Medical Policies - Radiology


Coronary Computed Tomography Angiography (CCTA), Including Noninvasive Fractional Flow Reserve (FFR)

Number:RAD604.007

Effective Date:10-15-2018

Coverage:

*CAREFULLY CHECK STATE REGULATIONS AND/OR THE MEMBER CONTRACT*

Contrast-Enhanced Coronary Computed Tomography Angiography

Contrast-enhanced coronary computed tomography angiography (CCTA) for evaluation of individuals without known coronary artery disease (CAD) who present with acute chest pain in the emergency room or emergency department setting may be considered medically necessary.

Contrast-enhanced CCTA for evaluation of symptomatic individuals with suspected ischemic heart disease, who meet guideline criteria for a noninvasive test in the outpatient setting may be considered medically necessary (refer to NOTE 1 below).

NOTE 1: A noninvasive test should be performed on individuals with at least intermediate risk for coronary artery disease (10%-90% risk by standard risk prediction instruments/pre-test probability assessments). The choice of test will depend on:

1. Interpretability of the electrocardiogram; and

2. Ability to exercise; and

3. Presence of comorbidities.

(Class I recommendation from the 2012 American College of Cardiology Foundation/American Heart Association Task Force on use of noninvasive testing in patients with suspected stable ischemic heart disease. See the Description section for definitions, guidelines, and pre-test probability assessment identified by the Task Force.)

Contrast-enhanced CCTA for evaluation of anomalous (native) coronary arteries in individuals in whom abnormal coronary arteries are suspected may be considered medically necessary.

CCTA, with or without contrast enhancement, as an adjunct to other testing, may be considered medically necessary for the evaluation of cardiac structure and function to:

Assess complex congenital heart disease, including anomalies of coronary circulation, great vessels, and cardiac chambers and valves; OR

Assess suspected arrhythmogenic right dysplasia, left ventricular function when cardiomyopathy is suspected or established, and right ventricular function when right ventricular dysfunction is suspected in individuals with technically limited images from echocardiography (ECG), magnetic resonance imaging (MRI), or transesophageal echocardiography (TEE); OR

Assess suspected or established dysfunction of prosthetic cardiac valves in individuals with technically limited images from ECG, MRI, or TEE; OR

Assess coronary arteries in individuals with new onset heart failure when ischemia is the suspected etiology and cardiac catheterization and nuclear stress test are not planned; OR

Assess a cardiac mass (suspected tumor or thrombus) in individuals with technically limited images from ECG, MRI, or TEE; OR

Assess a pericardial condition (such as, pericardial mass, constrictive pericarditis, pericardial effusion, or complications of cardiac surgery in patients) with technically limited images from ECG, MRI, or TEE; OR

Perform non-invasive coronary vein mapping prior to placement of a biventricular pacemaker; OR

Perform non-invasive coronary arterial mapping, including internal mammary artery prior to repeat cardiac surgical revascularization; OR

Evaluate pulmonary vein anatomy prior to invasive radiofrequency ablation for atrial fibrillation; OR

Evaluate cardiac aneurysm and pseudoaneurysm; OR

Evaluate thoracic aortic aneurysm (TAA) (such as suspected aneurysm in individuals who have not undergone computed tomography (CT) or MRI within the preceding 60 days, confirmed TAA in individuals with new or worsening symptoms, or suspected aortic dissection (with or without worsening symptoms or pre-operative planning); OR

Assess coronary arteries in asymptomatic patients scheduled for open heart surgery for valvular heart disease in lieu of invasive coronary arteriography.

CCTA, with or without contrast enhancement, for coronary artery evaluation is considered experimental, investigational and/or unproven for all other indications, including but not limited to:

Screening asymptomatic individuals for CAD; OR

Evaluating asymptomatic individuals with cardiac risk factors in lieu of cardiac evaluation and standard non-invasive cardiac testing; OR

Evaluating individuals for any other indication not listed above, including but not limited to high or low pretest probability (low risk defined as <10% and high risk as >90%) of CAD.

CCTA performed using a multi-detector row CT scanner with less than 64-slice scanner is considered experimental, investigational and/or unproven.

Noninvasive Fractional Flow Reserve Computed Tomography

The use of noninvasive fractional flow reserve (FFR) following a positive CCTA may be considered medically necessary to guide decisions about the use of invasive coronary angiography in patients with stable chest pain at intermediate risk (refer to NOTE 1 above) of CAD (i.e., suspected or presumed stable ischemic heart disease).

The use of noninvasive FFR computed tomography (FFRCT) simulation not meeting the criteria above is considered experimental, investigational and/or unproven.

NOTE 2: If CT imaging is done of the blood vessels it is not necessarily a CCTA. A CCTA must include reconstruction post-processing of the angiographic images and interpretations, which is a key distinction between a CCTA and conventional CT. If the reconstruction post-processing is not done, it is not considered a CCTA study.

NOTE 3: For any CT to detect coronary artery calcification, see policy RAD604.009.

Description:

Contrast-enhanced coronary computed tomography angiography (CCTA) is a noninvasive imaging test that requires the use of intravenously administered contrast material and high-resolution, high-speed computed tomography (CT) machinery to obtain detailed volumetric images of blood vessels. It is a potential diagnostic alternative to current tests for cardiac ischemia (i.e., noninvasive stress testing and/or invasive coronary angiography [ICA]).

Background

Contrast-Enhanced Coronary Computed Tomography Angiography

A variety of noninvasive tests are used to diagnose coronary artery disease (CAD). They can be broadly classified as those that detect functional or hemodynamic consequences of obstruction and ischemia (exercise treadmill testing, myocardial perfusion imaging [MPI], stress echocardiography with or without contrast), and others that identify the anatomic obstruction itself (CTA, coronary magnetic resonance imaging [MRI]). (1) Functional testing involves inducing ischemia by exercise or pharmacologic stress and detecting its consequences. However, not all patients are candidates. For example, obesity or obstructive lung disease can make obtaining echocardiographic images of sufficient quality difficult. Conversely, the presence of coronary calcifications can impede detecting coronary anatomy with CTA.

Some tests will be unsuitable for particular patients. The presence of dense arterial calcification or an intracoronary stent can produce significant beam-hardening artifacts and may preclude a satisfactory imaging. The presence of an uncontrolled rapid heart rate or arrhythmia hinders the ability to obtain diagnostically satisfactory images. Evaluation of the distal coronary arteries is generally more difficult than visualization of the proximal and mid-segment coronary arteries due to greater cardiac motion and the smaller caliber of coronary vessels in distal locations.

Evaluation of obstructive CAD involves quantifying arterial stenoses to determine whether significant narrowing is present. Lesions with stenosis more than 50% to 70% in diameter accompanied by symptoms are generally considered significant. It has been suggested that CCTA may help rule out CAD and avoid ICA in patients with a low clinical likelihood of significant CAD. Also of interest is the potential important role of non-obstructive plaques (i.e., those associated with <50% stenosis) because their presence is associated with increased cardiac event rates. (2) CCTA also can visualize the presence and composition of these plaques and quantify plaque burden better than conventional angiography, which only visualizes the vascular lumen. Plaque presence has been shown to have prognostic importance.

Congenital coronary arterial anomalies (i.e., abnormal origin or course of a coronary artery) that lead to clinically significant problems are relatively rare. Symptomatic manifestations may include ischemia or syncope. Clinical presentation of anomalous coronary arteries is difficult to distinguish from other more common causes of cardiac disease; however, an anomalous coronary artery is an important diagnosis to exclude, particularly in young patients who present with unexplained symptoms (e.g., syncope). There is no specific clinical presentation to suggest a coronary artery anomaly.

Levels of radiation delivered with current generation scanners using reduction techniques (prospective gating and spiral acquisition) have declined substantially - typically to under 10 mSv. For example, an international registry developed to monitor CCTA radiation exposure recently reported a median of 2.4 mSv (interquartile range, 1.3-5.5). (3) By comparison, radiation exposure accompanying rest-stress perfusion imaging ranges varies by isotope used - approximately 5 mSv for rubidium-82 (positron emission tomography [PET]), 14 mSv for fluorodeoxyglucose fluorine 18 (PET), 9 mSv for sestamibi (single-photon emission computed tomography [SPECT]), and 41 mSv for thallium; during diagnostic invasive coronary angiography, approximately 7 mSv is delivered. (4) Electron beam computed tomography (EBCT) using electrocardiogram (ECG) triggering delivers the lowest dose (0.7-1.1 mSv with 3-mm sections). Any cancer risk due to radiation exposure from a single cardiac imaging test depends on age (higher with younger age at exposure) and sex (greater for women). (5-7) Empirical data have suggested that every 10 mSv of exposure is associated with a 3% increase in cancer incidence over 5 years. (8)

American College of Cardiology (ACC) and American Heart Association (AHA) Guidelines and Definitions:

In 1999, the ACC and the AHA released a joint scientific statement describing the assessment of cardiovascular or coronary heart disease (CHD) risk to categorize patients for selection of appropriate interventions (available in the ACC website <http://www.acc.org>). (24) The statement defines CHD, as derived from the Framingham Heart Study, to include angina pectoris, unstable angina or coronary insufficiency, and unrecognized myocardial infarction (MI) (defined by EKG). The ACC/AHA scientific statement further states, “The first step in determining the patient’s risk is to calculate the number of Framingham points for each risk factor”, by using the Framingham Global Risk Assessment Scoring:

Table 1. Framingham Global Risk Assessment Scoring and Calculating Final Score

Risk Factor

Risk Points

Men

Women

Age by year:

Less than 34

-1

-9

35 – 39

0

-4

40 – 44

1

0

45 – 49

2

3

50 – 54

3

6

55 – 59

4

7

60 – 64

5

8

65 – 69

6

8

70 - 74

7

8

Total Cholesterol, mg/dL*:

Less than 160

-3

-2

169 – 199

0

0

200 – 239

1

1

240 – 279

2

2

Greater than or equal to 280

3

3

HDL cholesterol, mg/dL*:

Less than 35

2

5

35 – 44

1

2

45 – 49

0

1

50 – 59

0

0

Greater than or equal to 60

-2

-3

Systolic blood pressure, mm Hg**:

Less than 120

0

-3

120 – 129

0

0

130 – 139

1

1

140 – 159

2

2

Greater than 160

3

3

Diabetes:

No

0

0

Yes

2

4

Smoker:

No

0

0

Yes

2

2

Adding Up the Points

Age:

Cholesterol:

HDL – C:

Blood Pressure:

Diabetes:

Smoker:

Total Points:

Table Key:

* mg dL = milligrams/deciliter

** mm Hg = millimeter of mercury as it relates to a unit of pressure equal to 0.001316 atmosphere.

Additionally, the 1999 ACC/AHA scientific statement explained the following tables as demonstrating the relative and absolute risk estimates for CHD in men and women as determined for Framingham scoring, including this explanation for table information, “Relative risk estimates for each age range are compared with baseline risk conferred by age alone (in the absence of other major risk factors).” (24) Additionally, described was, “Average risk refers to that observed in the Framingham population. Absolute risk estimates are given in the two right hand columns. Absolute risk is expressed as the percentage likelihood of developing CHD per decade. Total CHD risk equates to all forms of clinical CHD, whereas hard CHD includes clinical evidence of MI and coronary death. Hard CHD estimates are approximated from published Framingham data.”

In the following grids, the intermediate risk estimates (classified as moderately above average risk) will be identified as bolded and high risk as underlined. Following the last grid (for women), the keys for these symbols “*”, “#”, “++”, and “**” will be defined below the last table.

Table 2. Intermediate Risk Estimates for Men and Women

MEN

Age

30-34

35-39

40-44

45-49

50-54

55-59

60-64

65-69

70-74

Low Risk Level*

(2%

(3%)

(3%)

(4%)

(5%)

(7%)

(8%)

(10%)

(13%)

Absolute Risk

Absolute Risk ++

Points#

Total CHD++

Hard CHD**

0

1.0

2%

2%

1

1.5

1.0

1.0

3%

2%

2

2.0

1.3

1.3

1.0

4%

3%

3

2.5

1.7

1.7

1.3

1.0

5%

4%

4

3.5

2.3

2.3

1.8

1.4

1.0

7%

5%

5

4.0

2.6

2.6

2.0

1.6

1.1

1.0

8%

6%

6

5.0

3.3

3.3

2.5

2.0

1.4

1.3

1.0

10%

7%

7

6.5

4.3

4.3

3.3

2.6

1.9

1.6

1.3

1.0

13%

9%

8

8.0

5.3

5.3

4.0

3.2

2.3

2.0

1.6

1.2

16%

13%

9

10.0

6.7

6.7

5.0

4.0

2.9

2.5

2.0

1.5

20%

16%

10

12.5

8.3

8.3

6.3

5.0

3.6

3.1

2.5

1.9

25%

20%

11

15.5

10.3

10.3

7.8

6.1

4.4

3.9

3.1

2.3

31%

25%

12

18.5

12.3

12.3

9.3

7.4

5.2

4.6

3.7

2.8

37%

30%

13

22.5

15.0

15.0

11.3

9.0

6.4

5.6

4.5

3.5

45%

35%

>14

26.5

>17.7

>17.7

>13.3

>10.6

>7.6

>6.6

>5.3

>4.1

>53%

>45%

WOMEN

Age

40-44

45-49

50-54

55-59

60-64

65-69

70-74

Low Risk Level*

(2%)

(3%)

(5%)

(7%)

(8%)

(8%)

(8%)

Absolute Risk

Absolute Risk ++

Points#

Total CHD++

Hard CHD**

0

1.0

2%

1%

1

1.0

2%

1%

2

1.5

1.0

3%

2%

3

1.5

1.0

3%

2%

4

2.0

1.3

4%

2%

5

2.0

1.3

4%

2%

6

2.5

1.7

1.0

5%

2%

7

3.0

2.0

1.2

6%

3%

8

3.5

2.3

1.4

1.0

7%

3%

9

4.0

2.7

1.6

1.1

1.0

1.0

1.0

8%

3%

10

5.0

3.3

2.0

1.4

1.3

1.3

1.3

10%

4%

11

5.5

3.7

2.2

1.6

1.4

1.4

1.4

11%

7%

12

6.5

4.3

2.6

1.9

1.6

1.6

1.6

13%

8%

13

7.5

5.0

3.0

2.1

1.9

1.9

1.9

15%

11%

14

9.0

6.0

3.6

2.6

2.3

2.3

2.3

18%

13%

15

10.0

6.7

4.0

2.9

2.5

2.5

2.5

20%

15%

16

12.0

8.0

4.8

3.4

3.0

3.0

3.0

24%

18%

>17

>13.5

>9.0

>5.4

>3.9

5.4

5.4

5.4

>27%

>20%

Table Key:

* Low absolute risk level = 10-year risk for CHD end points for the person the same age, blood pressure less than 120 mm Hg systolic and less than 80 mm Hg diastolic, serum total cholesterol - 160 to 199 mg/dL, LDL-C - 100 to 129 mg/dL (LDL = low-density lipoprotein), HDL-C - greater or equal to 45 mg/dL in men and greater or equal to 55 mg/dL in women, nonsmoker, and no diabetes mellitus. Percentages show 10-year absolute risks for total CHD endpoints.

# Points = number of points estimated from the Framingham Global Risk Assessment Scoring.

++ 10-year absolute risk for total CHD end points estimated from the Framingham data corresponding to the Framingham (Global Risk Assessment Scoring) points.

** 10-year absolute risk for hard CHD end points approximated from the Framingham data corresponding to the Framingham (Global Risk Assessment Scoring) points.

In 2010, the ACC and the AHA released a joint scientific report describing the appropriate use criteria for CCTA. (57) Within the joint report, ACC/AHA defined the following risk and probability terminology:

Absolute risk – the probability of developing CHD, including myocardial infarction (MI) or CHD death over a given period of time. The National Heart, Lung, and Blood Institute specifies absolute risk for CHD as being over the next 10 years, referring to 10-year risk for any hard-cardiac event.

CHD Risk-Low – the age-specific risk level that is below average. In general, low risk will correlate with a 10-year absolute CHD risk <10%.

CHD Risk-Intermediate – the age-specific risk level that is average or above average. In general, moderate risk will correlate with a 10-year absolute CHD risk ranging from 10% to 20%. Among women and younger men, an expanded intermediate risk range of 6% to 20% may be appropriate.

CHD Risk-High – the presence of diabetes mellitus in a patient ≥ 40 year of age, peripheral artery disease or other coronary risk equivalents, or the 10-year absolute CHD risk of > 20%.

Pretest probability – the likelihood of the presence of a condition before a diagnostic test.

Very low pretest probability – < 5% pretest probability of CAD.

Low pretest probability – < 10% pretest probability of CAD.

Intermediate pretest probability – Between 10% and 90% pretest probability of CAD.

High pretest probability – > 90% pretest probability of CAD.

Typical angina (definite) – substernal chest pain, or ischemic equivalent discomfort that is provoked by exertion or emotional stress AND relieved by rest and/or nitroglycerin.

Atypical angina (probable) – chest pain or discomfort with two characteristics of definite or typical angina.

Non-anginal chest pain – chest pain or discomfort that meets one or none of the typical anginal characteristics.

Acute coronary syndrome – includes those patients whose clinical presentations covering the following range of diagnoses: unstable angina, MI without ST-elevation, and MI with ST-elevation.

EKG (uninterpretable) – EKG with resting ST-segment depression, complete left bundle-branch block, pre-excitation (Wolff-Parkinson-White syndrome), or paced rhythm.

Able to exercise – able to complete a diagnostic exercise treadmill examination.

The ACC/AHA also provided clinicians, within the 2010 guidelines, a pretest probability of CAD by age, sex, and symptoms table to make their assessments, using the pretest categories of very low, low, intermediate, and high as defined just above (10):

Table 3. Pretest Probability of Coronary Artery Disease

Age

Sex

Typical/Definite

Angina Pectoris

Atypical/Probable Angina Pectoris

Non-Anginal Pain

Asymptomatic

< 39

Men

Intermediate

Intermediate

Low

Very Low

< 39

Women

Intermediate

Very Low

Very Low

Very Low

40-49

Men

High

Intermediate

Intermediate

Low

40-49

Women

Intermediate

Low

Very Low

Very Low

50-59

Men

High

Intermediate

Intermediate

Low

50-59

Women

Intermediate

Intermediate

Low

Very Low

> 60

Men

High

Intermediate

Intermediate

Low

> 60

Women

High

Intermediate

Intermediate

Low

Regulatory Status

Multidetector-row helical CT (MDCT) or multi-slice CT scanning is a technologic evolution of helical CT, which uses CT machines equipped with an array of multiple x-ray detectors that can simultaneously image multiple sections of the patient during a rapid volumetric image acquisition. MDCT machines currently in use have 64 or more detectors. CCTA is performed using MDCT, and multiple manufacturers have been cleared for marketing by the U.S. Food and Drug Administration (FDA) 510(k) clearance process. Current machines are equipped with at least 64 detector rows. Lower detector row machines are no longer used for CCTA. Intravenous iodinated contrast agents used for CCTA also have received FDA approval.

Noninvasive Fractional Flow Reserve Computed Tomography

A noninvasive imaging test, performed prior to ICA as a gatekeeper, that can distinguish candidates who may benefit from early revascularization (e.g., patients with unprotected left main stenosis ≥50% or hemodynamically significant disease) from those unlikely to benefit could avoid unnecessary invasive procedures and their potential adverse consequences.

Gatekeepers to ICA

Imposing an effective noninvasive gatekeeper strategy with one or more tests before planned ICA to avoid unnecessary procedures is compelling. The most important characteristic of a gatekeeper test is its ability to accurately identify and exclude clinically insignificant disease where revascularization would offer no potential benefit. From a diagnostic perspective, an optimal strategy would result in few false-negative tests while avoiding an excessive false-positive rate, it would provide a low posttest probability of significant disease. Such a test would then have a small and precise negative likelihood ratio and high negative predictive value. An effective gatekeeper would decrease the rate of ICA while increasing the diagnostic yield (defined by the presence of obstructive CAD on ICA). At the same time, there should be no increase in major adverse cardiac events. A clinically useful strategy would satisfy these diagnostic performance characteristics and impact the outcomes of interest. Various tests have been proposed as potentially appropriate for a gatekeeper function prior to planned ICA, including CCTA, MRI, SPECT, PET, and stress echocardiography (SECHO). More recently, adding noninvasive measurement of fractional flow reserve (FFR) using CCTA has been suggested, combining functional and anatomic information.

Fractional Flow Reserve

Invasive FFR is rarely used in the U.S. to guide percutaneous coronary intervention (PCI). For example, using the National Inpatient Sample, Pothineni et al. (2016) reported that 201,705 PCIs were performed in 2012, but just 21,365 FFR procedures. (66) Assuming the intention of FFR is to guide PCI, it would represent just 4.3% of PCI procedures. Whether noninvasively obtained FFR will influence decisions concerning ICA, over and above anatomic considerations, is therefore important to empirically establish.

Randomized controlled trials (RCTs) and observational studies have demonstrated that FFR-guided revascularization can improve cardiovascular outcomes, reduce revascularizations, and decrease costs. (67) For example, the Fractional Flow Reserve versus Angiography for Multi-Vessel Evaluation (FAME) trial randomized 1005 patients with multi-vessel disease and planned PCI. (65, 68) At 1 year, compared with PCI guided by angiography alone, FFR-guided PCI reduced the number of stents placed by approximately 30% - followed by lower rates (13.2% versus 18.3%) of major cardiovascular adverse events (myocardial infarction, death, repeat revascularization) and at a lower cost. The clinical benefit persisted through 2 years, although by 5 years events rates were similar between groups. (69)

European guidelines (2013) for stable CAD have recommended that FFR be used “to identify hemodynamically relevant coronary lesion(s) when evidence of ischaemia is not available” (class Ia), and “[r]evascularization of stenoses with FFR <0.80 is recommended in patients with angina symptoms or a positive stress test.” (70) Guidelines (2014) have also recommended using “FFR to identify haemodynamically relevant coronary lesion(s) in stable patients when evidence of ischaemia is not available” (class Ia recommendation). (71) U.S. guidelines (2012) have stated that an FFR of 0.80 or less provides level Ia evidence for revascularization for “significant stenoses amenable to revascularization and unacceptable angina despite guideline directed medical therapy.” (24) In addition, the importance of FFR in decision making appears prominently in the 2017 appropriate use criteria for coronary revascularization in patients with stable ischemic heart disease (SIHD). (72)

Measuring FFR during ICA can be accomplished by passing a pressure-sensing guidewire across a stenosis. Coronary hyperemia (increased blood flow) is then induced and pressure distal and proximal to the stenosis is used to calculate flow across it. FFR is the ratio of flow in the presence of a stenosis to flow in its absence. FFR levels less than 0.75 to 0.80 are considered to represent significant ischemia while those 0.94 to 1.0 normal. Measurement is valid in the presence of serial stenoses, is unaffected by collateral blood flow, (73) and reproducibility is high. (74) Potential complications include adverse events related to catheter use such as vessel wall damage (dissection); the time required to obtain FFR during a typical ICA is less than 10 minutes.

FFR using CCTA requires at least 64-slice CCTA and cannot be calculated when images lack sufficient quality (75) (11% to 13% in recent studies from Koo et al., 2011; Min et al., 2012; Nakazato et al., 2013; Nørgaard et al., 2014 [76-79]), e.g., in obese individuals (e.g., body mass index, >35 kg/m2). The presence of dense arterial calcification or an intracoronary stent can produce significant beam-hardening artifacts and may preclude satisfactory imaging. The presence of an uncontrolled rapid heart rate or arrhythmia hinders the ability to obtain diagnostically satisfactory images. Evaluation of the distal coronary arteries is generally more difficult than visualization of the proximal and mid-segment coronary arteries due to greater cardiac motion and the smaller caliber of coronary vessels in distal locations.

FFR can be modeled noninvasively using images obtained during CCTA (80) – “so-called fractional flow reserve using coronary computed tomography angiography” (FFRCT; HeartFlow software termed FFRCT; Siemens cFFR) using routinely collected CCTA imaging data. The process involves constructing a digital model of coronary anatomy and calculating FFR across the entire vascular tree using computational fluid dynamics. FFRCT can also be used for “virtual stenting” to simulate how stent placement would be predicted to improve vessel flow. (81)

Only the HeartFlow FFRCT software has been cleared by the FDA. Imaging analyses require transmitting data to a central location for analysis, taking 1 to 3 days to complete. Other prototype software is workstation-based with onsite analyses. FFRCT requires at least 64-slice CCTA and cannot be calculated when images lack sufficient quality (82) (11% to 13% in recent studies [76-79]), e.g., in obese individuals (e.g., body mass index, >35 kg/m2).

Regulatory Status

In November 2014, FFRCT simulation software (HeartFlow, Inc., Redwood City, California) was cleared for marketing by the FDA through the de novo 510(k) process (class II, special controls; FDA product code: PJA). In January 2016, the FFRCT v2.0 device was cleared through a subsequent 510(k) process.

HeartFlow FFRCT post-processing software is cleared “for the clinical quantitative and qualitative analysis of previously acquired Computed Tomography [CT] DICOM [Digital Imaging and Communications in Medicine] data for clinically stable symptomatic patients with coronary artery disease. It provides FFRCT [fractional flow reserve using coronary computed tomography angiography], a mathematically derived quantity, computed from simulated pressure, velocity and blood flow information obtained from a 3D computer model generated from static coronary CT images. FFRCT analysis is intended to support the functional evaluation of coronary artery disease. The results of this analysis [FFRCT] are provided to support qualified clinicians to aid in the evaluation and assessment of coronary arteries. The results of HeartFlow FFRCT are intended to be used by qualified clinicians in conjunction with the patient’s clinical history, symptoms, and other diagnostic tests, as well as the clinician’s professional judgment.” (82)

Rationale:

This policy was created in 2007 and has been updated regularly with searches of peer reviewed scientific literature in the MedLine database. The most recent literature search was done through October 17, 2017. The following is a summary of the key literature.

Contrast-Enhanced Coronary Computed Tomography Angiography

The policy was originally based on a literature search from MedLine and the May 2005 Blue Cross Blue Shield Association (BCBSA) Technology Evaluation Center (TEC) Assessment. (9) The policy also contains several joint reports and guidelines from the American College of Cardiology Foundation (ACCF), which includes key specialty and subspecialty societies. (57, 58, 59, 60) Additional BCBSA TEC Assessments in 2006 and 2011 were included in the review of the key literature to date. (10, 11)

NOTE 4: The societies represented within the task force are: the American College of Cardiology (ACC), the American Heart Association (AHA), the American College of Radiology (ACR), the Society of Cardiovascular Computed Tomography (SCCT), the American Society of Echocardiography (ASE), the American Society of Nuclear Cardiology (ASNC), the North American Society of Cardiovascular Imaging (NASCI), the Society of Cardiovascular Angiography (SCA), and the Society of Cardiovascular Magnetic Resonance (SCMR). Within this medical policy, reference to these reports and guidelines will be shown as ACC/AHA.

The objective of the 2005 BCBSA TEC Assessment was to evaluate the clinical effectiveness of CTA using either electron beam computed tomography (EBCT) or multi-detector-row computed tomography (MDCT) as a noninvasive alternative to invasive coronary angiography (ICA), particularly in patients with a low probability of significant coronary artery stenosis. (9) Evaluation of the coronary artery anatomy and morphology was the most frequent use of cardiac CTA and primary focus of the TEC Assessment. The Assessment considered multiple indications, but computed tomography (CT) technology used in studies reviewed is now outdated (studies employed 16-slice scanners). The TEC Assessment concluded that the use of contrast-enhanced cardiac CTA for screening or diagnostic evaluation of the coronary arteries did not meet TEC criteria.

The 2006 BCBSA TEC Assessment was undertaken to determine the usefulness of cardiac CTA as a substitute for ICA for 2 indications: in the diagnosis of coronary artery stenosis and in the evaluation of acute chest pain in the emergency department (ED). (10) Seven studies in the ambulatory setting and utilizing 40- to 64-slice scanners were identified. Two studies performed in the ED used 4- or 16-slice scanners. Evidence was judged insufficient to form conclusions. Available studies at the time were inadequate to determine the effect of cardiac CTA on health outcomes for the diagnosis of coronary artery stenosis in patients referred for angiography or for evaluation of acute chest pain in the ED.

Three major indications for cardiac or coronary CTA (CCTA) are considered in the current policy:

1. Patients with acute chest pain without known coronary disease presenting in the ED setting,

2. Evaluation of stable patients with signs and symptoms of coronary artery disease (CAD) in the non-ED setting, and

3. Evaluation of anomalous coronary arteries.

In 2016, the Agency for Healthcare Research and Quality (AHRQ) published a comparative effectiveness review on noninvasive testing for CAD. (12) The review found that:

After CCTA, clinical outcomes for patients with an intermediate pretest risk:

o Were similar when compared with usual care or functional testing (low-to-moderate strength of evidence).

o Were similar when compared with single-photon emission computed tomography (SPECT) (low strength of evidence).

After CCTA, referral for ICA and revascularization:

o Was more common than after functional testing (high strength of evidence).

o Was similar compared with SPECT and usual care (low strength of evidence).

After CCTA, additional testing in the ED setting:

o Was less common compared with usual care (moderate strength of evidence).

o Was more common than after SPECT (high strength of evidence).

After CCTA, hospitalization:

o Was less common compared to usual care in the ED setting (moderate to low strength of evidence).

o Was similar to functional testing in the outpatient setting (moderate strength of evidence).

Overall, the AHRQ review found no clear differences between strategies for clinical or management outcomes, although CCTA may lead to a higher frequency of referral for ICA and revascularization.

In August 2016, noninvasive fractional flow reserve (FFR) using CTA (FFRCT) was added to this medical policy and was based on literature search assessing the technical performance, diagnostic accuracy, effect of FFRCT on patient outcomes, and postadoption studies.

Patients with Acute Chest Pain Presenting to the Emergency Setting: CCTA

Diagnostic Validity

The diagnostic characteristics of CCTA have not been directly assessed in patients in the ED setting. Because patients who test negative on CCTA are discharged from care and their disease status is unknown, there is verification bias and diagnostic characteristics of CCTA cannot be determined. The diagnostic characteristics of CCTA, previously established in other studies, were assumed to apply to patients in the ED setting and were tested in randomized trials to establish clinical utility.

Effect on Health Outcomes

A 2011 BCBSA TEC Assessment examined evidence on patients with acute chest pain and without known CAD. (11) Randomized controlled trials (RCTs) and prospective observational studies were identified. RCTs of CCTA procedures conducted in ED settings are described in Table 1.

A 2007 RCT by Goldstein et al. randomized 197 patients from a single center without evidence of acute coronary syndromes to CCTA (n=99) or usual care (n=98). (13) Over a 6-month follow-up, no cardiac events occurred in either arm. ICA rates were somewhat higher in the CCTA arm. Diagnosis was achieved more quickly after CCTA.

The CT-STAT RCT evaluated a similar sample of 699 patients from 16 centers. (14) Over a 6-month follow-up, there were no deaths in either arm; there were 2 cardiac events in the CCTA arm and 1 in the perfusion imaging arm. ICA rates were similar in both arms. A second noninvasive test was obtained more often after CCTA (10.2% versus 2.1%), but cumulative radiation exposure in the CCTA arm (using retrospective gating) was significantly lower (mean, 11.5 mSv versus 12.8 mSv [millisievert]). Time to diagnosis was shorter and estimated ED costs lower with CCTA.

A 2012 RCT (AC RIN-PA) by Litt et al. also evaluated the safety of CCTA in patients in the ED. (15) Although the trial was a randomized comparison with traditional care, the principal outcome was safety after negative CCTA examinations. No patients who had negative CCTA examinations (n=460) died or had a myocardial infarction (MI) within 30 days. Compared with traditional care, patients in the CCTA group had higher rates of discharge from the ED (49.6% versus 22.7%), shorter lengths of stay, and higher rates of detection of coronary disease.

A 2012 RCT (ROMICAT II) by Hoffmann et al. compared length of stay and outcomes in patients evaluated with CCTA versus usual care. (16) For patients in the CCTA arm, mean length of hospital stay was reduced by 7.6 hours, and more patients were discharged directly from the ED (47% versus 12%). There were no undetected coronary syndromes or differences in adverse events at 28 days. However, in the CCTA arm, there was more subsequent diagnostic testing and higher cumulative radiation exposure. Cumulative costs of care were similar between groups.

A 2014 RCT (CT-COMPARE) by Hamilton-Craig et al. assessed length of stay and patient costs in 562 patients presenting to the ED with low-to-intermediate risk chest pain who received CCTA or exercise stress testing. (17) Costs within 30 days of presentation were significantly lower in the CCTA group (mean, $2193) than in the exercise testing group (mean, $2704; p<0.001). Length of stay was significantly reduced in the CCTA patients compared with the exercise testing patients. Clinical outcomes at 30 days and at 12 months did not differ.

In 2015, Linde et al. reported long-term follow-up from the CATCH trial. (18, 19) This trial randomized 600 patients to a CCTA-guided strategy or to standard of care (SOC). For the CCTA-guided strategy, referral for ICA required coronary stenosis greater than 70%. This trial differed in design from the other trials, because patients had been discharged from the ED, and if there was intermediate stenosis (50%-70%) on CCTA, a stress test was used. The referral rate for ICA was 17% for the CCTA strategy versus 12% with SOC (p=NS [not significant]). At a median 18.7-month follow-up, a major cardiac event was observed in 5 patients in the CCTA-strategy arm compared to 14 in the SOC group (hazard ratio [HR], 0.36; 95% confidence interval [CI], 0.16 to 0.95; p=0.04). Three other follow-up studies reported no cardiac events after a negative CCTA in the ED after 12 (N=481), (20) 24 (N=368), (21) or 47 months (N=506). (22)

Table 4. RCTs Comparing CCTA to SOC in the Evaluation of Acute Chest Pain

Study (year)

N

Study Design

FU, mo

MI in Neg CTA* arm

LOS,

h (p)

ICA (CTA* vs Control)

Goldstein et al.

(2007) (13)

197

CTA* versus SPECT

6

0

3.4 versus 15

12.1% versus 7.1%

Goldstein et al.

(2011) (14)

699

CTA* versus SPECT

6

0

2.9 versus 6.3

7.2% versus 6.5%

Litt et al.

(2012) (15)

1370

CTA* versus SOC

1

0

18 versus 24

9.0% versus 3.5%

Hoffmann et al.

(2012) (16)

1000

CTA* versus SOC

1

0

23.2 versus 30.8

11% versus 7%

Hamilton-Craig et al.

(2014) (17)

562

CTA* versus SOC

12

0

13.5 versus 20.7

8.0% versus 3.8%

(Adapted from Marcus et al. [2016]. [23])

Table Key:

SOC: standard of care;

N: number;

FU: follow-up;

mo: months;

MI: myocardial infarction;

Neg: negative;

CTA*: coronary computed tomography angiography;

LOS: length of stay;

h (p): hours, p-value;

ICA: invasive coronary angiography;

vs: versus;

SPECT: single-photon emission computed tomography.

Section Summary: Acute Chest Pain Presenting to the Emergency Setting: CCTA

The high negative predictive value (NPV) of CCTA in patients presenting to the ED with chest pain permits ruling out coronary disease with high accuracy. The efficiency of the workup is improved, because patients are safely and quickly discharged from the ED with no adverse outcomes among patients with negative CCTA examinations.

Other important outcomes that require consideration in comparing technologies include ICA rates, use of a second noninvasive test, radiation exposure, and follow-up of any incidental findings. Some studies have shown that subsequent invasive testing is more frequent in patients who received CCTA. Studies have differed over which treatment strategies result in higher overall radiation exposure. Incidental findings after CCTA are common and lead to further testing, but the impact of these findings on subsequent health outcomes is uncertain.

Stable Patients with Angina and Suspected CAD: CCTA

Before use of CCTA, the initial noninvasive test in a diagnostic strategy was always a functional test. Current practice guidelines recommend a noninvasive test be performed in patients with intermediate risk of CAD. The choice of functional test is based on clinical factors such the predicted risk of disease, electrocardiogram (ECG) interpretability, and ability to exercise. When disease is detected, treatment alternatives include medical therapy or revascularization (percutaneous coronary intervention [PCI] or coronary artery bypass graft [CABG] surgery). If revascularization is indicated, patients undergo ICA to confirm the presence of stenosis. Which approach to adopt is based on the extent of anatomic disease, symptom severity, evidence of ischemia from functional testing, and, more recently, fractional flow reserve (FFR) obtained during invasive angiography. Many studies have shown that only a subset of anatomically defined coronary lesions are clinically significant and benefit from revascularization. Other studies have shown only limited benefits of treating coronary stenoses in stable patients. Thus an assessment of the diagnostic characteristics of CCTA alone is insufficient to establish clinical utility. A difficulty in evaluating a noninvasive diagnostic test for CAD is that patient outcomes depend not only on the test results, but also the management and treatment strategy. The most convincing evidence of clinical utility compares outcomes after anatomic-first (CCTA) and functional-first (e.g., perfusion imaging, stress echocardiography) strategies.

Relevant studies reviewed here include those comparing diagnostic performance of CCTA with angiography, studies of outcomes of patients undergoing CTA versus alternative tests, and studies of incidental findings and radiation exposure.

Diagnostic Accuracy

There is a fairly large body of evidence evaluating the diagnostic characteristics of CCTA for identifying coronary lesions. The best estimate of the diagnostic characteristics of CCTA can be obtained from recent meta-analyses and systematic reviews. Table 2 shows ranges of sensitivity and specificity for functional noninvasive tests from studies of the diagnosis and management of stable angina reviewed by Fihn et al. (24) Sensitivities tended to range between 70% and 90%, depending on the test and study, and specificities ranged between 70% and 90%.

For CCTA, estimates of sensitivity from various systematic reviews are considerably higher (see Table 3). The guideline statement from Fihn et al. cited studies reporting sensitivities between 93% and 97%. (24) A meta-analysis by Ollendorf et al. of 42 studies showed a summary sensitivity estimate of 98% and a specificity of 85%. (25) A meta-analysis of 8 studies conducted by the Ontario Health Ministry showed a summary sensitivity estimate of 97.7% and a specificity of 79%. (26) In the meta-analysis by Nielsen et al., sensitivity of CCTA varied between 98% and 99% (depending on the analysis group). (27)

Table 5: Summary of Estimates of Sensitivity and Specificity of Functional Noninvasive Tests from Recent Guideline Statement (Fihn et al. [24])

Noninvasive Test

Sensitivity (Range or Single Estimates

Specificity (Range or Single Estimate

Exercise electrocardiography

61%

70%-77%

Pharmacologic stress echocardiography

85%-90%

79%-90%

Exercise stress echocardiography

70%-85%

77%-89%

Exercise myocardial perfusion imaging

82%-88%

70%-88%

Pharmacologic stress myocardial perfusion imaging

88%-91%

75%-90%

Table 6: Estimates of Sensitivity and Specificity of CCTA from Guidelines and Meta-Analyses

Study

Sensitivity (Range or Single Estimates

Specificity (Range or Single Estimate

Fihn et al. (2012) guideline statement (24)

93%-97%

80%-90%

Ollendorf et al. (2011) meta-analysis (25)

98%

85%

Health Quality Ontario (2010) meta-analysis (26)

97.7%

79%

Nielsen et al. (2014) meta-analysis (27)

98%-99%

82%-88%

Effect on Health Outcomes - Randomized Controlled Trials

For patients at intermediate risk of CAD, 3 major RCTs were identified comparing net health outcomes following a CCTA strategy with outcomes from other noninvasive testing strategies.

The PROMISE (PROspective Multicenter Imaging Study for Evaluation of Chest Pain) trial randomized 10,003 patients to CCTA or exercise ECG, nuclear stress testing, or stress echocardiography (as determined by physician preference) as the initial diagnostic evaluation. (28) For the composite end point of death, MI, hospitalization for unstable angina, or major procedural complication, the outcome rates between the 2 groups showed no statistically significant difference (HR=1.04; 95% CI, 0.83 to 1.29). CCTA also did not meet prespecified noninferiority criteria compared with alternative testing. Some clinical outcomes assessed at 12 months favored CCTA, but the differences were nonsignificant. Coronary catheterization rates and revascularization rates were higher in the CCTA group.

In the SCOT-HEART (Scottish COmputed Tomography of the HEART) trial, 4146 patients were randomized to CCTA or SOC. (29) The primary end point was the change in the proportion of patients with a more certain diagnosis (presence or absence) of angina pectoris. Secondary outcomes included death, MI, revascularization procedures, and hospitalizations for chest pain. Analysis of the primary outcome showed that patients who underwent CCTA had an increase in the certainty of their diagnosis relative to those in usual care (relative risk, 1.79; 95% CI, 1.62 to 1.96). Regarding health outcomes, the rates of heart disease death and MI were lower with CCTA (1.3% versus 2.0%; HR=0.62; p=0.053), but results were of marginal statistical significance.

The CAPP (Cardiac CT for the Assessment of Pain and Plaque) trial randomized 500 patients with stable chest pain to CCTA or exercise stress testing. (30) The primary outcome was the change difference in scores of Seattle Angina Questionnaire domains at 3 months. Patients were also followed for further diagnostic tests and management. In the CCTA arm, 15.2% of subjects underwent revascularization. In the exercise stress testing arm, 7.7% underwent revascularization. For the primary outcome, angina stability and quality of life showed significantly greater improvement in the CCTA arm than in the exercise stress testing arm.

Effect on Health Outcomes - Nonrandomized Controlled Trials

Nonrandomized studies comparing outcomes of patients following a CCTA strategy with outcomes following other noninvasive testing strategies were also identified. Some studies have emphasized downstream utilization of diagnostic testing and procedures rather than patient outcomes.

Nielsen et al. conducted an observational trial comparing patients who underwent CCTA or exercise stress testing. (31) Patients had a low-to-intermediate pretest probability of CAD and presented with suspected angina. Patients were followed for 12 months after the initial test, and assessed for occurrence of major adverse events (e.g., cardiac death, nonfatal MI). Subsequent utilization of cardiovascular tests and therapy were also compared between groups. Clinical outcomes were not compared formally because there were few clinical events. No deaths were reported during the follow-up period. Three patients in the exercise testing group had MIs within 12 months. For downstream test utilization, the exercise test group had greater subsequent use of perfusion imaging (9% versus 4%, p=0.03) and greater mean total 1-year costs (€1777 versus €1510, p=0.03). Rates of ICA and revascularization did not differ significantly.

Shreibati et al. used Medicare claims data to compare all-cause mortality, subsequent utilization of several cardiac tests, treatment, and total costs in patients who underwent initial noninvasive testing with CCTA, stress echocardiography, myocardial perfusion imaging (MPI), or exercise ECG. (32) In this study, patients undergoing CCTA had higher rates of several types of utilization subsequent to their tests than patients undergoing MPI. The study also presented outcomes for both stress echocardiography and exercise electrocardiography, but they tended not to differ from outcomes for MPI. There were increased rates of ICA (22.9% versus 12.1%) and revascularization (11.4% versus 4.6%). Total spending and CAD-related spending were also higher for CCTA than for MPI. There was no significant difference in all-cause mortality between CCTA and MPI. Although the mortality rate for CCTA (1.05%) was slightly lower than the mortality rate for MPI (1.28%), the adjusted odds ratio (OR) showed a higher risk of mortality, which may be due to unusual confounding. However, there was a slightly lower likelihood of hospitalization for MI (adjusted OR=0.60; p=0.04).

In Min et al. (2008), costs and clinical outcomes for patients undergoing initial CCTA were compared with patients undergoing initial MPI. (33) The data source for this study was a proprietary claims database from 2 regional health plans. Utilization of medical care was lower after CCTA. Overall costs were lower, the proportion receiving ICA was lower, and the proportion receiving revascularization was lower after CCTA. In terms of clinical outcomes, the proportion with a hospitalization for angina was lower in the CCTA group. The CCTA group also had a lower rate of a combined outcome of angina or MI hospitalization (HR=0.70; 95% CI, 0.55 to 0.90).

In 2825 patients evaluated for stable angina and suspected CAD in Japan, Yamauchi et al. examined outcomes after initial CCTA (n=625), MPI (n=1205), or angiography (n=950). (34) Average follow-up was 1.4 years. In a Cox proportional hazards model adjusted for potential confounders, the relative hazard rates of major cardiac events after MPI or CCTA were lower than after angiography; annual rates were 2.6%, 2.1%, and 7.0%, respectively. Revascularization rates were higher after CCTA than MPI (OR=1.6; 95% CI, 1.2 to 2.2).

Incidental Findings

A number of studies using scanners using 64 or more detector rows were identified. (35-43) Incidental findings were frequent (26.6%-68.7%) with pulmonary nodules typically the most common and cancers rare (»5/1000 or less). Aglan et al. (2010) compared the prevalence of incidental findings when the field of view was narrowly confined to the cardiac structures with that when the entire thorax was imaged. (35) As expected, incidental findings were less frequent in the restricted field (clinically significant findings in 14% versus 24% when the entire field was imaged).

Radiation Exposure

Exposure to ionizing radiation increases lifetime cancer risk. (44) Three studies have estimated excess cancer risks due to radiation exposure from CCTA. (6, 7, 45) Assuming a 16-mSv dose, Berrington de Gonzalez et al. (2009) estimated that the 2.6 million CCTAs performed in 2007 would result in 2700 cancers or approximately 1 per 1000. (45) Smith-Bindman et al. (2009) estimated that cancer would develop in 1 of 270 women and 1 of 600 men age 40 undergoing CCTA with a 22-mSv dose. (7) Einstein et al. (2007) employed a standardized phantom to estimate organ dose from 64-slice CCTA. (6) With modulation and exposures of 15 mSv in men and 19 mSv in women, calculated lifetime cancer risk at age 40 was 7 per 1000 men (1/143) and 23 per 1000 women (1/43). However, estimated radiation exposure used in these studies was considerably higher than received with current scanners - now typically under 10 mSv and often less than 5 mSv with contemporary machines and radiation reduction techniques. For example, in the 47-center PROTECTION I (Prospective Multicenter Study on Radiation Dose Estimates of Cardiac CT Angiography) study enrolling 685 patients, the mean radiation dose was 3.6 mSv, using a sequential scanning technique. (46) In a 2012 study of patients undergoing an axial scanning protocol, mean radiation dose was 3.5 mSv, and produced equivalent ratings of image quality compared with helical scan protocols, which had much higher mean radiation doses of 11.2 mSv. (47)

Section Summary: Stable Angina and Suspected CAD: CCTA

A number of studies have evaluated the diagnostic accuracy of CTA for diagnosing CAD in an outpatient population. In general, these studies have reported high sensitivity and specificity, although there is some variability in these parameters across studies. Meta-analysis of these studies have shown that, for detection of anatomic disease, CCTA has a sensitivity greater than 95%, which is superior to all other functional noninvasive tests. Specificity is at least as good as other noninvasive tests. However, the link between improved diagnosis and health outcomes is not as clear, and thus outcome studies are necessary to demonstrate the clinical utility of CCTA.

Direct clinical trial evidence comparing CCTA and other strategies in the diagnostic management of stable patients with suspected CAD has not demonstrated the superiority of CCTA in any of the single clinical trials. Clinical trials demonstrated greater utilization of ICA and subsequent revascularization procedures after CCTA. An important problem of interpreting the clinical trials is that the comparator strategies differ: in the PROMISE trial, the CAPP trial, and Min et al. (2012), CCTA was compared with an alternative noninvasive test; in other studies, CCTA was supplement to usual care (which may or may not have included a noninvasive test). This design difference in the clinical trials is likely a reflection of how CCTA is used in clinical practice - either as a substitute for another noninvasive test or as an addition to other noninvasive tests. The PROMISE trial explicitly compared CCTA with an alternative functional test as the initial diagnostic test. Although the trial did not show the superiority of CCTA and did not meet pre-specified criteria for noninferiority, examination of some secondary clinical outcomes supports a conclusion of “at least” noninferiority. The results of the other randomized trials are consistent with noninferiority of CCTA with other established noninvasive tests. Thus, the randomized studies indicate that outcomes of patients are likely to be similar with CCTA versus other noninvasive tests.

The non-randomized studies of CCTA have several methodologic shortcomings including reliance on administrative data and inability to fully assess and adjust for potential confounding. The findings generally show little difference in patient outcomes between diagnostic strategies. Downstream utilization of medical care showed variable findings.

Although studies of incidental findings and radiation exposure raise issues regarding the potential for adverse effects of CCTA, there is not sufficient evidence that the magnitude of these effects is important for ascertaining the net benefit or risk of CCTA in this setting.

Suspected Anomalous Coronary Arteries

Anomalous coronary arteries are an uncommon finding during angiography, occurring in approximately 1% of coronary angiograms completed for evaluation of chest pain. However, these congenital anomalies can be clinically important depending on the course of the anomalous arteries. A number of case series have consistently reported that CCTA is able to delineate the course of these anomalous arteries, even when conventional angiography cannot. (48-51) However, none of the studies reported results when the initial reason for the study was to identify these anomalies, nor did any of the studies discuss impact on therapeutic decisions. Given the uncommon occurrence of these symptomatic anomalies, it is unlikely that a prospective trial of CCTA could be completed.

Other Diagnostic Uses of CCTA

Given its ability to define coronary artery anatomy, there are many other potential diagnostic uses of CCTA including patency of coronary artery bypass grafts, in-stent restenosis, screening, and preoperative evaluation:

Evaluating patency of vein grafts is generally less of a technical challenge due to vein size and lesser motion during imaging. In contrast, internal mammary grafts may be more difficult to image due to their small size and presence of surgical clips. Finally, assessing native vessels distal to grafts presents difficulties, especially when calcifications are present, due to their small size. For example, a 2008 meta-analysis including results from 64-slice scanners, reported high sensitivity 98% (95% CI, 95 to 99; 740 segments) and specificity 97% (95% CI, 94 to 97). (52) Other small studies have reported high sensitivity and specificity. (53, 54) Lacking are multicenter studies demonstrating likely clinical benefit, particularly given the reasonably high disease prevalence in patients evaluated.

Use of CCTA for evaluation of in-stent restenosis presents other technical challenges - motion, beam hardening, and partial volume averaging. Whether these challenges can be sufficiently overcome to obtain sufficient accuracy and impact outcomes has not been demonstrated.

Use for screening a low-risk population was recently evaluated in 1000 patients undergoing CCTA compared with a control group of 1000 similar patients. (55) Findings were abnormal in 215 screened patients. Over 18 months of follow-up, screening was associated with more invasive testing, statin use, but without difference in cardiac event rates.

CCTA for preoperative evaluation before noncardiac surgery has been suggested, but evaluated only in small studies and lacking demonstrable clinical benefit.

Ongoing and Unpublished Clinical Trials: CCTA

Some currently unpublished trials that might influence this review are listed in Table 7.

Table 7. Summary of Key Trials

NCT Number

Title

Enrollment

Completion Date

Ongoing

NCT01384448

Stress Echocardiography and Heart Computed Tomography (CT) Scan in Emergency Department Patients With Chest Pain

400

Feb 2017

NCT01559467

The Supplementary Role of Non-invasive Imaging to Routine Clinical Practice in Suspected Non-ST-elevation Myocardial Infarction (CARMENTA)

300

May 2017

NCT01283659

IMAGE-HF Project I-C: Computed Tomographic Coronary Angiography for Heart Failure Patients (CTA-HF)

250

Jun 2017

NCT02400229

Diagnostic Imaging Strategies for Patients with Stable Chest Pain and Intermediate Risk of Coronary Artery Disease (DISCHARGE)

3546

Sep 2019

NCT01083134

The Correlation of Heart Hemodynamic Status Between 320 Multi-detector Computed Tomography, Echocardiography and Cardiac Catheterization in Patients With Coronary Artery Disease

100

Mar 2020

Unpublished

NCT00991835

Plaque Registration and Event Detection In Computed Tomography (PREDICT)

2015

Dec 2014 (unknown)

NCT02291484

Comprehensive Cardiac CT Versus Exercise Testing in Suspected Coronary Artery Disease (2) (CRESCENT2)

250

May 2016 (completed)

Table Key:

NCT: National Clinical Trial.

Practice Guidelines and Position Statements: CCTA

American College of Cardiology Foundation (ACCF) et al.

The ACCF and several other medical societies (American Heart Association, American College of Physicians, American Association for Thoracic Surgery, Preventive Cardiovascular Nurses Association, Society for Cardiovascular Angiography and Interventions, and Society of Thoracic Surgeons, known as the AHA/ACP/AATS/PCNA/SCAI/STS) issued joint guidelines for management of patients with stable ischemic heart disease in 2012 (see Table 8). (24)

Table 8. Joint Guidelines on Management of Stable Ischemic Heart Disease

Diagnosis

Recommendation

Class

LOE

Unknown

Able to Exercise

“Coronary CTA might be reasonable for patients with an intermediate pretest probability of IHD [ischemic heart disease] who have at least moderate physical functioning or no disabling comorbidity.”

IIb

B

Unable to Exercise

“Coronary CTA is reasonable for patients with a low to intermediate pretest probability of IHD who are incapable of at least moderate physical functioning or have disabling comorbidity.”

IIa

B

“Coronary CTA is reasonable for patients with an intermediate pretest probability of IHD who a) have continued symptoms with prior normal test findings, or b) have inconclusive results from prior exercise or pharmacological stress testing, or c) are unable to undergo stress with nuclear MPI or echocardiography.”

IIa

C

Known Coronary Disease

Able to Exercise

“Coronary CTA may be reasonable for risk assessment in patients with SIHD (stable ischemic heart disease) who are able to exercise to an adequate workload but have an uninterpretable ECG.”

IIb

B

Able to Exercise

“Pharmacological stress imaging (nuclear MPI, echocardiography, or CMR) or coronary CTA is not recommended for risk assessment in patients with SIHD who are able to exercise to an adequate workload and have an interpretable ECG.”

III

B

Unable to Exercise

“Pharmacological stress CMR is reasonable for risk assessment in patients with SIHD who are unable to exercise to an adequate workload regardless of interpretability of ECG.”

IIa

B

“Coronary CTA can be useful as a first-line test for risk assessment in patients with SIHD who are unable to exercise to an adequate workload regardless of interpretability of ECG.”

IIa

C

Unable to Exercise

“A request to perform either a) more than 1 stress imaging study or b) a stress imaging study and a coronary CTA at the same time is not recommended for risk assessment in patients with SIHD.”

III

C

Regardless of Patients’ Ability to Exercise

“Coronary CTA might be considered for risk assessment in patients with SIHD unable to undergo stress imaging or as an alternative to invasive coronary angiography when functional testing indicates a moderate- to high-risk result and knowledge of angiographic coronary anatomy is unknown.”

IIb

C

Table Key:

LOE: level of evidence;

CCTA: coronary computed tomography angiography;

IHD: ischemic heart disease;

MPI: myocardial perfusion imaging;

SIHD: stable ischemic heart disease;

ECG: electrocardiography;

CMR: cardiac magnetic resonance.

Appropriate use criteria (57, 58) and expert consensus documents (59) published jointly by ACCF/ACR/AHA/NASCI/SAIP/SCAI/SCCT addresses CCTA in the emergency setting: “In the context of the emergency department evaluation of patients with acute chest discomfort, currently available data suggest that CCTA may be useful in the evaluation of patients presenting with an acute coronary syndrome (ACS) who do not have either acute electrocardiogram (ECG) changes or positive cardiac markers. However, existing data are limited, and large multicenter trials comparing CTA with conventional evaluation strategies are needed to help define the role of this technology in this category of patients.”

In 2013, ACCF/AHA/ASE/ASNC/HFSA/HRS/SCAI/SCCT/SCMR/STS published appropriate use criteria for detection and risk assessment of stable ischemic heart disease. (60) CCTA was considered appropriate for:

Symptomatic patients with intermediate (10%-90%) pre-test probability of CAD and uninterpretable ECG or inability to exercise;

Patients with newly diagnosed systolic heart failure;

Patients who have had a prior exercise ECG or stress imaging study with abnormal or unknown results;

Patients with new or worsening symptoms and normal exercise ECG.

National Institute for Health and Care Excellence (NICE)

The NICE considers CCTA indicated for patients with stable chest pain and Agatston coronary artery calcium score less than 400, when the pretest likelihood is between 10% and 29%. (61)

U.S. Preventive Services Task Force (USPSTF) Recommendations

No USPSTF recommendations screening asymptomatic individuals using CCTA have been identified.

Summary of Evidence: Coronary Computed Tomography Angiography

For individuals who have acute chest pain and suspected coronary artery disease (CAD) in the emergency setting, at intermediate to low risk, who receive coronary computed tomography angiography (CCTA), the evidence includes several randomized controlled trials. Relevant outcomes are overall survival, morbid events, and resource utilization. Trials have shown similar patient outcomes, with faster patient discharges from the emergency department (ED), and lower short-term costs. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have stable chest pain, intermediate risk of CAD, meeting guideline criteria for noninvasive testing (i.e., intermediate risk) who receive CCTA, the evidence includes studies of diagnostic accuracy of CCTA, randomized trials comparing CCTA with alternative diagnostic strategies, and observational studies comparing CCTA with alternative diagnostic strategies. Relevant outcomes are overall survival, test accuracy, morbid events, and resource utilization. Studies of diagnostic accuracy have shown that CCTA has higher sensitivity and similar specificity to alternative noninvasive tests. Although randomized trials have not shown the superiority of CCTA over other diagnostic strategies, results are consistent with noninferiority (i.e., similar health outcomes) to other diagnostic strategies. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

For individuals who have suspected anomalous coronary arteries who receive CCTA, the evidence includes case series. Relevant outcomes are overall survival, test accuracy, morbid events, and resource utilization. Series have shown that CCTA can detect anomalous coronary arteries missed by other diagnostic modalities. Anomalous coronary arteries are rare, and formal studies to assess clinical utility are unlikely to be performed. In most situations, these case series alone would be insufficient to determine whether the test improves health outcomes. However, in situations where patient management will be affected by CCTA results (e.g., with changes in surgical planning), an indirect chain of evidence indicates that health outcomes are improved. The evidence is sufficient to determine that the technology results in a meaningful improvement in the net health outcome.

Noninvasive Fractional Flow Reserve Computed Tomography

The literature reviewed assessed the potential impact of noninvasive imaging, particularly focusing on use of coronary computed tomography angiography (CCTA) and noninvasive fractional flow reserve (FFR), to guide use of invasive coronary angiography (ICA) in patients with stable chest pain at intermediate risk of coronary artery disease (CAD; i.e., suspected or presumed stable ischemic heart disease [SIHD]) being considered for ICA. Assessment of a diagnostic technology typically focuses on 3 categories of evidence: 1) its technical performance (test-retest reliability or interrater reliability); 2) diagnostic accuracy (sensitivity, specificity, and positive and negative predictive value) in relevant populations of patients; and 3) clinical utility demonstrating that the diagnostic information can be used to improve patient outcomes.

CCTA with Selective Noninvasive FFR

Clinical Context and Test Purpose

The purpose of selective noninvasive FFR using CCTA (FFRCT) in patients with stable chest pain who have suspected SIHD and who are being considered for ICA is to select patients who may be managed safely with observation only, instead of undergoing ICA in the short term.

Technical Performance

Data supporting technical performance derive from the test-retest reliability of FFRCT and invasively measured FFR (reference standard). Other technical performance considerations were summarized in the U.S. Food and Drug Administration (FDA) documentation. (75, 82)

Johnson et al. (2015) reported on the repeatability of invasive FFR. (83) Data from 190 paired assessments were analyzed (patients measured twice over 2 minutes). The test-retest coefficient of variation of 2.5% (r2=98.2%) was reported using a “smart minimum” in the analyses (“the lowest average of 5 consecutive cardiac cycles of sufficient quality within a run of 9 consecutive quality beats”). Hulten and Di Carli (2015) noted that based on the Johnson results, an FFR of 0.8 would have a 95% confidence interval (CI) of 0.76 to 0.84. (84) Gaur et al. (2014) analyzed data from 28 patients (58 vessels) with repeated FFRCT and invasive FFR measurements. (85) They reported coefficients of variation of 3.4% (95% CI, 1.5% to 4.6%) for FFRCT and 2.7% (95% CI, 1.8% to 3.3%) for invasive FFR. Although reproducibility was acceptable, whether test-retest reliability over time might be similar is unclear.

The ability to obtain FFRCT measurements is directly related to the quality of imaging data and values are not calculated for small vessels (<1.8 mm). Nitrate administration is recommended (generally standard practice unless contraindicated) for vasodilatation, and a lack of nitrates can affect FFRCT results. In addition, the FDA de novo summary lists factors that can adversely impact FFRCT results, including: imaging data quality, incorrect brachial pressure, myocardial dysfunction and hypertrophy, and abnormal physiology (e.g., congenital heart disease). Coronary calcium might also impact measurements. (86)

Section Summary: Technical Performance

Reported results have indicated that the test-retest reliability is acceptable and other known factors can impact variability of FFRCT results.

Diagnostic Accuracy

Studies Included in FFRCT Systematic Reviews: Per-Patient Diagnostic Accuracy

Twenty-six studies have contributed patient-level results to a 2015 meta-analysis that examined 5 non-FFRCT imaging modalities (see Table 9). (87) Five studies contributed results to 2 meta-analyses, Wu et al. (2016) (88) and Danad et al. (2017), (89) evaluating the diagnostic accuracy of FFRCT using patients as the unit of analysis. Only the FDA-cleared HeartFlow software has been evaluated prospectively across multiple sites. Two small retrospective studies have reported per-patient performance characteristics for the prototype Siemens workstation-based software. (90, 91) The 3 HeartFlow FFRCT studies used successive software versions with reported improvement in specificity (from 54% to 79%) between versions 1.2 and 1.4. (76, 72, 92) The NXT (HeartFlow Analysis of Coronary Blood Flow Using Coronary CT Angiography [HFNXT]) Trial, the basis for device clearance by the FDA, was conducted at 11 sites in 8 countries (Canada, EU [European Union], Asia). (79) Although not examined in the 2 included meta-analyses, subgroup analyses suggested little variation in results by sex and age. (93) Effectively, the entirety of the data was obtained in patients of white or Asian decent; almost all patients were appropriate for testing according to FDA clearance.

Danad et al. (2017) included 23 studies published between January 2002 and February 2015 evaluating the diagnostic performance of CCTA, FFRCT, single-photon emission computed tomography (SPECT), stress echocardiography (SECHO), magnetic resonance imaging (MRI), or ICA compared with an invasive FFR reference standard. (89) The 3 included FFRCT studies used the HeartFlow software and had performed FFR in at least 75% of patients. A cutoff of 0.75 defined significant stenosis in 8 (32%) studies and in the remainder 0.80 (the current standard used in all FFRCT studies). Per-patient and per-vessel meta-analyses were performed. Study quality was assessed using QUADAS-242; no significant biases were identified in FFRCT studies but a high risk of biased patient selection was judged in 10 (43.4%) of other studies. HeartFlow funded publication Open Access; 1 author was a consultant to, and another a cofounder of, HeartFlow.

On the patient level, MRI had the highest combined sensitivity (90%; 95% CI, 75% to 97%) and specificity (94%; 95% CI, 79% to 99%) for invasive FFR, but were estimated from only 2 studies (70 patients). FFRCT had similar sensitivity (90%; 95% CI, 85% to 93%), but lower specificity (71%; 95% CI, 65% to 75%), and accordingly a lower positive likelihood ratio (3.34; 95% CI, 1.78 to 6.25) than MRI (10.31; 95% CI, 3.14 to 33.9). The negative likelihood ratios were low (lower is better) for both FFRCT (0.16; 95% CI, 0.11 to 0.23) and MRI (0.12; 95% CI, 0.05 to 0.30); however, the confidence interval is more narrow for FFRCT due to larger sample for FFRCT. CCTA had a slightly higher negative likelihood ratio (0.22; 95% CI, 0.10 to 0.50). Results for the per-vessel area under the summary receiver operating characteristic curve were similar except for CCTA where per-patient results were considerably worse (e.g., C statistic of 0.57 versus 0.85). Reviewers noted heterogeneity in many estimates (e.g., CCTA sensitivity, I2=80%). Finally, pooled results for some imaging tests included few studies.

In 2016, Wu et al. identified 7 studies (833 patients, 1377 vessels) comparing FFRCT with invasively measured FFR from searches of PubMed, Cochrane, EMBASE, Medion, and meeting abstracts through January 2016. (88) Studies included patients with established or suspected SIHD. In addition to the 3 FFRCT studies pooled by Danad et al., (89) 1 additional study using HeartFlow technique (44 patients; 48 vessels) and 3 additional studies (180 patients; 279 vessels) using Siemens cFFR software (not FDA approved or cleared) were identified. An invasive FFR cutoff of 0.80 was the reference standard in all studies. Per-patient results reported in 5 studies were pooled and reported in Table 9. All studies were rated at low risk of bias and without applicability concerns using the QUADAS-2 tool. (94) Appropriate bivariate meta-analyses (accounting for correlated sensitivity and specificity) were used.

As expected given study overlap, FFRCT performance characteristics were similar to those reported by Danad et al., (89) but with a slightly higher specificity (see Table 9). The pooled per-vessel C statistic was lower (0.86) than the per-patient result (0.90). No evidence of publication bias was detected, but the number of studies was too small to adequately assess. Reviewers noted that, in 2 studies, FFRCT results were uninterpretable in 12.0% (79) and 8.2% (95) of participants.

Takx et al. (2015) identified studies reporting on the ability of perfusion CT, MRI, SECHO, PET, and SPECT to detect hemodynamically significant CAD as measured by ICA with invasive FFR. (87) Studies published through May 2014 were eligible for inclusion; PubMed, EMBASE, and Web of Science were searched. QUADAS-2 was used to assess study quality (94); studies generally rated poorly on blinding of the index test result from the assessor and study population selection. Reviewers designated the negative likelihood ratio as the diagnostic characteristic of interest (i.e., ability to exclude disease) noting that myocardium perfusion scan (MPI) (e.g., MRI, SPECT, PET, or CT) has been proposed to be a gatekeeper to ICA. No funding was obtained for the review and the study was registered on PROSPERO (96) (the 2 other meta-analyses were not).

The pooled negative likelihood ratios for MRI, PET, and perfusion CT were similar in magnitude (0.12 to 0.14; see Table 9) although the confidence interval for PET was wide. Heterogeneity among studies included in the pooled patient-level results was considered high for PET (I2=84%), moderate for CT (I2=70%) and SPECT (I2=55%), and low for MRI (I2=0%) and SECHO (I2=0%). Publication bias, when able to be assessed, was not suspected. With respect to ability to detect hemodynamically significant ischemia, reviewers concluded that “MPI with MRI, CT, or PET has the potential to serve as a gatekeeper for invasive assessment of hemodynamic significance by ICA and FFR.” Studies of FFRCT were not included in the analysis.

Table 9. Pooled Per-Patient Pooled Diagnostic Performance of Noninvasive Tests for Invasive FFR

Test

Studies

N

Sensitivity (95% CI)

Specificity (95% CI)

C

LR+

(95% CI)

LR-

(95% CI)

Danad et al. (2017) (89)

MRI

2

70

90%

(75 to 97)

94%

(79 to 99)

0.94

10.3

(3.14 to 33.9)

0.12

(0.05 to 0.30)

FFRCT

3

609

90%

(85 to 93)

71%

(65 to 75)

0.94

3.3

(1.78 to 6.25)

0.16

(0.11 to 0.23)

CTA

4

694

90%

(86 to 93)

39%

(34 to 44)

0.57

1.5

(1.25 to 1.90)

0.22

(0.10 to 0.50)

SECHO

2

115

77%

(61 to 88)

75%

(63 to 85)

0.82

3.0

(1.94 to 4.65)

0.34

(0.17 to 0.66)

SPECT

3

110

70%

(59 to 80)

78%

(68 to 87)

0.79

3.4

(1.04 to 11.1)

0.40

(0.19 to 0.83)

ICA

2

954

69%

(65 to 75)

67%

(63 to 71)

0.75

2.5

(1.25 to 5.13)

0.46

(0.39 to 0.55)

Wu et al. (2016) (88)

FFRCT

5

683

89%

(85 to 93)

76% (64 to 84)

0.90

3.7

(2.41 to 5.61)

0.14

(0.09 to 0.21)

Takx et al. (2015) (87)

MRI

10

798

89%

(86 to 92)

87%

(83 to 90)

0.94

6.3

(4.88 to 8.12)

0.14

(0.10 to 0.18)

PCT

5

316

88%

(82 to 92)

80%

(73 to 86)

0.93

3.8

(1.94 to 7.40)

0.12

(0.04 to 0.33)

SECHO

4

177

69%

(56 to 79)

84%

(75 to 90)

0.83

3.7

(1.89 to 7.15)

0.42

(0.30 to 0.59)

SPECT

8

533

74%

(67 to 79)

79%

(74 to 83)

0.82

3.1

(2.09 to 4.70)

0.39

(0.27 to 0.55)

PET

2

224

84%

(75 to 91)

87%

(80 to 92)

0.93

6.5

(2.83 to 15.1)

0.14

(0.02 to 0.87)

Table Key:

N: number;

CI: confidence interval;

C: C-statistic;

LR: likelihood ratio;

CT: computed tomography;

MRI: magnetic resonance imaging;

FFRCT: fractional flow reserve computed tomography;

CTA: computed tomography angiography;

SECHO: stress echocardiography;

SPECT: single photon emission computed tomography;

PCT: perfusion computed tomography;

ICA: invasive coronary angiography.

Section Summary: Diagnostic Accuracy

Three studies including 609 patients have evaluated diagnostic accuracy of the FDA-cleared HeartFlow software. Software used in successive studies was also revised to improve performance characteristics, particularly specificity. For example, using an earlier software version, the DeFACTO (DEtermination of Fractional Flow Reserve by Anatomic Computed TOmographic Angiography)Trial reported a specificity of 54%. (97) Accordingly, pooled results from the Danad systematic review must be interpreted carefully. (89) In addition, there is some uncertainty in the generalizability of results obtained in these studies conducted under likely controlled conditions (e.g., data from the NXT Trial [79] forming the basis for FDA clearance).

Given the purpose to avoid ICA, the negative likelihood ratio, or how a negative result might dissuade a clinician from proceeding to ICA, is of primary interest - i.e., excluding a patient with vessels having a high FFR from ICA. While confidence intervals are relatively wide and overlapping, the negative likelihood ratio estimates of FFRCT for excluding physiologically significant coronary stenoses tended to be lower (i.e., better) than CCTA alone, SECHO, SPECT, and ICA. Only MRI yielded a similarly low or lower negative likelihood ratio than FFRCT.

Clinical Utility

Indirect Evidence

Diagnostic performance can offer indirect evidence of clinical utility, assuming providers act according to a test result. As previously noted, an effective gatekeeper strategy must be able to decrease the probability of disease (rule out) sufficiently that a planned ICA would not be performed. Ruling out disease is a function of the negative likelihood ratio that defines the degree to which a negative test decreases the posttest odds (and probability) of disease.

Table 10 illustrates how a negative test would lower the probability of a hemodynamically significant obstruction from pretest probabilities of 0.25, 0.50, or 0.75 for the various tests examined in the meta-analyses. For example, according to the results of Danad et al., if the pretest probability was 0.50, following a negative CCTA study the posttest probability would be 0.18 (95% CI, 0.09 to 0.33); and following a negative SECHO, 0.25 (95% CI, 0.15 to 0.40) or SPECT, 0.29 (95% CI, 0.16 to 0.45). (89) In contrast, beginning with a pretest probability of 0.50, a negative FFRCT would yield a posttest probability of 0.14 (95% CI, 0.10 to 0.19) (Danad et al., [89]) and 0.12 (95% CI, 0.08 to 0.17) (Wu et al., [88]). Overall, the negative likelihood ratios and posttest probability estimates for FFRCT are slightly better than CCTA as well as SECHO and SPECT.

Table 10. Change in Disease Probability Following a Negative Test

Posttest Probability (95% CI) After Negative Test

Study

Modality

Negative LR

(95% CI)

Pretest Probability

0.25

Pretest Probability

0.50

Pretest Probability 0.75

Danad et al. (2017) (89)

MRI

0.12

(0.05 to 0.30)

0.04

(0.02 to 0.09)

0.11

(0.05 to 0.23)

0.26

(0.13 to 0.47)

FFRCT

0.16

(0.11 to 0.23)

0.05

(0.04 to 0.07)

0.14

(0.10 to 0.19)

0.32

(0.25 to 0.41)

CTA

0.22

(0.10 to 0.50)

0.07

(0.03 to 0.14)

0.18

(0.09 to 0.33)

0.40

(0.23 to 0.60)

SECHO

0.34

(0.17 to 0.66)

0.10

(0.05 to 0.18)

0.25

(0.15 to 0.40)

0.50

(0.34 to 0.66)

SPECT

0.40

(0.19 to 0.83)

0.12

(0.06 to 0.22)

0.29

(0.16 to 0.45)

0.55

(0.36 to 0.71)

ICA

0.46

(0.39 to 0.55)

0.13

(0.12 to 0.15)

0.32

(0.28 to 0.35)

0.58

(0.54 to 0.62)

Wu et al. (2016) (88)

FFRCT

0.14

(0.09 to 0.21)

0.04

(0.03 to 0.07)

0.12

(0.08 to 0.17)

0.30

(0.21 to 0.39)

Takx et al. (2015) (87)

MRI

0.14

(0.10 to 0.18)

0.04

(0.03 to 0.06)

0.12

(0.09 to 0.15)

0.30

(0.23 to 0.35)

PCT

0.12

(0.04 to 0.33)

0.04

(0.01 to 0.10)

0.11

(0.04 to 0.25)

0.26

(0.11 to 0.50)

SECHO

0.42

(0.30 to 0.59)

0.12

(0.09 to 0.16)

0.30

(0.23 to 0.37)

0.56

(0.47 to 0.64)

SPECT

0.39

(0.27 to 0.55)

0.12

(0.08 to 0.15)

0.28

(0.21 to 0.35)

0.54

(0.45 to 0.62)

PET

0.14

(0.02 to 0.87)

0.04

(0.01 to 0.22)

0.12

(0.02 to 0.47)

0.30

(0.06 to 0.72)

Table Key:

CI: confidence interval;

LR: likelihood ratio;

CT: computed tomography;

MRI: magnetic resonance imaging;

FFRCT: fractional flow reserve computed tomography;

CTA: computed tomography angiography;

PET: positron emission tomography;

SECHO: stress echocardiography;

SPECT: single photon emission computed tomography;

PCT: perfusion computed tomography;

ICA: invasive coronary angiography.

One study was identified (Curzen et al., 2016) that examined 200 consecutive individuals selected from the NXT trial population “to reproduce the methodology of the invasive RIPCORD [Does RoutIne Pressure Wire Assessment Influence Management Strategy at CORonary Angiography for Diagnosis of Chest Pain?] study” with elective management of stable chest pain. (98) All subjects received CCTA including FFRCT “in at least 1 vessel with diameter ≥ 2 mm and diameter stenosis ≥ 30%” as well as ICA within 60 days of CCTA. Three experienced interventional cardiologists reviewed the CCTA results (initially without the FFRCT results) and selected a management plan from the following 4 options: “1) optimal medical therapy (OMT) alone; 2) PCI [percutaneous coronary intervention] + OMT; 3) coronary artery bypass graft + OMT; or 4) more information about ischemia required – they committed to option 1 by consensus.” Following the initial decision, results from the FFRCT were shared with the same group of interventional cardiologists who again made a decision by consensus based on the same 4 options. A cutoff of 0.80 or less was considered significant on FFRCT. A stenosis was considered significant on CCTA or ICA with 50% or more diameter narrowing. Change in management between the first decision based on CCTA only and the second decision based on CCTA plus FFRCT was the primary end point of this study. Secondary end points included analysis of the vessels considered to have significant stenosis based on CCTA alone versus CCTA plus FFRCT as well as vessels identified as targets for revascularization based on CCTA alone versus CCTA plus FFRCT.

NOTE 5: This study was conducted by investigators in the United Kingdom and Denmark. Funding was provided by HeartFlow and multiple authors reported receiving fees, grants, and/or support from HeartFlow.

Results for the primary end-point (see Table 11) yielded a change in management category for 72 of 200 (36%) individuals. For the 87 individuals initially assigned to PCI based on CCTA alone, the addition of the FFRCT results shifted management for 26 of 87 (30%) to OMT (i.e., no ischemic lesion on FFRCT) and an additional 16 (18%) individuals remained in the PCI category but FFRCT identified a different target vessel for PCI. These findings provide supportive information that the improved diagnostic accuracy of FFRCT in particular related to its better negative likelihood ratio compared to CCTA alone would likely lead to changes in management that would be expected to improve health outcomes.

Table 11. Summary of Overall Changes to Management in Patients Using CCTA versus CCTA + FFRCT

Management Category Consensus

Decision

CCTA Alone,

n (%)

CCTA Plus FFRCT,

n (%)

Strategy Changea

(95% CI)

More data required

38 (19.0%)

0

-

Optimal medical therapy

67 (33.5%)

113 (56.5%)

23%

(18% to 29%)

Percutaneous coronary intervention

87 (43.5%)

78 (39.0%)

-5%

(-2% to -8%)

Coronary artery bypass graft surgery

8 (4.0%)

9 (4.5%)

0.5%

(0.1% to 3%)

Table Key:

CT: computed tomography;

CTA: computed tomography angiography;

FFRCT: fractional flow reserve computed tomography;

CI: confidence interval;

n: number;

a: p<0.001 for between-group change, CCTA alone versus CCTA plus FFRCT.

Direct Evidence

Two prospective comparative studies were identified, including 1 prospective nonrandomized study that compared an FFRCT strategy (CCTA with noninvasive FFR measurement when requested or indicated) with ICA and 1 RCT that examined CCTA as a gatekeeper to ICA (see Tables 12 and 13). In addition, 1 prospective cohort study and 2 retrospective cohort studies were identified, in which patients were referred for CCTA, which included FFRCT evaluation.

The PLATFORM (Prospective LongitudinAl Trial of FFRCT: Outcome and Resource IMpacts) Study compared diagnostic strategies with or without FFRCT in patients with suspected stable angina but without known CAD. (99, 100) The study was conducted at 11 EU sites. All testing was nonemergent. Patients were divided into 2 strata, according to whether the test planned prior to study enrollment was: 1) noninvasive or 2) ICA (the patient population of interest in this evidence review). Patients were enrolled in consecutive cohorts, with the first cohort undergoing a usual care strategy followed by a second cohort provided CCTA with FFRCT performed when requested (recommended if stenoses ≥30% were identified). Follow-up was scheduled at 90 days and 6 and 12 months after entry (99.5% of patients had 1-year follow-up data).

NOTE 6: Funding was provided by HeartFlow and multiple authors reported receiving fees, grants, and/or support from HeartFlow. Data analyses were performed by the Duke Clinical Research Institute.

ICA without obstructive disease at 90 days was the primary end-point in patients with planned invasive testing - “no stenosis ≥ 50% by core laboratory quantitative analysis or invasive FFR < 0.80.” Secondary end-points included ICA without obstructive disease following planned noninvasive testing, and 1) Major adverse cardiovascular events (MACE) at 1 year defined as a composite of all-cause mortality, myocardial infarction (MI), and urgent revascularization and 2) MACE and vascular events within 14 days. Quality of life (QOL) was evaluated using the Seattle Angina Questionnaire, and EQ-5D (5-item and 100-point visual analog scale). CCTA studies were interpreted by site investigators; quantitative coronary angiography measurements were performed at a central laboratory, as was FFRCT. Cumulative radiation was also assessed. A sample size of 380 patients in the invasive strata yielded a 90% power to detect a 50% decrease in the primary end point given a 30% event rate (ICA without obstructive disease) with a usual care strategy and a dropout rate up to 10%.

ICA was planned in 380 participants, of whom 193 (50.8%) had undergone prior noninvasive testing. The mean pretest probability in the planned ICA strata was approximately 50% (51.7% and 49.4% in the 2 groups). FFRCT was requested in 134 patients and successfully obtained in 117 of 134 (87.3%) in the FFRCT group. At 90 days, 73.3% of those in the usual care group had no obstructive findings on ICA compared with 12.4% in the FFRCT group based on core laboratory readings (56.7% and 9.3% based on site readings). The difference was similar in a propensity-matched analysis of a subset of participants (n=148 from each group or 78% of the entire sample). Prior noninvasive testing did not appear associated with non-obstructive findings. MACE rates were low and did not differ between strategies. Mean level of radiation exposure though 1 year was also similar in the usual care group (10.4 mSv) and the planned ICA group (10.7 mSv). No differences in QOL were found between groups. (101)

Results of the PLATFORM study support the notion that, in patients with planned ICA, FFRCT can decrease the rate of ICAs and unnecessary procedures (finding no significant obstructive disease) and that FFRCT may provide clinically useful information to physicians and patients. Study limitations include a nonrandomized design; high rate of no obstructive disease with a usual care strategy (73.3%), which was higher than the 30% rate assumed in the sample size estimates; and a sample size that was small with respect to evaluating adverse cardiac events. Although finding a large effect in patients with planned invasive testing, the nonrandomized design limits causal inferences and certainty that the magnitude of effect. The propensity-matched analysis (in a matched subset) offers some reassurance, but the sample size was likely too small to provide robust results.

Dewey et al. (2016) conducted the Coronary Artery Disease Management (CAD-Man) Trial, a single-center, parallel-group assignment trial examining CCTA as a gatekeeper to ICA in patients with atypical angina or chest pain and suspected CAD who were indicated for ICA. (102) Patients were randomized to direct ICA or to ICA only if a prior CCTA was positive (a stenosis ≥70% stenosis in any vessel or ≥50% in the left main coronary artery). The trialists reported that when obstructive disease was suspect following CCTA, late enhancement MRI was performed to evaluate the extent of viable myocardium (completed in 17 patients) to guide revascularization; however, the study protocol clarified that MRI was not used for decisions to proceed to ICA. A major procedural complication (death, stroke, MI, or event requiring >24-hour hospitalization) within 24 hours was the primary outcome; secondary outcomes included ICA with obstructive CAD (diagnostic yield), revascularizations, and MACE during long-term follow-up. The trial was performed in Germany. Patients were excluded if they had evidence of ischemia or signs of MI and just over half (56.5%) were inpatients at the time of enrollment. Obstructive disease was defined as “at least one 50% diameter stenosis in the left main coronary artery or at least one 70% diameter stenosis in other coronary arteries.” Allocation concealment appeared adequate, but the trial was unblinded owing to the nature of the intervention. In addition, the mean pretest probability of CAD at baseline was higher in the ICA-only arm (37.3% versus 31.3%; see Table 12). The research was supported by public funding.

ICAs were reduced by 85.6% in the CCTA arm and by 80.9% for ICA with no obstructive disease. A major procedural complication (the primary outcome) occurred in a single patient undergoing CCTA. PCIs were less frequent when CCTA was performed - 9.6% versus 14.2% (p<0.001). Over a median follow-up of 3.3 years, MACE rates were similar in the trial arms (4.2% in the CCTA group versus 3.7% with ICA; adjusted hazard ratio [HR], 0.90; 95% CI, 0.30 to 2.69). In the CCTA arm, there was 1 death, 2 patients with unstable angina, and 6 revascularizations; in the ICA arm there was 1 MI, 1 stroke, and 5 revascularizations.

The trial demonstrated that CCTA as a gatekeeper to planned ICA can avoid a large number of procedures, a corresponding increase in the diagnostic yield, and fewer revascularizations. Of note, the prevalence of obstructive CAD found on ICA in this study population was 13% (43/334 eligible for primary outcome analysis), which is lower than the prevalence of obstructive CAD in the PLATFORM population (26.7%). Thus, the subset of individuals who went onto ICA following CCTA findings of obstructive CAD was 20 (12%) of 167 eligible for primary outcome analysis and only 3 (1.7%) were found to have no obstructive CAD on ICA. MACE rates did not differ between arms. The trial was powered neither to detect a difference nor to assess noninferiority - implications of the absence of a difference are limited. Finally, although the patient population included those scheduled for elective ICA, it was heterogeneous, including those with recent onset and longer standing chest pain. The single-center nature of the trial is an additional limitation; a subsequent multicenter Diagnostic Imaging StrateGies for Patients with Stable CHest Pain And Intermediate Risk of Coronary Artery DiseasE Trial (DISCHARGE) is ongoing.

Table 12. Characteristics of Comparative Studies

Characteristics

Nonrandomized

Randomized

PLATFORM

CAD-Man

ICA

FFRCT

ICA

CCTA

(n=187)

(n=193)

(n=162)

(n=167)

Age (Standard Deviation), years

63.4 (10.9)

60.7 (10.2)

60.4 (11.4)

60.4 (11.3)

Female, n (%)

79 (42.2%)

74 (38.3%)

88 (52.7%)

78 (48.1%)

Race/ethnic minority, n (%)

2 (1.1%)

1 (0.5%)

-

Pretest probability obstructive CAD, %

51.7%

49.4% (17.2%)

37.3% (24.8%)

31.3%

Angina (%)

-

-

-

-

Typical

52 (27.8%)

45 (23.3%)

-

-

Atypical

122 (65.2%)

142 (73.6%)

79 (48.8%)

65 (38.9%)

Non-cardiac

12 (7.0%)

5 (2.6%)

80 (49.4%)

97 (58.1%)

Other chest discomfort

-

-

3 (1.8%)

5 (3.0%)

Prior noninvasive testing, n (%)

92 (49.2%)

101 (52.3%)

84 (50.3%)

92 (56.8%)

Diabetes, n (%)

36 (19.3%)

30 (15.5%)

30 (18.5%)

15 (9.0%)

Current smoker

-

-

34 (21.0%)

41 (24.5%)

Current or past smoker

103 (55.1%)

101 (52.3%)

85 (52.4%)

88 (52.6%)

Table Key:

PLATFORM: Prospective Longitudinal Trial of FFRCT: Outcome And Resource Impacts Study;

CAD-MAN: Coronary Artery Disease Management Trial;

CAD: coronary artery disease;

CT: computed tomography;

CTA: computed tomography angiography;

FFRCT: fractional flow reserve computed tomography;

ICA: invasive coronary angiography;

n: number.

Table 13. Results of Comparative Studies

Outcomes

Nonrandomized

Randomized

PLATFORM

CAD-Man

ICA

FFRCT

ICA

CCTA

(n=187)

(n=193)

(n=162)

(n=167)

Noninvasive FFRCT

-

-

-

-

Requested, n (%)

-

134 (69.4%)

-

-

Successfully performed, n (%)

-

117 (60.1%)

-

-

ICA no obstructive disease, n (%)

137 (73.3%)

24 (12.4%)

137 (84.5%)

6 (3.6%)

Absolute difference (95% CI), %

60.8% (53.0% to 68.7%)

80.9% (74.6% to 87.2%)

ICA, n (%)

187 (100%)

76 (39.4%)

162 (100%)

24 (14.4%)

Absolute difference (95% CI), %

60.6% (53.7% to 67.5%)

85.6% (80.3% to 90.9%)

Revascularization, n (%)

-

-

-

-

PCI

49 (26.2%)

55 (28.5%)

-

-

CABG

18 (9.6%)

10 (5.2%)

-

-

Any

67 (35.8%)

65 (33.7%)

23 (14.2%)

16 (9.6%)

1-year outcomes, n (%)

-

-

-

-

MACEa

2 (1.1%)

2 (1.0%)

-

-

MACEb

-

-

6 (3.7%)

7 (4.2%)

Table Key:

PLATFORM: Prospective Longitudinal Trial of FFRCT: Outcome And Resource Impacts Study;

CAD-MAN: Coronary Artery Disease Management Trial;

CAD: coronary artery disease;

CT: computed tomography;

CTA: computed tomography angiography;

FFRCT: fractional flow reserve computed tomography;

ICA: invasive coronary angiography;

n: number

CI: confidence interval;

PCI: percutaneous coronary intervention;

CABG: coronary artery bypass grafting;

MACEa: major adverse cardiovascular events, Death, myocardial infarction, unplanned urgent revascularization;

MACEb: major adverse cardiovascular events, Cardiac death, myocardial infarction, stroke, unstable angina, any revascularization.

Møller Jensen et al. (2017) reported on a single-institution study of 774 consecutive individuals with suspicion of CAD referred for nonemergent ICA or CCTA. (103) Subjects were analyzed in 2 groups: a low-intermediate-risk group accounting for 76% of patients with mean pretest probability of CAD 31% and a high-risk group accounting for 24% of patients with mean pretest probability of CAD 67%. Among the 745 who received CCTA, FFRCT was selectively ordered in 28% of patients overall (23% in the low-intermediate-risk group, 41% in the high-risk group). CCTA was considered inconclusive in 3% of subjects and among those with conclusive CCTA, FFRCT yielded few inconclusive results, with less than 3% of cases. During a minimum 90-day follow-up, the combined testing strategy of selective FFRCT following CCTA resulted in avoiding ICA in 91% of low-intermediate-risk and 75% of high-risk individuals. None of the patients who avoided ICA based on CCTA with selective FFRCT were associated with serious clinical adverse events over an average of 157 days of follow-up.

Nørgaard et al. (2017) reported on results from symptomatic patients referred for CCTA at a single center in Denmark from May 2014 to April 2015. (104) All data were obtained from medical records and registries; the study was described as a “review” of diagnostic evaluations and apparently retrospectively conducted. Follow-up through 6 to 18 months was ascertained. From 1248 referred patients, 1173 underwent CCTA; 858 received medical therapy, 82 underwent ICA, 44 MPI, and 189 FFRCT (185 [98%] obtained successfully). Of the 185 individuals who successfully obtained FFRCT, FFRCT demonstrated values of 0.80 or less in 1 or more vessels in 57 (31%) patients and 49 (86%) went on to ICA; whereas of the 128 with higher FFRCT values, only 5 (4%) went on to ICA. Assuming ICA was planned for all patients undergoing FFRCT, these results are consistent with FFRCT being able to decrease the rate of ICA. However, implications are limited by the retrospective design, performance at a single center, and lack of a comparator arm including one for CCTA alone.

Lu et al. (2017) retrospectively examined a subgroup referred to ICA (105) from the completed PROspective Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE) trial. PROMISE was a pragmatic trial comparing CCTA with functional testing for the initial evaluation of patients with suspected SIHD. (106) Of 550 participants referred to ICA within 90 days, 279 were not considered for the analyses due to CCTA performed without nitroglycerin (n=139), CCTA not meeting slice thickness guidelines (n=90), or Non-diagnostic studies (n=50). Of the remaining 271 patients, 90 scans were inadequate to obtain FFRCT, leaving 181 (33%) of those referred to ICA for analysis. Compared with those excluded, patients in the analytic sample were less often obese, hypertensive, diabetic, minority, or reported a CAD equivalent symptom. The 2 groups had similar pretest probabilities of disease, revascularization rates, and MACE, but the distribution of stenoses in the analytic sample tended to be milder (p=0.06). FFRCT studies were performed in a blinded manner and not available during the conduct of PROMISE for decision making.

Severe stenoses (≥70%) or left main disease (≥50%) were present in 110 (66%) patients by CCTA result and in 54% by ICA. Over a 29-month median follow-up, MACE (death, nonfatal MI, hospitalization for unstable angina) or revascularization occurred in 51% of patients (9% MACE, 49% revascularization). A majority (72%) of the sample had at least 1 vessel with an FFRCT ≤0.80, which was also associated with a higher risk of revascularization but with a wide confidence interval (HR = 5.1; 95% CI, 2.6 to 11.5). If reserved for patients with an FFRCT of 0.80 or less, ICAs might have been avoided in 50 patients (i.e., reduced by 28%) and the rate of ICA without 50% or more stenosis from 27% (calculated 95% CI, 21% to 34%) to 15% (calculated 95% CI, 10% to 23%). If the 90 patients whose images sent for FFRCT but were unsatisfactory proceeded to ICA - as would have occurred in practice - the rate of ICA might have decreased by 18% and ICA without significant stenosis from 31% to 25%.

The authors suggested that when CCTA is used as the initial evaluation for patients with suspected SIHD, adding FFRCT could have decreased the referral rate to ICA in PROMISE from 12.2% to 9.5%, or close to the 8.1% rate observed in the PROMISE functional testing arm. They also noted similarity of their findings to PLATFORM and concluded, “In this hypothesis-generating study of patients with stable chest pain referred to ICA after [coronary]CTA, we found that adding FFRCT may improve the efficiency of referral to ICA, addressing a major concern of an anatomic [coronary]CTA strategy. FFRCT has incremental value over anatomic [coronary]CTA in predicting revascularization or major adverse cardiovascular events.”

This retrospective observational subgroup analysis from PROMISE suggests that when CCTA is the initial noninvasive test for the evaluation of suspected SIHD, FFRCT prior to ICA has the potential to reduce unnecessary ICAs and increase the diagnostic yield. However, study limitations and potential generalizability are important to consider. First, analyses included only a third of CCTA patients referred to ICA and some characteristics of the excluded group differed from the analytic sample. Second, conclusions assume that an FFRCT greater than 0.80 will always dissuade a physician from recommending ICA and even in the presence of severe stenosis (e.g., ≥70% in any vessel or ≥50% in the left main) - or almost half (46%) of patients with an FFRCT greater than 0.80. Finally, estimates including patients with either non-diagnostic coronary studies (n=50) or studies inadequate for calculating FFRCT (n=90) are more appropriate because most likely those patients would proceed in practice to ICA. Accordingly, the estimates are appropriately considered upper bounds for what might be seen in practice. It is also important to note that in strata of the PLATFORM trial enrolling patients for initial noninvasive testing (not planned ICA), ICA was more common following CCTA and contingent FFRCT than following usual care (18.3% versus 12.0%) and ICA, with no obstructive disease more frequent in the FFRCT arm (12.5% versus 6.0%).

Section Summary: Clinical Utility

The evidence on the diagnostic performance characteristics, particularly showing higher specificity of FFRCT and better negative likelihood ratio as compared to CCTA alone, may be combined with indirect evidence that CCTA with a selective FFRCT strategy would likely lead to changes in management that would be expected to improve health outcomes, particularly by limiting unnecessary invasive coronary angiography testing. Moreover, there is direct evidence, provided by 2 prospective and 2 retrospective studies, that compares health outcomes observed during 90-day to 1-year follow-up for strategies using CCTA particularly in combination with selective FFRCT with strategies using ICA or other noninvasive imaging tests. The available evidence provides support that use of CCTA with selective FFRCT is likely to reduce the use of ICA in individuals with stable chest pain who are unlikely to benefit from revascularization by demonstrating the absence of functionally significant obstructive CAD. In addition, the benefits are likely to outweigh potential harms given that rates of revascularization for functionally significant obstructive CAD appear to be similar and cardiac-related adverse events do not appear to be increased following a CCTA with selective FFRCT strategy. While individual studies are noted to have specific methodologic limitations and some variation is noted in the magnitude of benefit across studies, in aggregate the evidence provides reasonable support that the selective addition of FFRCT following CCTA results in a meaningful improvement in the net health outcome.

Ongoing and Unpublished Clinical Trials: FFRCT

Some currently unpublished trials that might influence this review are listed in Table 14.

Table 14. Summary of Key Trials

NCT Number

Title

Enrollment

Completion Date

Ongoing

NCT02173275

Computed Tomographic Evaluation of Atherosclerotic Determinants of Myocardial Ischemia

618

Jul 2017

NCT02400229

Diagnostic Imaging Strategies for Patients with Stable Chest Pain and Intermediate Risk of Coronary Artery Disease: Comparative Effectiveness Research of Existing Technologies) - A Pragmatic Randomised Controlled Trial of CT versus ICA

3546

Sep 2019

NCT02973126

Assessment of Fractional Flow Reserve Computed Tomography versus Single Photon Emission Computed Tomography in the Diagnosis of Hemodynamically Significant Coronary Artery Disease. (AFFECTS)

270

Oct 2020

NCT02499679a

Assessing Diagnostic Value of Non-invasive FFRCT in Coronary Care (ADVANCE)

5000

Feb 2021

NCT02208388

Prospective Evaluation of Myocardial Perfusion Computed Tomography Trial

1000

Apr 2024

Unpublished

NCT01810198a

Coronary Computed Tomographic Angiography for Selective Cardiac Catheterization (CONSERVE)

1631

Mar 2016

(completed)

NCT02805621

Machine Learning Based CT Angiography Derived FFR: A Multicenter, Registry

352

Jan 2017

(completed)

Table Key:

NCT: National Clinical Trial;

a: Denotes industry-sponsored or cosponsored trial.

Practice Guidelines and Position Statements: FFRCT

National Institute for Health and Care Excellence (NICE)

In 2017, the NICE endorsed FFR using CCTA, with the following conclusions: “The committee concluded that the evidence suggests that HeartFlow FFRCT is safe, has high diagnostic accuracy, and that its use may avoid the need for invasive investigations.” (107)

Recommendations included:

“The case for adopting HeartFlow FFRCT for estimating fractional flow reserve from coronary CT angiography (CCTA) is supported by the evidence. The technology is non-invasive and safe, and has a high level of diagnostic accuracy.”

“HeartFlow FFRCT should be considered as an option for patients with stable, recent onset chest pain who are offered CCTA as part of the NICE pathway on chest pain. Using HeartFlow FFRCT may avoid the need for invasive coronary angiography and revascularization. For correct use, HeartFlow FFRCT requires access to 64-slice (or above) CCTA facilities.”

U.S. Preventive Services Task Force (USPSTF) Recommendations

No USPSTF recommendations for FFRCT have been identified.

Summary of Evidence: FFRCT

For individuals with stable chest pain at intermediate risk of coronary artery disease (CAD; i.e., suspected or presumed stable ischemic heart disease) being considered for invasive coronary angiography (ICA) who receive noninvasive fractional flow reserve (FFR) measurement following positive coronary computed tomography angiography (CCTA), the evidence includes both direct and indirect evidence: 2 meta-analyses on diagnostic performance; 1 prospective, multicenter nonrandomized comparative study; 1 prospective cohort; 2 retrospective cohort studies; and a study reporting changes in management associated with CCTA-based strategies with selective addition of fractional flow reserve using coronary computed tomography angiography (FFRCT) and a randomized controlled trial (RCT) of CCTA alone compared with ICA.

Relevant outcomes are test accuracy and validity, morbid events, quality of life, resource utilization, and treatment-related morbidity. The meta-analyses indicated that CCTA has high sensitivity but moderately low specificity for hemodynamically significant obstructive disease. Given the available evidence that CCTA alone has been used to select patients to avoid ICA, the studies showing higher specificity of FFRCT and lower negative likelihood ratio of FFRCT compared with CCTA alone, may be used to build a chain of evidence that CCTA with a selective FFRCT strategy would likely lead to changes in management that would be expected to improve health outcomes by further limiting unnecessary ICA testing. Moreover, there is direct evidence, provided by 2 prospective and 2 retrospective studies, that compares health outcomes observed during 90-day to 1-year follow-up for strategies using CCTA particularly in combination with selective FFRCT with strategies using ICA or other noninvasive imaging tests. The available evidence provides support that use of CCTA with selective FFRCT is likely to reduce the use of ICA in individuals with stable chest pain who are unlikely to benefit from revascularization by demonstrating the absence of functionally significant obstructive CAD. In addition, the benefits are likely to outweigh potential harms because rates of revascularization for functionally significant obstructive CAD appear to be similar and treatment-related adverse events do not appear to increase following CCTA with a selective FFRCT strategy. While individual studies are noted to have specific methodologic limitations and some variation has been noted in the magnitude of benefit across studies, in aggregate the evidence provides reasonable support that the selective addition of FFRCT following CCTA results in a meaningful improvement in the net health outcome. The evidence is sufficient to determine that the technology results in meaningful improvements in the net health outcome.

Contract:

Each benefit plan, summary plan description or contract defines which services are covered, which services are excluded, and which services are subject to dollar caps or other limitations, conditions or exclusions. Members and their providers have the responsibility for consulting the member's benefit plan, summary plan description or contract to determine if there are any exclusions or other benefit limitations applicable to this service or supply. If there is a discrepancy between a Medical Policy and a member's benefit plan, summary plan description or contract, the benefit plan, summary plan description or contract will govern.

Coding:

CPT code 71250, 71260, 71270 describe CT (computed tomography) of thorax without contrast, with contrast or without contrast, followed by contrast administration. These codes are not applicable for documenting computed tomography angiography (CTA).

Using CPT code 71275 for CTA of the chest is not the appropriate code for heart or coronary vessel testing. This code reflects the use for screening or diagnostic testing to rule out pulmonary emboli or mediastinal masses.

The correct CPT codes are 75572, 75573, and 75574 CCTA of heart and/or coronary arteries.

There is no specific code to identify noninvasive fractional flow reserve using computed tomography (FFRCT).

CODING:

Disclaimer for coding information on Medical Policies

Procedure and diagnosis codes on Medical Policy documents are included only as a general reference tool for each policy. They may not be all-inclusive.

The presence or absence of procedure, service, supply, device or diagnosis codes in a Medical Policy document has no relevance for determination of benefit coverage for members or reimbursement for providers. Only the written coverage position in a medical policy should be used for such determinations.

Benefit coverage determinations based on written Medical Policy coverage positions must include review of the member’s benefit contract or Summary Plan Description (SPD) for defined coverage vs. non-coverage, benefit exclusions, and benefit limitations such as dollar or duration caps.

CPT/HCPCS/ICD-9/ICD-10 Codes

The following codes may be applicable to this Medical policy and may not be all inclusive.

CPT Codes

75572, 75573, 75574, 0501T, 0502T, 0503T, 0504T, 0523T

HCPCS Codes

None

ICD-9 Diagnosis Codes

Refer to the ICD-9-CM manual

ICD-9 Procedure Codes

Refer to the ICD-9-CM manual

ICD-10 Diagnosis Codes

Refer to the ICD-10-CM manual

ICD-10 Procedure Codes

Refer to the ICD-10-CM manual


Medicare Coverage:

The information contained in this section is for informational purposes only. HCSC makes no representation as to the accuracy of this information. It is not to be used for claims adjudication for HCSC Plans.

The Centers for Medicare and Medicaid Services (CMS) does have a national Medicare coverage position for coronary computed tomography angiography; however, CMS does not have a national Medicare coverage position for fractional flow reserve computed tomography.

A national coverage position for Medicare may have been changed/developed since this medical policy document was written. See Medicare's National Coverage at <http://www.cms.hhs.gov>.

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Policy History:

Date Reason
10/15/2018 Reviewed. No changes.
12/1/2017 Document updated with literature review. The following changes were made to coverage section: 1) The word “asymptomatic” was added to the experimental, investigational and/or unproven criterion, “Evaluating asymptomatic individuals with cardiac risk factors in lieu of cardiac evaluation and standard non-invasive cardiac testing”; 2) The use of noninvasive fractional flow reserve (FFR) following a positive CCTA may be considered medically necessary to guide decisions about the use of invasive coronary angiography in patients with stable chest pain at intermediate risks (refer to NOTE 1 above) of CAD (i.e., suspected or presumed stable ischemic heart disease); and 3) The use of noninvasive FFR CT simulation not meeting the criteria above is considered experimental, investigational and/or unproven.
5/15/2017 Document updated with literature review. The following was removed from the contrast-enhanced coronary tomography angiography evaluation of anomalous (native) coronary arteries medically necessary coverage statement, “when conventional angiography is unsuccessful or equivocal and when the results will impact treatment.” Title changed from, “Coronary Computed Tomography Angiography (CTA).”
12/1/2016 Document updated with literature review. The following change was made to Coverage: medical necessity criteria for computed tomography angiography assessment or evaluation of cardiac structure and function (including thoracic aorta region) was added.
8/15/2016 Document updated with literature review. The following coverage statements for contrast-enhanced computed tomography angiography were simplified to: 1) Contrast-enhanced computed tomography (CT) angiography (CTA) for evaluation of patients without known coronary artery disease (CAD) who present with acute chest pain in the emergency room or emergency department setting may be considered medically necessary; and, 2) Contrast-enhanced CTA for evaluation of anomalous (native) coronary arteries in patients in whom they are suspected may be considered medically necessary when conventional angiography is unsuccessful or equivocal and when the results will impact treatment. The following coverage statements were added: 1) Contrast-enhanced CTA for evaluation of patients with suspected ischemic heart disease, who meet guideline criteria (refer to NOTE 1 below) for a noninvasive test in the outpatient setting may be considered medically necessary. NOTE 1: A noninvasive test should be performed on patients with at least intermediate risk for coronary artery disease (10%-90% risk by standard risk prediction instruments/pre-test probability assessments). The choice of test will depend on: * Interpretability of the electrocardiogram; * Ability to exercise; and * Presence of comorbidities. (Class I recommendation from the 2012 American College of Cardiology Foundation/American Heart Association Task Force on use of noninvasive testing in patients with suspected stable ischemic heart disease. See the Description section for definitions, guidelines, and pre-test probability assessment identified by the Task Force.), and 2) The use of noninvasive fractional flow reserve CT simulation to evaluate and assess coronary blood flow quantity and velocity for any cardiac condition, with or without a prior CCTA, is considered experimental, investigational and/or unproven. The following changes were made to the “Contrast-enhanced CTA for coronary artery evaluation is considered experimental, investigational and/or unproven for all other indications, including but not limited” coverage statement: 1) “very” was removed from “Evaluate individuals for any other indication not listed above, including but not limited to high or low pretest probability of CAD”; and 2) “low risk defined as <10% and high risk as >90%” was added to the same criteria bullet.
5/15/2015 Document updated with literature review. Coverage unchanged. Title changed from Contrast-Enhanced Coronary Computed Tomography Angiography (CTA).
4/1/2014 Document updated with literature review. The following was added: 1) Low pretest probability for symptomatic individuals was added as medically necessary; and 2) high or very low pretest probability for CAD was added as examples that are considered experimental, investigational and/or unproven. The Description and Rationale were significantly revised. The title was changed from: Computed Tomography (CT) Angiography (CTA) Using Advanced CT Systems.
2/1/2013 The following was added: Computed tomography angiography, with or without contrast enhancement or media, utilizing 64-slice or greater multi-detector computed tomography scanner, for the evaluation of patient with acute chest pain and without known coronary artery disease in the emergency room or emergency department may be considered medically necessary.
9/1/2009 CPT/HCPCS code(s) updated
2/1/2009 CPT/HCPCS code(s) updated
9/1/2007 Revised/updated entire document
2/15/2007 New medical document

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