Original articleGated myocardial perfusion single photon emission computed tomography in the clinical outcomes utilizing revascularization and aggressive drug evaluation (COURAGE) trial, Veterans Administration Cooperative study no. 424
Section snippets
The usefulness of nuclear imaging to detect significant obstructive coronary disease (substudy 0—preteatment gSPECT)
Coronary atherosclerotic disease comprises a complex sequence of events beginning with plaque deposition and storage in an inflammatory milieu resulting and ending with plaque rupture and coronary thrombosis, often with an intermediate stage of coronary stenosis with reduced blood flow to the subtended myocardium under stress conditions. Gated SPECT is useful in assessing myocardial blood flow, specifically defining the hemodynamic significance of coronary stenosis. With respect to dynamic
Assessing recurrent symptoms (substudy 1—Posttreatment gSPECT)
After initial treatment with medical therapy alone or combined with PCI, it was expected that some patients would have recurrent chest-pain symptoms. The conceptual algorithm for assessment of recurrent angina in the COURAGE trial is shown in Figure 2. Based on this algorithm, it was recommended that patients with unstable chest-pain symptoms (ie, CCSC III and IV) undergo repeat coronary angiography. To assess restenosis in patients randomized to PCI, a lower threshold for repeat angiography
Effects of anti-ischemic therapies on stress-induced myocardial perfusion (substudy 2—pretreatment and posttreatment gated SPECT)
The final substudy in the COURAGE trial examined the value of sequential monitoring of medical or PCI treatments by using preintervention and postintervention gSPECT in 300 patients. This testing strategy varies from that used to diagnose coronary disease or for risk-stratification purposes. When sequential monitoring is used, the main goal of imaging is to determine on the second scan whether the patient’s therapeutic regimen is adequate to reduce or ameliorate their pretreatment ischemic
Effects of lipid-lowering therapies on stress-induced myocardial perfusion
More recent studies show that ischemia can also be ameliorated by treatment with statins, an exciting addition to our current medical armamentarium.52, 53 Previous studies in hypercholesterolemic patients demonstrated that cholesterol reduction restores peripheral and coronary endothelium-dependent vasodilation and increases myocardial perfusion.46, 47, 48 It is hypothesized that statins exhibit alterations in coronary flow by improving vessel wall elasticity, stabilizing the endothelium, and
Core laboratory protocols and procedures
A nuclear core laboratory at Ceders-Sinai Medical Center (Los Angeles, Calif) was employed for site certification quality assurance, and image analysis for all gSPECT studies in the COURAGE trial.
Field site qualification
Before the COURAGE trial, sites electing to participate in the nuclear substudy underwent field site qualifications. The qualification process included submission of gamma camera quality control (QC) data and a sample patient study. Gamma camera QC and patient forms sent to each site were returned to the core laboratory with the QC and sample patient data. This field site qualification was used to define sites with sufficient high-quality data. A site was considered acceptable under the
Defining a good-quality study
All data received by the core laboratory was transferred to a gamma camera computer system. At that time, each raw projection SPECT image underwent a standard QC examination. The visual assessment for quality included notation of patient motion or inadequate count density. Cardiac motion, if detected, was corrected by software (if possible). For the COURAGE trial, each site was informed individually and regularly of its quality ratings. An annual report was provided to the COURAGE executive
Data processing
For all COURAGE studies, each scan was processed by expert core laboratory technologists using automated reconstruction techniques on a processing station employing a dedicated core laboratory work station equipped with the Ceders-Sinai suite of software programs for reconstruction and analysis. During the reconstruction process, the accuracy of the reconstructed data was verified. The reconstructed tomograms were then formatted according to standard displays for myocardial perfusion imaging
Protection of electronically stored data
For the COURAGE trial, all images were stored digitally on a secure server in a data center with access by designated nuclear core laboratory personnel only. All patient-related information was stored on the same secure server in a password-protected database. Backups were performed daily by information-systems personnel, and copies were stored on and off site. The core laboratory conforms to good clinical practice standards, with each protocol approved and supervised by the Investigational
Data analysis
For the data included in the COURAGE trial, only approved sites with qualified cameras with acceptable quality were included in the data analysis for the nuclear substudy. For the COURAGE trial, the procedure for expert visual interpretation involves each reader being blinded to all patient information, as well as the date of the study, including name, clinical history, and stress-related data. This was particularly relevant for substudy 2 that involves serial imaging before treatment and then
Specifics of image interpretation
Between initial planning of the COURAGE trial and enrollment and follow-up, several new developments in image interpretation were added to our proposed analysis that initially relied on risk stratification by using the 20-segment myocardial model (the summed stress score). We added to the analysis the percentage of ischemic myocardium based on the work by Hachamovitch et al9 calculated by ([summed stress score – summed rest score] / 68) * 100 = % ischemic myocardium. We have previously
Technical aspects of substudy 2 in the COURAGE trial
Perhaps most intriguing of the nuclear substudies, substudy 2 examines the usefulness of sequential imaging in 300 patients. Substudy 2 is the most challenging in terms of defining the optimal timing for the second SPECT scan to elicit a therapeutic benefit from both PCI and medical therapy (Figure 3). The use of myocardial perfusion imaging very early post-PCI has been associated with false-positive results with evidence supporting testing beyond 1 month post-PCI.19, 20 Furthermore, aggressive
Examples of sequential monitoring of substudy 2 in the COURAGE trial
An example of sequential myocardial perfusion imaging was previously published.55 In a related example (Figure 6A and B), a significant reduction in stress defect extent and severity is noted. At the second scan, global improvements in risk factors occurred concomitant with improvement in myocardial perfusion. A contrasting example is shown in Figure 6C and D, showing a patient with worsening symptoms after treatment initiation and an increase in the extent and severity of the stress perfusion
Other current clinical trials using sequential SPECT monitoring
Several other controlled clinical trials are ongoing in which sequential monitoring with SPECT imaging is being investigated by other core laboratories, including the “Bypass angioplasty revascularization investigation in diabetics” (BARI 2-D; principal investigator, Ami Iskandrian, MD, University of Alabama, Birmingham) and “Adenosine sestamibi spect post-infarction evaluation” (INSPIRE; principal investigator, John J. Mahmarian, MD, Baylor College of Medicine, Houston, Tex).57
Conclusions
Emerging evidence on the application of gSPECT in multinational, large randomized trials such as COURAGE, defines a new era for nuclear cardiology. The application of gSPECT in the COURAGE trial is made possible by the wealth of outcome evidence from large observational cohorts. The evidence derived from COURAGE will demonstrate the usefulness of nuclear imaging to guide the intensity and type of therapeutic intervention in patients with CAD. In addition, our substudy with sequential monitoring
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The COURAGE trial was supported by the Cooperative Studies Program of the Department of Veterans Affairs Office of Research and Development in collaboration with the Canadian Institutes of Health Research. Unrestricted research grants were obtained from Merck & Co; Pfizer Pharmaceuticals; Bristol-Myers Squibb Medical Imaging; Astellas Pharma; Kos Pharmaceuticals; Data Scope; Astra Zeneca Pharmaceuticals; Astra-Zeneca-Canada; Schering-Plough Coorporation, Ltd; Sanofi-Aventis, Inc; First Horizon; and GE Healthcare. All industrial funding for this trial was directed through the Department of Veterans Affairs. Additional funding for this substudy was provided by grants to the Department of Veterans Affairs and Canadian Institutes of Health Research from Astellas Pharma and Bristol-Myers-Squibb Medical Imaging.