HeartFlow FFRCT for estimating fractional flow reserve from coronary CT angiography

Evidence-based recommendations on HeartFlow FFRCT for estimating fractional flow reserve from coronary CT angiography.

# Recommendations
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 in line with the NICE guideline on chest pain. Using HeartFlow FFRCT may avoid the need for invasive coronary angiography and revascularisation. For correct use, HeartFlow FFRCT requires access to 64slice (or above) CCTA facilities.
Based on the current evidence and assuming there is access to appropriate CCTA facilities, using HeartFlow FFRCT may lead to cost savings of 391 per patient . By adopting this technology, the NHS in England may save a minimum of 9.4 million by 2022 through avoiding invasive investigation and treatment .# The technology

# Description of the technology
HeartFlow FFRCT (developed by HeartFlow) is coronary physiology simulation software used for the qualitative and quantitative analysis of previously acquired computerised tomography DICOM data. The software provides a non-invasive method of estimating fractional flow reserve (FFR) using standard coronary CT angiography (CCTA) image data. FFR is the ratio between the maximum blood flow in a narrowed artery and the maximum blood flow in a normal artery. FFR is currently measured invasively using a pressure wire placed across a narrowed artery.
After a clinician decides to request a HeartFlow test, anonymised data from a CCTA scan (of at least 64 slices) are sent from the local imaging system, by secure data transfer to HeartFlow's central processing centre in the US. A case analyst employed by the company then uses the image data to create 3D computer models of the coronary arteries, incorporating coronary flow characteristics. The results are presented in a report which is sent, by secure data transfer, to the referring clinician within 48 hours. The report includes both 3D images of the coronary anatomy and calculated functional information, including the estimated FFR values (known as FFRCT values). Clinicians can then use the report to help guide the management of suspected coronary artery disease.
HeartFlow FFRCT is intended for use in patients with stable, recent-onset chest pain and suspected angina. Because the safety and effectiveness of FFRCT analysis has not been evaluated in other patient subgroups, HeartFlow FFRCT is not recommended in patients who have an acute coronary syndrome or have had a coronary stent, coronary bypass surgery or myocardial infarction in the past month.
The company first received a CE mark in July 2011, covering all 1.X versions of the technology, including the current version, 1.7.
HeartFlow FFRCT costs 700 per test. A higher price of 888 is used in the company submission and assessment report. The cost was reduced in May 2015.
The claimed benefits of HeartFlow FFRCT in the case for adoption presented by the company were as follows:
Analysis is done using standard CCTA scans, without the need for additional imaging, radiation or medication.
It provides the same accuracy in excluding coronary artery disease as CCTA, and characterises the coronary arteries from both functional and anatomical perspectives, differentiating between ischaemic and non-ischaemic vessels in a way that CCTA cannot.
It allows physicians to evaluate anatomical coronary artery disease and accurately determine which coronary lesions are responsible for myocardial ischaemia, avoiding unnecessary invasive diagnostic or therapeutic procedures and related complications.
It reduces the need for revascularisation in patients after identifying anatomical stenosis by invasive coronary angiography (ICA) alone, by more accurately identifying if those stenoses are ischaemic.
It improves the diagnostic accuracy for coronary artery disease compared with CCTA alone against the gold standard of invasive FFR, and provides both functional and anatomical assessment of coronary arteries.
It has better diagnostic performance than CCTA alone, or other non-invasive or invasive tests (such as nuclear myocardial perfusion, magnetic resonance perfusion, stress echocardiography, exercise treadmill testing, invasive angiography or intravascular ultrasound) for detecting and excluding coronary artery lesions that cause ischaemia.
It reduces costs arising from inconclusive or inaccurate diagnostic tests.
It avoids staff and procedure costs for unnecessary ICAs.
It avoids staff and procedure costs for unnecessary interventions (such as angioplasty).
It provides a more effective use of high-cost invasive procedure suites, providing the opportunity to reduce waiting times for these facilities and increase patient turnaround.

# Current management
The NICE guideline on chest pain recommends diagnostic testing for people in whom stable angina cannot be excluded by clinical assessment alone.
The guideline recommends offering 64slice (or above) CCTA as the first-line diagnosis test when clinical assessment indicates typical or atypical angina; or non-anginal chest pain but 12lead resting ECG has been done and indicates STT changes or Q waves.
Subsequent diagnostic tests can be requested dependent on the CCTA results. The guideline recommends offering non-invasive functional imaging for myocardial ischaemia if 64slice (or above) CCTA has shown coronary artery disease of uncertain functional significance, or is non-diagnostic. Non-invasive functional imaging includes:
myocardial perfusion scintigraphy with single-photon emission CT (MPS with SPECT)
stress echocardiography
first-pass contrast-enhanced MR perfusion
MR imaging for stress-induced wall motion abnormalities.ICA should be offered as a second-line investigation when the results of non-invasive functional imaging are inconclusive.
When ICA is used to determine the presence and severity of coronary stenosis, it may be combined with the invasive measurement of FFR using a pressure wire. Although the NICE guideline on chest pain does not consider FFR, other guidelines (such as those of the European Society of Cardiology and American College of Cardiology) state that lesions with an FFR of 0.80 or less are functionally significant and revascularisation may be considered.# Clinical evidence
The key clinical outcomes for HeartFlow FFRCT presented in the decision problem were:
measures of diagnostic accuracy (sensitivity and specificity, positive and negative likelihood ratios, area-under curve) using invasive fractional flow reserve (FFR) as the reference standard
rates of diagnostic coronary angiography, percutaneous coronary intervention and coronary artery bypass surgery
adverse events (test-related, major adverse cardiac events, radiation exposure and so on)
quality of life
mortality.

# Summary of diagnostic accuracy evidence
The company conducted a literature search on the diagnostic accuracy of FFRCT and the existing tests in the current treatment pathway for patients with a 10% to 90% pre-test likelihood of coronary artery disease, against a reference standard of invasive FFR testing. This review identified 5 relevant meta-analysis studies and 23 individual studies, 1 of which was unpublished. Based on the 22 published studies, and using FFR as the reference standard, the company presented diagnostic accuracy per-patient results for HeartFlow FFRCT compared with:
invasive coronary angiography (ICA)
single-photon emission CT (SPECT)
stress echocardiogram (ECHO)
magnetic resonance imaging (MRI)
coronary CT angiography (CCTA). If there were multiple studies for a test, the company conducted a meta-analysis; for example, 3 studies were included in the meta-analysis for HeartFlow FFRCT (Koo et al. 2011, Min et al. 2012 and Nrgaard et al. 2014). The methodology and results of the meta-analyses are reported as academic in confidence.
The external assessment centre (EAC) reviewed the company's selection of studies and considered that although they addressed the scope in terms of the comparators, reference test and outcomes, most included a mixture of patients with both high (over 90%) and intermediate (10% to 90%) pre-test likelihoods of disease. It also disagreed with the company's decision only to include studies that provided FFR measurements in more than 75% of blood vessels. The EAC considered this criterion not to be reflective of clinical practice, where visual assessment is sometimes used before proceeding with FFR measurements. The EAC also noted that this criterion did not reflect the company's proposed changes to the clinical pathway, where CCTA would be used to decide if HeartFlow FFRCT should be used.
To address these concerns, the EAC conducted a diagnostic literature search using extra keywords related to comparators and outcomes. It included only studies in which most patients had an intermediate pre-test likelihood of disease. The EAC identified 7 diagnostic studies, including 3 presented by the company (Bernhardt et al. 2012, Nrgaard et al. 2014 and Stuijfzand et al. 2014) and 3 that the company had identified but excluded (Danad et al. 2013, Kajander et al. 2010 and Ponte et al. 2014). Only 1 of these, Nrgaard et al. 2014, involved HeartFlow FFRCT.
Nrgaard et al. (2014) reported on a multicentre study (the NXT trial) involving 2 UK centres, which compared HeartFlow FFRCT (v1.4) with CCTA for diagnosing myocardial ischaemia in 254 patients with suspected stable coronary artery disease scheduled to have ICA. Most patients in the study (87%) were considered to have an intermediate likelihood of coronary artery disease. Invasive FFR was measured in all vessels (n=484). The study reported the diagnostic performance of HeartFlow FFRCT and CCTA for diagnosing ischaemia compared with FFR measured during ICA as the reference standard. The diagnostic accuracy of each test was presented on a per-patient and a per-vessel basis compared with the reference standard, an FFR value of 0.80. Per-vessel FFRCT was correlated to FFR (Pearson's correlation coefficient 0.82, p>0.001), with a slight underestimation of FFRCT compared with FFR. The authors concluded that HeartFlow FFRCT can identify functionally significant coronary artery disease with high sensitivity and specificity. Furthermore, adding FFRCT measurements to CCTA led to a marked increase in specificity.
The EAC identified 6 studies which both used the comparator tests and included patients with an intermediate likelihood of coronary artery disease. Bernhardt et al. (2012) compared the diagnostic performance of 1.5 T and 3 T MRI scanners using FFR as a reference standard in 34 patients with stable angina and suspected or known coronary artery disease. The authors studied an intermediate-risk population with a mean PROCAM score of 42.7 (a risk assessment metric which estimates the 10year risk of developing a coronary event). Ponte et al. (2014) compared the diagnostic accuracy of CCTA and MRI for detecting functionally significant coronary artery disease in patients referred with suspected coronary artery disease, using ICA with FFR as the reference standard. The study included 95 patients with a 15% to 85% pre-test likelihood of coronary artery disease. Stuijfzand et al. (2014) evaluated CCTA and transluminal attenuation gradient compared with CCTA alone for diagnosing functionally significant lesions, using invasive FFR as the reference standard. The study included 85 patients (253 vessels) with an intermediate likelihood of coronary artery disease. Neglia et al. (2015) assessed the accuracy of several imaging techniques  CCTA, SPECT and ECHO  in 475 patients with an intermediate likelihood of coronary artery disease. Danad et al. (2013) evaluated the diagnostic accuracy of CCTA in 120 patients with suspected coronary artery disease who had cardiac positron emission topography (PET), CCTA and ICA. CCTA was done using a hybrid PET/CT scanner. Kajander et al. (2010) evaluated the diagnostic accuracy of PET and CCTA in 107 patients with a history of stable chest pain and a 30% to 70% pre-test likelihood of coronary artery disease. All patients had ICA independently of the non-invasive imaging results, and treatment decisions were based on both ICA and FFR.
Table 1 summarises the EAC's analysis of diagnostic accuracy for HeartFlow FFRCT and its comparators at both per-vessel and per-patient levels, as shown in table 1. When there was more than 1 diagnostic accuracy study available, the EAC conducted a meta-analysis.
Type of analysis
Index test
N
Sensitivity
(95% CI)
Specificity
(95% CI)
Positive likelihood ratio
(95% CI)
Negative likelihood ratio
(95% CI)
Patient based
HeartFlow FFR
                    CT
(Nrgaard, 2014: NXT trial)
to 0.93
to 0.85
to 5.49
to 0.31
Patient based
CCTA
(6 studies)
to 0.97
to 0.71
to 6.47
to 0.16
Patient based
ECHO
(Neglia, 2015)
to 0.57
to 0.94
to 7.45
to 0.76
Patient based
ICA
(Nrgaard, 2014)
to 0.74
to 0.88
to 5.33
to 0.59
Patient based
MRI
(2 studies)
to 0.95
to 0.97
to 17.9
to 0.26
Patient based
SPECT
(Neglia, 2015)
to 0.81
to 0.74
to 2.79
to 0.57
Vessel based
HeartFlow FFR
                    CT
(Nrgaard, 2014)
to 0.91
to 0.89
to 7.75
to 0.29
Vessel based
CCTA
(4 studies)
to 0.89
to 0.77
to 7.23
to 0.32
Vessel based
ICA
(Nrgaard, 2014)
to 0.65
to 0.93
to 7.89
to 0.62
Vessel based
MRI
(Bernhardt, 2012)
to 0.96
to 1.00
to 390
to 0.30
Abbreviations: CCTA, coronary CT angiography; CI, confidence interval; ECHO, stress echocardiogram; FFRCT, fractional flow reserve CT; ICA, invasive coronary angiography; MRI, magnetic resonance imaging; SPECT, single-photon emission CT.
The EAC considered that despite the limitations associated with patients having a different reference test in some studies, all contributed to the decision problem and provided data for synthesis. It judged that the Nrgaard (2014) study had a low risk of bias for flow and timing, index and reference test. It noted that there was a risk of patient selection bias because an inclusion criterion was that patients had to have been referred for ICA, but it noted no other risks of bias or applicability concerns. Although it acknowledged that there were no studies directly comparing all the tests, it concluded that HeartFlow FFRCT has:
similar sensitivity but higher specificity compared with CCTA
higher sensitivity but lower specificity compared with ECHO
similar sensitivity but lower specificity compared with MRI
higher sensitivity and specificity compared with SPECT.

# Summary of clinical-effectiveness evidence
The company conducted a literature search for evidence on the clinical outcomes specified in the decision problem for HeartFlow FFRCT, and the existing treatments, against any comparator. It identified 16 studies of which 5 included HeartFlow FFRCT, 1 published (Guar et al. 2014) and 4 unpublished (PLATFORM, Radiation FFRCT, Real World Usage FFRCT and FFRCT RIPCORD).
The EAC included extra intervention and comparator keywords and identified 11 studies, 4 of which had already been identified by the company: 2 published studies (Hachamovitch et al. 2012 and Douglas et al. 2015) and 2 unpublished studies. The EAC noted that only the 2 unpublished studies fully matched the population, intervention, comparators and outcomes defined in the scope; the other 9 included various comparators but not HeartFlow FFRCT. The 2 unpublished studies including HeartFlow FFRCT were PLATFORM (see section 3.18) and Radiation FFRCT; the company provided both in the form of interim results for the former and an abstract for the latter. Two studies (Real World Usage FFRCT and FFRCT RIPCORD) included HeartFlow FFRCT but were excluded because they did not provide information on patients' pre-test likelihood of coronary artery disease.
Radiation FFRCT is a single-centre modelling study, based in Canada, investigating the potential effect of HeartFlow FFRCT on radiation dose exposure and downstream clinical event rate. In the modelling, a clinical pathway in which CCTA plus FFRCT was the initial diagnostic test was compared with 3 clinical pathways instead utilising SPECT, ECHO or CCTA as initial diagnostic tests. The model included 100 patients with suspected coronary artery disease, 34% of whom had intermediate disease. Patients were stratified into 3 categories of likelihood of disease: 50% low, 40% moderate and 10% high. No clinical outcomes were measured in this modelled population. The primary outcome was the estimated radiation dose and the secondary outcome was death or myocardial infarction estimates at 1 year after the test. Of the 4 diagnostic pathways studied, ECHO had the lowest radiation dose (5.3 mSv) but had a higher clinical event rate related to both false-positive and false-negative findings. The FFRCT pathway had lower cumulative radiation exposure (9.4 mSv) than SPECT (26.4 mSv) or CCTA (13.9 mSv) and also had the lowest clinical adverse event rate for low and intermediate-risk patients. For high-risk patients, the lowest clinical event rate was with ICA.
The PROMISE study (Douglas et al. 2015) is a USbased multicentre randomised controlled trial involving over 10,000 patients, with a median followup of 25 months. Although the study did not include FFRCT, the EAC considered it relevant to the decision problem because it provides further evidence on a diagnostic pathway based on CCTA. Patients with a mean pre-test likelihood of coronary artery disease of 53.321.4% were randomly assigned to either CCTA or functional imaging as a first-line diagnostic test. The composite primary end point was death, myocardial infarction, hospitalisation for unstable angina, or major procedural complication. Secondary end points included invasive cardiac catheterisation that did not show obstructive coronary artery disease and radiation exposure. Results showed that 164 of 4,996 (3.3%) patients in the CCTA group and in 151 of 5,007 (3.0%) in the functional testing group (adjusted hazard ratio, 1.04; 95% confidence interval, 0.83 to 1.29; p=0.75) achieved the primary end point. CCTA was associated with fewer catheterisations showing no obstructive coronary artery disease than functional imaging (3.4% compared with 4.3%, p=0.02), although more patients in the CCTA group had catheterisation within 90 days of randomisation (12.2% compared with 8.1%). The median cumulative radiation exposure per patient was lower in the CCTA group than in the functional testing group (10.0 mSv compared with 11.3 mSv), but 32.6% of the patients in the functional testing group had no exposure. As such, overall exposure was higher in the CCTA group (mean 12.0 mSv compared with 10.1 mSv; p<0.001).
The EAC identified 9 published studies containing information on clinical outcomes in comparator diagnostic technologies. Further information about these studies can be found in the assessment report.

## Chest pain guideline update: second literature search
During the assessment of HeartFlow FFRCT for this guidance, NICE updated its guideline on chest pain. Because this included new recommendations for investigating chest pain, it became necessary to update the evidence and cost modelling for the HeartFlow FFRCT assessment. The EAC repeated the evidence searches up to February 2016 and asked the company to identify any recent and ongoing studies. In total, the EAC assessed 7 new studies, 6 of which included HeartFlow FFRCT.
Tanaka et al. (2016) is a technical study on a subgroup of the NXT study investigating the association between FFRCT and invasive FFR in coronary arteries with serial lesions. The authors investigated patients (n=18 patients and 18 vessels) with stable angina and clinically suspected coronary artery disease. There was no clinical followup. The primary outcome was the per-segment correlation between FFRCT and invasive FFR values, expressed as translesional delta (the difference between the proximal and distal FFR measurement of all sequential lesions). Values of translesional delta for FFR and FFRCT were 0.100.09 and 0.090.10 in distal segments, and 0.170.10 and 0.220.13 in proximal segments respectively. The coefficient of correlation between translesional delta FFR and FFRCT in each segment was 0.92 (p<0.001). The authors concluded that translesional delta FFR is highly correlated with FFRCT.
Thompson et al. (2015) investigated the diagnostic performance of FFRCT in relation to patients' sex and age, using invasive FFR measurements as the reference standard for a subgroup of the DeFACTO study. Previous evidence from DeFACTO was not considered eligible because it included patients with a high pre-test likelihood of coronary artery disease (Min et al. 2012). Thompson et al. (2015) was included because it reports results based on subgroup analyses for age and sex. The baseline pre-test likelihood did not differ in statistical significance within these subgroups, so it is not expected to bias the results. The authors investigated 252 patients (407 vessels) with stable angina, clinically suspected coronary artery disease and at least 1 coronary stenosis of 30% to 90%. For their analysis, the authors used a clinical rule that included all vessels of diameter 2 mm and assigned an FFR value of 0.90 for vessels with stenoses 90%. There was no clinical followup. The primary outcome was per-patient and vessel diagnostic performance of FFRCT. Using this clinical rule, diagnostic performance improved in both sexes with no statistically significant differences between them. There were no differences in the discrimination of FFRCT after application of the clinical use rule when stratified by age 65 or <65 years. The authors concluded that FFRCT had similar diagnostic accuracy and discriminatory power to FFR for ischaemia detection in men and women irrespective of age using a cutoff point of 65 years.
The other 4 studies on HeartFlow FFRCT looked at clinical outcomes. The PLATFORM study (Douglas et al. 2015b and 2016) was presented to the committee as academic in confidence in June 2015 (Douglas et al. 2015a). The study included 584 patients recruited at 11 international centres. They were prospectively assigned to have either functional imaging (n=287) or CCTA/FFRCT (n=297). Each cohort was subdivided into 2 groups based on the evaluation plan decided before enrolment in the study: non-invasive testing (any form of stress testing or CCTA without FFRCT) or ICA (invasive testing).
Douglas et al. (2015b) report the study results at 3month followup. The primary end point was the percentage of patients with planned ICA in whom no significant obstructive coronary artery disease (no stenosis 50% by core laboratory quantitative analysis or invasive FFR <0.80) was found at ICA within 90 days. Secondary end points included a composite measure of major adverse cardiac events consisting of death, myocardial infarction and unplanned revascularisation, all of which were independently and blindly assessed. Among patients with intended ICA (CCTA/FFRCT=193; functional imaging=187), no obstructive coronary artery disease was found with ICA in 24 patients (12%) in the CCTA/FFRCT arm and 137 patients (73%) in the functional imaging arm (risk difference 61%, 95% CI 53 to 69, p<0.0001). Among patients intended for non-invasive testing, the rates of finding no obstructive coronary artery disease with ICA were 13% in the CCTA/FFRCT arm and 6% in the functional imaging arm (p=0.95). ICA was cancelled in 61% of patients after reviewing the CCTA/FFRCT results. There were low numbers of MACE and vascular complications in all groups.
Douglas et al. (2016) report outcomes from the same study at 1 year. The clinical end points measured were MACE and MACE plus vascular events within 14 days of procedure. Quality of life and resource use outcomes were also collected. There were 2 MACE events in each arm of the planned invasive group (risk difference -0.03 ) and 1 in the planned non-invasive group (risk difference -1.00 ). Cumulative 1year radiation exposure in patients in the intended invasive evaluation cohort was similar between the usual care strategy (mean: 10.46.7 mSv) and CCTA/FFRCT-guided strategy (mean: 10.79.6 mSv; p=0.21), whereas in the non-invasive testing cohort it was higher in patients with a CCTA/FFRCT-guided strategy than usual care strategy (mean: 9.610.6 mSv compared with 6.47.6 mSv, p<0.001). Functional status and quality of life improved from baseline to 1year followup in the planned non-invasive group (p<0.001 for all measures), with greater improvements on the EQ5D in patients having CCTA/FFRCT compared with patients having functional imaging (mean change: 0.12 for CCTA/FFRCT compared with 0.07 for functional imaging, p=0.02).
Lu et al. (2015) used a subgroup analysis of the PROMISE trial (n=181) to investigate the added value of FFRCT compared with CCTA in improving efficiency of referral to ICA. End points for the subgroup analysis were rate of revascularisation and ICA that did not show obstructive coronary artery disease and MACE. Over a median followup of 25 months, the addition of FFRCT increased the rate of ICA with revascularisation from 49% to 61%. The rate of angiography without obstructive disease decreased from 27% to 11%. No patient with FFRCT >0.80 had an adverse event which ICA would have prevented.
Nrgaard (2016) reports on the real-world experience of using CCTA with FFRCT as gatekeeper to ICA in patients with stable coronary artery disease and intermediate-range coronary lesions (n=189). Patients were followed up for a median of 12 months. The primary end point was the impact of FFRCT on further downstream diagnostic testing. Other end points were the agreement between FFRCT and invasive FFR, and the short-term clinical outcome after FFRCT testing defined as the occurrence of MACE (death and acute myocardial infarction) or an angina episode leading to hospital admission or visit in the outpatient clinic. The authors concluded that FFRCT testing is feasible in real-world scenarios involving patients with intermediate-range coronary stenosis determined by CCTA. They also concluded that implementing FFRCT for clinical decision-making may influence the downstream diagnostic workflow, and patients with an FFRCT >0.80 who are not referred for ICA have a favourable short-term prognosis. The authors highlight that in patients with FFRCT ranging between 0.76 and 0.80, a non-negligible number of false-positive results may be expected.
The EAC considered that the 1year followup data from the PLATFORM study supported the company's claims about resource use, rates of ICA and percutaneous coronary intervention, and quality of life with HeartFlow FFRCT. Additionally, the 1year followup evidence from the PLATFORM supports the company's claim that MACE outcomes are equivalent between the current pathway and one that uses FFRCT, whereas the PROMISE study showed that MACE outcomes at 1 year were equivalent between CCTA alone and functional testing. The EAC also considered that the evidence from the PLATFORM study showed higher 1year radiation exposure in the HeartFlow FFRCT group in patients intended for non-invasive evaluation. However, this is to be expected because many patients in the non-invasive evaluation had a non-invasive test which did not need the use of radiation. The EAC concluded that the submitted evidence on clinical outcomes supports the value proposition of an FFRCT-guided strategy compared with standard of care, mainly in patients with planned invasive investigation, with equivalent results between FFRCT and functional imaging in the non-invasive group.

## Committee considerations
The committee considered that the evidence showed high diagnostic accuracy and increased specificity with HeartFlow FFRCT compared with CCTA alone. It also noted promising results from the PLATFORM study, in a population which closely matches that in the scope. The evidence was sufficient to conclude that HeartFlow FFRCT has a high diagnostic accuracy for coronary artery disease, and that its use has the potential to reduce the need for invasive coronary investigations.
The committee considered the technology to be innovative and understood that its adoption may serve to simplify a complex patient pathway. The committee heard from clinical experts that they had confidence in the diagnostic accuracy of HeartFlow FFRCT, and that it could provide an effective early rule-out test for coronary artery disease. This would reduce the need for ICA and invasive FFR measurement, and potentially reduce radiation exposure.
The committee understood that there are differences in the local implementation of the patient pathway for diagnosing coronary artery disease. It was advised by clinical experts that the choice of functional imaging test depends on local access, available expertise and clinician preference. It heard that although HeartFlow FFRCT has the potential to reduce the number of tests that are done, the other non-invasive functional imaging tests that are part of the current patient pathway offer different functionality and in some cases provide additional information. Overall, the committee concluded that HeartFlow FFRCT should be considered for use as a non-invasive investigation for diagnosing angina in patients with stable, recent-onset chest pain of suspected cardiac origin, and that it provides the clinician with additional functional information to determine which coronary lesions are responsible for myocardial ischaemia. The committee considered that further clinical studies would be helpful to clarify the wider applicability of HeartFlow FFRCT in routine clinical practice.
The committee considered the evidence from the PLATFORM study to be most relevant to the decision problem. It considered that the results demonstrate the potential of FFRCT to avoid ICA and improve quality of life.
The committee discussed the relative importance of a per-patient or a per-vessel diagnosis. It heard from experts that per-patient diagnostic accuracy was more important for initial diagnosis, and that a per-vessel assessment provides additional information to inform patient management. The committee concluded that per-patient level figures were the most reliable and relevant to the diagnosis of coronary artery disease.# NHS considerations

# System impact
The company's claimed system benefits included reduced costs from fewer inconclusive or inaccurate diagnostic tests and avoidance of unnecessary staff and procedure costs. It claimed that this would lead to more effective use of invasive procedure suites.
The company confirmed that, with specific reference to the updated NICE guideline on chest pain, the proposed place in the diagnostic pathway for HeartFlow FFRCT (to inform management following a positive coronary CT angiography  result) was unchanged.
Conservative estimates by the NICE resource impact assessment team suggest that by 2021/22, when fully implemented, HeartFlow FFRCT will potentially be used in around 40,000 patients a year. This would equate to national savings of at least 9.1 million a year.
During selection and routing, the committee asked for additional information on compliance with data protection legislation, and the reproducibility of HeartFlow FFRCT analysis, especially in the face of an increasing workload which might be expected to arise from adoption of the technology in the NHS. The external assessment centre (EAC) produced a technical report that concluded:
The company has a quality assurance process in place that fulfils data quality needs. This includes checks by different team members, and the separation of tasks to ensure that no single analyst is fully responsible for a diagnosis. After the procedure, a more experienced analyst reviews the process, focusing mainly on areas of stenosis. Expert clinician advice is also available should it be needed.
Although the analytical process is largely automated, any part of it can be manually changed by the analyst. This may affect the fractional flow reserve CT (FFRCT) estimate. Manual editing is part of the quality assurance process, negating the risk of spurious results generated from the automated analysis. Gaur et al. (2014) suggest that reproducibility is within acceptable 95% confidence interval limits of agreement. FFRCT reproducibility was found to be equivalent to invasive FFR reproducibility.
The reproducibility of outlining the coronary artery lumen, part of the FFRCT computation analysis, decreases in the distal portion of the vessel (Gage repeatability and reproducibility=29.4%). This could be a result of different factors including lower CT quality, lower CT resolution, smaller vessel diameter at the distal end and higher disease burden.
The company monitors FFRCT reproducibility by re-processing 5% of its case volume on a weekly basis. The company has confirmed that this has shown a reproducibility rate consistent with the literature (Gaur et al. 2014).
The company fulfils regulatory approval standards for data confidentiality and integrity protection for remote processing. It offers NHS customers the option to upload fully anonymised DICOM data to comply with UK data protection law.

## Committee considerations
The committee was satisfied with the EAC's conclusions on reproducibility (see section 4.4). It accepted that the company has protocols in place to manage an increased demand for HeartFlow FFRCT.
The committee considered the protection and oversight of data transferred during the administration of HeartFlow FFRCT to be an important factor in the device's adoption. The committee was satisfied, on the basis of the information available, that the company's data transfer protocols meet regulatory requirements. The committee noted that patients should be informed when sending personal data outside the European Economic Area with HeartFlow FFRCT, and that it may be necessary to obtain written consent.
The committee considered the availability of CCTA facilities. It understood that the cost model assumed access to CCTA facilities, but heard from experts that access to CCTA varies across the NHS despite recommendations in NICE's previous guideline on chest pain. Furthermore, because CT scanners are used for many purposes, a constraint currently exists with regard to both the availability of scanners and scanning time. The committee heard from experts that a sizable investment would be needed for the wider implementation of HeartFlow FFRCT, but acknowledged that this consideration was beyond the scope of the current assessment. It understood that adopting 64slice CCTA was ongoing in the NHS, in line with the recommendations in the previous NICE guideline on chest pain.# Cost considerations

# Cost evidence
The company conducted a search of the health economics literature on HeartFlow FFRCT and the comparators specified in the decision problem. They identified a total of 174 studies, 24 of which it considered relevant to the decision problem.
The external assessment centre (EAC) reviewed this search, and considered that most of the studies included neither an appropriate patient population nor a treatment pathway. Only 1 published study, Rajani et al. (2015), was considered by the EAC to be relevant to the decision problem. It conducted a further review of the literature up to February 2016 and identified an additional relevant published study, Hlatky et al. (2015).
Rajani et al. (2015) was a single-centre retrospective cost analysis of 410 patients referred to a rapid-access chest pain clinic in Guy's and St Thomas' Hospital, London, from April 2012 to March 2013. Patients were grouped into pre-test likelihood categories and diagnostic imaging was done based on standardised protocols as recommended in the previous NICE guideline on chest pain. A standardised unit cost for each test and procedure was taken from the NHS National Tariff 2013/14. A decision-tree economic model was used to evaluate the cost of 1,000 patients passing through the current treatment pathway compared with the same 1,000 patients after incorporating HeartFlow FFRCT. The authors found that introducing HeartFlow FFRCT to the pathway resulted in cost savings of 200 per patient. The EAC noted that although the derivation of costs in the study is explicit, details of the decision model structure are unclear.
Hlatky et al. (2015) investigated the quality-of-life and economic outcomes of fractional flow reserve CT (FFRCT) in the PLATFORM study (see section 3.17). Cumulative medical costs were measured over 90 days for each patient by multiplying a standardised cost weight for each medical resource by the number of resources used by the patient. Medicare reimbursement rates (the national average of technical and professional fees in the US) from 2015 were applied because cost weights and online pharmacy costs were used for drugs. Patients were prospectively assigned to either functional imaging (usual care, n=287) or coronary CT angiography (CCTA)/HeartFlow FFRCT (n=297). In the planed invasive group, mean costs were $7,343 among the CCTA/FFRCT patients and $10,734 among functional imaging patients (p<0.0001). In the planned non-invasive group, mean costs were not significantly different (p=0.26) between the CCTA/FFRCT patients ($2,679) and the functional imaging patients ($2,137). Overall, each quality-of-life (EQ5D) score improved at 90 days compared with baseline in the study population (p<0.0001), and scores improved more in CCTA/FFRCT patients than in functional imaging patients. In the invasive group, quality-of-life improvements were similar in both arms.
Douglas et al. (2016) published data on the 1year economic outcomes of FFRCT in the PLATFORM study. Costs were calculated in the same manner as the 90day results in Hlatky et al. (2015). In the planned invasive arm, the mean per-patient cost was $8,127 in FFRCT patients and $12,145 for usual care patients (p<0.0001). The cost savings at 1 year increased by 1.5% from the cost savings at 90 days. In the non-invasive arm, mean costs were not significantly different (p=0.82) between the FFRCT patients ($3,049) and the usual care patients ($2,579).

## Economic model
The company presented a decision-tree model based on integrating HeartFlow FFRCT into the existing diagnostic pathway at the time of its submission. A theoretical population of 1,000 patients with suspected coronary artery disease was allocated to either the current treatment pathway (based on the previous NICE guideline on chest pain) or the company's revised pathway, which included HeartFlow FFRCT. The cost consequences of the treatment pathways were compared based on the mix of diagnostic technologies used in each. The model had a 1year time horizon, included the impact of different testing strategies, and relevant clinical outcomes.
The proportion of patients eligible for CCTA as a first-line test and their probability of having coronary artery disease were taken from Rajani et al. (2015). In the model, 10% of patients were assumed to be ineligible for invasive coronary angiography (ICA), have an inconclusive CCTA result and have an uncertain single-photon emission CT (SPECT) result.
The diagnostic accuracy of HeartFlow FFRCT and its comparators in the company's model were based on per-patient level results reported in selected papers, as follows:
HeartFlow FFRCT: sensitivity 86%, specificity 79% (Nrgaard et al. 2014)
SPECT: sensitivity 76%, specificity 38% (Melikian et al. 2010)
CCTA: sensitivity 94%, specificity 48% (Meijboom et al. 2008)
ICA: sensitivity 69%, specificity 67% (Meijboom et al. 2008).The cost of HeartFlow FFRCT (888) was based on the company's original list price. Costs for comparator tests were based on 2014/15 hospital resource group (HRG) tariffs, as follows:
SPECT: 220 (HRG code RA37Z, nuclear medicine category 3)
CCTA: 136 (HRG code RA14Z, CT scan, more than 3 areas)
Calcium scoring: 77 (HRG code RA08Z, CT scan, 1 area, no contrast)
ICA: 1,241 (HRG code EA36A, catheter 19 years and over)
Percutaneous coronary intervention (PCI): 2,832 (weighted average of 2 tariffs, assuming that 25% of patients needing PCI will need more than 2 stents. HRG codes EA31Z  and EA49Z ).
The company's base-case results reported an average per-patient cost of 2,239 using the current pathway and 2,080 using the adapted pathway with HeartFlow FFRCT, representing an average saving of 159 per patient.
The company conducted 1way sensitivity analyses on the sensitivity and specificity of HeartFlow FFRCT and the comparator tests, as well as the costs of HeartFlow FFRCT. The analyses showed that HeartFlow FFRCT continued to be cost saving until its price reached 1,126. With regard to changes in the sensitivity and specificity, HeartFlow FFRCT remained cost saving for nearly all the values tested when considered in the context of the entire patient population.

## Revisions by the external assessment centre
The EAC incorporated the changes to the updated NICE guideline on chest pain in the company economic model. In this context, the EAC assumed that HeartFlow FFRCT would be used following an initial CCTA, and that non-invasive functional imaging tests would subsequently be used only if the CCTA result were uncertain or non-diagnostic. The EAC reviewed the parameters and costs used in the company's model. It revised the company's sensitivity and specificity parameters for the comparator diagnostic tests, based on its own analyses of diagnostic accuracy (see table 1).
The EAC used the company's revised list price of 700 for HeartFlow FFRCT, instead of 888 as used in the company's model.
The EAC used the updated NICE guideline on chest pain to determine the costs of all comparator tests except MRI, to ensure that they were consistent with 2014/15 reference costs. The cost of MRI was taken from the Payment by Results tariff, because the chest pain guideline committee determined this to be more representative of the true cost. These costs were as follows:
SPECT: 367 (RN21Z, myocardial perfusion scan, stress only )
CCTA: 122 (RD28Z, complex CT scan)
ECHO: 271 (EY50Z, complex echocardiogram)
ICA: 1,685 (EY43A to EY43F, standard cardiac catheterisation)
MRI: 515 (RA67Z, cardiac MRI scan, pre and post contrast)
PCI: 2,865 (weighted average of 2 tariffs, assuming that 25% of patients needing PCI will need more than 2 stents. HRG codes EA31Z  and EA49Z ). Includes an estimated annual cost of 33 for medication following a PCI .
The EAC noted that the company's model did not include costs of drug therapy for patients having PCI. It consulted the NICE guideline on stable angina and estimated an annual drug treatment cost for these patients of 33 based on British national formulary (2015) prescription costs for aspirin and clopidogrel, and used a cost of 2,865 (PCI tariff with drug costs) in its revised model.
The EAC included a cost for optimal medical therapy. It obtained expert advice that optimal medical therapy usually consists of aspirin, statins, nitrates and beta blockers. Based on this information it estimated an annual cost of 84 (aspirin, simvastatin, glyceryl trinitrate and propranolol hydrochloride) from the British national formulary (2015) and used it in the revised model.
Using these updated assumptions, the EAC found a base-case cost saving of 214 per patient for HeartFlow FFRCT compared with the current treatment pathway for all functional imaging tests (SPECT, MRI and ECHO).
The EAC ran a number of sensitivity analyses, varying: the price of HeartFlow FFRCT; the diagnostic accuracy of the functional imaging tests, HeartFlow FFRCT, ICA and CCTA; and the proportion of uncertain CCTA and functional imaging tests. It also used estimates of diagnostic accuracy for CCTA and ICA from the updated NICE guideline on chest pain. In all instances, HeartFlow FFRCT remained cost saving.

## Committee considerations
The committee considered the cost modelling done by the EAC to be both appropriate and plausible. The committee heard from experts that percutaneous or surgical revascularisation is only offered to patients following ICA, and sometimes a confirmatory invasive FFR. The availability of data from HeartFlow FFRCT may help to plan treatment in individual vessels and patients.
For the guidance review, the EAC revised the model to reflect 2021 costs. There were no changes to the cost of the technology. The main parameter change was the cost of comparator tests. Further details of the 2021 revised model are in the cost update in the review decision.
Based on the 2021 guidance review updated cost model, the EAC found a base-case cost saving of 391 per patient for HeartFlow FFRCT compared with the current treatment pathway for all functional imaging tests (SPECT, MRI and ECHO). This cost saving will increase if the cost of HeartFlow FFRCT is reduced.# 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.
The committee concluded that cost savings of 214 per patient are plausible and likely to be realised in practice, providing that sites adopting HeartFlow FFRCT have access to 64slice (or above) coronary CT angiography.