Randomized Evaluation of Patients With Stable Angina Comparing Diagnostic Examinations

Study Overview
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Brief Summary
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This randomized, controlled, diagnostic, multicenter trial will compare two diagnostic imaging pathways--coronary computed tomography angiography (CCTA) and single photon emission tomography (SPECT) myocardial perfusion imaging (MPI)--to determine the incidence of major adverse coronary events (MACE), defined as myocardial infarction (MI) or cardiac-related death, and cross-over to revascularization. CCTA may be used to direct patients with symptoms of stable angina or angina equivalent to optimal medical therapy (OMT). The use of CCTA as a diagnostic tool for angina symptoms will be associated with no increase in MACE or revascularization, decreased cost, reduced risks (e.g., less radiation exposure), additional insights into alternate explanations of chest pain, and increased cost-effectiveness in comparison with use of SPECT MPI/invasive coronary angiography (ICA).

Detailed Description
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The Randomized Evaluation of Patients with Stable Angina Comparing Utilization of Diagnostic Examinations (RESCUE) is a multi-center randomized, controlled trial responding to the need for comparative analysis of these imaging technologies and the role of OMT in clinical care. A total of 4300 patients will be randomized to CCTA or SPECT MPI/ICA for diagnostic assessment of angina at up to 80 institutions internationally. This study builds on the results of the COURAGE trial by comparing CCTA and SPECT MPI/ICA integrated into a care paradigm featuring initial treatment with OMT for patients diagnosed using computer-aided diagnosis (CAD) without significant disease in the left main coronary artery. Participants will be followed for a composite endpoint of MACE and cross-over to revascularization over a follow-up period up to two years (two to six time points depending on diagnostic results and time of enrollment into the trial). The primary endpoint of the study is a combined endpoint of occurrence of MACE and revascularization. We will calculate differences in the combined MACE/revascularization endpoint between the CCTA and SPECT MPI/ICA arms. Participant outcomes will be assessed by age, gender, comorbidity, and angina classification class at presentation. Several comparative-effectiveness analyses will be performed. We hypothesize that the CCTA arm will be associated with no increase in MACE or revascularization, decreased cost, reduced risks (e.g., less radiation exposure), additional insights into or alternate explanations of chest pain, and increased cost-effectiveness in comparison with SPECT MPI/ICA. Findings are expected to result in validation of an evolving new standard of care for patients with stable angina that takes advantage of CCTA and OMT to more cost-effectively drive appropriate care while reducing the need for invasive diagnosis and increased radiation exposure with SPECT MPI/ICA.

Official Title
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ACRIN-4701 RESCUE: Randomized Evaluation of Patients With Stable Angina Comparing Utilization of Diagnostic Examinations

Conditions
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Chest Pain, Stable Angina Pectoris, CCS Class I to III, Angina Equivalent, Coronary Artery Disease

Intervention / Treatment
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* Device: CCTA
* Device: SPECT MPI/ICA


Participation Criteria
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Eligibility Criteria
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Inclusion Criteria: Willing and able to provide a written informed consent; 40 years or older; Presentation with symptoms of stable angina (CCS Class I to III) or angina equivalent with or without known CAD; Planned non-invasive imaging for CAD diagnosis; Able to tolerate CCTA or SPECT MPI per randomization as required by protocol, to be performed at an ACRIN-qualified facility with a RESCUE-qualified scanner. Exclusion Criteria: Prior revascularization; Not suitable to undergo CT with an iodinated contrast agent: Known allergy-like reaction to contrast media as defined by the American College of Radiology (ACR) (see www.acr.org/SecondaryMainMenuCategories/quality_safety/contrast_manual.aspx for reaction definition) or moderate to severe allergic reactions to more than one allergen; Renal failure, as determined by glomerular filtration rate (GFR) < 30 mL/min/1.73 m2 based on a serum creatinine level obtained within 28 days prior to registration; Renal insufficiency at the time of enrollment, as determined by GFR 30 to 60 mL/min/1.73 m2 based on a serum creatinine level obtained within 28 days prior to registration, unless permitted by the institution's policy and/or ACR guidance for risk reduction strategies (see www.acr.org/SecondaryMainMenuCategories/quality_safety/contrast_manual.aspx for guidance on contrast selection and pre-treatment strategies); Atrial fibrillation or significant arrhythmia judged to potentially limit quality of CCTA; Acute ischemia; Acute myocardial infarction; Severe myocardial ischemia: known markedly positive exercise treadmill stress test (ST) [significant ST segment depressions or hypotensive response during stage I of the Bruce protocol]; Unable to suspend respiration for 15 seconds or to follow instructions to do so; Unstable angina and symptoms refractory to maximal oral and intravenous medical therapy (persistent CCS Class IV); History of known left ventricular ejection fraction < 45%; Pulmonary edema or heart failure unresponsive to standard medical therapy; Pacemaker; Valvular heart disease likely to require surgery in the next 18 months; Congenital heart disease or cardiomyopathy likely to affect prognosis during follow up; Significant systemic hypertension (blood pressure > 200/100 mm Hg) unresponsive to medical therapy; Severe noncardiovascular comorbidity limiting survival (e.g., cancer or other life threatening illness for which the patient is expected to live less than 12 months); Prior imaging evaluation for this episode of symptoms (e.g., SPECT MPI or CCTA within the previous 72 hours); BMI > 40 kg/m2; Pregnancy or intent to become pregnant (if a female is of childbearing potential-defined as a premenopausal female capable of becoming pregnant-a pregnancy test should be done prior to enrollment).

Ages Eligible for Study
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Minimum Age: 40 Years

Sexes Eligible for Study
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All

Accepts Healthy Volunteers
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No

Study Plan
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How is the study designed?
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Design Details

Primary Purpose: Diagnostic
Allocation: Randomized
Intervention Model: Parallel Assignment
Interventional Model Description: This randomized, controlled, diagnostic, multicenter trial will follow participants at 6-month intervals for up to 24 months to determine the incidence of MACE, defined as myocardial infarction (MI) or cardiac-related death, and cross-over to revascularization.
Masking: None (Open Label)


Arms and Interventions

| Participant Group/Arm | Intervention/Treatment |
| --- | --- |
| Experimental: Group A: CCTA Diagnostic<br>Participants randomized to diagnostic evaluation using coronary computed tomographic angiography (CCTA) to determine therapeutic course of action. | Device: CCTA<br>* Complete diagnostic CCTA per protocol specifications.<br>* Other names: coronary computed tomographic angiography;|
| Active Comparator: Group B: SPECT MPI/ICA Diagnostic<br>Standard-of-care diagnostic assessment using single photon emission computed tomography myocardial perfusion imaging (SPECT MPI), possibly followed by diagnostic invasive coronary angiography (ICA) dependent on SPECT MPI results. | Device: SPECT MPI/ICA<br>* Perform SPECT MPI per institutional standard practice; diagnostic ICA will be performed only as indicated per protocol.<br>* Other names: single photon emission computed tomography (SPECT) myocardial perfusion imaging (MPI);|

What is the study measuring?
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Primary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Time-dependent Rates of the Composite Primary Endpoint Major Adverse Cardiovascular Event (MACE: Comprising Cardiac-related Death or Acute Myocardial Infarction (AMI), and Revascularization) | To compare outcomes of participants with symptoms of stable angina or angina equivalent evaluated with an anatomic imaging strategy using CCTA as initial method of computer-aided diagnosis (CAD) (Group A) to a combined functional and anatomic imaging strategy of SPECT MPI/ICA (Group B) as a guide to Optimal Medical Therapy (OMT) alone. The analysis was conducted from an intent-to-treat perspective | up to 24 Months (depends on time of trial enrollment and funding duration) | 

Secondary Outcome Measures

| Outcome Measure | Measure Description | Time Frame |
| --- | --- | --- |
| Prediction of Response (MACE/Revascularization) at 1 Year Using: Modified Duke Score or CCTA + AHA 16 Predictor/CCTA+AHA 16+Clinical Data Predictor or SPECT% Reversible Defect Size Reported as Receiver Operating Characteristic (ROC) Area Under Curve (AUC) | AUC is a unitless measure of performance ranging form 0.5 (guessing) to 1.0 (perfect predictor) that can be thought of a the proportion of correct classifications in a 2-alternative-forced-choice experiment - and for binary outcomes, it is equivalent to the C-statistic. It will be used to evaluate and compare the ability of available prognostic indices and SPECT-MPI % reversible defect size to predict revascularization or MACE using CCTA information: A CCTA Modified Duke index A CCTA index including the 16 individual American Heart Association (AHA) segments A CCTA including the 16 individual AHA segments and clinical data and compare them to the SPECT % reversible defect size results | 1 year | 
| Short Form-36 Survey (SF-36v2) and Seattle Angina Questionnaire (SAQ) Score | SF36+SAQ at baseline and to a subset of participants, stratified by diagnostic examination, at 12 months after enrollment to monitor angina symptoms and their impact on Quality of life. The Short Form-36 (SF36) is a 36 item overall health status/Quality of Life collected in 8 domains. Scales are standardized with scores ranging from 0-100. Higher scores= better health status. The Seattle Angina Questionnaire (SAQ) is a self-administered, 19-item, cardiac disease-related quality-of-life measure collected in 5 domains. scales are standardized with scores ranging from 0-100. Higher scores= better health status. Positive cardiac findings on diagnostic testing are defined as: 50% stenosis on CCTA or un-evaluable left main, or proximal and mid segments of all other epicardial arteries (right coronary artery, left anterior descending artery, or left circumflex artery); and 10% reversible defect on SPECT MPI or evidence of Transient Ischemic Dilation (TID) accompanied by ECG | baseline and 12 months | 
| The Effectiveness of Each Arm Will be Measured in Terms of Life Years and Quality of Life Years (QALY). | International medical records will be used to determine mortality which may not be feasible at all participating international sites. Utilities will be based on Quality of Well Being scores converted from the SF-36 assessments The analysis will be performed assuming a societal perspective and lifetime time horizon | Baseline and 1 year | 

 Terms related to the study
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Keywords Provided by Centre Hospitalier Valida
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stable angina, recurrent chest pain, chest pain, angina equivalent, diagnosis, coronary artery disease