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1.  High-Efficiency SPECT MPI: Comparison of Automated Quantification, Visual Interpretation, and Coronary Angiography 
Background
Recently introduced high-efficiency (HE) SPECT cameras with solid-state CZT detectors have been shown to decrease imaging time and reduce radiation exposure to patients. An automated, computer derived quantification of HE MPI has been shown to correlate well with coronary angiography on one HE SPECT camera system (D-SPECT), but has not been compared to visual interpretation on any of the HE SPECT platforms.
Methods
Patients undergoing a clinically indicated Tc-99m sestamibi HE SPECT (GE Discovery 530c with supine and prone imaging) study over a one year period followed by a coronary angiogram within 2 months were included. Only patients with a history of CABG surgery were excluded. Both MPI studies and coronary angiograms were reinterpreted by blinded readers. One hundred and twenty two very low (risk of CAD < 5%) or low (risk of CAD < 10%) likelihood subjects with normal myocardial perfusion were used to create normal reference limits. Computer derived quantification of the total perfusion deficit (TPD) at stress and rest was obtained with QPS software. The visual and automated MPI quantification were compared to coronary angiography (≥ 70% luminal stenosis) by receiver operating curve (ROC) analysis.
Results
Of the 3,111 patients who underwent HE SPECT over a one year period, 160 patients qualified for the correlation study (66% male, 52% with a history of CAD). The ROC area under the curve (AUC) was similar for both the automated and visual interpretations using both supine only and combined supine and prone images (0.69-0.74). Using thresholds determined from sensitivity and specificity curves, the automated reads showed higher specificity (59-67% versus 27-60%) and lower sensitivity (71-72% versus 79-93%) than the visual reads. By including prone images sensitivity decreased slightly but specificity increased for both. By excluding patients with known CAD and cardiomyopathies, AUC and specificity increased for both techniques (0.72-0.82). The use of a difference score to evaluate ischemic burden resulted in lower sensitivities but higher specificities for both automated and visual quantification. There was good agreement between the visual interpretation and automated quantification in the entire cohort of 160 unselected consecutive patients (r = 0.70-0.81, p < 0.0001).
Conclusions
Automated and visual quantification of high-efficiency SPECT MPI with the GE Discovery camera provide similar overall diagnostic accuracy when compared to coronary angiography. There was good correlation between the two methods of assessment. Combined supine and prone stress imaging provided the best diagnostic accuracy.
doi:10.1007/s12350-013-9735-x
PMCID: PMC3820488  PMID: 23737160
CZT SPECT MPI; High-Efficiency SPECT MPI; Automated Quantification; Coronary Angiography
2.  Positron Emission Tomography for the Assessment of Myocardial Viability 
Executive Summary
In July 2009, the Medical Advisory Secretariat (MAS) began work on Non-Invasive Cardiac Imaging Technologies for the Assessment of Myocardial Viability, an evidence-based review of the literature surrounding different cardiac imaging modalities to ensure that appropriate technologies are accessed by patients undergoing viability assessment. This project came about when the Health Services Branch at the Ministry of Health and Long-Term Care asked MAS to provide an evidentiary platform on effectiveness and cost-effectiveness of non-invasive cardiac imaging modalities.
After an initial review of the strategy and consultation with experts, MAS identified five key non-invasive cardiac imaging technologies that can be used for the assessment of myocardial viability: positron emission tomography, cardiac magnetic resonance imaging, dobutamine echocardiography, and dobutamine echocardiography with contrast, and single photon emission computed tomography.
A 2005 review conducted by MAS determined that positron emission tomography was more sensitivity than dobutamine echocardiography and single photon emission tomography and dominated the other imaging modalities from a cost-effective standpoint. However, there was inadequate evidence to compare positron emission tomography and cardiac magnetic resonance imaging. Thus, this report focuses on this comparison only. For both technologies, an economic analysis was also completed.
The Non-Invasive Cardiac Imaging Technologies for the Assessment of Myocardial Viability is made up of the following reports, which can be publicly accessed at the MAS website at: www.health.gov.on.ca/mas or at www.health.gov.on.ca/english/providers/program/mas/mas_about.html
Positron Emission Tomography for the Assessment of Myocardial Viability: An Evidence-Based Analysis
Magnetic Resonance Imaging for the Assessment of Myocardial Viability: An Evidence-Based Analysis
Objective
The objective of this analysis is to assess the effectiveness and safety of positron emission tomography (PET) imaging using F-18-fluorodeoxyglucose (FDG) for the assessment of myocardial viability. To evaluate the effectiveness of FDG PET viability imaging, the following outcomes are examined:
the diagnostic accuracy of FDG PET for predicting functional recovery;
the impact of PET viability imaging on prognosis (mortality and other patient outcomes); and
the contribution of PET viability imaging to treatment decision making and subsequent patient outcomes.
Clinical Need: Condition and Target Population
Left Ventricular Systolic Dysfunction and Heart Failure
Heart failure is a complex syndrome characterized by the heart’s inability to maintain adequate blood circulation through the body leading to multiorgan abnormalities and, eventually, death. Patients with heart failure experience poor functional capacity, decreased quality of life, and increased risk of morbidity and mortality.
In 2005, more than 71,000 Canadians died from cardiovascular disease, of which, 54% were due to ischemic heart disease. Left ventricular (LV) systolic dysfunction due to coronary artery disease (CAD)1 is the primary cause of heart failure accounting for more than 70% of cases. The prevalence of heart failure was estimated at one percent of the Canadian population in 1989. Since then, the increase in the older population has undoubtedly resulted in a substantial increase in cases. Heart failure is associated with a poor prognosis: one-year mortality rates were 32.9% and 31.1% for men and women, respectively in Ontario between 1996 and 1997.
Treatment Options
In general, there are three options for the treatment of heart failure: medical treatment, heart transplantation, and revascularization for those with CAD as the underlying cause. Concerning medical treatment, despite recent advances, mortality remains high among treated patients, while, heart transplantation is affected by the limited availability of donor hearts and consequently has long waiting lists. The third option, revascularization, is used to restore the flow of blood to the heart via coronary artery bypass grafting (CABG) or through minimally invasive percutaneous coronary interventions (balloon angioplasty and stenting). Both methods, however, are associated with important perioperative risks including mortality, so it is essential to properly select patients for this procedure.
Myocardial Viability
Left ventricular dysfunction may be permanent if a myocardial scar is formed, or it may be reversible after revascularization. Reversible LV dysfunction occurs when the myocardium is viable but dysfunctional (reduced contractility). Since only patients with dysfunctional but viable myocardium benefit from revascularization, the identification and quantification of the extent of myocardial viability is an important part of the work-up of patients with heart failure when determining the most appropriate treatment path. Various non-invasive cardiac imaging modalities can be used to assess patients in whom determination of viability is an important clinical issue, specifically:
dobutamine echocardiography (echo),
stress echo with contrast,
SPECT using either technetium or thallium,
cardiac magnetic resonance imaging (cardiac MRI), and
positron emission tomography (PET).
Dobutamine Echocardiography
Stress echocardiography can be used to detect viable myocardium. During the infusion of low dose dobutamine (5 – 10 μg/kg/min), an improvement of contractility in hypokinetic and akentic segments is indicative of the presence of viable myocardium. Alternatively, a low-high dose dobutamine protocol can be used in which a biphasic response characterized by improved contractile function during the low-dose infusion followed by a deterioration in contractility due to stress induced ischemia during the high dose dobutamine infusion (dobutamine dose up to 40 ug/kg/min) represents viable tissue. Newer techniques including echocardiography using contrast agents, harmonic imaging, and power doppler imaging may help to improve the diagnostic accuracy of echocardiographic assessment of myocardial viability.
Stress Echocardiography with Contrast
Intravenous contrast agents, which are high molecular weight inert gas microbubbles that act like red blood cells in the vascular space, can be used during echocardiography to assess myocardial viability. These agents allow for the assessment of myocardial blood flow (perfusion) and contractile function (as described above), as well as the simultaneous assessment of perfusion to make it possible to distinguish between stunned and hibernating myocardium.
SPECT
SPECT can be performed using thallium-201 (Tl-201), a potassium analogue, or technetium-99 m labelled tracers. When Tl-201 is injected intravenously into a patient, it is taken up by the myocardial cells through regional perfusion, and Tl-201 is retained in the cell due to sodium/potassium ATPase pumps in the myocyte membrane. The stress-redistribution-reinjection protocol involves three sets of images. The first two image sets (taken immediately after stress and then three to four hours after stress) identify perfusion defects that may represent scar tissue or viable tissue that is severely hypoperfused. The third set of images is taken a few minutes after the re-injection of Tl-201 and after the second set of images is completed. These re-injection images identify viable tissue if the defects exhibit significant fill-in (> 10% increase in tracer uptake) on the re-injection images.
The other common Tl-201 viability imaging protocol, rest-redistribution, involves SPECT imaging performed at rest five minutes after Tl-201 is injected and again three to four hours later. Viable tissue is identified if the delayed images exhibit significant fill-in of defects identified in the initial scans (> 10% increase in uptake) or if defects are fixed but the tracer activity is greater than 50%.
There are two technetium-99 m tracers: sestamibi (MIBI) and tetrofosmin. The uptake and retention of these tracers is dependent on regional perfusion and the integrity of cellular membranes. Viability is assessed using one set of images at rest and is defined by segments with tracer activity greater than 50%.
Cardiac Magnetic Resonance Imaging
Cardiac magnetic resonance imaging (cardiac MRI) is a non-invasive, x-ray free technique that uses a powerful magnetic field, radio frequency pulses, and a computer to produce detailed images of the structure and function of the heart. Two types of cardiac MRI are used to assess myocardial viability: dobutamine stress magnetic resonance imaging (DSMR) and delayed contrast-enhanced cardiac MRI (DE-MRI). DE-MRI, the most commonly used technique in Ontario, uses gadolinium-based contrast agents to define the transmural extent of scar, which can be visualized based on the intensity of the image. Hyper-enhanced regions correspond to irreversibly damaged myocardium. As the extent of hyper-enhancement increases, the amount of scar increases, so there is a lower the likelihood of functional recovery.
Cardiac Positron Emission Tomography
Positron emission tomography (PET) is a nuclear medicine technique used to image tissues based on the distinct ways in which normal and abnormal tissues metabolize positron-emitting radionuclides. Radionuclides are radioactive analogs of common physiological substrates such as sugars, amino acids, and free fatty acids that are used by the body. The only licensed radionuclide used in PET imaging for viability assessment is F-18 fluorodeoxyglucose (FDG).
During a PET scan, the radionuclides are injected into the body and as they decay, they emit positively charged particles (positrons) that travel several millimetres into tissue and collide with orbiting electrons. This collision results in annihilation where the combined mass of the positron and electron is converted into energy in the form of two 511 keV gamma rays, which are then emitted in opposite directions (180 degrees) and captured by an external array of detector elements in the PET gantry. Computer software is then used to convert the radiation emission into images. The system is set up so that it only detects coincident gamma rays that arrive at the detectors within a predefined temporal window, while single photons arriving without a pair or outside the temporal window do not active the detector. This allows for increased spatial and contrast resolution.
Evidence-Based Analysis
Research Questions
What is the diagnostic accuracy of PET for detecting myocardial viability?
What is the prognostic value of PET viability imaging (mortality and other clinical outcomes)?
What is the contribution of PET viability imaging to treatment decision making?
What is the safety of PET viability imaging?
Literature Search
A literature search was performed on July 17, 2009 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from January 1, 2004 to July 16, 2009. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. In addition, published systematic reviews and health technology assessments were reviewed for relevant studies published before 2004. Reference lists of included studies were also examined for any additional relevant studies not already identified. The quality of the body of evidence was assessed as high, moderate, low or very low according to GRADE methodology.
Inclusion Criteria
Criteria applying to diagnostic accuracy studies, prognosis studies, and physician decision-making studies:
English language full-reports
Health technology assessments, systematic reviews, meta-analyses, randomized controlled trials (RCTs), and observational studies
Patients with chronic, known CAD
PET imaging using FDG for the purpose of detecting viable myocardium
Criteria applying to diagnostic accuracy studies:
Assessment of functional recovery ≥3 months after revascularization
Raw data available to calculate sensitivity and specificity
Gold standard: prediction of global or regional functional recovery
Criteria applying to prognosis studies:
Mortality studies that compare revascularized patients with non-revascularized patients and patients with viable and non-viable myocardium
Exclusion Criteria
Criteria applying to diagnostic accuracy studies, prognosis studies, and physician decision-making studies:
PET perfusion imaging
< 20 patients
< 18 years of age
Patients with non-ischemic heart disease
Animal or phantom studies
Studies focusing on the technical aspects of PET
Studies conducted exclusively in patients with acute myocardial infarction (MI)
Duplicate publications
Criteria applying to diagnostic accuracy studies
Gold standard other than functional recovery (e.g., PET or cardiac MRI)
Assessment of functional recovery occurs before patients are revascularized
Outcomes of Interest
Diagnostic accuracy studies
Sensitivity and specificity
Positive and negative predictive values (PPV and NPV)
Positive and negative likelihood ratios
Diagnostic accuracy
Adverse events
Prognosis studies
Mortality rate
Functional status
Exercise capacity
Quality of Life
Influence on PET viability imaging on physician decision making
Statistical Methods
Pooled estimates of sensitivity and specificity were calculated using a bivariate, binomial generalized linear mixed model. Statistical significance was defined by P values less than 0.05, where “false discovery rate” adjustments were made for multiple hypothesis testing. Using the bivariate model parameters, summary receiver operating characteristic (sROC) curves were produced. The area under the sROC curve was estimated by numerical integration with a cubic spline (default option). Finally, pooled estimates of mortality rates were calculated using weighted means.
Quality of Evidence
The quality of evidence assigned to individual diagnostic studies was determined using the QUADAS tool, a list of 14 questions that address internal and external validity, bias, and generalizibility of diagnostic accuracy studies. Each question is scored as “yes”, “no”, or “unclear”. The quality of the body of evidence was then assessed as high, moderate, low, or very low according to the GRADE Working Group criteria. The following definitions of quality were used in grading the quality of the evidence:
Summary of Findings
A total of 40 studies met the inclusion criteria and were included in this review: one health technology assessment, two systematic reviews, 22 observational diagnostic accuracy studies, and 16 prognosis studies. The available PET viability imaging literature addresses two questions: 1) what is the diagnostic accuracy of PET imaging for the assessment; and 2) what is the prognostic value of PET viability imaging. The diagnostic accuracy studies use regional or global functional recovery as the reference standard to determine the sensitivity and specificity of the technology. While regional functional recovery was most commonly used in the studies, global functional recovery is more important clinically. Due to differences in reporting and thresholds, however, it was not possible to pool global functional recovery.
Functional recovery, however, is a surrogate reference standard for viability and consequently, the diagnostic accuracy results may underestimate the specificity of PET viability imaging. For example, regional functional recovery may take up to a year after revascularization depending on whether it is stunned or hibernating tissue, while many of the studies looked at regional functional recovery 3 to 6 months after revascularization. In addition, viable tissue may not recover function after revascularization due to graft patency or re-stenosis. Both issues may lead to false positives and underestimate specificity. Given these limitations, the prognostic value of PET viability imaging provides the most direct and clinically useful information. This body of literature provides evidence on the comparative effectiveness of revascularization and medical therapy in patients with viable myocardium and patients without viable myocardium. In addition, the literature compares the impact of PET-guided treatment decision making with SPECT-guided or standard care treatment decision making on survival and cardiac events (including cardiac mortality, MI, hospital stays, unintended revascularization, etc).
The main findings from the diagnostic accuracy and prognosis evidence are:
Based on the available very low quality evidence, PET is a useful imaging modality for the detection of viable myocardium. The pooled estimates of sensitivity and specificity for the prediction of regional functional recovery as a surrogate for viable myocardium are 91.5% (95% CI, 88.2% – 94.9%) and 67.8% (95% CI, 55.8% – 79.7%), respectively.
Based the available very low quality of evidence, an indirect comparison of pooled estimates of sensitivity and specificity showed no statistically significant difference in the diagnostic accuracy of PET viability imaging for regional functional recovery using perfusion/metabolism mismatch with FDG PET plus either a PET or SPECT perfusion tracer compared with metabolism imaging with FDG PET alone.
FDG PET + PET perfusion metabolism mismatch: sensitivity, 89.9% (83.5% – 96.4%); specificity, 78.3% (66.3% – 90.2%);
FDG PET + SPECT perfusion metabolism mismatch: sensitivity, 87.2% (78.0% – 96.4%); specificity, 67.1% (48.3% – 85.9%);
FDG PET metabolism: sensitivity, 94.5% (91.0% – 98.0%); specificity, 66.8% (53.2% – 80.3%).
Given these findings, further higher quality studies are required to determine the comparative effectiveness and clinical utility of metabolism and perfusion/metabolism mismatch viability imaging with PET.
Based on very low quality of evidence, patients with viable myocardium who are revascularized have a lower mortality rate than those who are treated with medical therapy. Given the quality of evidence, however, this estimate of effect is uncertain so further higher quality studies in this area should be undertaken to determine the presence and magnitude of the effect.
While revascularization may reduce mortality in patients with viable myocardium, current moderate quality RCT evidence suggests that PET-guided treatment decisions do not result in statistically significant reductions in mortality compared with treatment decisions based on SPECT or standard care protocols. The PARR II trial by Beanlands et al. found a significant reduction in cardiac events (a composite outcome that includes cardiac deaths, MI, or hospital stay for cardiac cause) between the adherence to PET recommendations subgroup and the standard care group (hazard ratio, .62; 95% confidence intervals, 0.42 – 0.93; P = .019); however, this post-hoc sub-group analysis is hypothesis generating and higher quality studies are required to substantiate these findings.
The use of FDG PET plus SPECT to determine perfusion/metabolism mismatch to assess myocardial viability increases the radiation exposure compared with FDG PET imaging alone or FDG PET combined with PET perfusion imaging (total-body effective dose: FDG PET, 7 mSv; FDG PET plus PET perfusion tracer, 7.6 – 7.7 mSV; FDG PET plus SPECT perfusion tracer, 16 – 25 mSv). While the precise risk attributed to this increased exposure is unknown, there is increasing concern regarding lifetime multiple exposures to radiation-based imaging modalities, although the incremental lifetime risk for patients who are older or have a poor prognosis may not be as great as for healthy individuals.
PMCID: PMC3377573  PMID: 23074393
3.  Flurpiridaz F 18 PET: Phase II Safety and Clinical Comparison with SPECT Myocardial Perfusion Imaging for Detection of Coronary Artery Disease 
Objectives
Phase II trial to assess flurpiridaz F 18 for safety and compare its diagnostic performance for PET myocardial perfusion imaging (MPI) to Tc-99m SPECT-MPI regarding image quality, interpretative certainty, defect magnitude and detection of coronary artery disease (CAD)(≥ 50% stenosis) on invasive coronary angiography (ICA).
Background
In preclinical and phase I studies, flurpiridaz F 18 has shown characteristics of an essentially ideal MPI tracer.
Methods
143 patients from 21 centers underwent rest-stress PET and Tc-99m SPECT-MPI. Eighty-six patients underwent ICA, and 39 had low-likelihood of CAD. Images were scored by 3 independent, blinded readers.
Results
A higher % of images were rated as excellent/good on PET vs. SPECT on stress (99.2% vs. 88.5%, p<0.01) and rest (96.9% vs. 66.4, p<0.01) images. Diagnostic certainty of interpretation (% cases with definitely abnormal/normal interpretation) was higher for PET vs. SPECT (90.8% vs. 70.9%, p<0.01). In 86 patients who underwent ICA, sensitivity of PET was higher than SPECT [78.8% vs. 61.5%, respectively (p=0.02)]. Specificity was not significantly different (PET:76.5% vs. SPECT:73.5%). Receiver operating characteristic curve area was 0.82±0.05 for PET and 0.70±0.06 for SPECT (p=0.04). Normalcy rate was 89.7% with PET and 97.4% with SPECT (p=NS). In patients with CAD on ICA, the magnitude of reversible defects was greater with PET than SPECT (p=0.008). Extensive safety assessment revealed that flurpiridaz F 18 was safe in this cohort.
Conclusions
In this Phase 2 trial, PET MPI using flurpiridaz F 18 was safe and superior to SPECT MPI for image quality, interpretative certainty, and overall CAD diagnosis.
doi:10.1016/j.jacc.2012.11.022
PMCID: PMC4316725  PMID: 23265345
Flurpiridaz F18; Myocarial Perfusion; SPECT
4.  Assessment of the relationship between stenosis severity and distribution of coronary artery stenoses on multislice computed tomographic angiography and myocardial ischemia detected by single photon emission computed tomography 
Journal of Nuclear Cardiology  2010;17(5):791-802.
Background
The relationship between luminal stenosis measured by coronary CT angiography (CCTA) and severity of stress-induced ischemia seen on single photon emission computed tomographic myocardial perfusion imaging (SPECT-MPI) is not clearly defined. We sought to evaluate the relationship between stenosis severity assessed by CCTA and ischemia on SPECT-MPI.
Methods and Results
ECG-gated CCTA (64 slice dual source CT) and SPECT-MPI were performed within 6 months in 292 patients (ages 26-91, 73% male) with no prior history of coronary artery disease. Maximal coronary luminal narrowing, graded as 0, ≥25%, 50%, 70%, or 90% visual diameter reduction, was consensually assessed by two expert readers. Perfusion defect on SPECT-MPI was assessed by computer-assisted visual interpretation by an expert reader using the standard 17 segment, 5 point-scoring model (stress perfusion defect of ≥5% = abnormal). By SPECT-MPI, abnormal perfusion was seen in 46/292 patients. With increasing stenosis severity, positive predictive value (PPV) increased (42%, 51%, and 74%, P = .01) and negative predictive value was relatively unchanged (97%, 95%, and 91%) in detecting perfusion abnormalities on SPECT-MPI. In a receiver operator curve analysis, stenosis of 50% and 70% were equally effective in differentiating between the presence and absence of ischemia. In a multivariate analysis that included stenosis severity, multivessel disease, plaque composition, and presence of serial stenoses in a coronary artery, the strongest predictors of ischemia were stenosis of 50-89%, odds ratio (OR) 7.31, P = .001, stenosis ≥90%, OR 34.05, P = .0001, and serial stenosis ≥50% OR of 3.55, P = .006.
Conclusions
The PPV of CCTA for ischemia by SPECT-MPI rises as stenosis severity increases. Luminal stenosis ≥90% on CCTA strongly predicts ischemia, while <50% stenosis strongly predicts the absence of ischemia. Serial stenosis of ≥50% in a vessel may offer incremental value in addition to stenosis severity in predicting ischemia.
doi:10.1007/s12350-010-9230-6
PMCID: PMC2940027  PMID: 20425027
Myocardial perfusion imaging; SPECT; computed tomography (CT); ischemia; myocardial; SPECT; coronary artery disease
5.  Predictors and Diagnostic Significance of the Adenosine Related Side Effects on Myocardial Perfusion SPECT/CT Imaging 
Objective: The aim of this study was to investigate the relationship between patient characteristics and adenosine-related side-effects during stress myocard perfusion imaging (MPI). The effect of presence of adenosine-related side-effects on the diagnostic value of MPI with integrated SPECT/CT system for coronary artery disease (CAD), was also assessed in this study.
Methods: Total of 281 patients (109 M, 172 F; mean age:62.6±10) who underwent standard adenosine stress protocol for MPI, were included in this study. All symptoms during adenosine infusion were scored according to the severity and duration. For the estimation of diagnostic value of adenosine MPI with integrated SPECT/CT system, coronary angiography (CAG) or clinical follow-up were used as gold standard.
Results: Total of 173 patients (61.6%) experienced adenosine-related side-effects (group 1); flushing, dyspnea, and chest pain were the most common. Other 108 patients completed pharmacologic stress (PS) test without any side-effects (group 2). Test tolerability were similar in the patients with cardiovascular or airway disease to others, however dyspnea were observed significantly more common in patients with mild airway disease. Body mass index (BMI) ≥30 kg/m2 and age ≤45 years were independent predictors of side-effects. The diagnostic value of MPI was similar in both groups. Sensitivity of adenosine MPI SPECT/CT was calculated to be 86%, specificity was 94% and diagnostic accuracy was 92% for diagnosis of CAD.
Conclusion: Adenosine MPI is a feasible and well tolerated method in patients who are not suitable for exercise stress test as well as patients with cardiopulmonary disease. However age ≤45 years and BMI ≥30 kg/m2 are the positive predictors of adenosine-related side-effects, the diagnostic value of adenosine MPI SPECT/CT is not affected by the presence of adenosine related side-effects.
doi:10.4274/mirt.85057
PMCID: PMC4288229  PMID: 25541932
Adenosine; myocardial perfusion imaging; side effects; single-photon emission computerized tomography; computed tomography; X-ray
6.  Feasibility and diagnostic power of transthoracic coronary Doppler for coronary flow velocity reserve in patients referred for myocardial perfusion imaging 
Background
Myocardial perfusion imaging (MPI), using single photon emission computed tomography (SPECT) is a validated method for detecting coronary artery disease. Transthoracic Doppler echocardiography (TTDE) of flow at rest and during adenosine provocation has previously been evaluated in selected patient groups. We therefore wanted to compare the diagnostic ability of TTDE in the left anterior descending coronary artery (LAD) to that of MPI in an unselected population of patients with chest pain referred for MPI. Our hypothesis was that TTDE with high accuracy would identify healthy individuals and exclude them from the need for further studies, enabling invasive investigations to be reserved for patients with a high probability of disease.
Methods
Sixty-nine patients, 44 men and 25 women, age 61 ± 10 years (range 35–82), with a clinical suspicion of stress induced myocardial ischemia, were investigated. TTDE was performed at rest and during adenosine stress for myocardial scintigraphy.
Results
We found that coronary flow velocity reserve (CFVR) determined from diastolic measurements separated normal from abnormal MPI findings with statistical significance. TTDE identified coronary artery disease, defined from MPI, as reversible ischemia and/or permanent defect, with a sensitivity of 60% and a specificity of 79%. The positive predictive value was 43% and the negative predictive value was 88%. There was an overlap between groups which could be due to abnormal endothelial function in patients with normal myocardial perfusion having either hypertension or diabetes.
Conclusion
TTDE is an attractive non-invasive method to evaluate chest pain without the use of isotopes, but the diagnostic power is strongly dependent on the population investigated. Even in our heterogeneous clinical cardiac population, we found that CFVR>2 in the LAD excluded significant coronary artery disease detected by MPI.
doi:10.1186/1476-7120-6-12
PMCID: PMC2292686  PMID: 18373873
7.  Magnetic Resonance Imaging (MRI) for the Assessment of Myocardial Viability 
Executive Summary
In July 2009, the Medical Advisory Secretariat (MAS) began work on Non-Invasive Cardiac Imaging Technologies for the Assessment of Myocardial Viability, an evidence-based review of the literature surrounding different cardiac imaging modalities to ensure that appropriate technologies are accessed by patients undergoing viability assessment. This project came about when the Health Services Branch at the Ministry of Health and Long-Term Care asked MAS to provide an evidentiary platform on effectiveness and cost-effectiveness of noninvasive cardiac imaging modalities.
After an initial review of the strategy and consultation with experts, MAS identified five key non-invasive cardiac imaging technologies that can be used for the assessment of myocardial viability: positron emission tomography, cardiac magnetic resonance imaging, dobutamine echocardiography, and dobutamine echocardiography with contrast, and single photon emission computed tomography.
A 2005 review conducted by MAS determined that positron emission tomography was more sensitivity than dobutamine echocardiography and single photon emission tomography and dominated the other imaging modalities from a cost-effective standpoint. However, there was inadequate evidence to compare positron emission tomography and cardiac magnetic resonance imaging. Thus, this report focuses on this comparison only. For both technologies, an economic analysis was also completed.
A summary decision analytic model was then developed to encapsulate the data from each of these reports (available on the OHTAC and MAS website).
The Non-Invasive Cardiac Imaging Technologies for the Assessment of Myocardial Viability is made up of the following reports, which can be publicly accessed at the MAS website at: www.health.gov.on.ca/mas or at www.health.gov.on.ca/english/providers/program/mas/mas_about.html
Positron Emission Tomography for the Assessment of Myocardial Viability: An Evidence-Based Analysis
Magnetic Resonance Imaging for the Assessment of Myocardial Viability: An Evidence-Based Analysis
Objective
The objective of this analysis is to assess the effectiveness and cost-effectiveness of cardiovascular magnetic resonance imaging (cardiac MRI) for the assessment of myocardial viability. To evaluate the effectiveness of cardiac MRI viability imaging, the following outcomes were examined: the diagnostic accuracy in predicting functional recovery and the impact of cardiac MRI viability imaging on prognosis (mortality and other patient outcomes).
Clinical Need: Condition and Target Population
Left Ventricular Systolic Dysfunction and Heart Failure
Heart failure is a complex syndrome characterized by the heart’s inability to maintain adequate blood circulation through the body leading to multiorgan abnormalities and, eventually, death. Patients with heart failure experience poor functional capacity, decreased quality of life, and increased risk of morbidity and mortality.
In 2005, more than 71,000 Canadians died from cardiovascular disease, of which, 54% were due to ischemic heart disease. Left ventricular (LV) systolic dysfunction due to coronary artery disease (CAD) 1 is the primary cause of heart failure accounting for more than 70% of cases. The prevalence of heart failure was estimated at one percent of the Canadian population in 1989. Since then, the increase in the older population has undoubtedly resulted in a substantial increase in cases. Heart failure is associated with a poor prognosis: one-year mortality rates were 32.9% and 31.1% for men and women, respectively in Ontario between 1996 and 1997.
Treatment Options
In general, there are three options for the treatment of heart failure: medical treatment, heart transplantation, and revascularization for those with CAD as the underlying cause. Concerning medical treatment, despite recent advances, mortality remains high among treated patients, while, heart transplantation is affected by the limited availability of donor hearts and consequently has long waiting lists. The third option, revascularization, is used to restore the flow of blood to the heart via coronary artery bypass grafting (CABG) or, in some cases, through minimally invasive percutaneous coronary interventions (balloon angioplasty and stenting). Both methods, however, are associated with important perioperative risks including mortality, so it is essential to properly select patients for this procedure.
Myocardial Viability
Left ventricular dysfunction may be permanent, due to the formation of myocardial scar, or it may be reversible after revascularization. Reversible LV dysfunction occurs when the myocardium is viable but dysfunctional (reduced contractility). Since only patients with dysfunctional but viable myocardium benefit from revascularization, the identification and quantification of the extent of myocardial viability is an important part of the work-up of patients with heart failure when determining the most appropriate treatment path. Various non-invasive cardiac imaging modalities can be used to assess patients in whom determination of viability is an important clinical issue, specifically:
dobutamine echocardiography (echo),
stress echo with contrast,
SPECT using either technetium or thallium,
cardiac magnetic resonance imaging (cardiac MRI), and
positron emission tomography (PET).
Dobutamine Echocardiography
Stress echocardiography can be used to detect viable myocardium. During the infusion of low dose dobutamine (5 – 10 µg/kg/min), an improvement of contractility in hypokinetic and akentic segments is indicative of the presence of viable myocardium. Alternatively, a low-high dose dobutamine protocol can be used in which a biphasic response characterized by improved contractile function during the low-dose infusion followed by a deterioration in contractility due to stress induced ischemia during the high dose dobutamine infusion (dobutamine dose up to 40 ug/kg/min) represents viable tissue. Newer techniques including echocardiography using contrast agents, harmonic imaging, and power doppler imaging may help to improve the diagnostic accuracy of echocardiographic assessment of myocardial viability.
Stress Echocardiography with Contrast
Intravenous contrast agents, which are high molecular weight inert gas microbubbles that act like red blood cells in the vascular space, can be used during echocardiography to assess myocardial viability. These agents allow for the assessment of myocardial blood flow (perfusion) and contractile function (as described above), as well as the simultaneous assessment of perfusion to make it possible to distinguish between stunned and hibernating myocardium.
SPECT
SPECT can be performed using thallium-201 (Tl-201), a potassium analogue, or technetium-99 m labelled tracers. When Tl-201 is injected intravenously into a patient, it is taken up by the myocardial cells through regional perfusion, and Tl-201 is retained in the cell due to sodium/potassium ATPase pumps in the myocyte membrane. The stress-redistribution-reinjection protocol involves three sets of images. The first two image sets (taken immediately after stress and then three to four hours after stress) identify perfusion defects that may represent scar tissue or viable tissue that is severely hypoperfused. The third set of images is taken a few minutes after the re-injection of Tl-201 and after the second set of images is completed. These re-injection images identify viable tissue if the defects exhibit significant fill-in (> 10% increase in tracer uptake) on the re-injection images.
The other common Tl-201 viability imaging protocol, rest-redistribution, involves SPECT imaging performed at rest five minutes after Tl-201 is injected and again three to four hours later. Viable tissue is identified if the delayed images exhibit significant fill-in of defects identified in the initial scans (> 10% increase in uptake) or if defects are fixed but the tracer activity is greater than 50%.
There are two technetium-99 m tracers: sestamibi (MIBI) and tetrofosmin. The uptake and retention of these tracers is dependent on regional perfusion and the integrity of cellular membranes. Viability is assessed using one set of images at rest and is defined by segments with tracer activity greater than 50%.
Cardiac Positron Emission Tomography
Positron emission tomography (PET) is a nuclear medicine technique used to image tissues based on the distinct ways in which normal and abnormal tissues metabolize positron-emitting radionuclides. Radionuclides are radioactive analogs of common physiological substrates such as sugars, amino acids, and free fatty acids that are used by the body. The only licensed radionuclide used in PET imaging for viability assessment is F-18 fluorodeoxyglucose (FDG).
During a PET scan, the radionuclides are injected into the body and as they decay, they emit positively charged particles (positrons) that travel several millimetres into tissue and collide with orbiting electrons. This collision results in annihilation where the combined mass of the positron and electron is converted into energy in the form of two 511 keV gamma rays, which are then emitted in opposite directions (180 degrees) and captured by an external array of detector elements in the PET gantry. Computer software is then used to convert the radiation emission into images. The system is set up so that it only detects coincident gamma rays that arrive at the detectors within a predefined temporal window, while single photons arriving without a pair or outside the temporal window do not active the detector. This allows for increased spatial and contrast resolution.
Cardiac Magnetic Resonance Imaging
Cardiac magnetic resonance imaging (cardiac MRI) is a non-invasive, x-ray free technique that uses a powerful magnetic field, radio frequency pulses, and a computer to produce detailed images of the structure and function of the heart. Two types of cardiac MRI are used to assess myocardial viability: dobutamine stress magnetic resonance imaging (DSMR) and delayed contrast-enhanced cardiac MRI (DE-MRI). DE-MRI, the most commonly used technique in Ontario, uses gadolinium-based contrast agents to define the transmural extent of scar, which can be visualized based on the intensity of the image. Hyper-enhanced regions correspond to irreversibly damaged myocardium. As the extent of hyper-enhancement increases, the amount of scar increases, so there is a lower the likelihood of functional recovery.
Evidence-Based Analysis
Research Questions
What is the diagnostic accuracy of cardiac MRI for detecting myocardial viability?
What is the impact of cardiac MRI viability imaging on prognosis (mortality and other clinical outcomes)?
How does cardiac MRI compare with cardiac PET imaging for the assessment of myocardial viability?
What is the contribution of cardiac MRI viability imaging to treatment decision making?
Is cardiac MRI cost-effective compared with other cardiac imaging modalities for the assessment of myocardial viability?
Literature Search
A literature search was performed on October 9, 2009 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from January 1, 2005 until October 9, 2009. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria full-text articles were obtained. In addition, published systematic reviews and health technology assessments were reviewed for relevant studies published before 2005. Reference lists were also examined for any additional relevant studies not identified through the search. The quality of evidence was assessed as high, moderate, low or very low according to GRADE methodology.
Inclusion Criteria
English language full-reports
Published between January 1, 2005 and October 9, 2009
Health technology assessments, systematic reviews, meta-analyses, randomized controlled trials (RCTs), and observational studies
Patients with chronic, known coronary artery disease (CAD)
Used contrast-enhanced MRI
Assessment of functional recovery ≥ 3 months after revascularization
Exclusion Criteria
< 20 patients
< 18 years of age
Patients with non-ischemic heart disease
Studies conducted exclusively in patients with acute myocardial infarction (MI)
Studies where TP, TN, FP, FN cannot be determined
Outcomes of Interest
Sensitivity
Specificity
Positive predictive value (PPV)
Negative Predictive value (NPV)
Positive likelihood ratio
Negative likelihood ratio
Diagnostic accuracy
Mortality rate (for prognostic studies)
Adverse events
Summary of Findings
Based on the available very low quality evidence, MRI is a useful imaging modality for the detection of viable myocardium. The pooled estimates of sensitivity and specificity for the prediction of regional functional recovery as a surrogate for viable myocardium are 84.5% (95% CI: 77.5% – 91.6%) and 71.0% (95% CI: 68.8% – 79.2%), respectively.
Subgroup analysis demonstrated a statistically significant difference in the sensitivity of MRI to assess myocardial viability for studies using ≤25% hyperenhancement as a viability threshold versus studies using ≤50% hyperenhancement as their viability threshold [78.7 (95% CI: 69.1% - 88.2%) and 96.2 (95% CI: 91.8 – 100.6); p=0.0044 respectively]. Marked differences in specificity were observed [73.6 (95% CI: 62.6% - 84.6%) and 47.2 (95% CI: 22.2 – 72.3); p=0.2384 respectively]; however, these findings were not statistically significant.
There were no statistically significant differences between the sensitivities or specificities for any other subgroups including mean preoperative LVEF, imaging method for function recovery assessment, and length of follow-up.
There was no evidence available to determine whether patients with viable myocardium who are revascularized have a lower mortality rate than those who are treated with medical therapy.
PMCID: PMC3426228  PMID: 23074392
8.  Single Resting hsTnT Level Predicts Abnormal Myocardial Stress Test in Acute Chest Pain Patients With Normal Initial Standard Troponin 
JACC. Cardiovascular imaging  2013;6(1):72-82.
OBJECTIVES
The goal of this study was to determine the ability of a single, resting high-sensitivity troponin T (hsTnT) measurement to predict abnormal myocardial perfusion imaging (MPI) in patients presenting with acute chest pain to the emergency department (ED).
BACKGROUND
HsTnT assays precisely detect very low levels of troponin T, which may be a surrogate for the presence and extent of myocardial ischemia.
METHODS
We included all patients from the ROMICAT I (Rule Out Myocardial Infarction Using Computer Assisted Tomography) trial, an observational cohort study, who underwent both single-photon emission computed tomography (SPECT)-MPI stress testing and 64-slice computed tomography angiography (CTA) and in whom hsTnT measurements were available. We assessed the discriminatory value of hsTnT for abnormal SPECT-MPI and the association of reversible myocardial ischemia by SPECT-MPI and the extent of coronary atherosclerosis by CTA to hsTnT levels.
RESULTS
Of the 138 patients (mean age 54 ± 11 years, 46% male), 19 (13.7%) had abnormal SPECT-MPI. Median hsTnT levels were significantly different between patients with normal and abnormal SPECT-MPI (9.41 pg/ml [interquartile range (IQR): 5.73 to 19.20 pg/ml] vs. 4.89 pg/ml [IQR: 2.34 to 7.68 pg/ml], p = 0.001). Sensitivity of 80% and 90% to detect abnormal SPECT-MPI was reached at hsTnT levels as low as 5.73 and 4.26 pg/ml, respectively. Corresponding specificity was 62% and 46%, and negative predictive value was 96% and 96%, respectively. HsTnT levels had good discriminatory ability for prediction of abnormal SPECT-MPI (area under the curve: 0.739, 95% confidence interval: 0.609 to 0.868). Both reversible myocardial ischemia and the extent of coronary atherosclerosis (combined model r2 = 0.19 with partial of r2 = 0.12 and r2 = 0.05, respectively) independently and incrementally predicted the measured hsTnT levels.
CONCLUSIONS
In patients with acute chest pain, myocardial perfusion abnormalities and coronary artery disease are predicted by resting hsTnT levels. Prospective evaluations are warranted to confirm whether resting hsTnT could serve as a powerful triage tool in chest pain patients in the ED before diagnostic testing and improve the effectiveness of patient management.
doi:10.1016/j.jcmg.2012.08.014
PMCID: PMC3734805  PMID: 23328564
coronary computed tomographic angiography; high-sensitivity troponin T; myocardial perfusion imaging; single-photon emission computed tomography
9.  SPECT myocardial perfusion imaging as an adjunct to coronary calcium score for the detection of hemodynamically significant coronary artery stenosis 
Background
Coronary artery calcifications (CAC) are markers of coronary atherosclerosis, but do not correlate well with stenosis severity. This study intended to evaluate clinical situations where a combined approach of coronary calcium scoring (CS) and nuclear stress test (SPECT-MPI) is useful for the detection of relevant CAD.
Methods
Patients with clinical indication for invasive coronary angiography (ICA) were included into our study during 08/2005-09/2008. At first all patients underwent CS procedure as part of the study protocol performed by either using a multidetector computed tomography (CT) scanner or a dual-source CT imager. CAC were automatically defined by dedicated software and the Agatston score was semi-automatically calculated. A stress-rest SPECT-MPI study was performed afterwards and scintigraphic images were evaluated quantitatively. Then all patients underwent ICA. Thereby significant CAD was defined as luminal stenosis ≥75% in quantitative coronary analysis (QCA) in ≥1 epicardial vessel. To compare data lacking Gaussian distribution an unpaired Wilcoxon-Test (Mann–Whitney) was used. Otherwise a Students t-test for unpaired samples was applied. Calculations were considered to be significant at a p-value of <0.05.
Results
We consecutively included 351 symptomatic patients (mean age: 61.2±12.3 years; range: 18–94 years; male: n=240) with a mean Agatston score of 258.5±512.2 (range: 0–4214). ICA verified exclusion of significant CAD in 66/67 (98.5%) patients without CAC. CAC was detected in remaining 284 patients. In 132/284 patients (46.5%) with CS>0 significant CAD was confirmed by ICA, and excluded in 152/284 (53.5%) patients. Sensitivity for CAD detection by CS alone was calculated as 99.2%, specificity was 30.3%, and negative predictive value was 98.5%. An additional SPECT in patients with CS>0 increased specificity to 80.9% while reducing sensitivity to 87.9%. Diagnostic accuracy was 84.2%.
Conclusions
In patients without CS=0 significant CAD can be excluded with a high negative predictive value by CS alone. An additional SPECT-MPI in those patients with CS>0 leads to a high diagnostic accuracy for the detection of CAD while reducing the number of patients needing invasive diagnostic procedure.
doi:10.1186/1471-2261-12-116
PMCID: PMC3527199  PMID: 23206557
Computed tomography coronary calcium scoring; Single photon emission computed tomography myocardial perfusion imaging; Invasive coronary angiography; Coronary artery disease
10.  A combination of anatomical and functional evaluations improves the prediction of cardiac event in patients with coronary artery bypass 
BMJ Open  2013;3(11):e003474.
Objective
To study the usefulness of combined risk stratification of coronary CT angiography (CTA) and myocardial perfusion imaging (MPI) in patients with previous coronary-artery-bypass grafting (CABG).
Design
A retrospective, observational, single centre study.
Setting and patients
204 patients (84.3% men, mean age 68.7±7.6) undergoing CTA and MPI.
Main outcome measures
CTA defined unprotected coronary territories (UCT; 0, 1, 2 or 3) by evaluating the number of significant stenoses which were defined as the left main trunk ≥50% diameter stenosis, other native vessel stenosis ≥70% or graft stenosis ≥70%. Using a cut-off value with receiver-operating characteristics analysis, all patients were divided into four groups: group A (UCT=0, summed stress score (SSS)<4), group B (UCT≥1, SSS<4), group C (UCT=0, SSS≥4) and group D (UCT≥1, SSS≥4).
Results
Cardiac events, as a composite end point including cardiac death, non-fatal myocardial infarction, unstable angina requiring revascularisation and heart-failure hospitalisation, were observed in 27 patients for a median follow-up of 27.5 months. The annual event rates were 1.1%, 2%, 5.7% and 12.9% of patients in groups A, B, C and D, respectively (log rank p value <0.0001). Adding UCT or SSS to a model with significant clinical factors including left ventricular ejection fraction, time since CABG and Euro SCORE II improved the prediction of events, while adding UCT and SSS to the model improved it greatly with increasing C-index, net reclassification improvement and integrated discrimination improvement.
Conclusions
The combination of anatomical and functional evaluations non-invasively enhances the predictive accuracy of cardiac events in patients with CABG.
doi:10.1136/bmjopen-2013-003474
PMCID: PMC3831107  PMID: 24220113
11.  Assessment of internal mammary artery and saphenous vein graft patency and flow reserve using transthoracic Doppler echocardiography 
Heart  2001;86(4):424-431.
OBJECTIVE—To investigate transthoracic Doppler echocardiography in the identification of coronary artery bypass graft (CABG) flow for assessing graft patency.
DESIGN—The initial study group comprised 45 consecutive patients with previous CABG undergoing elective cardiac catheterisation for recurrent ischaemia. The Doppler variables best correlated with angiographic graft patency were then tested prospectively in a further 84 patients (test group).
SETTING—Three tertiary referral centres.
INTERVENTIONS—Flow velocities in grafts were recorded at rest and during hyperaemia induced by dipyridamole (0.56 mg/kg/4 min), under the guidance of transthoracic colour Doppler flow mapping. Findings on transthoracic Doppler were compared with angiography.
MAIN OUTCOME MEASURES—Feasibility of identifying open grafts by Doppler and diagnostic accuracy for Doppler detection of significant (⩾ 70%) graft stenosis.
RESULTS—In the test group the identification rate for mammary artery grafts was 100%, for saphenous vein grafts to left anterior descending coronary artery 91%, for vein grafts to right coronary artery 96%, and for vein grafts to circumflex artery 90%. Coronary flow reserve (the ratio between peak diastolic velocity under hyperaemia and at baseline) of < 1.9 (95% confidence interval 1.83 to 2.08) had 100% sensitivity, 98% specificity, 87.5% positive predictive value, and 100% negative predictive value for mammary artery graft stenosis. Coronary flow reserve of < 1.6 (95% CI 1.51 to 1.73) had 91% sensitivity, 87% specificity, 85.4% positive predictive value, and 92.3% negative predictive value for significant vein graft stenosis.
CONCLUSIONS—Transthoracic Doppler can provide non-invasive assessment of CABG patency.


Keywords: blood flow; coronary artery disease; coronary artery bypass graft; echocardiography
doi:10.1136/heart.86.4.424
PMCID: PMC1729941  PMID: 11559684
12.  Higher event rate in patients with known CAD despite a normal myocardial perfusion scan 
Objective
The negative predictive value of a normal single-photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI) is very high. However, prognostic implication of a normal SPECT MPI in patients with known coronary artery disease (CAD) is not clear. Objective of this study was to evaluate the cardiac event rate in patients with known CAD who had a normal stress SPECT MPI.
Methods
This prospective study accrued 428 consecutive patients with a history of CAD [revascularization or previous myocardial infarction (MI)] who had a normal stress (dynamic exercise or dipyridamole intervention) and rest Tc-99m-MIBI SPECT MPI. These patients were followed for 2-5 years (median: 3.1 years) for all-cause and cardiac mortality and non-fatal MI. Univariate and multivariate analyses were performed to identify predictors of outcome.
Results
During a follow-up period, all-cause mortality was found in 60 patients (14%) and 41 (10%) died of cardiac reasons. Non-fatal MI was found in 77 (18%) patients. Annualized cardiac mortality and non-fatal MI rates were 2% and 3.6% respectively. Smoking, congestive heart failure (CHF) and failure to achieve 85% age predicted heart rate were found to be predictors for all-cause and cardiac mortality. Diabetes, dyslipidemia, smoking and limited functional capacity (<7 METS) were found to be predictors for non-fatal MI.
Conclusions
Patients with known CAD had higher cardiac event rates despite a normal stress SPECT MPI. Diabetes, dyslipidemia, smoking and limited functional capacity were the predictors for fatal and non-fatal cardiac events. A cost effective but comprehensive surveillance strategy is warranted.
doi:10.3978/j.issn.2223-3652.2014.06.04
PMCID: PMC4069979  PMID: 25009792
Myocardial perfusion imaging (MPI); coronary artery disease (CAD); event rate; prognosis
13.  64-slice CT angiography for the detection of functionally significant coronary stenoses: comparison with stress myocardial perfusion imaging 
The British Journal of Radiology  2012;85(1012):368-376.
Objective
To evaluate the accuracy of 64-slice CT angiography (CTA) compared with single photon emission CT (SPECT) myocardial perfusion imaging (MPI), which served as the reference standard, for the detection of functionally significant coronary artery disease (CAD).
Methods
141 consecutive patients (60±10 years, 101 men) were investigated with 64-slice CTA and SPECT MPI; a subset of 35 patients had additional invasive coronary angiography (ICA). The data from CTA and ICA were compared with those from MPI for both cut-offs of ≥50% and ≥70% stenosis, respectively.
Results
The sensitivity, specificity, positive and negative predictive values, and accuracy of CTA, using a cut-off of ≥50% for significant stenosis, in detecting inducible perfusion defects on MPI were 96% [95% confidence interval (CI) 88–100%], 61% (95% CI 52–70%), 37% (95% CI 23–49%), 99% (95% CI 97–100%) and 68%, respectively, in patient-based analysis and 97% (95% CI 91–100%), 86% (95% CI 83–89%), 33% (95% CI 24–42%), 100% (95% CI 99–100%) and 87%, respectively, in vessel-based analysis. Applying a cut-off of ≥70% for significant stenosis, CTA yielded the following sensitivity, specificity, positive and negative predictive values, and accuracy for the detection of inducible MPI defects: by patient, 65% (95% CI 46–84%), 95% (95% CI 91–99%), 74% (95% CI 50–92%), 92% (95% CI 87–97%) and 89%, respectively; by vessel, 58% (95% CI 42–74%), 97% (95% CI 95–99%), 62% (95% CI 45–79%), 97% (95% CI 95–99%) and 95%, respectively.
Conclusion
64-slice CTA is a reliable tool to exclude functionally significant CAD when using a cut-off of ≥50% diameter stenosis. By contrast, a cut-off of ≥70% diameter narrowing is a strong predictor of ischaemia.
doi:10.1259/bjr/59249210
PMCID: PMC3486657  PMID: 21224298
14.  Single Photon Emission Computed Tomography for the Diagnosis of Coronary Artery Disease 
Executive Summary
In July 2009, the Medical Advisory Secretariat (MAS) began work on Non-Invasive Cardiac Imaging Technologies for the Diagnosis of Coronary Artery Disease (CAD), an evidence-based review of the literature surrounding different cardiac imaging modalities to ensure that appropriate technologies are accessed by patients suspected of having CAD. This project came about when the Health Services Branch at the Ministry of Health and Long-Term Care asked MAS to provide an evidentiary platform on effectiveness and cost-effectiveness of non-invasive cardiac imaging modalities.
After an initial review of the strategy and consultation with experts, MAS identified five key non-invasive cardiac imaging technologies for the diagnosis of CAD. Evidence-based analyses have been prepared for each of these five imaging modalities: cardiac magnetic resonance imaging, single photon emission computed tomography, 64-slice computed tomographic angiography, stress echocardiography, and stress echocardiography with contrast. For each technology, an economic analysis was also completed (where appropriate). A summary decision analytic model was then developed to encapsulate the data from each of these reports (available on the OHTAC and MAS website).
The Non-Invasive Cardiac Imaging Technologies for the Diagnosis of Coronary Artery Disease series is made up of the following reports, which can be publicly accessed at the MAS website at: www.health.gov.on.ca/mas or at www.health.gov.on.ca/english/providers/program/mas/mas_about.html
Single Photon Emission Computed Tomography for the Diagnosis of Coronary Artery Disease: An Evidence-Based Analysis
Stress Echocardiography for the Diagnosis of Coronary Artery Disease: An Evidence-Based Analysis
Stress Echocardiography with Contrast for the Diagnosis of Coronary Artery Disease: An Evidence-Based Analysis
64-Slice Computed Tomographic Angiography for the Diagnosis of Coronary Artery Disease: An Evidence-Based Analysis
Cardiac Magnetic Resonance Imaging for the Diagnosis of Coronary Artery Disease: An Evidence-Based Analysis
Pease note that two related evidence-based analyses of non-invasive cardiac imaging technologies for the assessment of myocardial viability are also available on the MAS website:
Positron Emission Tomography for the Assessment of Myocardial Viability: An Evidence-Based Analysis
Magnetic Resonance Imaging for the Assessment of Myocardial Viability: an Evidence-Based Analysis
The Toronto Health Economics and Technology Assessment Collaborative has also produced an associated economic report entitled:
The Relative Cost-effectiveness of Five Non-invasive Cardiac Imaging Technologies for Diagnosing Coronary Artery Disease in Ontario [Internet]. Available from: http://theta.utoronto.ca/reports/?id=7
Objective
The objective of the analysis is to determine the diagnostic accuracy of single photon emission tomography (SPECT) in the diagnosis of coronary artery disease (CAD) compared to the reference standard of coronary angiography (CA). The analysis is primarily meant to allow for indirect comparisons between non-invasive strategies for the diagnosis of CAD, using CA as a reference standard.
SPECT
Cardiac SPECT, or myocardial perfusion scintigraphy (MPS), is a widely used nuclear, non-invasive image acquisition technique for investigating ischemic heart disease. SPECT is currently appropriate for all aspects of detecting and managing ischemic heart disease including diagnosis, risk assessment/stratification, assessment of myocardial viability, and the evaluation of left ventricular function. Myocardial perfusion scintigraphy was originally developed as a two-dimensional planar imaging technique, but SPECT acquisition has since become the clinical standard in current practice. Cardiac SPECT for the diagnosis of CAD uses an intravenously administered radiopharmaceutical tracer to evaluate regional coronary blood flow usually at rest and after stress. The radioactive tracers thallium (201Tl) or technetium-99m (99mTc), or both, may be used to visualize the SPECT acquisition. Exercise or a pharmacologic agent is used to achieve stress. After the administration of the tracer, its distribution within the myocardium (which is dependent on myocardial blood flow) is imaged using a gamma camera. In SPECT imaging, the gamma camera rotates around the patients for 10 to 20 minutes so that multiple two-dimensional projections are acquired from various angles. The raw data are then processed using computational algorithms to obtain three-dimensional tomographic images.
Since its inception, SPECT has evolved and its techniques/applications have become increasingly more complex and numerous. Accordingly, new techniques such as attenuation correction and ECG gating have been developed to correct for attenuation due to motion or soft-tissue artifact and to improve overall image clarity.
Research Questions
What is the diagnostic accuracy of SPECT for the diagnosis of CAD compared to the reference standard of CA?
Is SPECT cost-effective compared to other non-invasive cardiac imaging modalities for the diagnosis of CAD?
What are the major safety concerns with SPECT when used for the diagnosis of CAD?
Methods
A preliminary literature search was performed across OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for all systematic reviews/meta-analysis published between January 1, 2004 and August 22, 2009. A comprehensive systematic review was identified from this search and used as a basis for an updated search.
A second comprehensive literature search was then performed on October 30, 2009 across the same databases for studies published between January 1, 2002 and October 30, 2009. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria, full-text articles were obtained. Reference lists were also hand-searched for any additional studies.
Systematic reviews, meta-analyses, controlled clinical trials, and observational studies
Minimum sample size of 20 patients who completed coronary angiography
Use of CA as a reference standard for the diagnosis of CAD
Data available to calculate true positives (TP), false positives (FP), false negatives (FN) and true negatives (TN)
Accuracy data reported by patient not by segment
English language
Non-systematic reviews, case reports
Grey literature and abstracts
Trials using planar imaging only
Trials conducted in patients with non-ischemic heart disease
Studies done exclusively in special populations (e.g., patients with left branch bundle block, diabetics, minority populations) unless insufficient data available
Summary of Findings
Eighty-four observational studies, one non-randomized, single arm controlled clinical trial, and one poorly reported trial that appeared to be a randomized controlled trial (RCT) met the inclusion criteria for this review. All studies assessed the diagnostic accuracy of myocardial perfusion SPECT for the diagnosis of CAD using CA as a reference standard. Based on the results of these studies the following conclusions were made:
According to very low quality evidence, the addition of attenuation correction to traditional or ECG-gated SPECT greatly improves the specificity of SPECT for the diagnosis of CAD although this improvement is not statistically significant. A trend towards improvement of specificity was also observed with the addition of ECG gating to traditional SPECT.
According to very low quality evidence, neither the choice of stress agent (exercise or pharmacologic) nor the choice of radioactive tracer (technetium vs. thallium) significantly affect the diagnostic accuracy of SPECT for the diagnosis of CAD although a trend towards accuracy improvement was observed with the use of pharmacologic stress over exercise stress and technetium over thallium.
Considerably heterogeneity was observed both within and between trials. This heterogeneity may explain why some of the differences observed between accuracy estimates for various subgroups were not statistically significant.
More complex analytic techniques such as meta-regression may help to better understand which study characteristics significantly influence the diagnostic accuracy of SPECT.
PMCID: PMC3377554  PMID: 23074411
15.  Diagnostic performance of fusion of myocardial perfusion imaging (MPI) and computed tomography coronary angiography 
Background
We evaluated the incremental diagnostic value of fusion images of coronary computed tomography angiography (CTA) and myocardial perfusion imaging (MPI) over MPI alone or MPI and CTA side-by-side to identify obstructive coronary artery disease (CAD > 50% stenosis) using invasive coronary angiography (ICA) as the gold standard.
Methods
50 subjects (36 men; 56 ± 11 years old) underwent rest-stress MPI and CTA within 12-26 days of each other. CTAs were performed with multi-detector CT-scanners (31 on 64-slice; and 19 on 16-slice). 37 patients underwent ICA while 13 subjects did not because of low (<5%) pre-test likelihood (LLK) of disease. Three blinded readers scored the images in sequential sessions using (1) MPI alone (2) MPI and CTA side-by-side, (3) fused CTA/MPI images.
Results
One or more critical stenoses during ICA were found in 28 patients and non-critical stenoses were found in 9 patients. MPI, side-by-side MPI-CTA, and fused CTA/MPI showed the same normalcy rate (NR:13/13) in LLK subjects. The fusion technique performed better than MPI and MPI and CTA side-by-side for the presence of CAD in any vessel (overall area under the curve (AUC) for fused images: 0.89; P = .005 vs MPI, P = .04 vs side-by-side MPI-CTA) and for localization of CAD to the left anterior descending coronary artery (AUC: 0.82, P < .001 vs MPI; P = .007 vs side-by-side MPI-CTA). There was a non-significant trend for better detection of multi-vessel disease with fusion.
Conclusions
Using ICA as the gold standard, fusion imaging provided incremental diagnostic information compared to MPI alone or side-by-side MPI-CTA for the diagnosis of obstructive CAD and for localization of CAD to the left anterior descending coronary artery.
doi:10.1007/s12350-008-9019-z
PMCID: PMC3086676  PMID: 19156478
Myocardial perfusion imaging; SPECT; PET imaging; computed tomography (CT); coronary artery disease; diagnostic and prognostic application
16.  Evaluation of contrast wash-in and peak enhancement in adenosine first pass perfusion CMR in patients post bypass surgery 
Background
Adenosine first pass perfusion cardiovascular magnetic resonance (CMR) yields excellent results for the detection of significant coronary artery disease (CAD). In patients with coronary artery bypass grafts (CABG) the kinetics of a contrast bolus may by altered only due to different distances through the bypass grafts compared to native vessels, thereby possibly imitating a perfusion defect. The aim of the study was to evaluate semiquantitative perfusion parameters in order to assess possible differences in epicardial contrast kinetics in areas supplied by native coronaries and CABG, both without significant stenosis.
Methods
Twenty patients with invasive exclusion of significant CAD (control group) and 38 patients with CABG without angiographically significant (≥50%) stenosis in unbypassed coronaries or grafts were retrospectively included in the study. They underwent adenosine first pass (0.05 mmol/kg Gd-DTPA) perfusion (3 short axis views/heart beat) and late gadolinium enhancement (LGE) imaging 1 day before invasive coronary angiography. Areas perfused by native coronaries and/or the different bypasses were identified in X-ray angiography using the 16 segment model. In each of these areas upslope and maximal signal intensity (SImax) relative to the left ventricular parameters, time to 50% maximal signal intensity (TSI50%max) and time to maximal signal intensity (TSImax) were calculated.
Results
In areas perfused by coronary arteries with bypasses compared to native coronaries relative upslope and relative SImax did not show a significant difference. TSI50%max and TSImax in native coronaries and bypasses were 7.2s ± 1.9s vs. 7.5s ± 1.9s (p < 0.05) and 12.6s ± 3.0s vs. 13.1s ± 3.0s (p < 0.05), respectively. The delay in Tmax resulted in a significant (p < 0.05) delay of 0.5 ± 1.1 heart beats (=images) when adjusted to the heart rate. Differences in time were most pronounced in areas perfused by left internal mammary artery grafts rather than by venous CABG, but were also present between native vessel territories in patients without CAD, albeit with smaller variability.
Conclusion
Adenosine perfusion CMR in patients post CABG may be associated with a short delay in contrast arrival. However, once the contrast is in the myocardium there is similar wash-in kinetics and peak enhancement. Therefore, since the delay is only short, the possibly differing contrast kinetics through grafts and native vessels does not seem to be a limiting factor for the accuracy of first pass adenosine perfusion in patients post CABG.
doi:10.1186/1532-429X-12-28
PMCID: PMC2887852  PMID: 20465836
17.  Comparative Analysis between SPECT Myocardial Perfusion Imaging and CT Coronary Angiography for Diagnosis of Coronary Artery Disease 
The study aims to discuss the relationship and difference between myocardial perfusion imaging (MPI) using SPECT and CT coronary angiography (CTCA) for diagnosis of coronary artery disease (CAD). Five hundred and four cases undergoing MPI and CTCA were comparatively analyzed, including fifty six patients undergoing invasive coronary angiography in the same period. Among patients with negative MPI results, negative or positive CTCA occupied 84.7% or 15.3%, respectively. Among patients with positive MPI, positive or negative CTCA occupied 67.2% or 32.8%, respectively. Among patients with negative CTCA, negative or positive MPI occupied 94.4% or 5.6%, respectively. Among patients with positive CTCA, positive or negative MPI occupied 40.2% or 59.8%, respectively. Negative predictive value was relatively higher than the positive predictive value for positive CTCA eliminating or predicting abnormal haemodynamics. And there was no significant difference for sensitivity, specificity, and accuracy of MPI or CTCA in diagnosing CAD. Both MPI and CTCA have good diagnostic performance for CAD. They provide different and complementary information for diagnosis and evaluation of CAD, namely, detection of ischemia versus detection of atherosclerosis, which are quite different but have a definite internal link for each other.
doi:10.1155/2012/253475
PMCID: PMC3405566  PMID: 22848809
18.  Positron Emission Tomography for the Assessment of Myocardial Viability 
Executive Summary
Objective
The objective was to update the 2001 systematic review conducted by the Institute For Clinical Evaluative Sciences (ICES) on the use of positron emission tomography (PET) in assessing myocardial viability. The update consisted of a review and analysis of the research evidence published since the 2001 ICES review to determine the effectiveness and cost-effectiveness of PET in detecting left ventricular (LV) viability and predicting patient outcomes after revascularization in comparison with other noninvasive techniques.
Background
Left Ventricular Viability
Heart failure is a complex syndrome that impairs the contractile ability of the heart to maintain adequate blood circulation, resulting in poor functional capacity and increased risk of morbidity and mortality. It is the leading cause of hospitalization in elderly Canadians. In more than two-thirds of cases, heart failure is secondary to coronary heart disease. It has been shown that dysfunctional myocardium resulting from coronary heart disease (CAD) may recover contractile function (i.e. considered viable). Dysfunctional but viable myocardium may have been stunned by a brief episode of ischemia, followed by restoration of perfusion, and may regain function spontaneously. It is believed that repetitive stunning results in hibernating myocardium that will only regain contractile function upon revascularization.
For people with CAD and severe LV dysfunction (left ventricular ejection fraction [LVEF] <35%) refractory to medical therapy, coronary artery bypass and heart transplantation are the only treatment options. The opportunity for a heart transplant is limited by scarcityof donor hearts. Coronary artery bypass in these patients is associated with high perioperative complications; however, there is evidence that revascularization in the presence of dysfunctional but viable myocardium is associated with survival benefits and lower rates of cardiac events. The assessment of left ventricular (LV) viability is, therefore, critical in deciding whether a patient with coronary artery disease and severe LV dysfunction should undergo revascularization, receive a heart transplant, or remain on medical therapy.
Assessment of Left Ventricular Viability
Techniques for assessing myocardial viability depend on the measurement of a specific characteristic of viable myocytes such as cell membrane integrity, preserved metabolism, mitochondria integrity, and preserved contractile reserve. In Ontario, single photon emission computed tomography (SPECT) using radioactive 201thallium is the most commonly used technique followed by dobutamine echocardiography. Newer techniques include SPECT using technetium tracers, cardiac magnetic resonance imaging, and PET, the subject of this review.
Positron Emission Tomography
PET is a nuclear imaging technique based on the metabolism of radioactive analogs of normal substrates such as glucose and water. The radiopharmaceutical used most frequently in myocardial viability assessment is F18 fluorodeoxyglucose (FDG), a glucose analog. The procedure involves the intravenous administration of FDG under controlled glycemic conditions, and imaging with a PET scanner. The images are reconstructed using computer software and analyzed visually or semi-quantitatively, often in conjunction with perfusion images. Dysfunctional but stunned myocardium is characterized by normal perfusion and normal FDG uptake; hibernating myocardium exhibits reduced perfusion and normal/enhanced FDG uptake (perfusion/metabolism mismatch), whereas scar tissue is characterized by reduction in both perfusion and FDG uptake (perfusion/metabolism match).
Review Strategy
The Medical Advisory Secretariat used a search strategy similar to that used in the 2001 ICES review to identify English language reports of health technology assessments and primary studies in selected databases, published from January 1, 2001 to April 20, 2005. Patients of interest were those with CAD and severe ventricular dysfunction being considered for revascularization that had undergone viability assessment using either PET and/or other noninvasive techniques. The outcomes of interest were diagnostic and predictive accuracy with respect to recovery of regional or global LV function, long-term survival and cardiac events, and quality of life. Other outcomes of interest were impact on treatment decision, adverse events, and cost-effectiveness ratios.
Of 456 citations, 8 systematic reviews/meta-analyses and 37 reports on primary studies met the selection criteria. The reports were categorized using the Medical Advisory Secretariat levels of evidence system, and the quality of the reports was assessed using the criteria of the Quality Assessment of Diagnostic Accuracy Studies (QUADAS) developed by the Centre for Dissemination of Research (National Health Service, United Kingdom). Analysis of sensitivity, specificity, predictive values and likelihood ratios were conducted for all data as well as stratified by mean left ventricular ejection fraction (LVEF). There were no randomized controlled trials. The included studies compared PET with one or more other noninvasive viability tests on the same group of patients or examined the long-term outcomes of PET viability assessments. The quality assessment showed that about 50% or more of the studies had selection bias, interpreted tests without blinding, excluded uninterpretable segments in the analysis, or did not have clearly stated selection criteria. Data from the above studies were integrated with data from the 2001 ICES review for analysis and interpretation.
Summary of Findings
The evidence was derived from populations with moderate to severe ischemic LV dysfunction with an overall quality that ranges from moderate to low.
PET appears to be a safe technique for assessing myocardial viability.
CAD patients with moderate to severe ischemic LV dysfunction and residual viable myocardium had significantly lower 2-year mortality rate (3.2%) and higher event-free survival rates (92% at 3 years) when treated with revascularization than those who were not revascularized but were treated medically (16% mortality at 2-years and 48% 3-year event-free survival).
A large meta-analysis and moderate quality studies of diagnostic accuracy consistently showed that compared to other noninvasive diagnostic tests such as thallium SPECT and echocardiography, FDG PET has:
Higher sensitivity (median 90%, range 71%–100%) and better negative likelihood ratio (median 0.16, range 0–0.38; ideal <0.1) for predicting regional myocardial function recovery after revascularization.
Specificity (median 73%, range 33%–91%) that is similar to other radionuclide imaging but lower than that of dobutamine echocardiography
Less useful positive likelihood ratio (median 3.1, range 1.4 –9.2; ideal>10) for predicting segmental function recovery.
Taking positive and negative likelihood ratios together suggests that FDG PET and dobutamine echocardiography may produce small but sometimes important changes in the probability of recovering regional wall motion after revascularization.
Given its higher sensitivity, PET is less likely to produce false positive results in myocardial viability. PET, therefore, has the potential to identify some patients who might benefit from revascularization, but who would not have been identified as suitable candidates for revascularization using thallium SPECT or dobutamine echocardiography.
PET appears to be superior to other nuclear imaging techniques including SPECT with 201thallium or technetium labelled tracers, although recent studies suggest that FDG SPECT may have comparable diagnostic accuracy as FDG PET for predicting regional and global LV function recovery.
No firm conclusion can be reached about the incremental value of PET over other noninvasive techniques for predicting global function improvement or long-term outcomes in the most important target population (patients with severe ischemic LV dysfunction) due to lack of direct comparison.
An Ontario-based economic analysis showed that in people with CAD and severe LV dysfunction and who were found to have no viable myocardium or indeterminate results by thallium SPECT, the use of PET as a follow-up assessment would likely result in lower cost and better 5-year survival compared to the use of thallium SPECT alone. The projected annual budget impact of adding PET under the above scenario was estimated to range from $1.5 million to $2.3 million.
Conclusion
In patients with severe LV dysfunction, that are deemed to have no viable myocardium or indeterminate results in assessments using other noninvasive tests, PET may have a role in further identifying patients who may benefit from revascularization. No firm conclusion can be drawn on the impact of PET viability assessment on long-term clinical outcomes in the most important target population (i.e. patients with severe LV dysfunction).
PMCID: PMC3385418  PMID: 23074467
19.  Myocardial perfusion imaging in patients with a recent, normal exercise test 
World Journal of Cardiology  2013;5(3):54-59.
AIM: To investigate the added value of myocardial perfusion scintigraphy imaging (MPI) in consecutive patients with suspected coronary artery disease (CAD) and a recent, normal exercise electrocardiography (ECG).
METHODS: This study was a retrospective analysis of consecutive patients referred for MPI during a 2-year period from 2006-2007 at one clinic. All eligible patients were suspected of suffering from CAD, and had performed a satisfactory bicycle exercise test (i.e., peak heart rate > 85% of the expected, age-predicted maximum) within 6 mo of referral, their exercise ECG was had no signs of ischemia, there was no exercise-limiting angina, and no cardiac events occurred between the exercise test and referral. The patients subsequently underwent a standard 2-d, stress-rest exercise MPI. Ischemia was defined based on visual scoring supported by quantitative segmental analysis (i.e., sum of stress score > 3). The results of cardiac catheterization were analyzed, and clinical follow up was performed by review of electronic medical files.
RESULTS: A total of 56 patients fulfilled the eligibility criteria. Most patients had a low or intermediate ATPIII pre-test risk of CAD (6 patients had a high pre-test risk). The referral exercise test showed a mean Duke score of 5 (range: 2 to 11), which translated to a low post-exercise risk in 66% and intermediate risk in 34%. A total of seven patients were reported with ischemia by MPI. Three of these patients had high ATPIII pre-test risk scores. Six of these seven patients underwent cardiac catheterization, which showed significant stenosis in one patient with a high pre-test risk of CAD, and indeterminate lesions in three patients (two of whom had high pre-test risk scores). With MPI as a gate keeper for catheterization, no significant, epicardial stenosis was observed in any of the 50 patients (0%, 95% confidence interval 0.0 to 7.1) with low to intermediate pre-test risk of CAD and a negative exercise test. No cardiac events occurred in any patients within a median follow up period of > 1200 d.
CONCLUSION: The added diagnostic value of MPI in patients with low or intermediate risk of CAD and a recent, normal exercise test is marginal.
doi:10.4330/wjc.v5.i3.54
PMCID: PMC3610007  PMID: 23538474
Single photon emission tomography; Ischemic heart disease; Myocardial perfusion imaging; Pre-test risk; Post-test risk; Added value; Exercise electrocardiography
20.  Stress Echocardiography with Contrast for the Diagnosis of Coronary Artery Disease 
Executive Summary
In July 2009, the Medical Advisory Secretariat (MAS) began work on Non-Invasive Cardiac Imaging Technologies for the Diagnosis of Coronary Artery Disease (CAD), an evidence-based review of the literature surrounding different cardiac imaging modalities to ensure that appropriate technologies are accessed by patients suspected of having CAD. This project came about when the Health Services Branch at the Ministry of Health and Long-Term Care asked MAS to provide an evidentiary platform on effectiveness and cost-effectiveness of non-invasive cardiac imaging modalities.
After an initial review of the strategy and consultation with experts, MAS identified five key non-invasive cardiac imaging technologies for the diagnosis of CAD. Evidence-based analyses have been prepared for each of these five imaging modalities: cardiac magnetic resonance imaging, single photon emission computed tomography, 64-slice computed tomographic angiography, stress echocardiography, and stress echocardiography with contrast. For each technology, an economic analysis was also completed (where appropriate). A summary decision analytic model was then developed to encapsulate the data from each of these reports (available on the OHTAC and MAS website).
The Non-Invasive Cardiac Imaging Technologies for the Diagnosis of Coronary Artery Disease series is made up of the following reports, which can be publicly accessed at the MAS website at: www.health.gov.on.ca/mas or at www.health.gov.on.ca/english/providers/program/mas/mas_about.html
Single Photon Emission Computed Tomography for the Diagnosis of Coronary Artery Disease: An Evidence-Based Analysis
Stress Echocardiography for the Diagnosis of Coronary Artery Disease: An Evidence-Based Analysis
Stress Echocardiography with Contrast for the Diagnosis of Coronary Artery Disease: An Evidence-Based Analysis
64-Slice Computed Tomographic Angiography for the Diagnosis of Coronary Artery Disease: An Evidence-Based Analysis
Cardiac Magnetic Resonance Imaging for the Diagnosis of Coronary Artery Disease: An Evidence-Based Analysis
Pease note that two related evidence-based analyses of non-invasive cardiac imaging technologies for the assessment of myocardial viability are also available on the MAS website:
Positron Emission Tomography for the Assessment of Myocardial Viability: An Evidence-Based Analysis
Magnetic Resonance Imaging for the Assessment of Myocardial Viability: an Evidence-Based Analysis
The Toronto Health Economics and Technology Assessment Collaborative has also produced an associated economic report entitled:
The Relative Cost-effectiveness of Five Non-invasive Cardiac Imaging Technologies for Diagnosing Coronary Artery Disease in Ontario [Internet]. Available from: http://theta.utoronto.ca/reports/?id=7
Objective
The objective of this report is to compare echocardiography (ECHO) performed with microsphere contrast agents (contrast echocardiography) to ECHO performed without contrast and to single photon emission computed tomography (SPECT).
Contrast ECHO
Contrast agents for ECHO have been available since the technology was first introduced in the 1990s. Composed of tiny ‘microbubbles’ of an inert gas encapsulated within a lipid, protein, or polymer coat, these agents act to scatter incident ultrasound waves at the gas/liquid interface to increase the strength of a returning ECHO signal. When injected into a patient’s arm, they are transported throughout even the smallest capillaries to greatly enhance the blood pool signal, which would otherwise appear black on conventional two dimensional ECHO. The enhanced signal then helps cardiologists to determine what parts of the patient’s heart muscle are poorly perfused.
The first commercially available microsphere contrast agent was Albunex, which received approval by the Food and Drug Administration in the United States in 1994. This original microsphere agent was limited by its rapid gas volume loss which caused a decline in the ultrasound signal. It worked well in the right chambers of the heart, but dissolved when passing through the pulmonary capillaries and so was unable to provide contrast in the left side. Second generation agents employed different gases that prolonged the life of the microbubbles within the circulation and increased the reproducibility of results.
Today, the most common use for contrast ECHO is to enhance the definition of the left ventricular (LV) endocardial border for cases of LV opacification. The aim of contrast ECHO is to provide better quantification of LV volume and assessment of LV wall motion than ECHO alone. The newest area of development in the research of contrast ECHO is myocardial perfusion assessment, also known as myocardial contrast ECHO. Theoretically, since myocardial ischemia and infarction affect both perfusion and contractility (wall motion), contrast ECHO could be an ideal non-invasive imaging test as it could assess both perfusion and contractility, simultaneously and in real time.
Notably, critically ill patients on ventilators and those with lung problems are more likely to generate poor or ‘suboptimal’ echocardiograms than other patients, as are obese patients and those who’ve undergone recent chest operations. Contrast agents can potentially be used in 10% to 15% of all studies and in approximately 33% of stress tests due to from such suboptimal echocardiograms. Stress can be induced either pharmaceutically (e.g., through dobutamine, dipyrimidamole, adenosine) or with exercise. Generally, contrast agents are used more in pharmaceutical stress echocardiograms than in exercise stress echocardiograms.
Evidence-Based Analysis
This MAS analysis sought to address the following research questions:
Is contrast ECHO more effective than 99-technetium SPECT in terms its ability to detect CAD?
What is the effectiveness of contrast ECHO in assessing patients with suboptimal echocardiograms?
Is contrast ECHO safe compared to other cardiac imaging modalities?
Is contrast ECHO cost-effective compared to other cardiac imaging modalities?
Literature Search
Literature searches were performed on June 22, 2009 and July 27, 2009 using OVID MEDLINE, MEDLINE In-Process and Other Non-Indexed Citations, EMBASE, the Cochrane Library, and the International Agency for Health Technology Assessment (INAHTA) for studies published from January 1, 2004 until June 30, 2009. Abstracts were reviewed by a single reviewer and, for those studies meeting the eligibility criteria; full-text articles were obtained. Reference lists were also examined for any relevant studies not identified through the search.
Inclusion Criteria
Systematic reviews, meta-analyses, randomized controlled trials, prospective observational studies, retrospective analyses
Minimum sample size of 20 enrolled patients (human only)
The contrast agent used in the study must be licensed by Health Canada
Comparison to reference standard (coronary angiography for the diagnosis of coronary artery disease)
Reporting accuracy data on individual patients (rather than accuracy data stratified by segments of the heart)
English language
Exclusion Criteria
Non-systematic reviews, case reports
Grey literature (e.g. conference abstracts)
Outcomes of Interest
Accuracy outcomes (sensitivity, specificity, positive predictive value, negative predictive value)
Adverse events
Costs
Summary of Findings
Twenty-three observational studies were identified that assessed the diagnostic accuracy of contrast ECHO for the diagnosis of CAD. All of these studies used stress ECHO with contrast. In addition, nine retrospective chart reviews were identified, which assessed the safety of contrast ECHO at rest or stress. Based on the results of these studies the following conclusions were made:
Stress ECHO with contrast has a higher diagnostic accuracy in the diagnosis of CAD than stress ECHO (without contrast).
Stress ECHO with contrast seems to have a similar diagnostic accuracy to 99 technetium SPECT.
The addition of contrast to ECHO in patients with suboptimal ECHO results significantly improves interpretability of the results.
There is not a statistically significantly higher mortality rate in patients who receive contrast compared to those who do not.
PMCID: PMC3377574  PMID: 23074387
21.  Adenosine Stress 64- and 256-Row Detector Computed Tomography Angiography and Perfusion Imaging A Pilot Study Evaluating the Transmural Extent of Perfusion Abnormalities to Predict Atherosclerosis Causing Myocardial Ischemia 
Background
Multidetector computed tomography coronary angiography (CTA) is a robust method for the noninvasive diagnosis of coronary artery disease. However, in its current form, CTA is limited in its prediction of myocardial ischemia. The purpose of this study was to test whether adenosine stress computed tomography myocardial perfusion imaging (CTP), when added to CTA, can predict perfusion abnormalities caused by obstructive atherosclerosis.
Methods and Results
Forty patients with a history of abnormal single-photon emission computed tomography myocardial perfusion imaging (SPECT-MPI) underwent adenosine stress 64-row (n=24) or 256-row (n=16) detector CTP and CTA. A subset of 27 patients had invasive angiography available for quantitative coronary angiography. CTA and quantitative coronary angiography were evaluated for stenoses ≥50%, and SPECT-MPI was evaluated for fixed and reversible perfusion deficits using a 17-segment model. CTP images were analyzed for the transmural differences in perfusion using the transmural perfusion ratio (subendocardial attenuation density/subepicardial attenuation density). The sensitivity, specificity, positive predictive value, and negative predictive value for the combination of CTA and CTP to detect obstructive atherosclerosis causing perfusion abnormalities using the combination of quantitative coronary angiography and SPECT as the gold standard was 86%, 92%, 92%, and 85% in the per-patient analysis and 79%, 91%, 75%, and 92% in the per vessel/territory analysis, respectively.
Conclusions
The combination of CTA and CTP can detect atherosclerosis causing perfusion abnormalities when compared with the combination of quantitative coronary angiography and SPECT.
doi:10.1161/CIRCIMAGING.108.813766
PMCID: PMC3035629  PMID: 19808590
imaging; atherosclerosis; ischemia; perfusion; myocardium
22.  Clinical evaluation of magnetic resonance imaging in coronary heart disease: The CE-MARC study 
Trials  2009;10:62.
Background
Several investigations are currently available to establish the diagnosis of coronary heart disease (CHD). Of these, cardiovascular magnetic resonance (CMR) offers the greatest information from a single test, allowing the assessment of myocardial function, perfusion, viability and coronary artery anatomy. However, data from large scale studies that prospectively evaluate the diagnostic accuracy of multi-parametric CMR for the detection of CHD in unselected populations are lacking, and there are few data on the performance of CMR compared with current diagnostic tests, its prognostic value and cost-effectiveness.
Methods/design
This is a prospective diagnostic accuracy cohort study of 750 patients referred to a cardiologist with suspected CHD. Exercise tolerance testing (ETT) will be preformed if patients are physically able. Recruited patients will then undergo CMR and single photon emission tomography (SPECT) followed in all patients by invasive X-ray coronary angiography. The order of the CMR and SPECT tests will be randomised. The CMR study will comprise rest and adenosine stress perfusion, cine imaging, late gadolinium enhancement and whole-heart MR coronary angiography. SPECT will use a gated stress/rest protocol. The primary objective of the study is to determine the diagnostic accuracy of CMR in detecting significant coronary stenosis, as defined by X-ray coronary angiography. Secondary objectives include an assessment of the prognostic value of CMR imaging, a comparison of its diagnostic accuracy against SPECT and ETT, and an assessment of cost-effectiveness.
Discussion
The CE-MARC study is a prospective, diagnostic accuracy cohort study of 750 patients assessing the performance of a multi-parametric CMR study in detecting CHD using invasive X-ray coronary angiography as the reference standard and comparing it with ETT and SPECT.
Trial Registration
Current Controlled Trials ISRCTN77246133
doi:10.1186/1745-6215-10-62
PMCID: PMC3224948  PMID: 19640271
23.  Dobutamine stress echocardiography versus quantitative technetium-99m sestamibi SPECT for detecting residual stenosis and multivessel disease after myocardial infarction 
Heart  2001;86(5):510-515.
OBJECTIVE—To compare the relative accuracy of dobutamine stress echocardiography (DSE) and quantitative technetium-99m sestamibi single photon emission computed tomography (mibi SPECT) for detecting infarct related artery stenosis and multivessel disease early after acute myocardial infarction.
DESIGN—Prospective study.
SETTING—University hospital.
METHODS—75 patients underwent simultaneous DSE and mibi SPECT at (mean (SD)) 5 (2) days after a first acute myocardial infarct. Quantitative coronary angiography was performed in all patients after imaging studies.
RESULTS—Significant stenosis (> 50%) of the infarct related artery was detected in 69 patients. Residual ischaemia was identified by DSE in 55 patients and by quantitative mibi SPECT in 49. The sensitivity of DSE and mibi SPECT for detecting significant infarct related artery stenosis was 78% and 70%, respectively, with a specificity of 83% for both tests. The combination of DSE and mibi SPECT did not change the specificity (83%) but increased the sensitivity to 94%. Mibi SPECT was more sensitive than DSE for detecting mild stenosis (73% v 9%; p = 0.008). The sensitivity of DSE for detecting moderate or severe stenosis was greater than mibi SPECT (97% v 74%; p = 0.007). Wall motion abnormalities with DSE and transient perfusion defects with mibi SPECT outside the infarction zone were sensitive (80% v 67%; NS) and highly specific (95% v 93%; NS) for multivessel disease.
CONCLUSIONS—DSE and mibi SPECT have equivalent accuracy for detecting residual infarct related artery stenosis of ⩾ 50% and multivessel disease early after acute myocardial infarction. DSE is more predictive of moderate or severe infarct related artery stenosis. Combined imaging only improves the detection of mild stenosis.


Keywords: myocardial infarction; dobutamine echocardiography; single photon emission computed tomography; SPECT; myocardial ischaemia
doi:10.1136/heart.86.5.510
PMCID: PMC1729965  PMID: 11602542
24.  Incremental value of contrast myocardial perfusion to detect intermediate versus severe coronary artery stenosis during stress-echocardiography 
Background
We aimed to compare the incremental value of contrast myocardial perfusion imaging (MPI) for the detection of intermediate versus severe coronary artery stenosis during dipyridamole-atropine echocardiography (DASE).
Wall motion (WM) assessment during stress-echocardiography demonstrates suboptimal sensitivity to detect coronary artery disease (CAD), particularly in patients with isolated intermediate (50%-70%) coronary stenosis.
Methods
We performed DASE with MPI in 150 patients with a suspected chest pain syndrome who were given clinical indication to coronary angiography.
Results and discussion
When CAD was defined as the presence of a ≥50% stenosis, the addition of MPI increased sensitivity (+30%) and decreased specificity (-14%), with a final increase in total diagnostic accuracy (+16%, p < 0.001). The addition of MPI data substantially increased the sensitivity to detect patients with isolated intermediate stenosis from 37% to 98% (p < 0.001); the incremental sensitivity was much lower in patients with severe stenosis, from 85% to 96% (p < 0.05), at the expense of a higher decrease in specificity and a final decrease in total diagnostic accuracy (-18%, p < 0.001).
Conclusions
The addition of MPI on top of WM analysis during DASE increases the diagnostic sensitivity to detect obstructive CAD, whatever its definition (≥50% or > 70% stenosis), but it is mainly driven by the sensitivity increase in the intermediate group (50%-70% stenosis).
The total diagnostic accuracy increased only when defining CAD as ≥50% stenosis, since in patients with severe stenosis (> 70%) the decrease in specificity is not counterbalanced by the minor sensitivity increase.
doi:10.1186/1476-7120-8-16
PMCID: PMC2877655  PMID: 20459632
25.  Rationale, design and methodology for a Prospective Randomized Study of graft patency in Off-pump and On-pump MultI-Vessel coronary artery bypasS Surgery (PROMISS) using multidetector computed tomography 
Trials  2008;9:44.
Background
Off-pump coronary artery bypass grafting has been accused of possibly compromising graft patency. Sixteen slice computed tomography has shown good diagnostic accuracy in the assessment of coronary bypass graft patency when compared with conventional coronary artery angiography and is less invasive. The study hypothesis is that coronary artery bypass grafting (CABG) performed without cardiopulmonary bypass (Off-Pump) has equivalent early graft patency as if performed with cardiopulmonary bypass (On-Pump) and may have reduced complication rate.
Methods/Design
The Prospective Randomized Comparison of Off-Pump and On-Pump MultI-vessel Coronary Artery BypasS Surgery (PROMISS) is a controlled, single blinded, single centre clinical trial, comparing early graft patency using 16-slice computed tomography in patients with multi-vessel coronary artery disease operated either without or with extracorporeal circulation. Inclusion criteria are multivessel disease with an indication for first time, isolated, non emergent coronary artery bypass grafting with a minimum of three distal anastomoses. Secondary end points are peri-operative mortality, combined morbidity, length of stay, neuro-cognitive testing at 6 weeks and adverse events, stress test and quality of life at 6 months and one year. The sample size of one hundred and fifty patients was calculated in order to enable the detection of a 5% difference in graft patency, with 80% power, considering a minimum of 3 distal anastomoses per patient. Enrolment started in April 2005 and ended July 2007 with study closure in July 2008.
Conclusion
The PROMISS trial aims to shed new light on the effect of Off-Pump as compared to On-Pump coronary artery bypass surgery on graft patency, assessed by multidetector computed tomography, in unselected patients with multivessel coronary artery disease.
Trial Registration
Current Controlled Trials ISRCTN58800729
doi:10.1186/1745-6215-9-44
PMCID: PMC2492837  PMID: 18637191

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