Coronary Artery Disease
Conditions
Keywords
Coronary Artery Disease Computed Fractional Flow Reserve
Brief summary
To determine the diagnostic performance of FFRCT by coronary computed tomographic angiography (cCTA), as compared to cCTA alone, for non-invasive determination of the presence of a hemodynamically significant coronary lesion, using direct measurement of fractional flow reserve (FFR) during cardiac catheterization as a reference standard.
Detailed description
Recently, coronary Computed Tomography Angiography (cCTA) of 64-detector rows or greater has emerged as a novel non-invasive imaging modality that is capable of providing high-resolution images of coronary artery lesions (Budoff 2008; Miller 2008; Meijboom 2008). While cCTA demonstrates good diagnostic performance for detection and exclusion of anatomic coronary artery stenoses, numerous prior studies have revealed an unreliable relationship between detection of obstructive anatomic coronary artery stenoses by cCTA and hemodynamically (HD)-significant coronary artery disease (CAD), identified by myocardial perfusion SPECT or fractional flow reserve (FFR) (Di Carli 2007; Klauss 2007; Rispler 2007; van Werkhoven 2009). Individual subjects may have HD-significant CAD despite cCTA assessment demonstrating angiographically mild (\<50%) maximal stenosis (Schuijf 2006). These findings emphasize the need for additional measures beyond anatomic stenosis severity for the detection and exclusion of HD-significant CAD. Measurement of FFR during invasive cardiac catheterization represents the gold standard for assessment of the hemodynamic significance of coronary artery lesions (Kern 2010). Anatomic coronary artery stenosis assessment by quantitative coronary angiography (QCA) also correlates very poorly with FFR Melikian 2010). This was highlighted by the results of the FAME study in which FFR-guided coronary revascularization improved healthcare and economic outcomes compared to the conventional angiographically guided strategy (Pijls 2010; Tonino 2009; Tonino 2010). The major disadvantage of FFR is that it has to be measured invasively. HeartFlow, Inc. ('HeartFlow') has recently developed a non-invasive method to determine FFR which computes the hemodynamic significance of CAD (FFRCT) from subject-specific cCTA data using computational fluid dynamics under rest and simulated maximal coronary hyperemic conditions. Preliminary results in subjects suggest that FFRCT accurately predicts the hemodynamic significance of coronary lesions when compared to directly-measured FFR during invasive cardiac catheterization (Koo 2011).
Interventions
PROCEDUREICA (Invasive Coronary Angiography)
Per the protocol, patients will have an Invasive Coronary Angiography.
PROCEDUREFFR (Fractional Flow Reserve)
Per the protocol, patients will have a Fractional Flow Reserve procedure.
Per the protocol, patients will have a coronary computed tomography angiography.
OTHERFFRct Analysis (Fractional Flow Reserve Computed Tomography)
Per the protocol, patients will have a fractional flow reserve computed tomography.
Sponsors
Case Western Reserve University
HeartFlow, Inc.
Study design
Allocation
NA
Intervention model
SINGLE_GROUP
Primary purpose
DIAGNOSTIC
Masking
DOUBLE
Masking description
No Masking
Intervention model description
prospective, multicenter study to evaluate the diagnostic performance of cCTA plus FFRCT employing ≥64-detector row CT scanners for the detection and exclusion of significant obstructive CAD, as defined by invasively-measured FFR, the reference standard
Eligibility
Sex/Gender
ALL
Age
18 Years to No maximum
Healthy volunteers
No
Inclusion criteria
* Age ≥18 years * Subject providing written informed consent * Scheduled to undergo a clinically indicated Invasive Coronary Angiogram (ICA) * Has had ≥64 multidetector row cCTA within 60 days prior to ICA or agrees to undergo cCTA with ≥64 multidetector row cCTA within 60 days prior to ICA
Exclusion criteria
* Percutaneous coronary intervention (PCI) has been performed any time prior to ICA. * Prior coronary artery bypass graft (CABG) surgery * Contraindication to beta blocker agents, nitrates, or adenosine, including 2nd or 3rd degree heart block; sick sinus syndrome; long QT syndrome; severe hypotension; severe asthma, severe COPD or bronchodilator-dependent COPD * Suspicion of acute coronary syndrome (acute myocardial infarction and unstable angina) * Recent prior myocardial infarction within 30 days prior to cCTA or between cCTA and ICA * Known complex congenital heart disease * Prior pacemaker or internal defibrillator lead implantation * Prosthetic heart valve * Tachycardia or significant arrhythmia * Impaired chronic renal function (serum creatinine \>1.5 mg/dl) * Subjects with known anaphylactic allergy to iodinated contrast * Pregnancy or unknown pregnancy status in subject of childbearing potential * Body mass index \>35 at time of cCTA * Subject requires an emergent procedure * Evidence of ongoing or active clinical instability, including acute chest pain (sudden onset), cardiogenic shock, unstable blood pressure with systolic blood pressure \<90 mmHg, and severe congestive heart failure (NYHA III or IV) or acute pulmonary edema * Any active, serious, life-threatening disease with a life expectancy of less than 2 months * Inability to comply with study procedures
Design outcomes
Primary
| Measure | Time frame | Description |
|---|---|---|
| AUC of FFRct Versus Coronary CTA for Demonstration of Ischemia (≤0.80) on a Per-patient Basis | 1 day; Outcome measures were comparing FFRct to FFR. Incident time for FFR was dependent on the length of time on the cath procedure. FFRct was done remotely at HeartFlow's processing center in Redwood City with a turnaround time of 24 hours from CT scan. | The primary statistical measure will be the area under the receiver operating characteristic curve (AUC of ROC) of a patient-based model to detect hemodynamically significant obstruction. ROC graphs the change in sensitivity as the cut-point for positive/negative diagnosis moves from its lower to upper limit. FFR is used as the reference standard to determine the presence or absence of hemodynamic obstruction. For FFR, hemodynamically-significant obstruction of a coronary artery is defined as an FFR≤0.80 in any major epicardial coronary artery segment with diameter ≥2.0 mm during adenosine-mediated hyperemia. For cCTA, hemodynamically-significant obstruction of a coronary artery is defined as a stenosis \>50% . FFRCT will be calculated for each patient as the minimum FFRCT in any coronary artery segment . cCTA stenosis will be calculated for each patient as the highest cCTA stenosis category for any vessel all measurements will take place only in segments with diameter ≥2.0 mm. |
Secondary
| Measure | Time frame |
|---|---|
| AUC of FFRct Versus Coronary CTA for Demonstration of Ischemia (≤0.80) on a Per-vessel Basis | 1 day |
| Per-Patient Analysis: Diagnostic Performance of FFRct, Coronary CTA, and ICA | 1 day; Outcome measures were comparing FFRct to FFR. Incident time for FFR was dependent on the length of time on the cath procedure. FFRct was done remotely at HeartFlow's processing center in Redwood City with a turnaround time of 24 hours from CT scan. |
| Per Vessel Diagnostic Performance of FFRct, Coronary CTA, and ICA | 1 day; Outcome measures were comparing FFRct to FFR. Incident time for FFR was dependent on the length of time on the cath procedure. FFRct was done remotely at HeartFlow's processing center in Redwood City with a turnaround time of 24 hours from CT scan. |
Countries
Denmark
Participant flow
Participants by arm
| Arm | Count |
|---|---|
| Standard of Care: FFR and ICA Single arm
Measured FFR (Fractional Flow Reserve) and ICA (Invasive Coronary Angiography) | 276 |
| Total | 276 |
Baseline characteristics
| Characteristic | Standard of Care: FFR and ICA |
|---|---|
| Age, Continuous | 64 years STANDARD_DEVIATION 10 |
| Body Mass Index, kg/m^2 | 26 kg/m^2 STANDARD_DEVIATION 4 |
| Creatinine, mg/dl | 0.9 mg/dl STANDARD_DEVIATION 0.2 |
| Current smoker Current Smoker | 50 participants |
| Current smoker Former Smoker | 106 participants |
| Current smoker Never Smoked | 118 participants |
| Current smoker Unknown | 2 participants |
| Diabetes With Diabetes | 62 participants |
| Diabetes Without Diabetes | 214 participants |
| Hyperlipidemia Unknown Hiperlipidemia Status | 2 participants |
| Hyperlipidemia With Hyperlipidemia | 214 participants |
| Hyperlipidemia Without Hyperlipidemia | 60 participants |
| Hypertension With Hypertension | 188 participants |
| Hypertension Without Hypertension | 88 participants |
| Left ventricular ejection fraction, % | 62 percent STANDARD_DEVIATION 7 |
| Previous myocardial infarction No Previous Myocardial Infarction | 271 participants |
| Previous myocardial infarction Previous Myocardial Infarction | 5 participants |
| Race (NIH/OMB) American Indian or Alaska Native | 0 Participants |
| Race (NIH/OMB) Asian | 91 Participants |
| Race (NIH/OMB) Black or African American | 0 Participants |
| Race (NIH/OMB) More than one race | 0 Participants |
| Race (NIH/OMB) Native Hawaiian or Other Pacific Islander | 0 Participants |
| Race (NIH/OMB) Unknown or Not Reported | 6 Participants |
| Race (NIH/OMB) White | 179 Participants |
| Sex: Female, Male Female | 101 Participants |
| Sex: Female, Male Male | 175 Participants |
Adverse events
| Event type | EG000 affected / at risk | EG001 affected / at risk | EG002 affected / at risk |
|---|---|---|---|
| deaths Total, all-cause mortality | — / — | — / — | — / — |
| other Total, other adverse events | 53 / 276 | 53 / 276 | 53 / 276 |
| serious Total, serious adverse events | 5 / 276 | 5 / 276 | 5 / 276 |
Outcome results
Primary
AUC of FFRct Versus Coronary CTA for Demonstration of Ischemia (≤0.80) on a Per-patient Basis
The primary statistical measure will be the area under the receiver operating characteristic curve (AUC of ROC) of a patient-based model to detect hemodynamically significant obstruction. ROC graphs the change in sensitivity as the cut-point for positive/negative diagnosis moves from its lower to upper limit. FFR is used as the reference standard to determine the presence or absence of hemodynamic obstruction. For FFR, hemodynamically-significant obstruction of a coronary artery is defined as an FFR≤0.80 in any major epicardial coronary artery segment with diameter ≥2.0 mm during adenosine-mediated hyperemia. For cCTA, hemodynamically-significant obstruction of a coronary artery is defined as a stenosis \>50% . FFRCT will be calculated for each patient as the minimum FFRCT in any coronary artery segment . cCTA stenosis will be calculated for each patient as the highest cCTA stenosis category for any vessel all measurements will take place only in segments with diameter ≥2.0 mm.
Time frame: 1 day; Outcome measures were comparing FFRct to FFR. Incident time for FFR was dependent on the length of time on the cath procedure. FFRct was done remotely at HeartFlow's processing center in Redwood City with a turnaround time of 24 hours from CT scan.
Population: 22 of the 276 enrolled subjects were excluded by the FFR/QCA Core Lab, leaving an ITD population of 254 subjects. 3 additional subjects were excluded from the ITD analysis due to missing cCTA 30%-90% stenosis by coronary CTA.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FFRct vs. FFR | AUC of FFRct Versus Coronary CTA for Demonstration of Ischemia (≤0.80) on a Per-patient Basis | .90 probablility |
| cCTA vs. FFR | AUC of FFRct Versus Coronary CTA for Demonstration of Ischemia (≤0.80) on a Per-patient Basis | .81 probablility |
95% CI: [0.04, 0.14]
Secondary
AUC of FFRct Versus Coronary CTA for Demonstration of Ischemia (≤0.80) on a Per-vessel Basis
Time frame: 1 day
Population: 22 of the 276 enrolled subjects were excluded by the FFR/QCA Core Lab, leaving an ITD population of 254 subjects. 3 additional subjects were excluded from the ITD analysis due to missing cCTA 30%-90% stenosis by coronary CTA.
| Arm | Measure | Value (NUMBER) |
|---|---|---|
| FFRct vs. FFR | AUC of FFRct Versus Coronary CTA for Demonstration of Ischemia (≤0.80) on a Per-vessel Basis | .93 probability |
| cCTA vs. FFR | AUC of FFRct Versus Coronary CTA for Demonstration of Ischemia (≤0.80) on a Per-vessel Basis | .79 probability |
95% CI: [0.09, 0.19]
Secondary
Per-Patient Analysis: Diagnostic Performance of FFRct, Coronary CTA, and ICA
Time frame: 1 day; Outcome measures were comparing FFRct to FFR. Incident time for FFR was dependent on the length of time on the cath procedure. FFRct was done remotely at HeartFlow's processing center in Redwood City with a turnaround time of 24 hours from CT scan.
Population: 22 of the 276 enrolled subjects were excluded from the analysis by the FFR/QCA Core Lab.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| FFRct vs. FFR | Per-Patient Analysis: Diagnostic Performance of FFRct, Coronary CTA, and ICA | Accuracy: ICA Stenosis >50% | 77 percentage of tests |
| FFRct vs. FFR | Per-Patient Analysis: Diagnostic Performance of FFRct, Coronary CTA, and ICA | Accuracy: FFRct ≤ 0.80 | 81 percentage of tests |
| FFRct vs. FFR | Per-Patient Analysis: Diagnostic Performance of FFRct, Coronary CTA, and ICA | Accuracy: Coronary CTA Stenosis >50% | 53 percentage of tests |
| FFRct vs. FFR | Per-Patient Analysis: Diagnostic Performance of FFRct, Coronary CTA, and ICA | Sensitivity: ICA Stenosis >50% | 64 percentage of tests |
| FFRct vs. FFR | Per-Patient Analysis: Diagnostic Performance of FFRct, Coronary CTA, and ICA | Sensitivity: FFRct ≤ 0.80 | 86 percentage of tests |
| FFRct vs. FFR | Per-Patient Analysis: Diagnostic Performance of FFRct, Coronary CTA, and ICA | Sensitivity: Coronary CTA Stenosis >50% | 94 percentage of tests |
| FFRct vs. FFR | Per-Patient Analysis: Diagnostic Performance of FFRct, Coronary CTA, and ICA | Specificity: ICA Stenosis >50% | 83 percentage of tests |
| FFRct vs. FFR | Per-Patient Analysis: Diagnostic Performance of FFRct, Coronary CTA, and ICA | Specificity: FFRct ≤ 0.80 | 79 percentage of tests |
| FFRct vs. FFR | Per-Patient Analysis: Diagnostic Performance of FFRct, Coronary CTA, and ICA | Specificity: Coronary CTA Stenosis >50% | 34 percentage of tests |
| FFRct vs. FFR | Per-Patient Analysis: Diagnostic Performance of FFRct, Coronary CTA, and ICA | Positive Predictive Value: ICA Stenosis >50% | 63 percentage of tests |
| FFRct vs. FFR | Per-Patient Analysis: Diagnostic Performance of FFRct, Coronary CTA, and ICA | Positive Predictive Value: FFRct ≤ 0.80 | 65 percentage of tests |
| FFRct vs. FFR | Per-Patient Analysis: Diagnostic Performance of FFRct, Coronary CTA, and ICA | Positive Predictive Value: cCTA Stenosis >50% | 40 percentage of tests |
| FFRct vs. FFR | Per-Patient Analysis: Diagnostic Performance of FFRct, Coronary CTA, and ICA | Negative Predictive Value: ICA Stenosis >50% | 83 percentage of tests |
| FFRct vs. FFR | Per-Patient Analysis: Diagnostic Performance of FFRct, Coronary CTA, and ICA | Negative Predictive Value: FFRct ≤ 0.80 | 93 percentage of tests |
| FFRct vs. FFR | Per-Patient Analysis: Diagnostic Performance of FFRct, Coronary CTA, and ICA | Negative Predictive Value: cCTA Stenosis >50% | 92 percentage of tests |
Secondary
Per Vessel Diagnostic Performance of FFRct, Coronary CTA, and ICA
Time frame: 1 day; Outcome measures were comparing FFRct to FFR. Incident time for FFR was dependent on the length of time on the cath procedure. FFRct was done remotely at HeartFlow's processing center in Redwood City with a turnaround time of 24 hours from CT scan.
Population: 22 of the 276 enrolled subjects were excluded from the analysis by the FFR/QCA Core Lab.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| FFRct vs. FFR | Per Vessel Diagnostic Performance of FFRct, Coronary CTA, and ICA | Accuracy: FFRct ≤ 0.80 | 86 percentage of tests |
| FFRct vs. FFR | Per Vessel Diagnostic Performance of FFRct, Coronary CTA, and ICA | Accuracy: Coronary CTA Stenosis >50% | 65 percentage of tests |
| FFRct vs. FFR | Per Vessel Diagnostic Performance of FFRct, Coronary CTA, and ICA | Sensitivity: ICA Stenosis >50% | 55 percentage of tests |
| FFRct vs. FFR | Per Vessel Diagnostic Performance of FFRct, Coronary CTA, and ICA | Sensitivity: FFRct ≤ 0.80 | 84 percentage of tests |
| FFRct vs. FFR | Per Vessel Diagnostic Performance of FFRct, Coronary CTA, and ICA | Accuracy: ICA Stenosis >50% | 82 percentage of tests |
| FFRct vs. FFR | Per Vessel Diagnostic Performance of FFRct, Coronary CTA, and ICA | Sensitivity: Coronary CTA Stenosis >50% | 83 percentage of tests |
| FFRct vs. FFR | Per Vessel Diagnostic Performance of FFRct, Coronary CTA, and ICA | Specificity: ICA Stenosis >50% | 90 percentage of tests |
| FFRct vs. FFR | Per Vessel Diagnostic Performance of FFRct, Coronary CTA, and ICA | Specificity: FFRct ≤ 0.80 | 86 percentage of tests |
| FFRct vs. FFR | Per Vessel Diagnostic Performance of FFRct, Coronary CTA, and ICA | Specificity: Coronary CTA Stenosis >50% | 60 percentage of tests |
| FFRct vs. FFR | Per Vessel Diagnostic Performance of FFRct, Coronary CTA, and ICA | Positive Predictive Value: ICA Stenosis >50% | 58 percentage of tests |
| FFRct vs. FFR | Per Vessel Diagnostic Performance of FFRct, Coronary CTA, and ICA | Positive Predictive Value: FFRct ≤ 0.80 | 61 percentage of tests |
| FFRct vs. FFR | Per Vessel Diagnostic Performance of FFRct, Coronary CTA, and ICA | Positive Predictive Value: cCTA Stenosis >50% | 33 percentage of tests |
| FFRct vs. FFR | Per Vessel Diagnostic Performance of FFRct, Coronary CTA, and ICA | Negative Predictive Value: ICA Stenosis >50% | 88 percentage of tests |
| FFRct vs. FFR | Per Vessel Diagnostic Performance of FFRct, Coronary CTA, and ICA | Negative Predictive Value: FFRct ≤ 0.80 | 95 percentage of tests |
| FFRct vs. FFR | Per Vessel Diagnostic Performance of FFRct, Coronary CTA, and ICA | Negative Predictive Value: cCTA Stenosis >50% | 92 percentage of tests |
Post Hoc
Per-Patient Diagnostic Performance of FFRct in Patients With Intermediate Stenosis Severity (30%-70%) According to Coronary CTA
Time frame: 1 day; Outcome measures were comparing FFRct to FFR. Incident time for FFR was dependent on the length of time on the cath procedure. FFRct was done remotely at HeartFlow's processing center in Redwood City with a turnaround time of 24 hours from CT scan.
Population: Patients with intermediate stenosis severity (30%-70%) according to coronary CTA.
| Arm | Measure | Group | Value (NUMBER) |
|---|---|---|---|
| FFRct vs. FFR | Per-Patient Diagnostic Performance of FFRct in Patients With Intermediate Stenosis Severity (30%-70%) According to Coronary CTA | Accuracy: FFRct ≤ 0.80 | 80 percentage of tests |
| FFRct vs. FFR | Per-Patient Diagnostic Performance of FFRct in Patients With Intermediate Stenosis Severity (30%-70%) According to Coronary CTA | Accuracy: Coronary CTA Stenosis > 50% | 51 percentage of tests |
| FFRct vs. FFR | Per-Patient Diagnostic Performance of FFRct in Patients With Intermediate Stenosis Severity (30%-70%) According to Coronary CTA | Sensitivity: FFRct ≤ 0.80 | 85 percentage of tests |
| FFRct vs. FFR | Per-Patient Diagnostic Performance of FFRct in Patients With Intermediate Stenosis Severity (30%-70%) According to Coronary CTA | Sensitivity: Coronary CTA Stenosis >50% | 93 percentage of tests |
| FFRct vs. FFR | Per-Patient Diagnostic Performance of FFRct in Patients With Intermediate Stenosis Severity (30%-70%) According to Coronary CTA | Specificity: FFRct ≤ 0.80 | 79 percentage of tests |
| FFRct vs. FFR | Per-Patient Diagnostic Performance of FFRct in Patients With Intermediate Stenosis Severity (30%-70%) According to Coronary CTA | Specificity: Coronary CTA Stenosis > 50% | 32 percentage of tests |
| FFRct vs. FFR | Per-Patient Diagnostic Performance of FFRct in Patients With Intermediate Stenosis Severity (30%-70%) According to Coronary CTA | Positive Predictive Value: FFRct ≤ 0.80 | 63 percentage of tests |
| FFRct vs. FFR | Per-Patient Diagnostic Performance of FFRct in Patients With Intermediate Stenosis Severity (30%-70%) According to Coronary CTA | Positive Predictive Value: cCTA Stenosis > 50% | 37 percentage of tests |
| FFRct vs. FFR | Per-Patient Diagnostic Performance of FFRct in Patients With Intermediate Stenosis Severity (30%-70%) According to Coronary CTA | Negative Predictive Value: FFRct ≤ 0.80 | 92 percentage of tests |
| FFRct vs. FFR | Per-Patient Diagnostic Performance of FFRct in Patients With Intermediate Stenosis Severity (30%-70%) According to Coronary CTA | Negative Predictive Value: cCTA Stenosis > 50% | 91 percentage of tests |