Noninvasive Fractional Flow Reserve Derived From Coronary CT Angiography (FFR_CT): Management and Outcomes in the PROMISE Trial

Abstract

Objectives

To determine whether noninvasive fractional flow reserve derived from computed tomography (FFR_CT) predicts coronary revascularization and outcomes and whether its addition improves efficiency of referral to invasive coronary angiography (ICA) after coronary CT angiography (CTA).

Background

FFR_CT may improve the efficiency of an anatomic CTA strategy for stable chest pain.

Methods

Observational cohort study of patients with stable chest pain enrolled in the PROMISE trial referred to ICA within 90 days after CTA. FFR_CT was measured at a blinded core lab, and FFR_CT results were unavailable to caregivers. We determined the agreement of FFR_CT (positive if ≤0.80) with stenosis on CTA and ICA (positive if ≥50% left main or ≥70% other coronary artery), and predictive value for a composite of coronary revascularization or MACE (death, myocardial infarction, or unstable angina). We retrospectively assessed whether adding FFR_CT ≤0.80 as a gatekeeper could improve efficiency of referral to ICA, defined as decreased rate of ICA without ≥50% stenosis and increased ICA leading to revascularization.

Results

FFR_CT was calculated in 67% (181/271) of eligible patients (mean age 62 years, 36% women). FFR_CT was discordant with stenosis in 31% (57/181) for CTA and 29% (52/181) for ICA. Most patients undergoing coronary revascularization had FFR_CT ≤0.80 (91%, 80/88). FFR_CT ≤0.80 was a significantly better predictor for revascularization or MACE than severe CTA stenosis (HR 4.3 [95% CI 2.4–8.9] versus 2.9 [1.8–5.1]; p=0.033). Reserving ICA for patients with FFR_CT ≤0.80 could decrease ICA without ≥50% stenosis by 44%, and increase the proportion of ICA leading to revascularization by 24%.

Conclusion

In this hypothesis-generating study of patients with stable chest pain referred to ICA from CTA, FFR_CT ≤0.80 was a better predictor of revascularization or MACE than severe stenosis on CTA. Adding FFR_CT may improve efficiency of referral to ICA from CTA alone.

More than 4 million Americans with stable chest pain undergo noninvasive diagnostic testing for suspected coronary artery disease (CAD) annually (1). Most have functional testing, which may lead to referral to invasive coronary angiography (ICA) and coronary revascularization. Coronary CT angiography (CTA) has emerged as an alternative whose strength is the accurate exclusion of significant coronary artery stenosis (negative predictive value: 97 to 99%). However, CTA has limited positive predictive value (64 to 86%), and so management of patients with stenosis on CTA is challenging (2,3). Furthermore, anatomic stenosis on CTA and ICA is often discordant with measures of hemodynamic significance such as invasive fractional flow reserve (FFR) (4,5). The importance of the latter to improve clinical outcomes has been demonstrated in randomized comparisons of invasive FFR-guided versus stenosis-guided coronary revascularization (6,7).

Emerging computational fluid dynamics modeling techniques allow calculation of FFR noninvasively from standard CTA images (FFR_CT) (8). FFR_CT correlates well (r = 0.82) with invasive FFR, with a per-patient sensitivity of 86% and specificity of 79% for invasive FFR ≤0.80 indicating ischemia (9). The Prospective Multicenter Imaging Study for Evaluation of Chest Pain (PROMISE), a pragmatic comparative effectiveness trial of coronary CTA in patients with stable chest pain, provides an opportunity to test the potential impact of adding FFR_CT to CTA as a gatekeeper to ICA against observed anatomic CTA-guided care. This PROMISE FFR_CT substudy assessed patients referred to ICA from CTA to determine the association of a positive FFR_CT ≤0.80 with coronary revascularization or MACE, to assess the agreement of FFR_CT with significant stenosis on CTA and ICA, and to predict whether the addition of FFR_CT to the CT-guided practice patterns observed in PROMISE could improve efficiency of an anatomic CTA strategy.

Methods

Study design

This retrospective observational cohort study was nested in PROMISE, a pragmatic North American multicenter comparative effectiveness trial that randomized patients with stable chest pain and without known CAD to anatomic coronary CTA versus functional testing between July 2010 and September 2013. The PROMISE trial has been described in detail elsewhere (10). For this study we included the subgroup randomized to CTA who subsequently underwent ICA as part of clinical care in the 90 days following CTA. Demographics and traditional cardiovascular risk factors were documented at enrollment. Institutional review board approval was obtained with waiver of informed consent.

CTA

Electrocardiogram-gated CTA had been performed on CT scanners with at least 64 detector rows (10). “Advanced” scanners were defined as each manufacturer’s most advanced model available during the trial (General Electric HD 750, Phillips Brilliance iCT, Siemens SOMATOM Definition Flash, Toshiba Aquilion One). CTA was interpreted for stenosis by local physicians who made all clinical decisions. Severe stenosis, defined as an anatomic stenosis of ≥50% in the left main or ≥70% in other major epicardial coronary arteries, constituted a per-patient “positive” CTA result.

ICA

Subjects were referred to ICA by local physicians based on the results of CTA and other clinical characteristics. ICA had been performed according to standard practice (11) and interpreted for stenosis by local physicians who made all clinical decisions, including whether to pursue revascularization. As with CTA, a severe stenosis constituted a per-patient “positive” ICA result.

Coronary revascularization and MACE

The primary endpoint was a composite of revascularization (percutaneous coronary intervention [PCI] or coronary artery bypass grafting [CABG]) or major adverse cardiovascular events (MACE: death, nonfatal myocardial infarction [MI] or hospitalization for unstable angina). All subjects had at least 12 months of follow-up. A blinded independent clinical events committee had adjudicated all events.

Eligibility for FFR_CT

Prospectively established exclusion criteria included CTA performed without nitroglycerin, image reconstructions not compliant with Society of Cardiovascular Computed Tomography (SCCT) guidelines for pixel resolution (field of view >250mm or slice thickness ≥1mm) (12), missing images, incomplete coverage of the heart or coronary arteries, or image quality graded nondiagnostic for stenosis by a single cardiac radiologist (MTL) (Figure 1). CTA performed without nitroglycerin was excluded, based on data suggesting that FFR_CT has better accuracy against invasive FFR when systemic nitrates are given (13).

Figure 1. Flow Diagram.

The analytic population included 181 subjects who had CTA, ICA, and FFR_CT.

Computation of FFR_CT from CTA

The FFR_CT implementation employed in this study is computationally intensive and currently only available at a single core lab (HeartFlow, Redwood City, California) as a “send off” test (8). CTA datasets meeting eligibility criteria were sent to the FFR_CT core lab. As previously validated in the NXT trial, the FFR_CT core lab applied a second set of quantitative criteria to determine whether there was adequate image quality for FFR_CT analysis based on whether the coronary artery lumen and myocardial boundaries could be clearly defined (9).

FFR_CT was calculated blinded to all aspects of clinical care including CTA interpretation and clinical outcomes. The results of FFR_CT were not available to care providers and did not affect clinical management. Techniques for calculation of FFR_CT have been detailed (8) and accuracy against invasive FFR validated (9) elsewhere. Briefly, 3-dimensional models of the coronary arterial tree and myocardium were segmented from the standard CTA images used for diagnosis in the trial. Computational fluid dynamics techniques modeled coronary arterial flow under simulated maximal hyperemia. FFR_CT was calculated as the ratio of mean simulated pressure to aortic pressure at all coronary artery locations measuring ≥1.8 mm. Occluded vessels were assigned a value of 0.5. The lowest per-patient FFR_CT value is reported; a FFR_CT ≤0.80 constituted a per-patient “positive” result.

Statistical analysis

Comparisons of baseline characteristics between the analytic group who had FFR_CT versus the excluded group who did not and between those with FFR_CT ≤0.80 versus >0.80 were performed with the Wilcoxon 2-sample test/Kruskal-Wallis analysis of variance for continuous variables and chi-square/Fisher’s exact test for categorical variables. The primary study objective was to determine whether the addition of a positive FFR_CT ≤0.80 was more strongly associated with the composite outcome of coronary revascularization or MACE than an anatomic-only finding of severe stenosis on CTA. Cox proportional hazards models were used to assess the relationship of a positive FFR_CT or positive CTA compared to a negative test result for the time to the first clinical event (or censoring) for the composite endpoint (14). Relative risks were expressed as hazard ratios with 95% confidence intervals derived from Cox models; hazard ratios for a positive FFR_CT versus positive CTA were compared with the chi-square test.

To project whether the addition of FFR_CT to the observed anatomical CTA strategy could improve the efficiency of referral to ICA from CTA, we prospectively defined an FFR_CT-guided decision rule that reserved ICA for patients with FFR_CT ≤0.80. The projected numbers of patients having ICA, ICA without ≥50% stenosis, and ICA leading to revascularization were described in comparison to what was observed in the trial. To determine the agreement of FFR_CT results with CTA and ICA findings of coronary artery stenosis, angiographic lesion severity per category and respective FFR_CT values were plotted in box-and-whisker plots. The proportion of subjects having FFR_CT ≤0.80 across stenosis strata on ICA and CTA were compared using the chi-square test. Statistical analysis was performed using SAS (version 9.4) and JMP Pro (version 12) from SAS Institute (Cary, North Carolina) with a two-sided level of significance of 0.05.

Results

Study population

Of the 609 patients who were randomized to the CTA arm of PROMISE and had ICA, 59 (9.7%) either did not have CT as their first diagnostic test, had ICA >90 days after CT, or had a non-contrast CT for calcium score only (no CTA). Of the remaining 550 patients, we excluded 139 (25%) because they did not receive nitroglycerin during CTA; 90 (16%) due to missing images, incomplete coverage of the heart, or CTA image reconstruction with field of view >250mm or slice thickness ≥1mm; and 50 (9%) whose CT images were nondiagnostic for the assessment of stenosis (Figure 1). Of the 271 patients (49%) who met prospectively defined inclusion criteria, 90 (33%) were inadequate for FFR_CT analysis. Thus, the analytic study population consisted of 181 patients who had complete information on CTA, ICA, and FFR_CT.

The average age was 62 years, 36% (66/181) were women, and 76% were at intermediate risk for obstructive CAD by the combined Diamond and Forrester and Coronary Artery Surgery Study risk score (Table 1) (15). Compared to those who did not have FFR_CT (n=369), the analytic population who had FFR_CT was less likely to be obese (34% versus 53%, p<0.001), consistent with the adverse effect of obesity on CT image quality. However, both groups had a similar burden of CAD, incident revascularization, and MACE (Supplemental Table 1). The 181 subjects were enrolled at 69 North American sites (mean: 2.6 per site). Coronary CTA datasets were acquired from all 4 major CT vendors (44% [80/181] General Electric, 11% [20/181] Phillips, 36% [66/181] Siemens, and 8% [15/181] Toshiba). Advanced CT scanners were used in 17% (31/181) of the CTAs evaluated with FFR_CT compared to 12% (43/369, p for comparison=0.08) of the CTAs not evaluated with FFR_CT.

Table 1.

Characteristics of PROMISE FFR_CT participants referred to ICA after CTA, according to FFR_CT ≤0.80 or >0.80

	FFRCT ≤0.80 N = 131	FFRCT >0.80 N = 50	p
Age — mean ± SD, yr	61.6 ± 8.1	62.5 ± 9.8	0.79
Female sex — no. (%)	42 (32%)	24 (48%)	0.046
Racial/ethnic minority — no. (%)	11 (8.5%)	7 (14%)	0.28
Cardiac Risk factors – no. (%)
BMI ≥30 kg/m2	42 (31%)	20 (40%)	0.27
Hypertension	83 (63%)	31 (62%)	0.87
Diabetes	25 (19%)	7 (14%)	0.42
Dyslipidemia	91 (70%)	31 (62%)	0.34
Family history premature CAD	58 (45%)	26 (52%)	0.17
Peripheral arterial disease	2 (1.5%)	1 (2.0%)	1.0
CAD equivalent	28 (21%)	13 (26%)	0.51
Metabolic syndrome	39 (30%)	13 (26%)	0.62
Smoking history	77 (59%)	24 (78%)	0.17
Combined Diamond and Forrester and CASS			0.066
Low (<25%)	7 (5.3%)	6 (12.0%)
Intermediate (25–75%)	98 (75%)	40 (80%)
High (>75%)	26 (20%)	4 (8.0%)
CTA radiation dose — mean ± SD, mSv	9.8 ± 6.4	9.8 ± 6.1	0.99

BMI = body mass index; CAD = coronary artery disease; CASS = Coronary Artery Surgery Study; CTA = coronary computed tomography angiography; FFR_CT = noninvasive fractional flow reserve derived from CTA; ICA = invasive coronary angiography.

CTA and ICA stenosis

Most patients had severe (≥70% or ≥50% left main) stenosis on coronary CTA (66%, 120/181) and ICA (54%, 97/181) (Table 2).

Table 2.

Stenosis, revascularization, and major adverse cardiovascular events (MACE) stratified by FFR_CT ≤0.80

	FFRCT ≤0.80 N = 131	FFRCT >0.80 N = 50	p
CTA stenosis – no. (%)			0.002
Mild (<50%)	8 (6%)	9 (18%)
Moderate (50–69%)	26 (20%)	18 (36%)
Severe (≥70% or ≥50% left main)	97 (74%)	23 (46%)
Left main	11 (8%)	3 (6%)	0.76
One vessel	65 (50%)	17 (34%)	0.004
Two vessel	24 (18%)	4 (8%)
Three vessel	8 (6%)	2 (4%)
ICA stenosis — no. (%)			<0.001
Mild (<50%)	20 (15%)	29 (58%)
Moderate (50–69%)	23 (18%)	12 (24%)
Severe (≥70% or ≥50% left main)	88 (67%)	9 (18%)
Left main	9 (7%)	0 (0%)	0.065
Single vessel	57 (44%)	8 (16%)	<0.001
Two vessel	17 (13%)	1 (2%)
Three vessel	14 (11%)	0 (0%)
Revascularization — no. (%)	80 (61%)	8 (16%)	<0.001
PCI	67 (51%)	8 (16%)
CABG	13 (10%)	0
MACE — no. (%)	14 (11%)	2* (4%)	0.24
Death	1 (0.8%)	0
Nonfatal myocardial infarction	1 (0.8%)	1 (2%)
Hospitalization for unstable angina	12 (9%)	1 (2%)
Composite of Revascularization or MACE — no. (%)	83 (63%)	10 (20%)	<0.001

^*Both patients with an event and FFR_CT >0.80 did not have severe stenosis on ICA and were not revascularized.

CABG = coronary artery bypass grafting; PCI = percutaneous coronary intervention; other abbreviations as in Table 1.

Coronary revascularization and MACE

During median follow-up of 29 months (IQR 18.9–36.3 months) the primary outcome of a composite of coronary revascularization or MACE occurred in 51% (93/181, Table 2). Overall, 49% (88/181) had coronary revascularization, including 75 PCI and 13 CABG. MACE occurred in 9% (16/181), including 1 death, 2 nonfatal MIs, and 13 hospitalizations for unstable angina.

FFR_CT measurements

With per-patient FFR_CT defined as the lowest FFR_CT value for that patient, mean per-patient FFR_CT was 0.71±0.13, with 72% (131/181) of patients having a FFR_CT ≤0.80. Patients with FFR_CT ≤0.80 were less likely to be women (32% versus 48%, p=0.046) but had otherwise similar demographics and risk factors compared to those with FFR_CT >0.80 (Table 1). Two representative cases are presented in Figure 2.

Figure 2. Representative CTA, FFR_CT, and ICA.

The first patient (A–C) was referred to ICA based on (A) CTA moderate stenosis in the left circumflex (white arrow). Severe stenosis in an obtuse marginal (red arrow) was missed by the CT reader, but detected by (B) FFR_CT of 0.76 and confirmed on (C) ICA showing severe stenosis, with subsequent PCI. Circumflex stenosis (white arrow) was mild and not revascularized. The second patient (D–F) was referred to ICA for (D) severe mid left anterior descending stenoses on CTA (red arrows). (E) FFR_CT of 0.83 suggests no hemodynamically significant stenosis; (F) ICA demonstrated mild stenosis that was not revascularized.

Agreement of FFR_CT with CTA and ICA

Compared to the degree of stenosis on CTA (worst per patient), mean FFR_CT (lowest per patient) decreased from 0.81±0.09 for mild stenosis (<50%) to 0.77±0.10 for moderate stenosis (50–69%) to 0.67±0.13 for severe stenosis (p<0.001). Similar results were seen for ICA (0.80±0.11, 0.75±0.08, and 0.64 ±0.12, respectively; p <0.001) (Figure 3). There was agreement between FFR_CT and CTA in 69% (124/181) of patients, among them 54% (97/181) with positive FFR_CT ≤0.80 who had severe CTA stenosis and 15% (27/181) with negative FFR_CT who had less than severe CTA stenosis (Table 2). A similar agreement rate of 71% (129/181) was seen between FFR_CT ≤0.80 and severe ICA stenosis. The disagreement rates with FFR_CT were 31% (57/181) for CTA and 29% (52/181) for ICA.

Figure 3. Box and Whisker Plots of Per-Patient FFR_CT by Categories of (A) CTA and (B) ICA Stenosis.

The horizontal line corresponds to the FFR_CT threshold for a positive test (FFR_CT ≤0.80). FFR_CT decreased with increasing degrees of stenosis on CTA and ICA (both p<0.001).

Association of FFR_CT with coronary revascularization and MACE

Patients with FFR_CT ≤0.80 were significantly more likely to have coronary revascularization (61%, 80/131 versus 16%, 8/50, hazard ratio (HR) 5.13 [95% CI 2.63–11.53; p<0.001] [Table 2]). There was a trend toward more patients with FFR_CT ≤0.80 experiencing a MACE (11%, 14/131 versus 4%, 2/50, HR 2.67 [95% CI 0.75–17.02; p=0.14]). There were 2 MACE events (one nonfatal MI and one hospitalization for unstable angina) with FFR_CT >0.80, both in patients with <70% stenosis on ICA who did not undergo coronary revascularization.

FFR_CT ≤0.80 was significantly associated with the composite endpoint of MACE or revascularization compared to those with FFR_CT >0.80 (63%, 83/131 versus 20%, 10/50, HR 4.31 [95% CI 2.35–8.88; p<0.001]). Severe stenosis on CTA was also significantly associated with the composite endpoint compared to lesser stenosis (63%, 76/120 versus 28%, 17/61, HR 2.90 [95% CI 1.76–5.10]; p<0.001]. However, FFR_CT ≤0.80 was significantly better than severe CTA stenosis at predicting the composite endpoint (HR 4.31 for FFR_CT versus 2.90 for CTA stenosis; p=0.033). This is notable as FFR_CT results were not available to physicians during the trial while the CTA results guided management.

Potential improvement in efficiency of referral to ICA by adding FFR_CT

Reserving ICA for patients with a positive FFR_CT (≤0.80) could reduce the number of ICA following CTA by 28% (50/181), decrease the rate of ICA without ≥50% stenosis by 44% (from 27% [49/181] to 15% [20/131]), and increase the rate of ICA leading to revascularization by 24% (from 49% [88/181] to 61% [80/131]). On the other hand, this rule would result in 9% fewer (8/88) coronary revascularizations (8 PCI, 0 CABG); the impact of which cannot be estimated in this study. On ICA, 6 of these patients had PCI of severe single-vessel stenosis (none involving the left main or proximal left anterior descending coronary arteries), and 2 had PCI of moderate (50 to 69%) proximal left anterior descending stenoses. Notably, none of these patients experienced a MACE.

In a sensitivity analysis, we recalculated these figures including the 90 patients whose images were sent to the FFR_CT core lab but were inadequate for FFR_CT analysis. Assuming a worst case that all 90 proceeded to ICA, we estimate a lesser reduction in the rate of ICA by 18% (50/271), decrease in the rate of ICA without ≥50% stenosis by 20% (from 31% [84/271] to 25% [55/221]), and increase in the rate of ICA leading to revascularization by 15% (from 49% [134/271] to 57% [126/221]).

Discussion

Our study demonstrates the potential impact of adding noninvasively calculated FFR_CT to an anatomic CTA strategy for evaluation of stable chest pain. In patients referred to ICA after CTA, we demonstrate that retrospectively obtained FFR_CT has better predictive value for the composite outcome of coronary revascularization or MACE than severe (≥70%) stenosis on CTA. Furthermore, our data suggest that adding information on FFR_CT to coronary CTA may improve the efficiency of referral to ICA by lowering the number of invasive angiograms, decreasing the proportion of ICA without ≥50% stenosis, and increasing the rate of subsequent coronary revascularization.

We demonstrate that noninvasive FFR_CT values decrease with increasing luminal stenosis, but also that there is substantial disagreement between anatomic significance (severe stenosis) and hemodynamic significance (FFR_CT ≤0.80) for both CTA (31%) and ICA (29%), similar to the 25% discrepancy rate between invasive FFR and ICA found in the FAME trial (4). In addition, patients with FFR_CT ≤0.80 were substantially more likely to suffer revascularization or MACE compared to those with FFR_CT >0.80 (HR 4.31, p<0.001). While the prognostic value of FFR has been shown in invasive studies such as DEFER (16) and FAME (7), it has not been previously reported for noninvasive FFR_CT in an observational setting where FFR_CT did not alter clinical management. Moreover, the association of FFR_CT with revascularization and MACE was significantly stronger than for severe stenosis on CTA (HR 4.31 versus 2.90, p=0.033), a notable result as stenosis guided the clinical decision for coronary revascularization, whereas FFR_CT was not available to caregivers in the trial.

Multicenter trials of CTA in patients with acute (17,18) and stable chest pain (10) suggest that CTA leads to greater referral to ICA compared to usual care. In PROMISE, patients in the CTA arm had 51% more ICA than those in the functional arm (12.2% versus 8.1%). Our results suggest that adding FFR_CT to anatomic CTA, with a positive FFR_CT ≤0.80 as a criterion for referral to ICA, may address this by reducing referral to ICA from CTA by up to 28%. Extrapolation to all 550 patients in PROMISE who underwent ICA as part of the anatomic CTA strategy should be interpreted with caution, but could decrease the rate of referral to ICA in the anatomic arm from 12.2% to 9.5%, which is more comparable to the ICA rate of 8.1% observed in the functional testing arm (10). Furthermore, adding FFR_CT to CTA could increase the proportion of ICA leading to coronary revascularization from 49% to 61%. Such projections may be justified as the burden of CAD and coronary revascularization were similar between the 181 patients in whom we measured FFR_CT and the 369 patients who were also referred for ICA but did not have FFR_CT (Supplemental Table 1).

Our study included PROMISE patients with stable chest pain referred to ICA after CTA. Thus FFR_CT was not assessed in isolation, but in the context of CTA findings that prompted referral to ICA. We did not include patients whose CTA results did not prompt referral to ICA, and so our results do not address use of FFR_CT in this broader group. Our findings suggesting that the addition of FFR_CT could be incremental to anatomic CTA as a gatekeeper to ICA within a North American trial support and expand on a recent European cohort study (PLATFORM: Prospective LongitudinAl Trial of FFR_CT Outcome and Resource IMpacts) of patients with planned ICA, which reported that combined CTA/FFR_CT led to a very low (12%) rate of ICA without ≥50% stenosis and a high rate of ICA leading to revascularization (72%), similar to the rates we found by adding FFR_CT to CTA in PROMISE (15% and 61%, respectively) (19). The similarity of these numbers are remarkable as all of our patients were referred to ICA from CTA, whereas this was not the case in PLATFORM.

In our study, 91% (80/88) of coronary revascularizations had a positive FFR_CT. This mirrors FAME, which found that 90% of patients considered for stenosis-guided revascularization had a positive invasive FFR (7). The sound agreement of positive FFR_CT with observed clinical decisions to pursue revascularization in PROMISE is notable, as FFR_CT was measured independent of clinical care and not available to caregivers. This finding is also important as in PROMISE nearly all revascularization decisions were made without the guidance of invasive FFR, which reflected practice in the community at that time (20). Although there was no significant difference in outcomes between CTA and functional arms of PROMISE, our data provide some reassurance that most coronary revascularizations were likely performed in hemodynamically significant lesions.

Limitations of the data and FFR_CT technique should be considered. One-half of patients referred to ICA from CTA were excluded by prespecified entry criteria, mostly because they did not follow SCCT guidelines for standard CTA including administration of nitroglycerin and high image pixel resolution (12). Guidelines recommend nitroglycerin and high resolution images for standard coronary CTA as they aid the diagnosis of stenosis; they are also necessary for FFR_CT as they provide a better approximation of the vessel anatomy under maximal hyperemia (13,21). Presumably more sites would have followed these now standard practices had they known that FFR_CT would be performed. Furthermore, CT technology has advanced rapidly since PROMISE, and the data likely do not represent the current state of the art. In PROMISE, most CTA was performed on standard 64-slice CT scanners, with only 17% using advanced CT scanners that have since been succeeded by a new generation of CT equipment.

FFR_CT has different image quality requirements than traditional assessment for stenosis. When confronted with motion artifact, physicians interpreting CTA for stenosis often integrate multiple cardiac phases to piece together a complete coronary artery. In contrast, the current implementation of FFR_CT requires that the entire coronary tree and myocardium be evaluable on a single cardiac phase. A third (33%) of the CTAs sent to the FFR_CT core lab were inadequate for FFR_CT analysis — this is higher than reported in dedicated FFR_CT trials such as NXT (13% inadequate, 10 European and Asian sites) and PLATFORM (12% inadequate, 11 European sites) (9,19). This may be explained by the fact that NXT and PLATFORM were dedicated FFR_CT studies_, with sites receiving specific FFR_CT training and feedback including standard administration of nitroglycerin and appropriate image reconstruction. In contrast, PROMISE sites did not know that FFR_CT would be performed and did not receive specific FFR_CT training or feedback.

In this observational study, the results of FFR_CT were not available to caregivers and did not affect clinical decision making. We can only project how physicians would have used the FFR_CT results had they been available. Six patients had PCI with a FFR_CT >0.80. Previous trials found that FFR_CT has good accuracy compared to invasive FFR and that revascularization can be safely deferred with a FFR_CT >0.80, but due to the observational design we cannot know for certain what would have happened in these 6 patients. A final limitation is the small sample size and low number of outcomes in keeping with the low event rate in the PROMISE trial. Hospitalization for unstable angina was the most common adverse event and had the potential for bias, as it may have been triggered by the knowledge that CAD was present on CTA.

Conclusions

In this hypothesis-generating study of patients with stable chest pain referred to ICA after CTA, we found that adding FFR_CT may improve the efficiency of referral to ICA, addressing a major concern of an anatomic CTA strategy. FFR_CT has incremental value over anatomic CTA in predicting revascularization or major adverse cardiovascular events.

Perspectives.

Competency in Medical Knowledge

Fractional flow reserve derived noninvasively from coronary CTA (FFR_CT) can assess the functional importance of coronary lesions.

Competency in Patient Care and Procedural Skills

Guidelines recommend determining the functional significance of coronary lesions prior to revascularization.

Translational Outlook

_CT substudy data suggest that FFR_CT is associated with observed revascularization and MACE. The addition of FFR_CT to CTA has the potential to improve efficiency of management of patients with stable chest pain who are referred to ICA after CTA.

Abbreviations

CABG

coronary artery bypass grafting

CAD

coronary artery disease

CTA

computed tomography angiography

FFR

invasive fractional flow reserve measured during ICA

FFR_CT

noninvasive fractional flow reserve derived from CTA

ICA

invasive coronary angiography

MI

myocardial infarction

PCI

percutaneous coronary intervention

PLATFORM

Prospective LongitudinAL Trial of FFR_CT: Outcome and Resource Impacts

PROMISE

PROspective Multicenter Imaging Study for Evaluation of Chest Pain