CCTA TECHNOLOGIES

Patients with chest pain and low to intermediate pre-test probability of stable CAD are typically evaluated noninvasively, commonly with standard exercise electrocardiogram (ECG) for patients who are able to exercise. For patients who cannot exercise or have an uninterpretable resting ECG, noninvasive functional imaging options include pharmacologic stress plus nuclear imaging (single-photon emission CT (SPECT) or positron emission tomography (PET) scanning) or pharmacologic echocardiography.³⁰ Noninvasive anatomical imaging with CCTA is another option for patients who cannot exercise and who have intermediate to high probability of significant coronary artery disease.^31,32

CCTA generally has a high sensitivity for functionally significant coronary lesions (range 86% to 95% in recent meta-analyses^2,3,33), with few false negatives. However, the specificity is 61% to 79%,^2,3,33 and the potential for false positives often leads to the use of invasive coronary angiography (ICA) to exclude the presence of significant CAD and assess its functional significance. The gold standard for detecting hemodynamically significant CAD is fractional flow reserve (FFR), or the fraction of maximum blood flow in a restricted artery.³⁴ Measurement of FFR requires an invasive procedure to place a pressure wire to calculate pressure and blood flow information,^35,36 and novel techniques have emerged to calculate FFR noninvasively from CCTA images (FFR_CT). The aim of FFR_CT is to gain both functional and anatomical information on the extent of coronary artery narrowing and the impact on blood flow.^36,37

2019 ESP CC REPORT ON FFR_CT TECHNOLOGIES

In 2019, the ESP prepared a white paper report synthesizing the evidence on the diagnostic accuracy and therapeutic and clinical impact of FFR_CT technologies for the diagnosis of CAD.²⁹ Key findings and evidence gaps from this report are summarized in Table 1. For diagnostic accuracy outcomes, 2 meta-analyses and several subsequent primary studies generally agreed that HeartFlow is more specific than CCTA alone, using a reference standard of invasive FFR. Studies examining reductions in ICA use fell into 3 clinical scenarios for the potential use of HeartFlow: (1) in patients who are planned to be directly referred to ICA in lieu of noninvasive evaluation, (2) as a substitute for other noninvasive testing, and (3) as a part of the clinical pathway for patients referred for CCTA. The PLATFORM trial¹¹ reported that HeartFlow reduced the use of coronary angiography in patients planned to be directly referred to ICA (scenario 1), but led to a higher rate of coronary angiography in patients planned for noninvasive testing (scenario 2). No studies reported on ICA use as a part of the clinical pathway for patients referred for CCTA (scenario 3). Evidence on the impact of the use of HeartFlow on clinical outcomes was limited to short-term (90-day to 1-year) findings.

As no trials were conducted in VA settings – and because the utility of HeartFlow depends on clinical practices and frequency of use of CCTA, the characteristics of patients who undergo CCTA, and on how decisions about ICA are made within a particular setting – the previous report concluded that additional trials were necessary to understand the potential impact of HeartFlow use within the VA. Additionally, further data on the long-term impact of HeartFlow on clinical outcomes were needed. Finally, existing evidence did not justify substituting CCTA with FFR_CT for other noninvasive tests, and direct evidence was needed about how HeartFlow compares to other noninvasive diagnostic tests, specifically those widely used in the VA.

Table 1

Summary of Findings and Evidence Gaps in 2019 ESP Report.

The goal of the present report was to provide an updated synthesis of the evidence on the use of HeartFlow for noninvasive diagnosis of CAD, focusing on evidence that is most relevant to the VA and most applicable to evidence gaps identified in the 2019 ESP review.

PROTOCOL

A preregistered protocol for this review can be found on the PROSPERO international prospective register of systematic reviews (http://www.crd.york.ac.uk/PROSPERO/; CRD42021243717).

KEY QUESTIONS

Key Question 1.

What is the diagnostic accuracy of HeartFlow FFR_CT analysis for diagnosing CAD?

Key Question 2.

What is the diagnostic and therapeutic impact of HeartFlow FFR_CT analysis in guiding the diagnosis and treatment of CAD?

Key Question 3.

What is the impact of the use of HeartFlow FFR_CT analysis on clinical outcomes and cost in the diagnosis and treatment of CAD?

ELIGIBILITY CRITERIA

The ESP included studies that met the following criteria:

• Population: Adult candidates for non-invasive evaluation for coronary disease or invasive coronary angiography
• Intervention: HeartFlow FFR_CT analysis
• Comparator: Any other diagnostic strategy for CAD (coronary computed tomography angiography [CCTA], exercise electrocardiogram [ECG], exercise or pharmacologic stress echocardiography, exercise or pharmacologic cardiac nuclear imaging with single-photon emission computed tomography [SPECT], positron emission tomography [PET], cardiovascular magnetic resonance [CMR], etc)
• Outcomes: Diagnostic accuracy (sensitivity, specificity, etc), use of invasive coronary angiography, changes in clinical or therapeutic management of patients, cost, major adverse cardiac events (MACE), other adverse clinical events (mortality, myocardial infarction, etc)
• Timing: Any
• Setting: Any
• Study design: Any, but we may prioritize articles using a best evidence approach to accommodate the timeline.

DATA SOURCES AND SEARCHES

To identify recent literature on diagnostic accuracy and clinical effectiveness, we searched MEDLINE, Cochrane Database of Systematic Reviews, and Cochrane Central Register of Controlled Trials using terms for HeartFlow, fractional flow reserve, and computed tomography angiography published since 2019, the end search date of our recent evidence review²⁹ (see Appendix A in supplemental materials for complete search strategies). The search was limited to publications involving human subjects available in the English language. Additional information was gathered by cross-checking reference lists, searching citing articles, reviewing FDA documents, searching for ongoing clinical trials, and consulting with content experts. One investigator first reviewed all titles, abstracts, and full-text articles, with a second investigator checking. All disagreements were resolved by consensus or discussion with a third reviewer.

DATA ABSTRACTION AND ASSESSMENT

We abstracted data on study design, population characteristics, diagnostic accuracy, and therapeutic and clinical impact outcomes from all included studies. All data abstraction was first completed by 1 reviewer then checked by another reviewer. We used predefined criteria to critically appraise all included studies, including the Cochrane ROBIS tool for systematic reviews,⁴⁷ the QUADAS-2 tool for diagnostic accuracy studies,⁴⁸ the Cochrane ROBINS-I tool for cohort studies,⁴⁹ and the tool developed by Murad et al⁵⁰ for case series. For noncomparative studies assessing changes in clinical management plans and real-world implications of utilizing HeartFlow, we used ROBINS-I to identify strengths and deficiencies of the studies. All included studies were appraised independently by 2 reviewers. Disagreements were resolved by consensus or discussion with a third reviewer.

We graded the strength of the evidence based on the AHRQ Methods Guide for Comparative Effectiveness Reviews.⁵¹ This approach provides a rating of confidence in reported findings based on study methodology (design, quality, and risk of bias), consistency (whether effects are in the same direction and have a consistent magnitude), directness (whether assessed outcomes are clinically important to patients and providers), and precision (narrowness of the range of confidence intervals). For this review, we applied the following general algorithm: high strength evidence consisted of multiple studies with low study limitations, direct outcomes, narrow confidence intervals, and consistent findings; moderate strength evidence consisted of multiple studies with low to moderate study limitations, direct outcomes, and consistent findings; low strength evidence consisted of single or multiple studies with moderate study limitations and wide confidence intervals and/or inconsistent findings; and insufficient evidence consisted of a single study with moderate or high study limitations, or no available trials. Strength of evidence ratings were applied to primary outcomes for all included studies.

SYNTHESIS

We synthesized available evidence narratively by outcome and clinical scenario. To improve our interpretation of the applicability of findings to current VA practice patterns, we retrieved data from the VA Corporate Data Warehouse (CDW) on the number of patients receiving CCTA tests and the number of these patients who went on to ICA within 90 days of CCTA testing. We accessed data through the VA Informatics and Computing Infrastructure.⁵² To better match VA patients with participants in trials of HeartFlow, we limited the data to patients without acute coronary syndrome, a diagnosis of CAD, a history of previous revascularization within the year prior to CCTA, or a history of ICA.¹¹ CDW codes used are available upon request. Finally, a technical expert panel (TEP) provided input on the clinical relevance of evidence and important considerations for use of HeartFlow within the VA.

LITERATURE FLOW

The literature flow diagram (Figure 1) summarizes the results of the study selection process (see Appendix B in supplemental materials for full list of excluded studies).

Figure 1

Literature Flow Chart. Abbreviations. CCRCT=Cochrane Central Register of Controlled Trials, CDSR=Cochrane Database of Systematic Reviews, SR=Systematic Review.

LITERATURE OVERVIEW

Among 740 potentially relevant citations, we included 3 systematic reviews^1–3 (1 new since 2019 ESP report) and 7 primary studies^4–10 (5 new since 2019 ESP report) on diagnostic accuracy, and 14 studies (in 23 publications)^{11–28,53–57} reporting diagnostic or therapeutic impact or clinical or cost outcomes (7 new since 2019 ESP report) (Table 2, see Appendix C in supplemental materials for full study details). We also identified 6 ongoing studies examining the use of HeartFlow. Most of these studies examine diagnostic accuracy, but a few examine clinical outcomes, including 1 ongoing trial comparing clinical and cost outcomes of using CCTA with selected FFR_CT or usual care (see Appendix D in supplemental materials for list of ongoing studies).

Therapeutic and Clinical Outcomes

Seven studies published since the 2019 ESP report examined therapeutic or clinical outcomes of HeartFlow.^{13,14,17,20,23,26,28} Most were noncomparative studies, reporting on real-world clinical experiences and changes in clinical management plans in patients with an intermediate risk of CAD undergoing CCTA; none were RCTs (Table 2). Several new sub-analyses of the Assessing Diagnostic Value of Noninvasive FFR_CT in Coronary Care (ADVANCE) registry, an international registry of over 5,000 patients with suspected CAD (> 30% stenosis on CCTA) undergoing HeartFlow FFR_CT analysis from 2015 to 2017, examined outcomes by various demographic factors (age, gender, etc).^{19,22,25,27,53–55} All but 2 studies included at least 200 patients (range: 75 to 5,083). Studies frequently had important methodological limitations, including lack of concurrent control groups, unclear methods for selecting patients into the study, baseline differences between comparison groups, lack of or unclear methods for statistical adjustment, and exclusion of patients with missing FFR_CT data.

Table 2

Characteristics of HeartFlow Studies with Therapeutic and/or Clinical Outcomes.

KEY QUESTION 1. DIAGNOSTIC ACCURACY OF HEARTFLOW

One new systematic review¹ agreed with previous findings, reporting good diagnostic accuracy of HeartFlow, and higher specificity for identifying obstructive coronary disease than CCTA alone in patients with suspected coronary disease using a reference standard of FFR during ICA (specificity range = 73% to 76% HeartFlow vs 61% to 64% CCTA alone) (Table 3).^1–3 The accuracy of HeartFlow was higher than that of CCTA (AUC range = 0.87 to 0.89 HeartFlow vs 0.82 CCTA alone), while sensitivities were similar (84% to 85% HeartFlow vs 86% to 88% CCTA).

Table 3

Diagnostic Accuracy of HeartFlow from Included Systematic Reviews.

Seven studies (5 new since 2019 ESP report) published after the most recent systematic reviews generally agreed with the findings of those reviews. Sensitivity (range = 81% to 92%), specificity (range = 68% to 94%), and accuracy (AUC range = 0.82 to 0.94) estimates for HeartFlow varied, but generally showed similar sensitivity and higher specificity and diagnostic accuracy than CCTA alone (Table 4).^4–10 The variation in estimates among studies may be due to differences in study populations, CCTA procedures (ie, imaging technique), or study methods (eg, whether clinicians interpreting HeartFlow had knowledge of reference standard findings). Multiple studies directly assessing the diagnostic accuracy of HeartFlow compared to FFR during ICA reported similar sensitivities, but higher specificities, than that of CCTA, strengthening our confidence in these findings. However, no studies have assessed diagnostic accuracy in a VA population.

All included studies used a FFR_CT cut-off value of ≤ 0.80. An evaluation of the diagnostic performance of HeartFlow according to different FFR_CT cut-off values in patients with suspected CAD undergoing invasive FFR found that specificity values were higher with a cut-off of FFR_CT ≤ 0.75 compared to FFR_CT ≤ 0.80 (75% and 59%, respectively), with acceptable sensitivity (95% for FFR_CT = 0.80 and 86% for FFR_CT = 0.75).⁵⁸Additionally, a sub-study from an observational Danish study found that in patients with intermediate stenoses on CCTA, an FFR_CT score < 0.75 was more predictive of ICA results than a score in the range 0.75 to 0.80.¹⁶

Table 4

Primary Studies on the Diagnostic Accuracy of HeartFlow.

KEY QUESTION 2. DIAGNOSTIC AND THERAPEUTIC IMPACT OF HEARTFLOW

Change in Clinical Management

Several new registry- or hospital system-based studies reported changes in clinical management plans or rates of ICA cancellation based on HeartFlow or CCTA alone^14–22 (Table 5). Most studies compared clinical management plans within a single group of patients, with clinicians making clinical decisions based on CCTA images or HeartFlow FFR_CT analyses of the same patients. Rates of changes in clinical management plans among the new studies varied (range = 24% to 55.8%)^17,20,22 but were generally lower than those previously reported (range = 36% to 66.9%).^18,19,21 Rates of ICA cancellation ranged from 48% to 91%.^15,16,21 The variability in these findings likely arises from differences in patient populations (ie, patients with suspected CAD vs those with known CAD or documented stenosis), local variation in clinical management and physician practices, and availability of ICA. One new study¹⁴ compared management plans between 2 heart teams, randomized to make a treatment decision between percutaneous coronary intervention (PCI) or coronary artery bypass grafting (CABG) based on coronary angiography or on CCTA. Each heart team then had to make a second treatment decision based on results from HeartFlow. Compared to CCTA or ICA, 7% and 6.6% of patients had a treatment decision change between PCI and CABG with the additional HeartFlow information, respectively.

Table 5

Changes in Clinical Management with HeartFlow.

Studies directly evaluated outcomes of clinical relevance in actual practice. However, our confidence in these findings is limited by important methodological weaknesses, including lack of control groups (all patients received HeartFlow in most studies) and unclear blinding of imaging results (ie, the same clinicians made clinical recommendations based on CCTA alone or HeartFlow) in several studies, which may have influenced changes in clinical management plans. Additionally, most studies did not assess whether HeartFlow affected actual clinical management of patients (treatment received) but focused on changes in the initial clinician management plan.

KEY QUESTION 3. IMPACT OF HEARTFLOW ON CLINICAL OUTCOMES AND COST

Rates of cardiovascular and other adverse events were low and were similar in those receiving HeartFlow or other diagnostic strategies, and in those whose clinical management plans were changed with HeartFlow (including in those who had ICA cancelled based on HeartFlow results) and those whose clinical management plans were not changed (Table 6).^{11,15,16,19,21,24,26,54} One new sub-analysis of the NXT trial (designed to examine the diagnostic accuracy of HeartFlow)⁵⁹ reported a longer-term rate of major adverse cardiac events (MACE; 9.7% at a median of 4.7 years) among patients receiving HeartFlow, but did not compare MACE rates to those in patients utilizing other diagnostic strategies.²⁶ Although MACE and other clinical event rates were consistently low, only the PLATFORM trial compared event rates in patients receiving HeartFlow to other diagnostic strategies, and only a single study included follow-up longer than 1 year.

Table 6

Cardiac and Clinical Events.

No new studies examined cost or quality of life outcomes. As previously described, quality of life scores in the PLATFORM trial^24,57 were generally similar between groups, with a greater improvement in quality of life reported with HeartFlow in the planned noninvasive subgroup. Mean costs at 90 days and 1 year were lower in the HeartFlow cohort compared to the usual care cohort in the subgroup of patients planned to receive ICA, but no differences in costs were observed between the groups in patients planned to receive noninvasive testing.^24,57

CONSIDERATIONS FOR THE USE OF HEARTFLOW IN VA

The potential impact of HeartFlow depends on the use of CCTA because CCTA images are needed for the HeartFlow FFR_CT analysis. The VA currently employs the 2012 American College of Cardiology Foundation and American Heart Association guidance for diagnosis of CAD, which recommends CCTA only for those who are unable to exercise or who have contraindications to stress testing.^60,61 Data from the VA national CDW shows that around 2,000 VA patients without a diagnosis of CAD or prior history of revascularization or ICA underwent CCTA testing each year from 2018 to 2020 (1,925 patients in 2018, 2,007 patients in 2019 and 1,828 patients in 2020). Among facilities performing at least 1 CCTA, more than 80% of VA sites reported fewer than 50 CCTAs during the calendar years 2018 to 2020 (Figure 2), with around 40% to 60% of VA sites performing 10 CCTAs or fewer. Only 3 to 4 VA sites reported doing 100 CCTAs or more per year from 2018 to 2020.

Figure 2

Usage of Coronary Computed Tomography Angiography (CCTA) Among VA Stations Performing at Least 1 CCTA Each Calendar Year.

Among VA patients undergoing CCTA, only 18.5% underwent ICA within 90 days after CCTA, indicating that most patients receiving CCTA have normal or non-obstructive results and do not end up requiring ICA or have extensive coronary artery disease not amenable to ICA intervention. In these cases, further imaging, including HeartFlow FFR_CT analysis, is usually not necessary. Similar rates of ICA after CCTA in patients with suspected but unknown CAD have been reported in other studies (9.6% to 16%).^62–65

CCTA is generally used less often in the US compared to Europe due to differences in guidance recommendations, reimbursement structures, and clinical practices and training.⁶⁶ Guidance from the European Society of Cardiology⁶⁷ and the National Institute for Health and Care Excellence⁶⁸ in the UK recommend use of CCTA as a first-line diagnostic strategy for patients with stable chest pain or chronic coronary syndrome. In an analysis of CCTA use among the Medicare population from 2006 to 2016, CCTA use in the US peaked in 2007 (210.3 per 100,000), and then declined until 2014, after which CCTA usage began to rise again, reaching 131.0 per 100,000 in 2016.⁶⁹ A recent American College of Cardiology State-of-the-Art Review outlined supportive evidence for expanded use of CCTA in the US.⁶⁶ However, barriers to increasing the use of CCTA in the US remain, including limited access to equipment, limited availability and support of technical training for clinicians, and lack of updated guidance for use of CCTA.

The potential impact of targeted HeartFlow use in patients referred for CCTA in the VA was estimated in the previous ESP report from data on the sensitivity and specificity of HeartFlow and CCTA alone. Using assumptions for the prevalence of patients with intermediate-stenosis lesions on CCTA, the proportion of these patients who have functionally significant CAD, and the proportion of patients with positive CCTA that undergo ICA, an estimated 34 ICAs could be prevented for every 1,000 patients undergoing CCTA.²⁹

ADEQUACY OF CCTA IMAGES FOR HEARTFLOW FFR_CT

HeartFlow FFR_CT analysis requires adequate-quality CCTA images to estimate FFR data. In studies on the therapeutic and clinical impact of HeartFlow reporting rates of acceptance of CCTA images, 79% to 98.6% of images were adequate for HeartFlow FFR_CT analysis. Variation in equipment quality and physician and CT technologist expertise may influence the adequacy of CCTA images and are important considerations for potential implementation of HeartFlow. When CCTA images are rejected due to poor image quality, CCTA must be repeated to use HeartFlow.

LIMITATIONS

There are several important limitations of the evidence base. No randomized controlled trials investigated the impact of HeartFlow on diagnostic or clinical outcomes. Cohort studies comparing HeartFlow to other noninvasive strategies (including CCTA alone) or ICA were often limited by unbalanced baseline patient characteristics (eg, type of chest pain, cardiac risk factors, demographics, etc). These differences may influence outcomes (ie, one group may be more likely to be referred to ICA due to type of chest pain or cardiac risk factors). Statistical adjustment for baseline differences between groups was inadequate, or unable to be fully assessed due to lack of information on adjustment methods. Without balanced comparison groups, differences in outcomes could have been due to patient characteristics linked to ICA referrals rather than use of HeartFlow. To determine the impact of HeartFlow compared to other diagnostic strategies, an ideal trial would enroll patients at a distinct point in their diagnostic workup (ie, at symptom onset) and randomize them to receive either HeartFlow or another invasive or noninvasive strategy for diagnosis of CAD, equalizing patient characteristics across groups. Adequate sample size, blinding of patients and outcome assessors, and standardized assessment of outcomes over a specific period of time are also important.

Limitations of our review methods include use of a second reviewer check during study selection and data abstraction rather than dual independent review. Additionally, only FDA-cleared FFR_CT technologies were eligible for this review, limiting our assessment to studies of HeartFlow FFR_CT analysis. No studies examined HeartFlow compared to other noninvasive FFR_CT technologies (locally developed algorithms, etc) and the clinical impact of these alternatives compared to HeartFlow is unknown.

EVIDENCE GAPS AND FUTURE RESEARCH

Substantial gaps in the evidence remain. Most importantly, no studies have assessed HeartFlow in a VA setting. The utility of HeartFlow depends on the characteristics of patients who undergo diagnostic testing and on how clinical decisions are made within a particular setting. Patient characteristics and clinical pathways may differ between non-VA and VA populations and settings, and the impact of HeartFlow within the VA remains unknown. Only 2 studies examined the impact of HeartFlow on the use of ICA in patients referred for noninvasive testing, and comparison of HeartFlow to specific noninvasive strategies is lacking. Clinical decisions and diagnostic pathways likely differ within the VA compared to those in community settings in studies of HeartFlow and direct evidence about how HeartFlow compares to diagnostic tests widely used in the VA is needed. Additionally, only a single study (with serious methodological limitations) examined the impact on ICA use of adding HeartFlow to the clinical pathway for patients referred for CCTA, which is the clinical scenario promoted on the manufacturer website.⁴⁰ Controlled studies of ICA rates in patients with suspected coronary disease receiving CCTA or other noninvasive strategies and comparing HeartFlow to specific noninvasive strategies are needed.

CONCLUSIONS

New evidence did not sufficiently address the evidence gaps identified in the 2019 ESP report. The impact of regularly utilizing HeartFlow for all patients referred for CCTA within the VA is likely low, given the relatively low number of CCTAs performed in the VA and the unclear impact of HeartFlow compared to noninvasive strategies currently used within the VA. However, use of HeartFlow in facilities with a high volume of CCTAs in specific clinical scenarios may have the potential to reduce unnecessary use of coronary angiography. Short-term rates of adverse cardiac events are likely low and do not differ in those receiving HeartFlow or other diagnostic strategies, but additional research is needed on longer-term clinical outcomes comparing rates of adverse cardiac events between HeartFlow and other diagnostic strategies. Research in VA settings and comparing HeartFlow to specific noninvasive strategies is needed to determine the potential impact of HeartFlow within the VA.

Operational Partners

Operational partners are system-level stakeholders who have requested the report to inform decision-making. They recommend Technical Expert Panel (TEP) participants; assure VA relevance; help develop and approve final project scope and timeframe for completion; provide feedback on the draft report; and provide consultation on strategies for dissemination of the report to the field and relevant groups.

• David Atkins, MD, MPH
  VA HSR&D Director

Technical Expert Panel (TEP)

To ensure robust, scientifically relevant work, the TEP guides topic refinement; provides input on key questions and eligibility criteria, advising on substantive issues or possibly overlooked areas of research; assures VA relevance; and provides feedback on work in progress. TEP members are listed below:

• Paul Hess, MD
  University of Colorado School of Medicine
• Jeffrey Chenoweth, MD
  Acting Director, VHA National Radiology Program

Peer Reviewers

The Coordinating Center sought input from external peer reviewers to review the draft report and provide feedback on the objectives, scope, methods used, perception of bias, and omitted evidence. Peer reviewers must disclose any relevant financial or non-financial conflicts of interest. Because of their unique clinical or content expertise, individuals with potential conflicts may be retained. The Coordinating Center and the ESP Center work to balance, manage, or mitigate any potential nonfinancial conflicts of interest identified.

APPENDIX A. SEARCH STRATEGIES

APPENDIX B. LIST OF EXCLUDED STUDIES

Exclude reasons: 1=Ineligible population (ie, acute coronary syndrome), 2=Ineligible intervention (ie, non HeartFlow FFRCT), 3=Ineligible comparator, 4=Ineligible outcome, 5=Ineligible setting, 6=Ineligible study design, 7=Ineligible publication type, 8=Outdated or ineligible systematic review, 9=Non-English language, 10=Unable to retrieve full text, 11=Trial included in prioritized systematic review

APPENDIX C. EVIDENCE TABLES

APPENDIX D. ONGOING HEARTFLOW FFR_CT STUDIES

APPENDIX E. DISPOSITION OF PEER REVIEWER COMMENTS

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