT Adenosine stress Echo 88 85 NR NR 99m Tc-SPECT versus PET Husmann et al., 200827 80 (SPECT) 70 (PET) ICA 201TICI SPECT or 99mTc-MIBI SPECT 85 NR NR NR Attenuation- corrected 13NH3 PET 96 NR NR NR Bateman et al., 200628 112 Clinical coronary angiogram reports 99mTc sestamibi SPECT 82 73 NR NR 82Rb-PET 87 93 NR NR CA = coronary angiography; CAD = coronary artery disease; CTA = computed tomography angiography; CTCA = computed tomography coronary angiography; Echo = echocardiography; ICA = invasive coronary angiography; MDCT= multidetector computed tomography; n = number of patients; 13NH3 = 13N-labelled ammonia; PET = positron emission tomography; 82Rb = rubidium-82; SPECT = single-photon emission computed tomography; 99mTc = Technitium-99m; 201Tl =Thallium-201; 201TICI = thallium-201 chloride; 99mTc-MIBI = 99mTc-sestamibi (technetium-99m-hexakismethoxy-isobutyl-isonitril). Based on the available evidence, the diagnostic accuracy of 99mTc-SPECT MPI is: minimally higher than stress CTCA similar to stress Echo minimally lower than stress MRI minimally lower than stress PET minimally higher than 201TI-SPECT stress imaging.
8	Relative risks associated with the test	Non–radiation-related risks The main risks of non-invasive preoperative assessment relate to the stress component of the tests. With exercise stress testing, there is a small risk of the patients sustaining an MI if they have significant coronary artery disease.42 With dipyridamole stress testing, there are multiple potential side effects, including headache, exacerbated asthma, and heart attack (risk of this event is low).42 With adenosine stress testing, side effects similar to dipyridamole may be experienced. Symptoms of chest pain or pressure may also occur, but these side effects quickly disappear once the adenosine administration stops.42 With dobutamine stress testing, some patients may experience light-headedness and nausea. There is a theoretical risk of inducing a fast and abnormal cardiac rhythm (i.e., atrial fibrillation, ventricular tachycardia, ventricular fibrillation); however, this is unlikely with the doses of dobutamine used. The overall risk of sustaining a heart attack from a stress test is estimated to be about 2 to 4 in 10,000.42 Apart from risks associated with stress testing, the radiopharmaceuticals used in SPECT imaging may cause reactions in some patients. These reactions are rare and include skin and anaphylactic reactions.43 With CTCA, some patients may experience mild, moderate, or severe side effects from the contrast. The frequency of severe, life-threatening reactions with gadolinium are extremely rare (0.001% to 0.01%) and the frequency of moderate reactions range are also rare (0.004% to 0.7%).44 Apart from risks associated with stress testing, there is a low risk of adverse events associated with the contrast used in stress Echo imaging. Apart from risks associated with stress testing, some patients may experience a reaction to the contrast agent Gd used in MRI. Reactions may include headaches, nausea, and metallic taste. The frequency of severe, life-threatening reactions with Gd are extremely rare (0.001% to 0.01%) and the frequency of moderate reactions range are also rare (0.004% to 0.7%)44 Apart from risks associated with stress testing, the Pharmacopeia Committee of the Society of Nuclear Medicine conducted a four-year prospective evaluation of adverse reactions to PET and reported no adverse reactions among the 33,925 scans conducted in 22 participating PET centres in the United States.45 The risks associated with stress testing would apply for cardiac imaging using PET. Radiation-related Risks Among the modalities to diagnose ischemia, SPECT MPI, CTCA, and stress PET expose the patient to ionizing radiation. The average effective dose of radiation delivered with each of these procedures can be found in the subsequent table. Effective Doses of Radiation Procedure Average Effective Dose (mSv) 99mTc-SPECT MPI 7 to 12.846 201Tl-SPECT MPI 17 to 4146,47 Cardiac 18FDG-PET 7(MIIMAC expert opinion) to 14 47 Cardiac 82Rb-PET 1.1 to 5.047-49 Cardiac 13NH3-PET 1.5 to 2.249 CTCA 2.1 to 1650,51 MRI 0 Echo 0 Average background dose of radiation per year 1-3.052-54 CTCA = computed tomography coronary angiography; CMPI = myocardial perfusion imaging; Echo = echocardiogram; 18FDG =18F-fluorodeoxyglucose; MIIMAC = Medical Isotopes and Imaging Modalities Advisory Committee; MRI = magnetic resonance imaging; mSv = millisievert; 13NH3 = 13N-labelled ammonia; PET = positron emission tomography; 82Rb = rubidium-82; SPECT = single-photon emission computed tomography; 99mTc = Technitium-99m. Overall, 99mTc-SPECT MPI: and CTCA have similar safety profiles and stress Echo have similar safety profiles and stress MRI have similar safety profiles and stress PET have similar safety profiles and 201TI-SPECT have similar safety profiles.
9	Relative availability of personnel with expertise and experience required for the test	In Canada, physicians involved in the performance, supervision, and interpretation of diagnostic nuclear imaging, CT scans, MRI, and U/S should be diagnostic radiologists or nuclear medical physicians. According to the CMA, there are 1,149 practicing cardiologists in Canada (CMA, 2011). Not all radiologists, nuclear medical physicians, nuclear cardiologists, or cardiologists have the expertise to conduct 99mTc-SPECT and all of its alternatives. For example, a 2002 report by the CCS reported that 43% of cardiologists do Echo. Assuming the necessary equipment is available, if 99mTc-SPECT imaging is not available, it is estimated that: 25% to 74% of the procedures can be performed in a timely manner using CTCA 25% to 74% of the procedures can be performed in a timely manner using Echo fewer than 25% of the procedures can be performed in a timely manner using MRI 25% to 74% of the procedures can be performed in a timely manner using PET more than 95% of the procedures can be performed in a timely manner using 201TI-SPECT.
10	Accessibility of alternative tests (equipment and wait times)	For SPECT MPI, nuclear medicine facilities with gamma cameras (including SPECT) are required. As of 2007, no nuclear medicine cameras are available in the Yukon, Northwest Territories, or Nunavut.55 No CT scanners are available in Nunavut.56 For CT scanners, the average weekly use ranged from 40 hours in PEI to 69 hours in Ontario, with a national average of 60 hours.55 In 2010, the average wait time for a CT scan in Canada is 4.2 weeks.57 The average wait time for a CTCA was not reported. Of note, not all CT scanners are capable of performing cardiac CT. No MRI scanners are available in the Yukon, Northwest Territories, or Nunavut.56 According to CIHI's National Survey of Selected Medical Imaging Equipment database, the average number of hours of operation per week for MRI scanners in 2006–2007 ranged from 40 hours in PEI to 99 hours in Ontario, with a national average of 71 hours.55 In 2010, the average wait time for MR imaging in Canada was 9.8 weeks.57 A 2010 Environmental Scan published by CADTH reported that there are approximately 31 Canadian centres equipped to perform PET scans.58 These centres are located in the provinces of British Columbia, Alberta, Manitoba, Ontario, Quebec, New Brunswick, and Nova Scotia.58 There are a total of 36 PET or PET/CT scanners in Canada, four of which are used for research purposes only.58 U/S machines are widely available across the country. According to the Fraser Institute, the average wait time for U/S in 2010 was 4.5 weeks.57 Assuming the necessary personnel is available, if 99mTc-SPECT imaging is not available, it is estimated that: 25% to 74% of the procedures can be performed in a timely manner using CTCA 75% to 94% of the procedures can be performed in a timely manner using Echo fewer than 25% of the procedures can be performed in a timely manner using MRI fewer than 25% of the procedures can be performed in a timely manner using PET more than 95% of the procedures can be performed in a timely manner using 201TI-SPECT.
11	Relative cost of the test	According to our estimates, the cost of MPI with 99mTc-based radioisotopes is $964.53. The cost of MPI with 201TI or with PET is assumed to be greater than imaging with 99mTc-based radioisotopes. Stress MRI is minimally less costly than MPI with 99mTc. CTCA and stress Echo are moderately less costly. Relative Costs Test Total Costs ($) Cost of Test Relative to 99mTc-based Test ($) 99mTc-SPECT MPI 964.53 Reference 201TI-SPECT MPI 964.53 +0.00 CTCA 506.03 -458.50 Stress Echo 466.90 -497.63 Stress MRI 835.16 -129.37 Stress PET 1128.60 +164.07

CA = coronary angiography; CAD = coronary artery disease; CCHS = Canadian Community Health Survey; CCS = Canadian Cardiovascular Society; CIHI = Canadian Institute for Health Information; CMA = Canadian Medical Association; CT = computed tomography; CTA = computed tomography angiography; CTCA = computed tomography coronary angiography; Echo = echocardiography ECG = electrocardiogram; ¹⁸FDG-PET = ¹⁸fluorodeoxyglucose-positron emission tomography; ICA = invasive coronary angiography; MAS = Medical Advisory Secretariat; MDCT = multidetector computed tomography; MI = myocardial infarction; MIIMAC = Medical Isotopes and Imaging Modalities Advisory Committee; MOHLTC = Ministry of Health and Long-Term Care; MPA = myocardial perfusion analyses; MPI = myocardial perfusion imaging; MRI = magnetic resonance imaging; mSv = millisievert; NA= not available; ¹³NH₃ = 13N-labelled ammonia; OMCAS = Ontario Multidetector Coronary Angiography; PHAC = Public Health Agency of Canada; PEI = Prince Edward Island; PET = positron emission tomography; ⁸²Rb = rubidium-82; SPECT = single-photon emission computed tomography; ^99mTc = Technitium-99m; ^99mTc-MIBI = ^99mTc-sestamibi (^99mTc-MIBI = ^99mTc-sestamibi (technetium-99m-hexakismethoxy-isobutyl-isonitril); ²⁰¹Tl =Thallium-201; U/S = ultrasound; WMA = wall motion analyses.

Criterion 1: Size of affected population (link to definition)

No precise estimates were found as to the size of the patient population which may potentially undergo cardiac imaging for the diagnosis of ischemia or the evaluation of myocardial viability.

According to the Canadian Institute for Health Information (CIHI) Hospital Morbidity Database, in 2005–2006, there were 160,323 hospitalizations, with ischemic heart disease as the condition most responsible for them; this corresponds to a crude rate hospitalization rate of 494.5 per 100,000 population (age-standardized rate = approximately 400 hospitalizations per 100,000 Canadians).³⁷ The size of the patient population which may undergo diagnostic imaging for the diagnosis of ischemia or the evaluation of myocardial viability would likely be greater than this. Although a single patient may be hospitalized more than once in a single year (leading to overestimation), a proportion of patients with ischemia will not require hospitalization, and a further proportion of patients undergoing diagnostic imaging for the diagnosis of ischemia or the evaluation of myocardial viability will never be diagnosed with ischemia (leading to underestimation).

The Canadian Community Health Survey (CCHS) is a cross-sectional survey targeting Canadians aged 12 years and older. The 2007 CCHS found that 4.8% of the Canadian population aged 12 years and older reported having heart disease (including heart attack, angina, and congestive heart failure) diagnosed by a health professional.³⁷ This may be a reasonable approximation to the size of the patient population which may undergo diagnostic imaging for the diagnosis of ischemia or the evaluation of myocardial viability. Although the data are self-reported and include only those patients diagnosed by a health professional (leading to underestimation), they report on broadly-defined heart disease, including heart attack, angina, and congestive heart failure (leading to overestimation).

Return to Summary Table.

Criterion 2: Timeliness and urgency of test results in planning patient management (link to definition)

According to the Wait Time Alliance, the benchmark for cardiac nuclear imaging is: immediate to 24 hours for emergent cases, within three days for urgent cases, and within 14 days for scheduled cases.³⁸

According to urgency classifications developed by the Saskatchewan Ministry of Health, MPI for the detection of CAD in cases of acute chest pain without ST-elevation and negative enzymes should be conducted within two to seven days of the request for imaging. (Patrick Au, Acute and Emergency Services Branch, Saskatchewan Ministry of Health: unpublished data, 2011)

MPI should be conducted within eight to 30 days of the request for imaging for the following indications:

• detection of CAD (symptomatic) evaluation of ischemic equivalent (non-acute)
• detection of CAD/risk assessment without ischemic equivalent (asymptomatic)
• risk assessment with prior test results and/or known chronic stable CAD
• risk assessment within three months of acute coronary syndrome
• risk assessment post-revascularization (percutaneous coronary intervention [PCI] or coronary artery bypass grafting [CABG])
• and assessment of viability/ischemia in ischemic cardiomyopathy with known severe left ventrical dysfunction.

(Patrick Au, Acute and Emergency Services Branch, Saskatchewan Ministry of Health: unpublished data, 2011.)

Return to Summary Table

Criterion 3: Impact of not performing a diagnostic imaging test on mortality related to the underlying condition (link to definition)

A report published by the Public Health Agency of Canada states that ischemic heart disease was responsible for 39,311 deaths (17.3% of all deaths) in 2004.³⁷ The rate of death is higher in men than in women and increases with age.

The Myoview Prognosis Registry provides data on 7,849 outpatients (from five tertiary medical centres in the United States) evaluated by stress MPI for suspected, or known, CAD.⁵⁹ A 2008 publication, based on data from this registry, investigated the relationship between cardiovascular outcomes and the extent and severity of ischemia, as well as perfusion defects on the resting MPI.⁵⁹ In two years of follow-up, 274 deaths were reported (3.5% of the study population) including 29 fatal MIs, 72 sudden cardiac deaths, 14 heart failures, and 16 fatal cerebrovascular accidents.⁵⁹ Although the study population was stratified by per cent ischemic myocardium (73% of the study cohort had 0% ischemic myocardium, 11% had 1% to 4.9% ischemic myocardium, 9% had 5% to 9.9% ischemic myocardium, and 7% had > 10% ischemic myocardium), the mortality rates for these subgroups were not reported.⁵⁹ It was noted that rest and ischemic defects on MPI were highly significant (P < 0.0001) estimators of the combined end point of CAD-related events (including fatal MI, non-fatal MI, and sickle-cell disease) according to univariate Cox models.⁵⁹ An earlier publication, based on this registry, reported that the annualized cardiac death rate among patients with a normal perfusion scan is less than one per cent.⁶⁰

A 2003 publication by Hachamovitch et al.⁶¹ compared the survival benefit associated with revascularization versus medical therapy. The final study population included 10,627 patients who underwent exercise or adenosine stress myocardial perfusion scintigraphy between 1991 and March 1997.⁶¹ The majority (n = 9,956) were prescribed medical therapy, while 671 patients underwent early revascularization.⁶¹ Patients were followed for an average of 1.9 years with cardiac death as the sole end point.⁶¹ The rate of cardiac death among revascularized patients was 2.8% versus 1.3% among the medical therapy group; however, the baseline characteristics of the two groups were found to differ significantly.⁶¹ Propensity scores were calculated, using logistic regression, in order to adjust for the lack of randomization.⁶¹ A Cox proportional hazards model was used to predict mortality rates in patients treated with revascularization versus medical therapy.⁶¹ The model predicted that patient mortality rates among those treated medically would increase significantly as a function of per cent myocardium ischemic, but that increased per cent myocardium ischemic would not be associated with an increase in mortality among revascularized patients (Table 2). This study highlights the importance of detecting and quantifying ischemia.

Table 2: Predicted Mortality Rates in Non-diabetic Patients Treated with Revascularization Versus Medical Therapy Based on Cox Proportional Hazards Model⁶¹

	% Myocardium Ischemic
	Small (5% to 10%)	Moderate (10% to 20%)	Large (> 20%)
Males
Medical therapy (%)	2.5	3.4	5.1
Revascularization (%)	2.3	1.8	1.9
Lives saved per 100 patients revascularized	0.2	1.6	3.2
Females
Medical therapy (%)	2.7	4.9	10.0
Revascularization (%)	3.9	3.7	2.5
Lives saved per 100 patients revascularized	-1.2	1.2	7.5

Overall, limited information was available to directly inform this criterion. Patients with intermediate pre-test likelihood of disease are most likely to benefit from a diagnostic and prognostic perspective, but high pre-test likelihood patients will also benefit from a prognostic perspective (Medical Isotopes and Imaging Modalities Advisory Committee [MIIMAC] expert opinion).

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Criterion 4: Impact of not performing a diagnostic imaging test on morbidity or quality of life related to the underlying condition (link to definition)

As part of a 2007 rapid systematic review and pragmatic randomized controlled trial conducted for the National Institute for Health Research in the United Kingdom on the management of CAD, Sharples et al.⁶² measured the health-related quality of life of patients at a tertiary cardiothoracic referral centre in the United Kingdom with known or suspected CAD requiring non-urgent angiography.⁶² The aim of the study was to determine the most cost-effective approach of the following four modalities to diagnose CAD: angiography, SPECT, MRI, and Echo. A total of 898 patients were assessed using various instruments for measuring health status. Using one of the tools — the 36-item Short Form Health Survey or SF-36 (a generic instrument containing eight domains: physical function, role-physical [limitations due to physical function], bodily pain, general health, vitality, social function, role-emotional [limitations due to emotional function], mental health — and two summary scores (physical component score and mental component score), the mean physical component scores at baseline for patients in this cohort randomized to the four modalities was statistically significantly lower than the mean for the general population (P < 0.001). An improvement in these scores was noted following treatment (coronary artery bypass grafting [CABG], percutaneous coronary intervention [PCI], or medical).⁶²

Overall, limited information was available to directly inform this criterion. The impact of not performing a diagnostic imaging test to diagnose a suspected case of CAD in a person deemed to be at high risk of an ischemic event because of a combination of clinical symptoms (including type of chest pain), clinical risk factors, and results from non-nuclear cardiac imaging tests such as an exercise stress test) would likely be significant. However, the impact on not performing a diagnostic imaging test on low-risk individuals would likely be low.

Patients with known CAD who did not receive a diagnostic imaging test to assist in risk stratification for treatment planning purposes, might not receive the appropriate treatment in a timely manner.

If a diagnostic imaging test to assess myocardial viability is not performed, patients with viable myocardium would not benefit from revascularization procedures. If the revascularization procedure was performed without diagnostic imaging information (i.e., with the assumption that there was viable myocardium), some patients who did not have viable myocardial tissue would undergo the invasive procedure unnecessarily.

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Criterion 5: Relative impact on health disparities (link to definition)

Female gender
In a 1994 study, Shaw et al⁶³ recruited patients referred for exercise stress testing or intravenous dipyridamole ²⁰¹TI myocardial imaging with clinically suspected CAD and compared male (449) and female (n = 391) patient outcomes in the two years (24 ± 7 months) following the test.⁶³ While the percentages of patients with initially abnormal exercise Echo results and MPI study results were similar between the two genders, additional diagnostic testing was done in only 38.0% of women, compared with 62.3 % of men (P = 0.002).⁶³ The lack of follow-up testing in women was associated with worsening rates of cardiac death or MI.⁶³ One study comparing 100 females with disabilities to 50 females without disabilities reported that baseline risk assessments including discussions of family medical history were less likely to be performed in women with disabilities than in their non-disabled counterparts.⁶⁴

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Criterion 6: Relative acceptability of the test to patients (link to definition)

SPECT
A 2004 British study compared patient satisfaction and preference toward SPECT with MRI adenosine stress myocardial perfusion scans and found little difference.³⁹ Forty-one patients who had undergone both SPECT and MRI were sent a retrospective questionnaire within two weeks of scan completion. Thirty-five completed questionnaires were returned. When asked "If the two tests (nuclear heart scan and MRI) could provide the same information, which of the two would you prefer?" 12 patients (34%) stated a preference for MRI, nine (26%) stated a preference for SPECT, and 14 (40%) stated no preference.³⁹ Patients rated the two tests similarly on overall preference, duration, comfort, and safety, with a non-significant preference for MRI on all of the afoementioned.³⁹ The only statistically significant finding was that the SPECT scan was preferred in terms of space on the scanner.³⁹ Three participants (9%) stated that they would not have an MRI again, while two patients (6%) said they would not repeat a SPECT.³⁹ The study authors recognized that the relatively small sample size may have affected their ability to demonstrate a statistically significant preference for one scan over the other.³⁹ Exercise or pharmacological agents used to induce stress conditions may be unpleasant for some patients.

Computed Tomography Coronary Angiography (CTCA)
Patients undergoing a CT scan may have concerns about radiation exposure and may also feel claustrophobic while in the scanner. This is less of a problem with new CT scanners (MIIMAC expert opinion).

Stress Echo
This test is likely to be well tolerated by patients. Echo may be preferred by some patients since there is no radiation exposure. Exercise or pharmacological agents used to induce stress conditions may be unpleasant for some patients.

Stress MRI
Because of the closed space of an MRI, patients may experience feelings of claustrophobia, as well as being bothered by the noise. This may be less of a problem with new MRI machines, if available (MIIMAC expert opinion). It has been reported that up to 30% of patients experience apprehension and 5% to 10% endure some severe psychological distress, panic, or claustrophobia.^40,41 Some patients may have difficulty remaining still during the scan. Patients are not exposed to radiation during an MRI scan, which may be more acceptable to some. Exercise or pharmacological agents used to induce stress conditions may be unpleasant for some patients.

Stress PET MPI (Rubidium-82 [⁸²Rb] or 13N-labelled ammonia [¹³NH₃ ])
Patients may have concerns about radiation exposure and the intravenous injection of a radiopharmaceutical agent. Exercise or pharmacological agents used to induce stress conditions may be unpleasant for some patients.

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Criterion 7: Relative diagnostic accuracy of the test (link to definition)

The literature search for health technology assessments (HTA)/systematic reviews/meta-analyses identified 131 studies, five of which are included in the current report.^15-19 These HTAs evaluated the use of non-invasive cardiac imaging technologies including stress Echo (with and without contrast agent),^13,14 MRI,¹⁵ CT,¹⁶ and SPECT¹⁷ for the diagnosis of CAD.

The literature search for primary studies identified 1,107 titles. When limited by date (so that only those studies published following the end of the search period of the corresponding HTA were included), 138 underwent full-text screening, and nine non-randomized studies were included in the final report.^20-28 No randomized controlled trials that met inclusion criteria were identified.

A summary of two position statements not meeting inclusion criteria — one a joint position statement published in 2007 by the Canadian Cardiovascular Society (CCS), Canadian Association of Radiologists, Canadian Association of Nuclear Medicine, Canadian Cardiovascular Society, and the Canadian Society of Cardiovascular Magnetic Resonance on the use of PET, MRI, and CT in the diagnosis of ischemic heart disease,⁶⁵ and a second released jointly in 2011 by the European Association of Nuclear Medicine, the European Society of Cardiac Radiology, and the European Council of Nuclear Cardiology on the use of hybrid cardiac imaging with SPECT or PET combined with CT (SPECT/CT, PET/CT) to image anatomical and physiologic cardiac abnormalities in a single setting⁶⁶ — is provided in
Appendix 3 as background information. The Canadian position statement⁶⁵ was based on a systematic review of the literature relating to PET, MRI, and CT; however, it did not assess ^99mTc-SPECT. The European consensus statement discussed SPECT/CT hybrid technology.

Health technology assessments
In July 2009, MAS of the Ontario Ministry of Health and Long-Term Care began an evidence-based review of the literature surrounding cardiac imaging modalities. Systematic reviews, meta-analyses, randomized controlled trials, prospective observational trials, and retrospective analyses with a sample size of 20 or more patients were included; non-systematic reviews, case reports, grey literature, and abstracts were excluded. The interventions of interest were cardiac MRI, SPECT (using ^99mTc or ²⁰¹Tl), 64-slice computed tomographic coronary angiography (CTCA), stress echocardiography, and stress echocardiography with contrast. The comparator was coronary angiography (CA). The outcomes of interest were accuracy, adverse events, and costs. The use of imaging for risk stratification purposes was not considered as part of the reports. A summary of the findings of the MAS reports on the use of non-invasive cardiac imaging technologies for the diagnosis of coronary artery disease^13-17 can be found in
Appendix 4.

^99mTc-SPECT MPI versus coronary angiography
A review of the literature was completed to assess the diagnostic accuracy of SPECT, in comparison to CA, for the diagnosis of CAD.¹⁷ From the search period of January 1, 2004 to August 22, 2009, a total of 86 studies (10,870 patients) were analyzed by MAS.¹⁷ For the purpose of this report, the results for ^99mTc-SPECT and ²⁰¹TI-SPECT are reported separately.¹⁷ A total of 39 (n = 3,488) studies looked exclusively at ^99mTc-SPECT in comparison with CA.¹⁷ The pooled sensitivity and specificity of ^99mTc-SPECT, relative to CA, in the diagnosis of CAD were 88% and 70%, respectively.¹⁷ It is not clear from the report whether the included studies considered recent technological advances in SPECT with attenuation correction.

The diagnostic accuracies of the five imaging modalities were calculated against the reference standard of coronary angiography; therefore, the evidence relating to each of the modalities is presented in this report.

CTCA versus CA
A review of the literature to assess the diagnostic accuracy of 64-slice CTCA, compared with CA, in the diagnosis of CAD in stable symptomatic patients was completed.¹⁶ From the search period of January 1, 2004 to July 20, 2009, a total of eight studies (1,513 patients) were included in the review.¹⁶ The pooled sensitivity and specificity of CTCA, relative to CA, in the diagnosis of CAD, were 97.7% and 78.8%, respectively.¹⁶ In February 2010, results of the Ontario Multidetector Coronary Angiography Study (OMCAS) were made available.¹⁶ This non-randomized double-blinded study (n=169) evaluated CTCA versus CA in the diagnosis of CAD and found the sensitivity of CTCA versus CA to be 81.2% and the specificity to be 95.8%.¹⁶ When the OMCAS results were added to the MAS meta-analysis, the specificity of CTCA was greater (81.5%), while the sensitivity dropped to 96.1%.¹⁶

²⁰¹TI-SPECT MPI versus CA
A total of 24 studies (n = 3,338) included in the MAS SPECT review evaluated ²⁰¹TI-SPECT in comparison with CA.¹⁷ The pooled sensitivity and specificity of ²⁰¹TI-SPECT, relative to CA, in the diagnosis of CAD were 84% and 71%, respectively.¹⁷

Stress Echo (with and without contrast) versus CA
A review of the literature was completed to assess the diagnostic accuracy of stress Echo, in comparison with CA, for the diagnosis of CAD.¹⁴ From the search period of January 1, 2004 to August 22, 2009, 127 studies (13,035 patients) were included in the review.¹⁴ The available evidence was pooled and the overall results indicated a sensitivity of 80% and a specificity of 84%.¹⁴ These estimates may not be generalizable outside of the setting of a strong research laboratory as stress Echo has been associated with low reproducibility (MIIMAC expert opinion).

A second report published by MAS evaluated contrast Echo, in comparison with CA, for the diagnosis of CAD.¹³ In patients with suspected CAD, in only (11 studies), the pooled sensitivity and specificity were 87%, and 86%, respectively.¹³ Twelve studies evaluated the diagnostic accuracy of contrast Echo in patients with suspected or known CAD — six based on myocardial perfusion analysis (MPA) and six based on wall motion analysis (WMA).¹³ When results from the MPA studies were pooled, the sensitivity was 88% and the specificity was 65%.¹³ The pooled WMA results indicated a sensitivity of 69% and a specificity of 79%.¹³

Stress MRI versus CA
A review of the literature was completed to assess the diagnostic accuracy of stress MRI, compared with CA, in the diagnosis of CAD.¹⁵ From the search period of January 1, 2005 to October 9, 2008, one meta-analysis and 11 primary studies were found.¹⁵ The studies from the meta-analysis were pooled with the new literature for a total of 37 studies using MPA and WMA imaging.¹⁵ The pooled results for diagnostic accuracy including MPA produced a sensitivity of 91% and a specificity of 79%.¹⁵ Regarding the WMA, the pooled sensitivity and specificity were 81% and 85%.¹⁵

Primary studies

The MAS report reviewed the available literature for the diagnostic accuracy of SPECT in comparison with CA for the diagnosis of CAD (January 1, 2004 to August 22, 2009). A search for studies published after August 2009 identified five studies on the relative diagnostic accuracy of ^99mTc-SPECT, as it pertains to the diagnosis of ischemia.^20-22,27,28 In addition, four studies^23-26 reported the diagnostic accuracy of one or more comparators in the diagnosis of ischemia, using ^99mTc–SPECT as the gold standard.

^99mTc-SPECT/CTA versus CA
A recent study by Kong et al. (2011)²⁰ compared the diagnostic accuracy of ^99mTc sestamibi SPECT/CTA 3-D fusion with that of invasive CA.²⁰ One-hundred and four patients (mean age: 63.6 years) with typical or atypical angina symptoms were included in this retrospective analysis.²⁰ SPECT/CTA, in comparison with CA, yielded a sensitivity of 100% and a specificity of 80.8%.²⁰ The positive predictive value and the negative predictive value of the test were 94% and 100%, respectively.²⁰ The authors stated that the results of this study support the use of SPECT/CTA for the diagnosis of CAD.²⁰

Also in 2011, Weustink et al.²¹ compared the diagnostic accuracy of bicycle testing/ CTCA (also referred to as CTA) and ^99mTc-sestamibi SPECT/CTCA in the diagnosis of CAD, using invasive CA as the gold standard.²¹ Three-hundred and seventy-six symptomatic patients (mean age: 60.4) participated in the study.²¹ A comparison between bicycle testing and SPECT was not made. In patients who underwent SPECT (n = 61), the sensitivity of SPECT (89%) was found to be statistically significantly less than that of CTCA (98%) (P= 0.021). CTCA was more specific than SPECT (82% compared to 77%), but this difference was not statistically significant (P = 1.0).²¹ The authors concluded that the results of this study demonstrate a high diagnostic performance for CT and SPECT.²¹

^99mTc –SPECT and stress Echo versus CA
In 2010, Lu et al.²² evaluated the diagnostic accuracy of SPECT (^99mTc sestamibi), stress Echo (dipyridamole and dobutamine), and CA for the detection of CAD in a population of 76 female hypertensive patients (mean age: 60 years) with no previous MI or history of CAD.²² CA was used as the reference standard.²² The results of this prospective study are provided in Table 3. The authors suggested that, based on these results, dobutamine Echo should be used as a first-line diagnostic in women with suspected CAD, due to its high diagnostic value.²²

Table 3: Relative Diagnostic Accuracy of SPECT and Echo for the Diagnosis of CAD in Female Hypertensive Patients²²

	Sensitivity	Specificity	Accuracy	Positive Predictive Value	Negative Predictive Value
SPECT	90	53	68	57	89
Dipyridamole Echo	61	91	79	83	77
Dobutamine Echo	87	82	84	77	90

CAD = coronary artery disease; Echo = echocardiography; SPECT = single-photon emission tomography.
CTCA versus ^99mTc –SPECT

A 2010 study by Cheng et al.²³ compared the relative diagnostic accuracy of dual-source CTCA (DS-CTCA) to gated SPECT (^99mTc tetrofosmin). A total of 55 patients had clinical symptoms of CAD (e.g., chest pain, shortness of breath), were asymptomatic but had risk factors, or had known CAD.²³ The mean age of the population was 60.7 years and the majority of the patients were male (58%).²³ All patients underwent both ^99mTc –SPECT and DS-CTCA.²³ A diagnosis of CAD was noted on the DS-CTCA if stenosis was a minimum of 50%, and was compared with SPECT at rest and during stress.²³ Compared to SPECT at rest, the sensitivity, specificity, and accuracy of DS-CTCA were 100%, 78%, and 83.6%.²³ Compared to SPECT using stress conditions, the sensitivity, specificity, and accuracy of DS-CTCA were 83.3%, 90.3%, and 87.3%.²³ However, when rest/stress-SPECT was used as the reference standard, the sensitivity of DS-CTCA to detect high-grade stenosis (a minimum of 50%) was 59% and the specificity was 89%. There was a lack of correlation between DS-CTCA and SPECT findings. The authors concluded that DS-CTCA may provide additional information regarding perfusion defects first identified by ^99mTc-SPECT.

A 2009 study by Bauer et al.²⁴ was conducted to determine the correlation between the diagnostic accuracy of 64-slice multidetector computed tomography (MDCT, referred to as CT) readings of calcification in comparison with ischemia detected by ^99mTc-SPECT with ^99mTc tetrofosmin.²⁴ Seventy-two patients with known (n = 23) or suspected (n = 49) CAD underwent CT angiography and stress-rest SPECT.²⁴ Stenosis was classified as insignificant (< 50%), significant (≥ 50%), or severe (≥ 70%) based on CT imaging.²⁴ SPECT images were reviewed for the presence of reversible and fixed perfusion defects.²⁴ Patient-based and vessel-based results were presented.²⁴ When the diagnostic outcomes were evaluated at the patient level for any perfusion defect on SPECT and ≥ 50% stenosis on CT, the sensitivity and specificity were 46% and 83%.²⁴ When the diagnostic outcomes were evaluated at the patient level for any perfusion defect on SPECT and ≥ 70% stenosis on CT, the sensitivity and specificity were 38% and 98%, respectively.²⁴ When the data was evaluated for reversible perfusion defects on SPECT compared with ≥50% stenosis on CT, the sensitivity and specificity were 33% and 83%, respectively.²⁴ The comparison between ≥ 70% stenosis on CT and the presence of reversible perfusion defects on SPECT provided a sensitivity estimate of 25% and specificity estimate of 98%.²⁴ The authors concluded that the degree of stenosis as determined by CT was not a reliable predictor of ischemia at stress-rest SPECT in this heterogeneous, clinically-representative patient group.²⁴

The performance of dual source dual energy computed tomography (DECT) for the integrative imaging of the coronary arteries was evaluated by Ruzsics et al.²⁵ in 2009. A total of 36 patients with known (n = 9) or suspected (n = 27) CAD were evaluated for a diagnosis of CAD with stenosis ≥ 50%.²⁵ DECT and ^99mTc-SPECT with tetrofosmin were performed in all patients and the images were compared for perfusion defects (fixed and reversible).²⁵ When the diagnostic outcomes were evaluated at the patient level for any perfusion defect on SPECT and ≥ 50% stenosis on CT, the sensitivity and specificity were 97% and 67% (as in Table 6).²⁵ When the data were evaluated for reversible perfusion defects on SPECT compared with ≥ 50% stenosis on CT, the sensitivity and specificity were 100% and 67%.²⁵ Data evaluated for fixed perfusion defects on SPECT compared with ≥ 50% stenosis on CT provided a sensitivity estimate of 94% and a specificity estimate of 67%.²⁵ The authors noted that, although their findings for DECT compared with SPECT were favourable, the study was limited by the small sample size and a higher prevalence of CAD than would be found in the general population.²⁵

Stress Echo versus ^99mTc –SPECT
Abdelmoneim et al.²⁶ evaluated the diagnostic accuracy of stress Echo, compared with SPECT (^99mTc sestamibi). Patients (n = 88) with known or suspected CAD underwent both stress Echo (adenosine) with contrast and SPECT.²⁶ The images for both tests were interpreted and compared.²⁶ Coronary deficiencies in Echo were interpreted by wall motion analysis (WMA) or real-time perfusion using myocardial contrast echocardiography (MCE) techniques.²⁶ In total, 88 patients were included in the final analysis of MCE and 73 patients for final analysis of WMA.²⁶ In comparison with SPECT, the sensitivity and specificity of stress Echo were determined to be 88% and 85%.²⁶ The authors concluded that adenosine MCE in real time is effective in the detection of myocardial defects.²⁶

^99mTc-SPECT versus PET
Husmann et al.²⁷ compared the diagnostic accuracy of MPI with PET or SPECT in two comparable patient cohorts with known or suspected CAD, using coronary angiography as the gold standard. The SPECT group consisted of 80 patients (15 female, 65 male; mean age 60 ± 9 years) and the ¹³NH₃-PET group consisted of 70 patients (14 female, 56 male; mean age 57 ± 10 years). The SPECT group included patients who received either ²⁰¹Tl chloride or ^99mTc sestamibi. Coronary angiography findings did not significantly differ between groups. All patients underwent a one-day stress/rest protocol. PET and SPECT images were transferred to external workstations and evaluated by two independent observers blinded to results of the angiography. In the detection of CAD, the overall sensitivity of SPECT was 85% compared with 96% for PET. For the SPECT group, the overall sensitivity and specificity for localization of stensosis was 77% and 84%, respectively. Comparatively, in the PET group, the sensitivity was 97% and the specificity 84%. For the detection of ischemia, the specificity was 74% for SPECT and 91% for PET. Husmann et al. concluded that MPI with ¹³NH₃-PET is more sensitive in the detection and localization of coronary stenosis, and more specific in the detection of ischemia than MPI using SPECT with either ^99mTc or ²⁰¹Tl. The Husmann et al. study was included in this report despite the fact that the authors did not provide separate analyses for ^99mTc and ²⁰¹Tl. It is possible that the sensitivity and specificity of ^99mTc is lower or higher than the pooled value. This study was included based on the limited available information for comparing ^99mTc-based imaging to PET; however, the limitations of the study should be noted.

Bateman et al. (2006)²⁸ compared the diagnostic accuracy of ^99mTc sestamibi SPECT and ⁸²Rb-PET for MPI of patients matched by gender, body mass index, and presence and extent of coronary disease.²⁸ Included patients were identified retrospectively from an electronic nuclear cardiology database and were categorized as having a low likelihood for CAD (n = 27) or had coronary angiography within 60 days (n = 27). Four experienced nuclear medicine cardiologists blinded to patients' clinical information interpreted scans obtained from 112 ^99mTc-SPECT and 112 ⁸²Rb-PET Echo-gated rest/pharmacologic stress studies. By consensus, the quality of the perfusion images were deemed superior with PET (78% and 79% for rest and stress scans, respectively) than SPECT (62% and 62%; both P > 0.05). Interpretive certainty was also rated higher with PET versus SPECT scans (96% versus 81%, P = 0.001). Diagnostic accuracy was better for PET over SPECT — for patients with a stenosis severity of 70% by angiography, the sensitivity was 82% for SPECT and 87% for PET (P = 0.41) and the specificity was 73% for SPECT versus 93% for PET (P = 0.02), resulting in a significant improvement in overall accuracy by PET (89% versus 79%, P = 0.03). For patients with 50% stenosis, the respective comparative accuracy was 71% for SPECT versus 87% for PET (P = 0.003). Bateman and colleagues conclude that for this patient population, a major benefit of PET over SPECT is higher diagnostic accuracy.

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Criterion 8: Relative risks associated with the test (link to definition)

Non–radiation-related risks

Cardiac Stress Tests
The main risks of non-invasive preoperative assessment relate to the stress component of the tests:

• With exercise stress testing, there is a small risk of the patient sustaining an MI if they have significant coronary artery disease.⁴²
• With dipyridamole stress testing, there are multiple potential side effects, including headache, exacerbated asthma, and heart attack (risk of this event is low).⁴²
• With adenosine stress testing, side effects similar to dipyridamole may be experienced. Symptoms of chest pain or pressure may also occur, but these side effects go away quickly once the adenosine administration stops.⁴²
• With dobutamine stress testing, some patients may experience light-headedness and nausea. There is a theoretical risk of inducing a fast and abnormal cardiac rhythm (i.e., atrial fibrillation, ventricular tachycardia, ventricular fibrillation); however, this is unlikely with the doses of dobutamine used. A slight risk of MI exists.⁴²

The overall risk of sustaining a heart attack from a stress test is estimated to be about 2 to 4 in 10,000.⁴²

Stress SPECT
Apart from risks associated with stress testing, a review of undesirable events with radiopharmaceuticals reported anaphylactic reactions and erythema multiforme (i.e., a type of skin reaction) with sestamibi, although these reactions may be rare.⁴³

CTCA
Some patients may experience an allergic reaction to the contrast agent (if required), which may worsen with repeated exposure.⁶⁷ In addition, patients may experience mild side effects such as nausea, vomiting, or hives from the contrast agent. A 2009 retrospective review of all intravascular doses of low-osmolar iodinated and gadolinium (Gd) contrast materials administered at the Mayo Clinic between 2002 and 2006 (456,930 doses) found that 0.15% of patients given CT contrast material experienced side effects, most of which were mild. A serious side effect was experienced by 0.005% of patients.⁶⁸ CT is contraindicated in patients with elevated heart rate, hypercalcemia, and impaired renal function. Patients must be able to take rate-lowering medications. Although rarely used in cardiac imaging, Gd is contraindicated in patients with renal failure or end-stage renal disease, as they are at risk of nephrogenic systemic fibrosis. According to the American College of Radiology Manual on Contrast Media,⁴⁴ the frequency of severe, life-threatening reactions with Gd are extremely rare (0.001% to 0.01%). Moderate reactions resembling an allergic response (i.e., rash, hives, urticaria) are also very unusual and range in frequency from 0.004% to 0.7%.⁴⁴

Stress Echo
Apart from risks associated with stress testing, three relatively large studies — with sample sizes of 42,408 patients (2009),⁶⁹ 26,774 patients (2009),⁷⁰ and 5069 patients (2008)⁷¹ —compared cardiac outcomes (non-fatal MI or death) between patients who underwent contrast-enhanced Echo with patients who had an Echo without contrast. All three studies concluded that the risk of an adverse event is low and is no different than for patients who received no contrast. No additional risks associated with Echo were identifed.

Stress MRI
Apart from risks associated with stress testing, MRI is contraindicated in patients with metallic implants including pacemakers.⁷² MRI is often used in conjunction with the contrast agent Gd. Some patients may experience an allergic reaction to the contrast agent (if required), which may worsen with repeated exposure.⁶⁷ Side effects of Gd include headaches, nausea, and metallic taste. Gd is contraindicated in patients with renal failure or end-stage renal disease, as they are at risk of nephrogenic systemic fibrosis. According to the American College of Radiology Manual on Contrast Media,⁴⁴ the frequency of severe, life-threatening reactions with Gd are extremely rare (0.001% to 0.01%). Moderate reactions resembling an allergic response (i.e., rash, hives, urticaria) are also very unusual and range in frequency from 0.004% to 0.7%.⁴⁴

Stress PET
The Pharmacopeia Committee of the Society of Nuclear Medicine conducted a four-year prospective evaluation of adverse reactions to PET and reported no adverse reactions among the 33,925 scans conducted in 22 participating PET centres in the United States.⁴⁵ The risks associated with stress testing would apply for cardiac imaging using PET.

Radiation-related Risks

Among the modalities to diagnose ischemia, SPECT MPI, CTCA, and stress PET expose the patient to ionizing radiation. The average effective dose of radiation delivered with each of these procedures can be found in Table 4.

Table 4: Effective Doses of Radiation

Procedure	Average Effective Dose (mSv)
99mTc-SPECT MPI	7 to 12.846
201Tl-SPECT MPI	17 to 4146,47
Cardiac 18FDG-PET	7 (MIIMAC expert opinion) to 1447
Cardiac 82Rb-PET	1.1 to 5.047-49
Cardiac 13NH3-PET	1.5 to 2.249
CTCA	2.1 to 1650,51
MRI	0
Echo	0
Average background dose of radiation per year	1-3.052-54

CTCA = computed tomography coronary angiography; Echo = echocardiography; ¹⁸FDG- PET = ¹⁸fluorodeoxyglucose-positron emission tomography; MPI = myocardial perfusion imaging; MRI = magnetic resonance imaging; mSv = millisevert; ¹³NH₃ = 13N-labelled ammonia; PET = positron emission tomography; ⁸²Rb = rubidium-82; SPECT = single-photon emission computed tomography; ^99mTc = Technitium-99m; ²⁰¹Tl =Thallium-201.

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Criterion 9: Relative availability of personnel with expertise and experience required for the test (link to definition)

The personnel required for the performance of the imaging tests to detect ischemia are presented by imaging modality. A summary of the availability of personnel required to detect ischemia, by SPECT or any of the alternative imaging modalities, is provided in Table 5.

^99mTc-labelled radiotracer SPECT MPI
In Canada, physicians involved in the performance, supervision, and interpretation of cardiac nuclear imaging (specifically MPI using ^99mTc-labelled radiotracer) should be nuclear medicine physicians with particular expertise in nuclear cardiology (nuclear cardiologists). Cardiologists also provide much of the nuclear cardiology services. According to the Canadian Medical Association (CMA), there are 1,149 practising cardiologists in Canada (CMA, 2011).

Nuclear medicine technologists are required to conduct MPI. Technologists must be certified by the Canadian Association of Medical Radiation Technologists (CAMRT) or an equivalent. A stress technologist or dedicated physician should be on hand to monitor any procedures involving stress testing.

All alternative imaging modalities
In Canada, physicians involved in the performance, supervision, and interpretation of diagnostic CT scans, MRI, and ultrasound should be diagnostic radiologists⁵⁵ and must have a Fellowship or Certification in Diagnostic Radiology with the Royal College of Physicians and Surgeons of Canada and/or the Collège des médecins du Québec. Foreign-trained radiologists also are qualified if they are certified by a recognized certifying body and hold a valid provincial license.⁷³ According to the CMA, there are 1,149 practicing cardiologists in Canada (CMA, 2011).

Medical radiation technologists (MRTs) must be certified by the CAMRT, or an equivalent licensing body. A stress technologist or dedicated physician should be on hand to monitor any procedures involving stress testing.

Service engineers are needed for system installation, calibration, and preventive maintenance of the imaging equipment at regularly scheduled intervals. The service engineer's qualification will be ensured by the corporation responsible for service and the manufacturer of the equipment used at the site.

Qualified medical physicists (on site or contracted-part time) should be available for the installation, testing, and ongoing quality control of CT scanners, MR scanners, and nuclear medicine equipment.⁷³

CTCA
CTCA is a CT-based test. Cardiologists provide much of the CTCA service. According to the CMA, there are 1,149 practicing cardiologists in Canada (CMA, 2011).

For the performance of CT scan, medical radiation technologists who are certified by the CAMRT, or an equivalent licensing body recognized by the CAMRT, are required. The training of technologists specifically engaged in CT should meet with the applicable and valid national and provincial specialty qualifications.

Stress Echo
Echo is a U/S based test. Cardiologists provide much of the Echo service. A 2002 report by the CCS reported that 43% of cardiologists do Echo. According to the CMA, there are 1,149 practicing cardiologists in Canada (CMA, 2011). It is assumed that less than 500 of them do Echo.

Sonographers (or ultrasonographers) should be graduates of an accredited school of sonography or have obtained certification by the Canadian Association of Registered Diagnostic Ultrasound Professionals. They should be members of their national or provincial professional organization. Sonography specialties include general sonography, vascular sonography, and cardiac sonography.⁵⁵ In Quebec, sonographers and medical radiation technologists are grouped together; in the rest of Canada, sonographers are considered a distinct professional group.⁵⁵ A stress technologist or dedicated physician should be on hand to monitor any procedures involving stress testing.

Stress MRI
Medical technologists must have CAMRT certification in magnetic resonance or be certified by an equivalent licensing body recognized by CAMRT. A stress technologist or dedicated physician should be on hand to monitor any procedures involving stress testing.

Stress PET
In Canada, physicians involved in stress PET scanning should be nuclear medicine physicians, nuclear cardiologists, or cardiologists with training and expertise in nuclear imaging. In Canada, physicians who perform PET imaging studies must be certified by either the Royal College of Physicians and Surgeons of Canada or le Collège des médecins du Quebec.

Technologists must be certified by CAMRT or an equivalent licensing body. A stress technologist or dedicated physician should be on hand to monitor any procedures involving stress testing.

Table 5: Medical Imaging Professionals in Canada, 2007⁵⁵

Jurisdiction	Diagnostic Radiology Physicians	Nuclear Medicine Physicians	MRTs	Nuclear Medicine Technologists	Sonographers	Medical Physicists
NL	46	3	263	15	NR	NR
NS	71	5	403	71	NR	NR
NB	47	3	387	55	NR	NR
PEI	7	0	57	3	NR	0
QC	522	90	3,342	460	NR	NR
ON	754	69	4,336	693	NR	NR
MB	58	8	501	42	NR	NR
SK	61	4	359	36	NR	NR
AB	227	18	1,229	193	NR	NR
BC	241	21	1,352	212	NR	NR
YT	0	0	0	0	NR	0
NT	0	0	26	1	NR	0
NU	0	0	0	0	NR	0
Total	2,034	221	12,255	1,781	2,900*	322*

AB = Alberta; BC = British Columbia; MB = Manitoba; MRT = medical radiation technologist; NB = New Brunswick; NL = Newfoundland and Labrador; NR = not reported by jurisdiction; NS = Nova Scotia; NT= Northwest Territories; NU = Nunavut; PEI= Prince Edward Island; ON = Ontario; QC = Quebec; YT = Yukon.
* This represents a total for all of the jurisdictions.

Return to Summary Table.

Criterion 10: Accessibility of alternative tests (equipment and wait times) (link to definition)

There are notable variations in the availability of medical imaging technologies across Canada. Table 6 provides an overview of the availability of equipment required to detect ischemia. Data for nuclear medicine cameras (including SPECT) are current to January 1, 2007. The number of CT, MRI, and SPECT/CT scanners is current to January 1, 2010. Information on the availability of PET and PET/CT scanners is current to November 30, 2010. Data were not available for Echo.

Table 6: Diagnostic Imaging Equipment in Canada^55,56,58

	Nuclear Medicine Cameras	CT Scanners	MRI Scanners	PET or PET/CT
Number of devices	60355	46056	21856	3658
Average number of hours of operation per week (2006-2007)	40	60	71	NA
Provinces and Territories with no devices available	YT, NT, NU	NU	YT, NT, NU	NL, PEI, SK, YT, NT, NU

CT = computed tomography; PET = positron emission tomography; MRI = magnetic resonance imaging; NB = New Brunswick; NL. = Newfoundland; NS = Nova Scotia; NU = Nunavut; NT = Northwest Territories; PEI = Prince Edward Island; SK = Saskatchewan; YT = Yukon.

^99mTc-labelled radiotracer SPECT
Nuclear medicine facilities with gamma cameras are required for SPECT imaging. Three jurisdictions — the Yukon, the Northwest Territories, and Nunavut — do not have any nuclear medicine equipment.⁵⁵

CT
No CT scanners are available in Nunavut.⁵⁶ The average weekly use of CT scanners ranged from 40 hours in PEI to 69 hours in Ontario, with a national average of 60 hours.⁵⁵ In 2010, the average wait time for a CT scan in Canada is 4.2 weeks.⁵⁷ The average wait time for CTCA was not reported.

Echo
No information was found to identify how many Echo machines are available in Canada.

MRI
No MRI scanners are available in the Yukon, Northwest Territories, or Nunavut.⁵⁶ According to the Canadian Institute for Health Information's National Survey of Selected Medical Imaging Equipment database, the average number of hours of operation per week for MRI scanners in 2006–2007 ranged from 40 hours in PEI to 99 hours in Ontario, with a national average of 71 hours.⁵⁵ In 2010, the average wait time for MRI in Canada was 9.8 weeks.⁵⁷

PET
A 2010 Environmental Scan published by CADTH reported that there are approximately 31 Canadian centres equipped to perform PET scans.⁵⁸ These centres are located in the provinces of British Columbia, Alberta, Manitoba, Ontario, Quebec, New Brunswick, and Nova Scotia.⁵⁸ There are 36 PET or PET/CT scanners in Canada, four of which are used for research purposes only.⁵⁸

Wait times
Wait time benchmarks for cardiac nuclear imaging set by the Wait Time Alliance³⁸ are immediate to 24 hours for emergency cases (immediate danger to life, limb, or organ); within three days for urgent cases (situation that is unstable and has the potential to deteriorate quickly and result in an emergency admission); and within 14 days for scheduled cases (situation involving minimal pain, dysfunction, or disability — routine or elective).

Return to Summary Table.

Criterion 11: Relative cost of the test (link to definition)

Fee codes from the Ontario Schedule of Benefits were used to estimate the relative costs of SPECT MPI and its alternatives. Technical fees are intended to cover costs incurred by the hospital (i.e., radiopharmaceutical costs, medical/surgical supplies, and non-physician salaries). Maintenance fees are not billed to OHIP — estimates here were provided by St. Michael's Hospital in Toronto. Certain procedures (i.e., PET scan, CT scan, MRI scan) are paid for, in part, out of the hospital's global budget; these estimates were provided by The Ottawa Hospital. It is understood that the relative costs of imaging will vary from one institution to the next.

According to our estimates (Table 7), the cost of MPI with ^99mTc-based radioisotopes is $964.53. The cost of MPI with ²⁰¹TI or with PET is assumed to be greater than imaging with ^99mTc-based radioisotopes. Stress MRI is minimally less costly than MPI with ^99mTc. CTCA and stress Echo are moderately less costly.

Table 7: Cost Estimates Based on the Ontario Schedule of Benefits for Physician Services Under the Health Insurance Act (September 2011)⁷⁴

Fee Code	Description	Tech. Fees ($)	Prof. Fees ($)	Total Costs ($)
99mTc-SPECT MPI
J866	Myocardial perfusion scintigraphy application of SPECT (maximum 1 per examination)	44.60	31.10	75.7
J813	Studies with ejection fraction	138.60	82.25	220.85
J807	Myocardial perfusion scintigraphy — resting, immediate post-stress	223.15	50.15	273.3
J808	MPI — delayed	82.15	27.45	109.6
G315/G319	Maximal stress ECG	44.60	62.65	107.25
G111/G112	Dipyridamole-thallium stress test	52.05	75.00	127.05
Maintenance fees — from global budget		50.78		50.78
TOTAL		635.93	328.6	964.53
201 TI-SPECT MPI
J866	Myocardial perfusion scintigraphy application of SPECT (maximum 1 per examination)	44.60	31.10	75.7
J813	Studies with ejection fraction	138.60	82.25	220.85
J807	Myocardial perfusion scintigraphy — resting, immediate post stress	223.15	50.15	273.3
J808	MPI — delayed	82.15	27.45	109.6
G315/G319	Maximal stress ECG	44.60	62.65	107.25
G111/G112	Dipyridamole-thallium stress test	52.05	75.00	127.05
Maintenance fees — from global budget		50.78		50.78
TOTAL		635.93	328.6	964.53
CTCA
X235	Cardiothoracic CT		155.25	155.25
Technical cost — from global budget		300.00		300.00
Maintenance fees — from global budget		50.78		50.78
TOTAL		350.78	155.25	506.03
Stress Echo
G570/G571	Complete study — 1 and 2 dimensions	76.45	74.10	150.55
G577/G578	Cardiac Doppler study, with or without colour Doppler, in conjunction with complete 1 and 2 dimension Echo studies	45.15	36.90	82.05
G315/G319	Maximal stress ECG	44.60	62.65	107.25
G111/G112	Dipyridamole-thallium stress test	52.05	75.00	127.05
TOTAL		218.25	248.65	466.90
Stress MRI
X441C	MRI — thorax — multislice sequence		77.20	77.20
X445C (×3)	Repeat (another plane, different pulse sequence — to a maximum of 3 repeats)		38.65 (×3) = 115.95	115.95
Table 7: Cost Estimates Based on the Ontario Schedule of Benefits for Physician Services Under the Health Insurance Act (September 2011)74
Fee Code	Description	Tech. Fees ($)	Prof. Fees ($)	Total Costs ($)
X499C	3-D MRI acquisition sequence, including post-processing (minimum of 60 slices; maximum 1 per patient per day)		65.40	65.40
G315/G319	Maximal stress ECG	44.60	62.65	107.25
X486C	When cardiac gating is performed (must include application of chest electrodes and ECG interpretation), add 30%		96.36	96.36
Technical cost — from global budget		300.00		300.00
Maintenance fees — from global budget		73.00		73.00
TOTAL		417.60	417.56	835.16
Stress PET
J866	Myocardial perfusion scintigraphy application of SPECT (maximum 1 per examination)		31.10	31.10
J813	Studies with ejection fraction		82.25	82.25
J807	Myocardial perfusion scintigraphy — resting, immediate post-stress		50.15	50.15
J808	MPI — delayed		27.45	27.45
G315/G319	Maximal stress ECG		62.65	62.65
G111/G112	Dipyridamole-thallium stress test		75.00	75.00
Technical cost — from global budget		800.00		800.00
TOTAL		800.00	328.60	1128.60

3-D = three-dimensional; CT = computed tomography; CTCA = computed tomography coronary angiography; ECG = electrocardiogram; MPI = myocardial perfusion imaging; MRI = magnetic resonance imaging; PET = positron emission tomography; Prof. = professional; SPECT = single-photon emission computed tomography; ^99mTc = technetium-99m; ²⁰¹TI = thallium-201; tech. = technical.

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70. College of Physicians and Surgeons of Ontario. Independent health facilities: clinical practice parameters and facility standards; magnetic resonance imaging [Internet]. 2nd ed. Toronto: The College; 2009. [cited 2011 Jun 13; revised 2010 Apr]. Available from: http://www.cpso.on.ca/uploadedFiles/policies/guidelines/facilties/MagneticRI.pdf
71. Royal College of Physicians and Surgeons of Canada. Objectives of training in nuclear medicine [Internet]. Ottawa: The College; 2009. [cited 2011 Jun 13]. Available from: http://rcpsc.medical.org/residency/certification/objectives/nucmed_e.pdf
72. Ontario Ministry of Health and Long-Term Care. Schedule of benefits for physician services under the Health Insurance Act: effective September 1, 2011 [Internet]. Toronto: OMHLTC; 2011. [cited 2011 Oct 5]. Available from: http://www.health.gov.on.ca/english/providers/program/ohip/sob/physserv/physserv_mn.html
73. Venes D, Taber CW. Taber's cyclopedic medical dictionary. Philadelphia: F.A. Davis Co; 1989.

 

Appendix 1: Multi-Criteria Decision Analysis Definitions

Domain 1: Criteria Related to the Underlying Health Condition
Criterion	Definition
1. Size of the affected population	The estimated size of the patient population that is affected by the underlying health condition and which may potentially undergo the test. The ideal measure is point prevalence, or information on how rare or common the health condition is.
2. Timeliness and urgency of test results in planning patient management	The timeliness and urgency of obtaining the test results in terms of their impact on the management of the condition and the effective use of health care resources.
3. Impact of not performing a diagnostic imaging test on mortality related to the underlying condition	Impact of not performing the test, in whatever way, on the expected mortality of the underlying condition. Measures could include survival curves showing survival over time, and/or survival at specific time intervals with and without the test.
4. Impact of not performing a diagnostic imaging test on morbidity or quality of life related to the underlying condition	Impact of not performing the test, in whatever way, on the expected morbidity or on the quality of life reduction of the underlying condition. Measures of impact may include natural morbidity outcome measures such as events or disease severity, or might be expressed using generic or disease-specific quality of life rating scales with and without the test.
Domain 2: Criteria Comparing 99mTc with an Alternative, or Comparing between Clinical Uses
Criterion	Definition
5. Relative impact on health disparities	Health disparities are defined as situations where there is a disproportionate burden (e.g., incidence, prevalence, morbidity, or mortality) amongst particular population groups (e.g., gender, age, ethnicity, geography, disability, sexual orientation, socioeconomic status, and special health care needs). Impact on health disparities is assessed by estimating the proportion of current clients of the 99mTc-based test that are in population groups with disproportionate burdens. (Explanatory note: The implication of this definition is that, everything else being the same, it is preferable to prioritize those clinical uses that have the greatest proportion of clients in groups with disproportionate burdens.)
6. Relative acceptability of the test to patients	Acceptability of the 99mTc-based test from the patient's perspective compared with alternatives. Patient acceptability considerations include discomfort associated with the administration of the test, out-of-pocket expenses or travel costs, factors that may cause great inconvenience to patients, as well as other burdens. This criterion does not include risks of adverse events but is about everything related to the experience of undergoing the test.
7. Relative diagnostic accuracy of the test	Ability of the test to correctly diagnose the patients who have the condition (sensitivity) and patients who do not have the condition (specificity) compared with alternatives.
8. Relative risks associated with the test	Risks associated with the test (e.g., radiation exposure, side effects, adverse events) compared with alternatives. Risks could include immediate safety concerns from a specific test or long-term cumulative safety concerns from repeat testing or exposure.
9. Relative availability of personnel with expertise and experience required for the test	Availability of personnel with the appropriate expertise and experience required to proficiently conduct the test and/or interpret the test findings compared with alternatives.
10. Accessibility of alternatives (equipment and wait times)	Availability (supply) of equipment and wait times for alternative tests within the geographic area. Includes consideration of the capacity of the system to accommodate increased demand for the alternatives. Excludes any limitation on accessibility related to human resources considerations.
11. Relative cost of the test	Operating cost of test (e.g., consumables, heath care professional reimbursement) compared with alternatives.

 

Appendix 2: Literature Search Strategy

OVERVIEW
Interface:			Ovid
Databases:			Ovid MEDLINE(R) In-Process & Other Non-Indexed Citations, Ovid MEDLINE(R) Daily and Ovid MEDLINE(R) <1946 to March 29, 2011>
Date of Search:			March 29, 2011
Alerts:			Monthly search updates began March 29, 2011 and ran until October 2011.
Study Types:			Health technology assessments; systematic reviews; meta-analyses; diagnostic accuracy studies
Limits:			English language Publication years 2006-2011 for diagnostic studies search; no date limits for systematic review search. Diagnostic accuracy studies search limited to human population
SYNTAX GUIDE
/		At the end of a phrase, searches the phrase as a subject heading
MeSH		Medical Subject Heading
.fs		Floating subheading
exp		Explode a subject heading
*		Before a word, indicates that the marked subject heading is a primary topic; or, after a word, a truncation symbol (wildcard) to retrieve plurals or varying endings
ADJ		Requires words are adjacent to each other (in any order)
ADJ#		Adjacency within # number of words (in any order)
.ti		Title
.ab		Abstract
.hw		Heading word: usually includes subject headings and controlled vocabulary
.tw		Text word: searches title, abstract, captions, and full text
.mp		Keyword search; includes title, abstract, name of substance word, subject heading word, and other text fields
.pt		Publication type
.nm		Name of substance word: used to search portions of chemical names and includes words from the CAS Registry/EC Number/Name (RN) fields
.jw		Journal words: searches words from journal names

 

Multi-database Strategy
#	Searches
1	exp Myocardial Ischemia/
2	((Myocardial or cardiac or heart or coronary) adj5 (ischemia* or ischemic or ischaemia* or ischaemic)).ti,ab.
3	(Coronary artery disease* or Coronary Arteriosclerosis or Coronary Atherosclerosis or atherosclerotic heart disease* or coronary heart disease* or coronary disease*).ti,ab.
4	or/1-3
5	Technetium/
6	exp Technetium Compounds/
7	exp Organotechnetium Compounds/
8	exp Radiopharmaceuticals/
9	(Technetium* or Tc-99* or Tc99* or Tc-99m* or Tc99m* or 99mTc* or 99m-Tc*).tw,nm.
10	Radionuclide Imaging/ or Perfusion Imaging/
11	radionuclide imaging.fs.
12	radioisotope*.mp.
13	((radionucl* or nuclear or radiotracer*) adj2 (imag* or scan* or test* or diagnos*)).ti,ab.
14	exp Tomography, Emission-Computed, Single-Photon/
15	(single-photon adj2 emission*).ti,ab.
16	(SPECT or scintigraph* or scintigram* or scintiphotograph*).ti,ab.
17	Myocardial Perfusion Imaging/
18	(myocardial perfusion imag* or 99MTC-SPECT or rest-stress test* or cardiac-stress test*).ti,ab.
19	(sestamibi or Hexamibi or Tc MIBI or Cardiolite* or tetrofosmin* or myoview*).ti,ab.
20	(109581-73-9 or 112144-90-8 or 113720-90-4).rn.
21	or/5-20
22	meta-analysis.pt.
23	meta-analysis/ or systematic review/ or meta-analysis as topic/ or exp technology assessment, biomedical/
24	((systematic* adj3 (review* or overview*)) or (methodologic* adj3 (review* or overview*))).ti,ab.
25	((quantitative adj3 (review* or overview* or synthes*)) or (research adj3 (integrati* or overview*))).ti,ab.
26	((integrative adj3 (review* or overview*)) or (collaborative adj3 (review* or overview*)) or (pool* adj3 analy*)).ti,ab.
27	(data synthes* or data extraction* or data abstraction*).ti,ab.
28	(handsearch* or hand search*).ti,ab.
29	(mantel haenszel or peto or der simonian or dersimonian or fixed effect* or latin square*).ti,ab.
30	(met analy* or metanaly* or health technology assessment* or HTA or HTAs).ti,ab.
31	(meta regression* or metaregression* or mega regression*).ti,ab.
32	(meta-analy* or metaanaly* or systematic review* or biomedical technology assessment* or bio-medical technology assessment*).mp,hw.
33	(medline or Cochrane or pubmed or medlars).ti,ab,hw.
34	(cochrane or health technology assessment or evidence report).jw.
35	or/22-34
36	4 and 21 and 35
37	limit 36 to english language
38	exp "Sensitivity and Specificity"/
39	Diagnostic Errors/
40	False Positive Reactions/
41	False Negative Reactions/
42	(sensitivit* or specificit* or distinguish* or differentiat* or enhancement or identif* or detect* or diagnos* or accura* or comparison*).ti.
43	(predictive adj4 value*).ti,ab.
44	Validation Studies.pt.
45	or/38-44
46	4 and 21 and 45
47	46 not case reports.pt.
48	exp animals/
49	exp animal experimentation/
50	exp models animal/
51	exp animal experiment/
52	exp vertebrate/
53	or/48-52
54	exp humans/
55	53 not 54
56	47 not 55
57	56
58	limit 57 to (english language and yr="2006 -Current")

 

OTHER DATABASES
PubMed	Same MeSH, keywords, limits, and study types used as per MEDLINE search, with appropriate syntax used.
The Cochrane Library (Issue 3, 2011)	Same MeSH, keywords, and date limits used as per MEDLINE search, excluding study types and Human restrictions. Syntax adjusted for Cochrane Library databases.

 

GREY LITERATURE SEARCHING
Dates for Search:	March 16-22, 2011
Keywords:	Included terms for myocardial ischemia, coronary artery disease, and radionuclide imaging
Limits:	English language

The following sections of the CADTH grey literature checklist, "Grey matters: a practical search tool for evidence-based medicine" (http://www.cadth.ca/en/resources/grey-matters) were searched:

• Health Technology Assessment Agencies (selected)
• Clinical Practice Guidelines
• Databases (free)
• Internet Search

 

Appendix 3: Position or Consensus Statements

In 2011, the European Association of Nuclear Medicine (EANM), the European Society of Cardiac Radiology (ESCR), and the European Council of Nuclear Cardiology (ECNC) released a joint position statement on use of hybrid cardiac imaging with single-photon emission computer tomography (SPECT) or positron emission tomography (PET) combined with computed tomography (CT) — (SPECT/CT, PET/CT) — to image anatomical and physiologic cardiac abnormalities in a single setting.⁶⁶ A review of the literature demonstrated that hybrid SPECT/CT and PET/CT imaging provides superior information compared with either stand-alone or side-by-side interpretation of patients with known or suspected coronary artery disease (CAD). Hybrid cardiac imaging has the advantage of being non-invasive and offering patient-friendly image acquisition in only one visit to the imaging department. Additionally, fewer personnel are required compared with two stand-alone scanners. Disadvantages include proper patient selection to ensure optimal diagnostic effectiveness and minimization of costs, and radiation dose (ranging between 1 and 20 millisievert [mSv]).

A 2007 position statement published by the Canadian Cardiovascular Society (CCS), the Canadian Association of Radiologists (CAR), the Canadian Association of Nuclear Medicine (CANM), and the Canadian Society of Cardiac Magnetic Resonance (CanSCMR) systematically reviewed the available scientific literature on cardiac imaging using PET, MRI, and multidetector computed tomographic angiography (MD-CTA) in the diagnosis and evaluation of ischemic heart disease.⁶⁵ The systematic review included literature on any of the three imaging modalities, for one or more of the following outcomes: diagnostic accuracy for the detection of CAD, CAD prognostication, myocardial viability detection, and viability prognostication.⁶⁵ Three-thousand six-hundred and fifty-five references were identified in the initial search.⁶⁵ Meta-analysis of 14 primary studies on the use of PET for detection of CAD produced sensitivity and specificity estimates of 89% (83% to 100%) and 89% (73% to 100%).⁶⁵ One systematic review and eight primary studies on the use of PET in the diagnosis of myocardial viability were included in the review, and provided sensitivity and specificity estimates of 91% (80% to 100%) and 61% (44% to 92%).⁶⁵ Nineteen primary studies were pooled to provide estimated sensitivity (87%) and specificity (96%) values for the ability of 16-slice multidetector computed tomography to define angiographic disease. Four studies described the detection of disease in patients using 64-slice multidetector computed tomography to be both sensitive (91%) and specific (95%).⁶⁵ Eight studies were used in the calculation of sensitivity (90%) and specificity (84%) of stress wall motion magnetic resonance imaging (MRI).⁶⁵ Eleven studies showed the average sensitivity and specificity of stress perfusion MRI to be 84% and 86%, respectively.⁶⁵ Finally, with late Gd enhancement, the sensitivity and specificity of MRI for predicting recovery of left ventricular function were estimated to be 81% and 83% (based on 13 studies).⁶⁵ This evidence was combined with clinical expertise and opinion to determine the CCS/CAR/CANM/CanSCMR recommendations.⁶⁵

 

Appendix 4: Comparative Diagnostic Accuracy

Diagnostic Accuracy Reported in MAS Review on the Use of Non-invasive Cardiac Imaging Technologies for the Diagnosis of Coronary Artery Disease13-17
Test	Reference Standard	Indication	Report	Period Reviewed	No. of Trials (patients)	Pooled Sensitivity (%) (95% CI)	Pooled Specificity (%) (95% CI)	DOR	AUC
99mTc -SPECT	Coronary angiography	Diagnosis of CAD	No. 817	Jan. 1, 2004 – Aug. 22, 2009	39 (3,488)	88 (85-91)	70 (64-76)	16.80 (10.88-22.71)	NR
201Tl-SPECT					24 (3,338)	84 (80-88)	71 (64-78)	12.88 (7.58-18.18)	NR
Stress Echo	Coronary angiography	Diagnosis of CAD	No. 914	Jan. 1, 2004 – Aug. 22, 2009	127* (13,035)	80 (77-82)	84 (82-87)	20.64 (16.63-24.64)	0.895
Contrast Echo	Coronary angiography	Diagnosis of CAD in patients with suspected CAD	No.1013	Jan. 1, 2004 – June 30, 2009	10	87.3 (83.2-90.8)	86.0 (82.0-89.4)	NR	0.944
		Diagnosis of CAD in patients with suspected or known CAD			12 (6 MPA and 6 WMA)	MPA: 87.8 (83.5-89.9)	MPA: 64.9 (59.1-70.4)	NR	MPA: 0.865
						WMA: 69.2 (64.8-73.4)	WMA: 79.4 (72.3-85.4)		WMA: 0.867
64-slice CTA	Coronary angiography	Diagnosis of CAD	No. 1114	Jan. 1, 2004 – June 20, 2009	8	97.7 (95.5-99.9)	78.8 (70.8-86.8)	NR	0.9435
					OMCAS trial (117 patients)	81.2 (71.9-89.6)	95.8 (85.7-99.5)	NR	NR
					8 studies + OMCAS trial	96.1 (94.0-98.3)	81.5 (73.0-89.9)	108.60 (30.22-186.97)	0.9622
Stress MRI	Coronary angiography	Diagnosis of CAD	No. 1215	Jan. 1, 2005 – Oct. 9, 2008	One MA + 11 studies	MPA: 91 (89-92)	MPA: 81 (77-85)	MPA: 37.91	MPA: 0.930
						WMA: 83 (79-88)	WMA: 86 (81-91)	WMA: 26.27	WMA: 0.926

AUC = area under the curve; CAD = coronary artery disease; CI = confidence interval; CTA = computed tomographic angiography; DOR = diagnostic odds ratio; echo = echocardiography; MA = meta-analysis; MAS = Medical Advisory Secretariat; MPA = myocardial perfusion analyses; MRI = magnetic resonance imaging; NR = not reported; OMCAS = Ontario Multidetector Coronary Angiography Study; SPECT = single-photon emission computed tomography; ^99mTc = technetium-99m; ²⁰¹Tl = thallium-201; WMA = wall motion analyses.
* A study was counted twice if data were reported on different stress agents.

Relative Diagnostic Accuracy of Computed Tomography, using 99mTc-SPECT as a Reference Standard23-25
Study Details		Population			Outcome
Author	Publication Date	N	Mean Age	Patient Characteristics	Reference Standard	Sens. (%)	Spec. (%)	Acc. (%)	PPV (%)	NPV (%)
Cheng23	2010	55	60.7	Patients with known or suspected CAD	Rest SPECT	100	78.0	83.6	60.9	100
					Stress SPECT	83.3	90.3	87.3	87.0	87.5
Bauer24	2009	73	56	Patients with known or suspected CAD	Any perfusion defect (99mTc-SPECT)	46	83	NR	58	75
					Reversible perfusion defect (99mTc-SPECT)	33	83	NR	33	83
Ruzsics25	2009	37	57	Patients with known or suspected CAD with pre-test probabilities of low (22%), intermediate (63%) and high (15%)	All perfusion defects (99mTc-SPECT)	97	67	92	93	80
					Fixed perfusion defects (99mTc-SPECT)	94	67	87	89	80
					Reversible perfusion defects (99mTc-SPECT)	100	67	89	87	100

Acc = accuracy; CAD = coronary artery disease; NPV = negative predictive value; PPV = positive predictive value; Sens. = sensitivity; Spec. = specificity; SPECT = single-photon emission computed tomography; ^99mTc = technetium-99m.

 

Appendix 5: Definitions

Angina (angina pectoris): severe pain and constriction around the heart.⁷⁵

Ischemia: insufficient blood supply to the heart muscle due to obstruction.⁷⁵

Myocardium: the middle layer of the walls of the heart, composed of cardiac muscle.⁷⁵

Stenosis (stenosis cardiac): A narrowing or constriction of any of the orifices leading into or from the heart, or between the chambers of the heart.⁷⁵