Noninvasive Fractional Flow Reserve Derived From Computed Tomography Angiography for Coronary Lesions of Intermediate Stenosis Severity

Introduction

Coronary computed tomography angiography (CCTA) is a noninvasive test that enables direct visualization of coronary artery disease (CAD) and correlates favorably with invasive coronary angiography (ICA) for measures of luminal diameter stenosis severity.¹ Yet, the accuracy of CCTA compared with ICA in clinical practice CCTA tends toward overestimation of stenosis severity, which may lead to increase in downstream testing, radiation dose, and cost.² Although current generation CCTA exhibits high negative predictive value (NPV) to exclude ≥50% obstructive coronary artery stenosis, CCTA cannot determine physiological significance of lesions, and even among CCTA-identified obstructive stenoses confirmed by ICA, fewer than half are ischemia causing.^3,4 Importantly, ischemia is present in an important minority of patients with stenoses of intermediate severity who experience reductions in coronary blood flow and myocardial ischemia beyond traditional angiographic definitions of obstructive stenoses.^5–7

Editorial see p 853Clinical Perspective on p 889

Fractional flow reserve (FFR) is a lesion-specific technique to determine the functional importance of a coronary stenosis.^8–12 FFR is often used for determination of the physiological significance of coronary lesions of intermediate stenosis severity. Its use as a guide to revascularization has been demonstrated to improve outcomes and reduce healthcare costs.^5,13,14

Recently, computation of FFR from CT (FFR_CT) has emerged as a novel noninvasive method that demonstrates high diagnostic performance for identification and exclusion of patients and coronary lesions that cause ischemia. To date, the diagnostic performance of FFR_CT for lesions of intermediate stenosis severity remains unexamined. To address this, we examined the performance of FFR_CT for assessment of coronary lesions of intermediate stenosis severity by CCTA within a subset of individuals enrolled in the prospective multicenter international DEtermination of Fractional flow reserve by Anatomic Computed TOmographic Angiography (DeFACTO) study.^15,16

Methods

Study Design and Patients

The rationale, design, and overall results of the DeFACTO study have been reported previously.^15,16 Briefly, DeFACTO was designed to evaluate the accuracy of FFR_CT to diagnose hemodynamically significant CAD, as defined by an invasive FFR reference standard, with a targeted population of subjects with suspected CAD who were referred for clinically indicated nonemergent ICA within 60 days of performance of CT. Patients with prior coronary artery bypass graft surgery and suspected in-stent restenosis on the basis of CCTA were excluded, and final population consisted of 252 patients with 407 vessels. The DeFACTO study was conducted at 17 centers in 5 countries (Belgium [n=1], Canada [n=1], Latvia [n=1], South Korea [n=2], and the United States [n=12]). The DeFACTO study protocol was designed by the Steering Committee and approved by the institutional review board at each site. All patients provided written informed consent. The study was consistent with the principles of the Declaration of Helsinki.

Image Acquisition and Analysis for CCTA

CCTA was performed on ≥64 detector row CT scanners by prospective or retrospective electrocardiographic gating.^17,18 CCTAs were transferred to a central core laboratory (Harbor UCLA Medical Center, Los Angeles, CA) for blinded interpretation using an 18-segment coronary model. CCTAs were evaluated for maximal patient-, vessel-, and segment-based diameter stenosis, which was categorized as 0%, 1% to 29%, 30% to 49%, 50% to 69%, or ≥70%. Lesions of ≥50% were categorized as angiographically obstructive. Per-patient stenosis was defined as the greatest stenosis within any coronary segment, whereas per-vessel stenosis was defined by a maximal stenosis in any segment within each major epicardial vessel distribution. Vessel distributions were categorized as left anterior descending artery (distribution including the first and second diagonal branches), left circumflex artery (distribution including the ramus intermedius, first, and second obtuse marginal branches, and left posterolateral branch), and right coronary artery (distribution including the right posterolateral branch and posterior descending artery). The posterior descending artery was included in the left circumflex artery distribution for left-dominant coronary systems. Stenoses of intermediate severity were defined as 30% to 69% diameter stenosis.

Image Acquisition and Analysis for ICA

Selective ICA was performed by standard protocol, with a minimum of 2 projections obtained per vessel distribution and with angles of projection optimized based on the cardiac position.¹⁹ Invasive coronary angiograms were transferred to a central angiographic core laboratory (University of British Columbia, Vancouver, Canada) for blinded quantitative coronary angiography of all vessels using commercially available software (Discovery Quinton).

Fractional Flow Reserve

FFR was performed at the time of ICA (PressureWire Certus, St Jude Medical Systems; ComboWire, Volcano Corp). Investigators performed FFR in vessels demonstrating an ICA stenosis and with clinical indication for FFR evaluation. After administration of nitroglycerin, a pressure-monitoring guidewire was advanced distal to a stenosis. Hyperemia was induced by intravenous or intracoronary administration of adenosine at a rate of 140 μg/kg per minute. FFR was calculated by dividing the mean distal coronary pressure by the mean aortic pressure during hyperemia. FFR was considered diagnostic of ischemia at a threshold of ≤0.80.⁵

Computation of FFR_CT

Computation of FFR_CT was performed in blinded fashion by the FFR_CT core laboratory (HeartFlow Inc, Redwood City, CA). Calculations of FFR_CT were performed by computational fluid dynamic modeling after semiautomated segmentation of coronary arteries and left ventricular mass. Three-dimensional (3D) blood flow simulations of the coronary arteries were performed, with blood modeled as a Newtonian fluid using incompressible Navier–Stokes equations and solved subject to appropriate initial and boundary conditions using a finite element method on a parallel supercomputer.²⁰ Because coronary flow and pressure were unknown a priori, a method to couple lumped parameter models of the microcirculation to the outflow boundaries of the 3D model was used. Coronary blood flow was simulated under conditions modeling adenosine-mediated coronary hyperemia. The FFR_CT ratio was obtained by dividing the mean pressure distal to the coronary stenosis by the mean aortic pressure.

Blinded Integration of FFR and CCTA

To enable direct comparison of FFR_CT with FFR at the precise location where the FFR was measured, a blinded core laboratory (Minneapolis Heart Institute, Minneapolis, MN) performed an integration step. This integration step involved matching the location on the CCTA to the location on the invasive angiogram where the distal FFR wire tip was placed and involved communication of this point to the FFR_CT core laboratory by an arrow on a 3D volume–rendered CT image of the coronary arteries.

Statistical Analyses

Analyses were conducted for FFR_CT on an intention-to-diagnose sample, defined as all patients with interpretable CCTAs as determined by the CT core laboratory with invasive FFR, which served as the reference standard. Categorical variables are presented as frequency and percentage and continuous variables as mean±SD. FFR and FFR_CT measurements were recorded on a continuous scale and dichotomized at the 0.80 threshold (values ≤0.80 were considered ischemia). Stenosis on CCTA was recorded on an ordinal scale and dichotomized at the 50% threshold, with stenosis of ≥50% considered obstructive. Intermediate stenosis lesions (30%–69%) by CCTA were further evaluated by subcategory with 30% to 49% and 50% to 69% stenosis.

Analyses were performed on per-patient and per-vessel basis. In per-patient analysis, vessels with the most adverse clinical status were selected to represent a given patient (minimum FFR, minimum FFR_CT, highest CT stenosis category). In per-patient analysis, the diagnostic performance of CT stenosis alone versus FFR_CT alone was evaluated for accuracy, sensitivity, specificity, positive predictive value (PPV), and NPV. Diagnostic measures of accuracy were obtained for binary FFR_CT predicting binary FFR (gold standard), both using the 0.80 threshold, stratified over low, intermediate, or high levels of pretest CADENZA likelihood of CAD.²¹

To account for the correlation of coronary artery segments within patients in an unbalanced design, a random effect logit model for binary data was applied, where the outcome (FFR ≤0.80) was modeled using a binomial distribution and a logit link function, with patient ID the random component.²² All diagnostic performance analyses were reported using this method. Bland–Altman analysis was performed using FFR as the reference standard. In addition, a per-vessel analysis was done in intermediate stenosis vessels grouped by proximal, mid, or distal location.

Discrimination was quantified using the area under the receiver operating characteristic curve, and area under the receiver operating characteristic curves were compared using the method of DeLong et al.²³ Further, we evaluated net reclassification improvement (NRI) of FFR_CT compared with CT stenosis on a per-patient basis for the intermediate stenosis group (n=82). To calculate the intermediate NRI, clinical cut points for low, intermediate, and high were defined by stenoses <30%, 30% to 69%, and ≥70% for CT stenosis and by >0.80, 0.75 to 0.80, and ≤0.75 for FFR_CT, respectively. For NRI calculations, cases were defined as patients having lesion-specific ischemia (FFR ≤0.80), whereas controls were defined as those without lesion-specific ischemia (FFR >0.80). Associations and differences were identified, and P values <0.05 were considered significant. Statistical analyses were performed using STATA software (version 11, StataCorp LP, College Station, TX).

Results

Patient Characteristics

Of the 252 patients in the DeFACTO study, 82 (33%) had 150 vessels with CCTA-confirmed maximal diameter stenosis 30% to 69%, which differed by 1 patient from our original report.¹⁶ In the current study, we restricted the patients for whom the maximal CT stenosis was intermediate in severity, thus resulting in the exclusion of a single patient with a high-grade lesion. Baseline characteristics of this study population are presented in Table 1 and were not different from the overall DeFACTO study population. Among the 150 vessels of intermediate stenosis severity interrogated by FFR, 35 (23%) were considered ischemic by FFR, whereas 64 (43%) were considered ischemic by FFR_CT. Prevalence of lesions with 30% to 49% and 50% to 69% stenosis was 71% (106 of 150) and 29% (44 of 150), respectively. Prevalence of lesion-specific ischemia was 22% (23 of 106) in 30% to 49% stenosis and 27% (12 of 44) in 50% to 69% stenosis. Distributions of FFR by CT stenosis category are shown in Figure I in the online-only Data Supplement.

FFR_CT and FFR

The correlation was moderate between FFR and quantitative coronary angiography (r=−0.42; P<0.0001) and between FFR and FFR_CT (r=0.50; P<0.0001; Figure 1A). Overall, Bland–Altman limits of agreement for FFR value ranged from −0.3 to 0.1, with slight underestimation of FFR_CT compared with FFR (bias −0.05; Figure 1B). Bland–Altman plots in each vessel are shown in Figure 1C to 1E. A difference in mean values between FFR and FFR_CT was observed (0.85±0.08 versus 0.80±0.11; P<0.0001).

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Diagnostic Performance of FFR_CT for Diagnosis of Ischemia

Among individuals with intermediate lesions, the per-patient diagnostic accuracy, sensitivity, specificity, PPV, and NPV were 73% (95% confidence interval [CI], 62%–82%), 82% (95% CI, 62%–94%), 69% (95% CI, 55%–81%), 56% (95% CI, 40%–72%), and 88% (95% CI, 75%–96%) for FFR_CT; 55% (95% CI, 43%–66%), 37% (95% CI, 19%–58%), 64% (95% CI, 50%–76%), 33% (95% CI, 17%–53%), and 67% (95% CI, 53%–80%) for CT stenosis, respectively. Per-vessel diagnostic performance of FFR_CT and CT stenosis for diagnosis of lesion-specific ischemia in lesions of intermediate severity is listed in Figure 2. For lesions of intermediate severity, FFR_CT demonstrated accuracy, sensitivity, specificity, PPV, and NPV of 69% (95% CI, 61%–76%), 74% (95% CI, 57%–88%), 67% (95% CI, 58%–75%), 41% (95% CI, 29%–54%), and 90% (95% CI, 81%–95%), whereas CT stenosis demonstrated accuracy, sensitivity, specificity, PPV, and NPV of 63% (95% CI, 55%–71%), 34% (95% CI, 19%–52%), 72% (95% CI, 63%–80%), 27% (95% CI, 15%–43%), and 78% (95% CI, 69%–86%), respectively.

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Agreement of stenosis grade between CCTA and quantitative coronary angiography was 58% for 30% to 49% CCTA stenosis and 57% for 50% to 69% CCTA stenosis. The diagnostic performance in subgroup with concordant lesions and discordant lesions is listed in Table 2.

In per-patient diagnostic performance as a function of pretest likelihood of CAD, NPV was high in both low to intermediate (<70%) and high (≥70%) pretest likelihood of CAD (Table I in the online-only Data Supplement). Diagnostic performance of lesion location for diagnosis of lesion-specific ischemia is shown in Table 3. NPV of FFR_CT was higher than CT stenosis for coronary lesions in proximal or mid segments (88%) and distal segments (100%).

Discrimination of Ischemia for Coronary Lesions of Intermediate Stenosis by FFR_CT and CCTA

On a per-patient basis, FFR_CT demonstrated superior discrimination over CT stenosis (area under the receiver operating characteristic curve, 0.81 [95% CI, 0.72–0.90] versus 0.50 [95% CI, 0.39–0.61]; difference, 0.31; P=0.0001) in predicting abnormal FFR ≤0.80 (Figure 3A). Similarly, on a per-vessel basis, FFR_CT also demonstrated superior discrimination over CT stenosis (area under the receiver operating characteristic curve, 0.79 [95% CI, 0.72–0.87] versus 0.53 [95% CI, 0.44–0.62]; difference, 0.26; P<0.0001; Figure 3B). Greater discriminatory power was demonstrated in FFR_CT compared with CCTA in both per-patient and per-vessel bases.

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FFR_CT demonstrated accuracy, sensitivity, specificity, PPV, and NPV of 81% (95% CI, 72%–88%), 74% (95% CI, 52%–90%), 83% (95% CI, 73%–91%), 55% (95% CI, 36%–73%), and 92% (95% CI, 83%–97%) for lesions of 31% to 49% stenosis and 66% (95% CI, 50%–80%), 42% (95% CI, 15%–72%), 75% (95% CI, 57%–89%), 39% (95% CI, 14%–68%), and 77% (95% CI, 59%–90%) for lesions of 50% to 69% stenosis. Receiver operating characteristic curves of FFR_CT for lesion-specific ischemia are depicted in Figure 2C and 2D for vessels with CT stenosis 31% to 49% and 50% to 69%, respectively.

NRI of Ischemic Lesions

Among a total of 82 patients of intermediate stenosis severity interrogated by FFR, 55 (67%) were considered nonischemic by FFR >0.80, whereas 27 (33%) were considered ischemic by FFR ≤0.80. Thirty-nine patients were correctly reclassified by FFR_CT over CT stenosis, whereas only 7 patients were incorrectly reclassified by FFR_CT over CT stenosis. FFR_CT enabled effective reclassification in the study population over CT stenosis (NRI, 0.45; 95% CI, 0.25–0.65; P=0.003). Representative examples of stenoses of intermediate severity that did versus did not cause ischemia are shown in Figures 4 and 5.

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Discussion

In the present study, we examined the performance of noninvasive FFR_CT for identification and exclusion of ischemia-causing lesions of intermediate stenosis severity as confirmed by a blinded CCTA core laboratory. Our study findings demonstrate improved diagnostic performance of FFR_CT over CT stenosis for diagnosis of ischemia-causing lesions.

In particular, a high NPV of FFR_CT suggests its use as a potential method to successfully exclude ischemia possible need of revascularization in lesions of intermediate stenosis severity. These findings are particularly important, given previous reports that have demonstrated that stenosis severity is often overestimated by CCTA, which may contribute to generally high rates of referral to ICA after CCTA.² The ability of FFR_CT to exclude physiologically significant coronary stenosis may empower clinicians to avoid unnecessary invasive procedures in a manner not possible from stenosis assessment alone. Nevertheless, the high NPV of FFR_CT must be viewed with caution, given that some patients with hemodynamically significant CAD may be missed even by this technology. Future large-scale studies will be required to determine the effect of this technology on health outcomes.

Importantly, FFR_CT enabled improved discrimination as well as effective reclassification of individuals for intermediate ischemic lesions over measures of CT stenosis. These findings are germane, especially for individuals whose stenoses do not meet the traditional criteria of angiographically severe, yet confer hemodynamic importance that may explain symptoms of angina. In this regard, it is notable that FFR_CT was consistently effective for proximal or mid/distal vessel segments and across all measures of pretest likelihood of CAD.

Current guidelines recommend that CAD evaluation should be differentially based on patient pretest risk assessment. Low-risk patients are recommended to receive only expectant medical management, whereas intermediate-to-high–risk patients are considered candidates for noninvasive testing with imaging.²⁴ To date, these noninvasive tests have been constrained to either an anatomic approach,—such as with CCTA,—to identify obstructive CAD or a physiological approach to determine ischemia by relative hypoperfusion or left ventricular wall motion via an array of available stress test types. To date, a combined anatomic-physiological assessment by a single noninvasive test has been lacking, with either anatomic or physiological approaches generally reliant on the other. This sequential testing has evoked concerns of excess resource utilization, higher radiation doses, and unnecessary invasive angiography.

By invasive methods, FFR is often used for determination of the physiological significance of coronary lesions of intermediate stenosis severity, and its performance enables guidance of percutaneous coronary interventions (PCIs) in a manner that results in improved event-free survival and reduced resource utilization.^5,13,14 In the current study, we analyzed the lesions of intermediate stenosis severity as visualized by CCTA. These types of lesions are difficult for diagnostic evaluation, given that they fall below conventional definitions of angiographically severe. Yet these lesions are often associated with considerable rates of ischemia. Diffuse mild luminal narrowing has been demonstrated to be associated with reduced stress-induced myocardial blood flow and abnormal epicardial coronary artery resistance even before a high-grade segmental stenosis is apparent.^6,7,25 Uren et al²⁵ assessed the relationship between the severity of stenosis in a coronary artery and the degree of impairment of myocardial blood flow using O15-water positron emission tomography. They found that among the patients with stenoses of ≥40% of diameter stenosis, myocardial blood flow during hyperemia and myocardial flow reserve progressively decreased as the degree of stenosis increased (40%–59% and 60%–79%). Myocardial blood flow during hyperemia in the patients with stenoses <40% was not significantly different from myocardial blood flow in patients with no stenosis, in keeping with the present study results.

Pathophysiologically, the totality of atherosclerosis proximal to a coronary lesion has been demonstrated as vital to the contribution of ischemia. De Bruyne et al reported that early stage coronary atherosclerosis with mild coronary stenoses is often associated with abnormal resistance of the epicardial coronary arteries before a high-grade segmental stenosis is apparent at angiography by ICA.⁶ In addition to the resistance caused by focal stenosis or by arteriolar vasomotor dysfunction, diffusely atherosclerotic epicardial coronary arteries without high-grade segmental stenoses often manifest a continuous pressure decline along their length and reduced coronary flow reserve, as well as induce myocardial ischemia. These findings suggest the importance of measuring the atherosclerotic plaque in high-grade stenotic lesions and the angiographically less severe lesions that may include diffuse atherosclerosis. This issue is underscored by the nearly one quarter of intermediate lesions in the current study, which were associated with ischemia, a finding that mirrors previous multicenter studies. In particular, in the present study, despite an angiographically milder appearance of 30% to 49% stenosis, 22% of such lesions were nevertheless causal of ischemia. The converse was also observed in that lesions between 50% and 69% luminal narrowing manifested ischemia only 27% of the time. These findings emphasize the need for functional assessment of the hemodynamic significance of intermediate coronary artery lesions, given that measurements of stenosis demonstrate an unreliability to ischemia presence. In this regard, FFR_CT may serve to advance the noninvasive diagnostic approach by providing a one-stop shop for integrated anatomic-physiological assessment of CAD. Importantly, in contradistinction to physiological stress testing methods, FFR_CT provides an index of epicardial stenosis–related ischemia and thus may provide an added diagnostic advantage of being able to pinpoint the specific lesion that causes ischemia. These features may allow for more judicious selection of patients for ICA and of vessels for coronary revascularization than methods that can only assess myocardial hypoperfusion that may occur from an array of causes that include epicardial stenosis but also endothelial dysfunction and microvascular disease.

Our current study findings, if proven, may also contribute substantively to assessing individuals’ prognosis. In the 2-year follow-up, Bech et al²⁶ reported that in patients referred for PCIs of intermediate stenosis without objective proof of ischemia by noninvasive testing, approximately half of these stenoses were not hemodynamically significant. PCIs in these patients neither reduce adverse cardiac events or the use of antianginal drugs nor result in a better functional angina class compared with medical treatment. In contrast, in patients with intermediate stenosis and ischemic FFR, which indicates hemodynamic significance, PCIs resulted in a significantly greater improvement in functional class. Subsequently, at 5-year follow-up, Pijls et al²⁷ reported that in patients with intermediate stenosis without evidence of ischemia by noninvasive test, the most important prognostic factor was myocardial ischemia by FFR. In those patients, even when treated by PCIs, clinical outcome is significantly worse than in patients with nonischemic FFR.

Recently, a subanalysis of the Diagnosis of Ischemia-Causing Stenoses Obtained via Noninvasive Fractional Flow Reserve (DISCOVER-FLOW) trial was reported.²⁸ In this study, high diagnostic performance of FFR_CT was observed for diagnosis of ischemia for lesions of intermediate stenosis severity, as judged by quantitative coronary angiography, as well as high discrimination of lesions that do versus do not cause ischemia. FFR_CT performed robustly against an invasive FFR reference standard, with good agreement to invasive FFR and without significant mean differences. The difference between the current study and the previous report is that the present data comprise all stenoses between 30% and 69% stenosis severity as judged by CCTA in individuals with a maximal stenosis severity in the intermediate range. Further, the current data were derived from a large prospective, international, multicenter study. Finally, the present study results directly extends previous investigation findings by examining the ability of FFR_CT to reclassify coronary artery lesions judged by CT stenosis to be ischemic versus nonischemic, with nearly half of all lesions correctly reclassified by FFR_CT.

Notably, FFR_CT also offers several operational advantages in that it does not require modification of CCTA protocols, does not require administration of additional medications beyond what is typically administered for CCTA, and does not confer any additional radiation.

This study is not without limitations. This present study was small, but represents the largest to date from a prospective multicenter study. We did not interrogate lesions <30%; previous studies have identified 30% angiographic stenosis as a threshold below which ischemia is rarely observed, and ethical considerations precluded our performing invasive FFR in vessels in which no significant CAD was present. We identified intermediate coronary stenoses by CCTA assessment at central core laboratory. Thus, whether the present study results can be universally applied to practitioners interpreting CCTA in clinical setting requires further study. At present, only 1 for-profit company possesses a computational fluid dynamic solution for the calculation of FFR_CT, with several other groups developing their own proprietary software. The workflow of how FFR_CT will be used in clinical practice,—whether on or off site,—remains to be determined because this technology is still in its investigational stage and not approved for commercial use in the United States.

Conclusions

FFR_CT provides higher diagnostic performance for lesions of intermediate stenosis severity, with a 2-fold increase in sensitivity and high NPV when compared with CCTA. These data suggest a role for FFR_CT to noninvasively exclude ischemia with high certainty.

Footnotes

CLINICAL PERSPECTIVE

Coronary computed tomography angiography (CCTA) is a noninvasive test that enables direct visualization of coronary artery disease and correlates with invasive coronary angiography for measures of luminal diameter stenosis severity. Although CCTA exhibits high negative predictive value to exclude obstructive coronary stenosis, CCTA cannot determine the physiological significance of coronary lesions even among CCTA-identified obstructive stenoses confirmed by invasive coronary angiography. Fractional flow reserve derived from computed tomography angiography (FFR_CT) has emerged as a novel noninvasive method for diagnosis of ischemic coronary lesions. In the present study, we examined the performance of noninvasive FFR_CT for identification and exclusion of ischemia-causing lesions of intermediate stenosis severity as confirmed by a blinded CCTA core laboratory. Our study findings demonstrate improved diagnostic performance of FFR_CT over CCTA stenosis for diagnosis of ischemia-causing lesions. In particular, a high negative predictive value of FFR_CT suggests its use as a potential method to successfully exclude ischemia possible need of revascularization in lesions of intermediate stenosis severity. These findings are particularly important, given prior reports that have demonstrated that in clinical practice, CCTA tends to overestimate stenosis severity, possibly leading to increase in downstream testing, radiation dose, and cost. It remains to be determined whether the improved ability of FFR_CT to exclude physiologically significant coronary stenosis may enable clinicians to avoid unnecessary invasive procedure in a manner not possible from stenosis assessment alone.