Coronary Artery Disease
Conditions
Keywords
suspected coronary artery disease
Brief summary
The study will be a prospective, pragmatic, randomized clinical trial of the comparative effectiveness of diagnostic evaluation strategies for stable CAD, to be performed in outpatient settings, including primary care and cardiology practices.
Detailed description
Objective was to test a modified initial cCTA strategy (PS) designed to improve clinical efficiency vs usual testing (UT). Patients from 65 North American and European sites with stable symptoms of suspected coronary artery disease (CAD) and no prior testing were randomly assigned 1:1 to precision strategy PS or UT. PS incorporated the Prospective Multicenter Imaging Study for the Evaluation of Chest Pain (PROMISE) minimal risk score to quantitatively select minimal-risk participants for deferred testing, assigning all others to cCTA with selective CT-derived fractional flow reserve (FFR-CT). UT included site-selected stress testing or catheterization. Site clinicians determined subsequent care.
Interventions
DIAGNOSTIC_TESTcCTA with selective FFRct
PRECISE will evaluate whether a precision evaluation strategy that combines contemporary risk stratification using the PROMISE Risk Tool with functional and anatomic non-invasive evaluation with cCTA with selective FFRct can improve outcomes over usual care in stable chest pain patients while safely deferring further testing in low-risk patients and reducing cost overall
Sponsors
Duke Clinical Research Institute
Cardiovascular Research Foundation, New York
HeartFlow, Inc.
Study design
Allocation
RANDOMIZED
Intervention model
PARALLEL
Primary purpose
OTHER
Masking
NONE
Intervention model description
Participants who meet all inclusion criteria and none of the exclusion criteria will be randomized in a ratio of 1:1 within a clinical center to either a precision evaluation strategy or usual care using an interactive web or voice-based system (IXRS). Randomization will be stratified by intended first test if randomized to usual care and by classification as minimal vs. elevated risk by the minimal risk model. The randomization scheme within a clinical center will be carried out by the method of random permuted block design with variable block size
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
(all must be present): 1. Age ≥18 years 2. Stable typical or atypical symptoms suggesting possible significant coronary artery disease (CAD) with further non-emergent testing or elective catheterization recommended to evaluate the presence of suspected significant CAD. Stable chest pain (or equivalent) includes those who have fully been ruled out for Acute Coronary Syndrome (ACS) and for whom elective testing is recommended, regardless of the venue in which they are seen. 3. If prior CV testing has occurred, it must have been performed greater than one year prior to randomization, and the following must be met: 1. cCTA or invasive coronary angiography (ICA) with stenosis \< 50% 2. Quantified coronary artery calcium (CAC) \< 100 AG 4. Safe performance of cCTA: 1. Creatinine clearance ≥45 ml/min per most recent measurement within 90 days 2. For a female participant of childbearing potential (those who have not been surgically sterilized or are not postmenopausal), a pregnancy test must be performed with negative results known within 7 days prior to randomization 5. Willingness to comply with all aspects of the protocol, including adherence to the assigned strategy and follow-up visits 6. Ability to provide written informed consent
Exclusion criteria
(all must be absent): 1. Acute chest pain (in patients who have not been ruled out for ACS) 2. Unstable clinical status 3. Noninvasive or invasive CV testing for CAD within 1 year. CV testing for CAD refers to any stress tests, invasive coronary angiography (ICA) and cCTA (including calcium scoring) only. a. Resting ECG, resting echocardiogram and resting CMR (MRI) are not exclusionary regardless of when were performed 4. Lifetime history of known obstructive CAD (prior myocardial infarction, CABG or PCI, stenosis ≥50%), known EF ≤40% or other moderate to severe valvular or congenital cardiac disease 5. Contraindications to cCTA including but not limited to creatinine clearance (GFR) \<45 ml/min as per most recent measurement taken within 90 days 6. Exceeds the site's weight or size limit for cCTA or cardiac catheterization 7. Any condition leading to possible inability to comply with the protocol procedures or follow-up 8. Any condition that might interfere with the study procedures or follow-up 9. Enrolled in an investigational trial that involves a non-approved cardiac drug or device which has not reached its primary endpoint 10. Life expectancy less than 2 years due to non-cardiovascular comorbidities
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| Primary Composite (Number) of Deaths / MIs / Invasive Coronary Angiography Without Obstructive Disease | 1 year | The centrally adjudicated (by Clinical Events Committee) primary end point was a composite of clinical efficiency as a gatekeeper to invasive testing (catheterization without obstructive CAD) and safety (death, non fatal myocardial infarction \[MI\]) at 1 year. Invasive cardiac catheterization without obstructive coronary artery disease defined as the absence of any ≥50% stenosis or hemodynamic indication of significance (no FFR ≤0.80 or iFR≤0.89) in any major epicardial vessel including side branches ≥2 mm in diameter, as determined by core-lab adjudicated quantitative coronary angiography (QCA) or if QCA not performed, by site report. A detailed description and information on the definitions of primary endpoint component definitions is provided in the current version of the study Protocol, Statistical Analysis Plan, and the published trial design article. |
Secondary
| Measure | Time frame | Description |
|---|---|---|
| Number of Unplanned Hospitalizations (Including Admissions With Death or MI) | 1 year | Urgent and unscheduled hospitalizations for cardiovascular causes include hospitalization for ischemic heart disease including myocardial infarction and unstable angina, cerebrovascular disease including stroke and TIA, heart failure, acute and/or critical limb ischemia, other thrombotic events including pulmonary embolism, arrhythmias, cardiac arrest and other clear cardiovascular causes for hospitalization that do not meet the criteria for the specific events listed here (e.g., hospitalization for acute cardiac chest pain that does not meet the criteria for MI or UA). |
| Number of Catheterization and Revascularization Procedures | 1 year | Catheterization efficiency was defined as the proportion of invasive cardiac catheterization patients who undergo revascularization (PCI or CABG) within 6 months. Revascularization may occur either percutaneously (PCI) or surgically (CABG) or as hybrid (PCI and CABG). For PCI, any intervention on a lesion in the coronary tree (including angioplasty, stenting, intravascular lithotripsy) whether successful or not will be considered a revascularization. For CABG the start of the surgical procedure (skin incision) was considered as CABG, whether the procedure was successful or not. Staged revascularization was considered as one revascularization event. |
| Number of Participants With Preventive Medication Use | 1 Year | Lipid-lowering agents included statins, ezetimibe, PCSK9 inhibitors. Antiplatelet agents included aspirin, clopidogrel, ticagrelor, or prasugrel. Antihypertensive medications included calcium channel blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, angiotensin-neprilysin inhibitor, beta blockers, nitrates, or diuretics. |
| Number of Participants With Quality of Life (Angina Frequency) Assessment | 1 year | Overall health status was assessed briefly using the EQ-5D-5L, a standardized generic measure that can also be used to link specific health states to general population-based utilities. The EQ-5D-5L consists of two parts: (1) a descriptive assessment of five dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression), each of which can take one of five responses corresponding to the level of severity within each dimension, and (2) a self-rating 0- 100 thermometer of current health-related quality of life. The proportion of participants with frequent angina (Seattle Angina Questionnaire angina frequency score \<80). |
| Cumulative Radiation Exposure From All Cardiovascular Procedures (12 M), MilliSievert (mSv) | 1 year | The cumulative radiation exposure over the 12 months following Randomization was calculated based on each participant's exposure to radiation for cardiovascular care. If data are missing in \> 80% or more of the diagnostic and procedural testing, a single fixed estimate of radiation based on the literature will be used to impute. Given high missingness in catheterization data, a fixed estimate of 6.6 mSv and 4.1 mSv was used for catheterization with and without revascularization, respectively, based on recent trial data. |
Countries
United States
Participant flow
Recruitment details
Participants were randomly assigned 1:1 to precision strategy (PS) or usual testing (UT), stratified by site, intended first test if randomly assigned to UT, and minimal vs moderate-high risk using the validated PROMISE minimal risk score(PMRS). All PS and UT testing was performed according to local protocols, and all subsequent testing and care decisions were made locally.
Participants by arm
| Arm | Count |
|---|---|
| Precision Strategy (PS) Participants were randomly assigned 1:1 to precision strategy (PS) or usual testing (UT), stratified by site, intended first test if randomly assigned to UT, and minimal vs moderate-high risk using the validated PROMISE minimal risk score(PMRS).
Participants in the PS group with a PROMISE minimal risk score (PMRS - validated tool) threshold value of greater than 0.46 were assigned to deferred testing. All other participants in the PS group (ie, those with a PMRS \<0.46), or those with known atherosclerosis such as vascular calcification on chest CT, received cCTA with selective FFR-CT for site-read 30% to 90% stenoses.
All PS and UT testing was performed according to local protocols, and all subsequent testing and care decisions were made locally. | 1,057 |
| Usual Testing (UT) Participants were randomly assigned 1:1 to precision strategy (PS) or usual testing (UT), stratified by site, intended first test if randomly assigned to UT, and minimal vs moderate-high risk using the validated PROMISE minimal risk score(PMRS).
Among participants in the UT group, site clinicians chose the initial testing modality, including exercise electrocardiogram, stress echocardiogram, stress nuclear myocardial perfusion imaging (single-photon emission CT or positron emission tomography), stress cardiovascular magnetic resonance imaging, or catheterization.
All PS and UT testing was performed according to local protocols, and all subsequent testing and care decisions were made locally. | 1,046 |
| Total | 2,103 |
Baseline characteristics
| Characteristic | Precision Strategy (PS) | Total | Usual Testing (UT) |
|---|---|---|---|
| Absence of any CV risk factors | 67 Participants | 128 Participants | 61 Participants |
| Age, Continuous | 58.0 years STANDARD_DEVIATION 11.5 | 58.4 years STANDARD_DEVIATION 11.5 | 58.9 years STANDARD_DEVIATION 11.6 |
| Body mass index | 30.2 kg/m^2 STANDARD_DEVIATION 6.6 | 30.0 kg/m^2 STANDARD_DEVIATION 6.4 | 29.9 kg/m^2 STANDARD_DEVIATION 6.2 |
| Current or past tobacco use | 544 Participants | 1098 Participants | 554 Participants |
| Diabetes | 176 Participants | 373 Participants | 197 Participants |
| Dyslipidemia | 668 Participants | 1349 Participants | 681 Participants |
| Family history of premature CAD | 404 Participants | 799 Participants | 395 Participants |
| Hypertension | 642 Participants | 1248 Participants | 606 Participants |
| Peripheral arterial or cerebrovascular disease | 65 Participants | 121 Participants | 56 Participants |
| Primary presenting symptom (Chest pain) | 870 Participants | 1746 Participants | 876 Participants |
| PROMISE minimal risk score >0.46 (minimal risk) | 214 Participants | 433 Participants | 219 Participants |
| Race (NIH/OMB) American Indian or Alaska Native | NA Participants | NA Participants | NA Participants |
| Race (NIH/OMB) Asian | NA Participants | NA Participants | NA Participants |
| Race (NIH/OMB) Black or African American | NA Participants | NA Participants | NA Participants |
| Race (NIH/OMB) More than one race | NA Participants | NA Participants | NA Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | NA Participants | NA Participants | NA Participants |
| Race (NIH/OMB) Unknown or Not Reported | NA Participants | NA Participants | NA Participants |
| Race (NIH/OMB) White | 892 Participants | 1767 Participants | 875 Participants |
| Sex: Female, Male Female | 508 Participants | 1047 Participants | 539 Participants |
| Sex: Female, Male Male | 549 Participants | 1056 Participants | 507 Participants |
| Type of angina (Atypical - possible cardiac) | 600 Participants | 1197 Participants | 597 Participants |
| Type of angina (Typical - cardiac) | 249 Participants | 506 Participants | 257 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk |
|---|---|---|
| deaths Total, all-cause mortality | 5 / 1,057 | 7 / 1,046 |
| other Total, other adverse events | 13 / 1,057 | 43 / 1,046 |
| serious Total, serious adverse events | 40 / 1,057 | 30 / 1,046 |
Outcome results
Primary
Primary Composite (Number) of Deaths / MIs / Invasive Coronary Angiography Without Obstructive Disease
The centrally adjudicated (by Clinical Events Committee) primary end point was a composite of clinical efficiency as a gatekeeper to invasive testing (catheterization without obstructive CAD) and safety (death, non fatal myocardial infarction \[MI\]) at 1 year. Invasive cardiac catheterization without obstructive coronary artery disease defined as the absence of any ≥50% stenosis or hemodynamic indication of significance (no FFR ≤0.80 or iFR≤0.89) in any major epicardial vessel including side branches ≥2 mm in diameter, as determined by core-lab adjudicated quantitative coronary angiography (QCA) or if QCA not performed, by site report. A detailed description and information on the definitions of primary endpoint component definitions is provided in the current version of the study Protocol, Statistical Analysis Plan, and the published trial design article.
Time frame: 1 year
Population: Statistical testing for recurrent events was performed using the negative binomial methods for recurrent events. The primary endpoint of this study is estimated as time to first occurrence of any of its three following components: All-cause death; Non-fatal MI; Invasive cardiac catheterization without obstructive CAD.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Precision Strategy (PS) | Primary Composite (Number) of Deaths / MIs / Invasive Coronary Angiography Without Obstructive Disease | Invasive cardiac catheterization without Obstructive coronary disease | 27 number of events |
| Precision Strategy (PS) | Primary Composite (Number) of Deaths / MIs / Invasive Coronary Angiography Without Obstructive Disease | Death or Nonfatal Myocardial Infarction (first event only) | 18 number of events |
| Precision Strategy (PS) | Primary Composite (Number) of Deaths / MIs / Invasive Coronary Angiography Without Obstructive Disease | Primary Composite End Point | 44 number of events |
| Precision Strategy (PS) | Primary Composite (Number) of Deaths / MIs / Invasive Coronary Angiography Without Obstructive Disease | Death from any cause | 5 number of events |
| Precision Strategy (PS) | Primary Composite (Number) of Deaths / MIs / Invasive Coronary Angiography Without Obstructive Disease | Nonfatal Myocardial Infarction | 13 number of events |
| Usual Testing (UT) | Primary Composite (Number) of Deaths / MIs / Invasive Coronary Angiography Without Obstructive Disease | Death from any cause | 7 number of events |
| Usual Testing (UT) | Primary Composite (Number) of Deaths / MIs / Invasive Coronary Angiography Without Obstructive Disease | Nonfatal Myocardial Infarction | 5 number of events |
| Usual Testing (UT) | Primary Composite (Number) of Deaths / MIs / Invasive Coronary Angiography Without Obstructive Disease | Invasive cardiac catheterization without Obstructive coronary disease | 107 number of events |
| Usual Testing (UT) | Primary Composite (Number) of Deaths / MIs / Invasive Coronary Angiography Without Obstructive Disease | Primary Composite End Point | 118 number of events |
| Usual Testing (UT) | Primary Composite (Number) of Deaths / MIs / Invasive Coronary Angiography Without Obstructive Disease | Death or Nonfatal Myocardial Infarction (first event only) | 12 number of events |
Comparison: Sample size and power calculations for this study are based on the hypothesis that the precision evaluation arm is superior to the usual care arm on the time-to-first event of the composite 3-component endpoint: all-cause death, non-fatal MI, or invasive cardiac catheterization without obstructive CAD over a 12-month of follow-up. Time to event analysis will use the date of the event, including the date of catheterization at which the absence of obstructive CAD is demonstrated.p-value: <0.00195% CI: [0.2, 0.41]Log Rank
Secondary
Cumulative Radiation Exposure From All Cardiovascular Procedures (12 M), MilliSievert (mSv)
The cumulative radiation exposure over the 12 months following Randomization was calculated based on each participant's exposure to radiation for cardiovascular care. If data are missing in \> 80% or more of the diagnostic and procedural testing, a single fixed estimate of radiation based on the literature will be used to impute. Given high missingness in catheterization data, a fixed estimate of 6.6 mSv and 4.1 mSv was used for catheterization with and without revascularization, respectively, based on recent trial data.
Time frame: 1 year
Population: In instances in which sufficient information required to assess actual dose is not available, data were imputed. For CCTA and nuclear imaging missing values were imputed based on distribution of data from participants. Cumulative radiation exposure from additional cardiac testing and procedures during the entire follow-up period were also collected or estimated based on accepted average exposures. Given high missingness in catheterization data, a fixed estimate of 6.6 mSv and 4.1 mSv was used.
| Arm | Measure | Value (MEAN) | Dispersion |
|---|---|---|---|
| Precision Strategy (PS) | Cumulative Radiation Exposure From All Cardiovascular Procedures (12 M), MilliSievert (mSv) | 5.2 mSv | Standard Deviation 5.4 |
| Usual Testing (UT) | Cumulative Radiation Exposure From All Cardiovascular Procedures (12 M), MilliSievert (mSv) | 4.7 mSv | Standard Deviation 6 |
Secondary
Number of Catheterization and Revascularization Procedures
Catheterization efficiency was defined as the proportion of invasive cardiac catheterization patients who undergo revascularization (PCI or CABG) within 6 months. Revascularization may occur either percutaneously (PCI) or surgically (CABG) or as hybrid (PCI and CABG). For PCI, any intervention on a lesion in the coronary tree (including angioplasty, stenting, intravascular lithotripsy) whether successful or not will be considered a revascularization. For CABG the start of the surgical procedure (skin incision) was considered as CABG, whether the procedure was successful or not. Staged revascularization was considered as one revascularization event.
Time frame: 1 year
Population: Additionally catheterization efficiency or cath yield is defined as the proportion of participants with an invasive coronary angiogram who underwent revascularization within 6 months of catheterization. Rates will be summarized by 2 groups.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Precision Strategy (PS) | Number of Catheterization and Revascularization Procedures | Invasive catheterization | 135 number of events |
| Precision Strategy (PS) | Number of Catheterization and Revascularization Procedures | PCI | 77 number of events |
| Precision Strategy (PS) | Number of Catheterization and Revascularization Procedures | CABG | 21 number of events |
| Precision Strategy (PS) | Number of Catheterization and Revascularization Procedures | Rate of finding obstructive CAD on catheterization | 108 number of events |
| Precision Strategy (PS) | Number of Catheterization and Revascularization Procedures | Total Revascularizations | 97 number of events |
| Usual Testing (UT) | Number of Catheterization and Revascularization Procedures | CABG | 18 number of events |
| Usual Testing (UT) | Number of Catheterization and Revascularization Procedures | Total Revascularizations | 54 number of events |
| Usual Testing (UT) | Number of Catheterization and Revascularization Procedures | Invasive catheterization | 177 number of events |
| Usual Testing (UT) | Number of Catheterization and Revascularization Procedures | PCI | 37 number of events |
| Usual Testing (UT) | Number of Catheterization and Revascularization Procedures | Rate of finding obstructive CAD on catheterization | 70 number of events |
Secondary
Number of Participants With Preventive Medication Use
Lipid-lowering agents included statins, ezetimibe, PCSK9 inhibitors. Antiplatelet agents included aspirin, clopidogrel, ticagrelor, or prasugrel. Antihypertensive medications included calcium channel blockers, angiotensin-converting enzyme inhibitors, angiotensin receptor blockers, angiotensin-neprilysin inhibitor, beta blockers, nitrates, or diuretics.
Time frame: 1 Year
Population: The number (%) will be summarized between the precision care arm and usual care arm.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Precision Strategy (PS) | Number of Participants With Preventive Medication Use | Antiplatelet | 321 Participants |
| Precision Strategy (PS) | Number of Participants With Preventive Medication Use | Lipid-lowering | 450 Participants |
| Precision Strategy (PS) | Number of Participants With Preventive Medication Use | Anti-hypertensive | 504 Participants |
| Usual Testing (UT) | Number of Participants With Preventive Medication Use | Antiplatelet | 237 Participants |
| Usual Testing (UT) | Number of Participants With Preventive Medication Use | Lipid-lowering | 365 Participants |
| Usual Testing (UT) | Number of Participants With Preventive Medication Use | Anti-hypertensive | 455 Participants |
Secondary
Number of Participants With Quality of Life (Angina Frequency) Assessment
Overall health status was assessed briefly using the EQ-5D-5L, a standardized generic measure that can also be used to link specific health states to general population-based utilities. The EQ-5D-5L consists of two parts: (1) a descriptive assessment of five dimensions (mobility, self-care, usual activities, pain/discomfort, anxiety/depression), each of which can take one of five responses corresponding to the level of severity within each dimension, and (2) a self-rating 0- 100 thermometer of current health-related quality of life. The proportion of participants with frequent angina (Seattle Angina Questionnaire angina frequency score \<80).
Time frame: 1 year
Population: Angina Frequency Score at Baseline was used as reference. Not all participants fully completed the questionnaire, therefore data were collected as presented below.
| Arm | Measure | Group | Value (COUNT_OF_PARTICIPANTS) |
|---|---|---|---|
| Precision Strategy (PS) | Number of Participants With Quality of Life (Angina Frequency) Assessment | More frequent angina: all participants | 141 Participants |
| Precision Strategy (PS) | Number of Participants With Quality of Life (Angina Frequency) Assessment | More frequent angina: participants with typical angina | 50 Participants |
| Usual Testing (UT) | Number of Participants With Quality of Life (Angina Frequency) Assessment | More frequent angina: all participants | 140 Participants |
| Usual Testing (UT) | Number of Participants With Quality of Life (Angina Frequency) Assessment | More frequent angina: participants with typical angina | 40 Participants |
Secondary
Number of Unplanned Hospitalizations (Including Admissions With Death or MI)
Urgent and unscheduled hospitalizations for cardiovascular causes include hospitalization for ischemic heart disease including myocardial infarction and unstable angina, cerebrovascular disease including stroke and TIA, heart failure, acute and/or critical limb ischemia, other thrombotic events including pulmonary embolism, arrhythmias, cardiac arrest and other clear cardiovascular causes for hospitalization that do not meet the criteria for the specific events listed here (e.g., hospitalization for acute cardiac chest pain that does not meet the criteria for MI or UA).
Time frame: 1 year
Population: For All Cause Hospitalization only a descriptive summary will be presented.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| Precision Strategy (PS) | Number of Unplanned Hospitalizations (Including Admissions With Death or MI) | For Unstable Angina | 9 number of events |
| Precision Strategy (PS) | Number of Unplanned Hospitalizations (Including Admissions With Death or MI) | Cardiovascular | 31 number of events |
| Usual Testing (UT) | Number of Unplanned Hospitalizations (Including Admissions With Death or MI) | Cardiovascular | 21 number of events |
| Usual Testing (UT) | Number of Unplanned Hospitalizations (Including Admissions With Death or MI) | For Unstable Angina | 5 number of events |