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Clinical outcomes of fractional flow reserve by
computed tomographic angiography-guided
diagnostic strategies vs. usual care in patients
with suspected coronary artery disease: the
prospective longitudinal trial of FFRct: outcome
and resource impacts study
Pamela S. Douglas1*, Gianluca Pontone2, Mark A. Hlatky3, Manesh R. Patel1,
Bjarne L. Norgaard4, Robert A. Byrne5, Nick Curzen6, Ian Purcell7,
Matthias Gutberlet8, Gilles Rioufol9, Ulrich Hink10, Herwig Walter Schuchlenz11,
Gudrun Feuchtner12, Martine Gilard13, Daniele Andreini2, Jesper M. Jensen4,
Martin Hadamitzky5, Karen Chiswell1, Derek Cyr1, Alan Wilk14, Furong Wang14,
Campbell Rogers14, and Bernard De Bruyne15, On Behalf of the PLATFORM
Investigators†
1
Duke Clinical Research Institute, Duke University School of Medicine, 7022 North Pavilion DUMC, PO Box 17969, Durham, NC 27715, USA;
2
Centro Cardiologico Monzino, IRCCS,
University of Milan, Milan, Italy;
3
Department of Health Research and Policy, Stanford University School of Medicine, Stanford, CA, USA;
4
Department of Cardiology, Aarhus University
Hospital, Aarhus Skejby, Denmark;
5
Deutsches Herzzentrum Mu¨nchen, Technische Universita¨t Mu¨nchen, Munich, Germany;
6
University Hospital Southampton NHS Trust,
Southampton, UK;
7
Freeman Hospital, Newcastle upon Tyne, UK;
8
University of Leipzig Heart Centre, Leipzig, Germany;
9
Hospices Civils de Lyon and CARMEN INSERM 1060, Lyon,
France;
10
Department of Cardiology, Johannes Gutenberg University Hospital, Mainz, Germany;
11
LKH Graz West, Graz, Austria;
12
Department of Radiology, Innsbruck Medical
University, Innsbruck, Austria;
13
Department of Cardiology, Cavale Blanche Hospital, Brest, France;
14
HeartFlow, Redwood City, CA, USA; and
15
Cardiovascular Centre Aalst, Aalst,
Belgium
Received 6 July 2015; revised 6 August 2015; accepted 12 August 2015
Aims In symptomatic patients with suspected coronary artery disease (CAD), computed tomographic angiography (CTA)
improves patient selection for invasive coronary angiography (ICA) compared with functional testing. The impact of
measuring fractional flow reserve by CTA (FFR
CT
) is unknown.
Methods
and results
At 11 sites, 584 patients with new onset chest pain were prospectivelyassigned to receive either usual testing (n¼287)
or CTA/FFR
CT
(n¼297). Test interpretation and care decisions were made by the clinical care team. The primary end-
point was the percentage of those with planned ICA in whom no significant obstructive CAD (no stenosis ≥50% by
core laboratory quantitative analysis or invasive FFR ,0.80) was found at ICA within 90 days. Secondary endpoints
including death, myocardial infarction, and unplanned revascularization were independently and blindly adjudicated.
Subjects averaged 61 +11 years of age, 40% were female, and the mean pre-test probability of obstructive CAD
was 49 +17%. Among those with intended ICA (FFR
CT
-guided ¼193; usual care ¼187), no obstructive CAD was
found at ICA in 24 (12%) in the CTA/FFR
CT
arm and 137 (73%) in the usual care arm (risk difference 61%, 95%
confidence interval 53– 69, P,0.0001), with similar mean cumulative radiation exposure (9.9 vs. 9.4 mSv,
*Corresponding author. Tel: +1 919 681 2690, Fax: +1 919 668 7059, Email: pamela.douglas@duke.edu
†
Members are listed in Appendix.
&The Author 2015. Published by Oxford University Press on behalf of the European Society of Cardiology.
This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License (http://creativecommons.org/licenses/by-nc/4.0/), which
permits non-commercial re-use, distribution, and reproduction in any medium, provided the original work is properly cited. For commercial re-use, please contact
journals.permissions@oup.com
European Heart Journal
doi:10.1093/eurheartj/ehv444
.....................................................................................................................................................................................
P¼0.20). Invasive coronary angiography was cancelled in 61% after receiving CTA/FFR
CT
results. Among those with
intended non-invasive testing, the rates of finding no obstructive CAD at ICA were 13% (CTA/FFR
CT
) and 6% (usual
care; P¼0.95). Clinical event rates within 90 days were low in usual care and CTA/FFR
CT
arms.
Conclusions Computed tomographic angiography/fractional flow reserve by CTA was a feasible and safe alternative to ICA and was
associated with a significantly lower rate of invasive angiography showing no obstructive CAD.
-----------------------------------------------------------------------------------------------------------------------------------------------------------
Keywords Angina †Coronary computed tomographic angiography †Fractional flow reserve †Non-invasive testing
Introduction
Stable chest pain is a common clinical presentation that often requires
further investigation using non-invasive or invasive testing.
1
The goals
of testing include clarifying the diagnosis, documenting the presence
or absence of coronary artery disease (CAD), and directing subse-
quent care, whether revascularization, intensified medical treatment,
or both, while maximizing efficiency and patient safety.
2
The recently
completed PROMISE
3
and SCOT-HEART
4
trials suggest that an
evaluation strategy based on coronary computed tomographic angi-
ography (CTA) increases diagnostic certainty, improves efficiency of
triage to invasive catheterization, and may reduce radiation exposure
when compared with functional stress testing, with similar rates of
cardiac events. Moreover, in PROMISE, CTA increased the rate of in-
vasive catheterization by almost 50% compared with functional test-
ing, and over a quarter of these patients did not have obstructive
CAD identified by invasive angiography. Since CTA provided only
anatomic information and invasive fractional flow reserve (FFR) was
rarely used, revascularizations guided by a CTA strategy were gener-
ally performed without evidence of the functional significance of cor-
onary stenoses, at variance with practice guidelines.
5
This is an
important consideration since CTA in PROMISE doubled the rate
of coronary revascularization compared with functional testing.
A diagnostic strategy that provides both anatomic and functional
data could address this limitation and potentiallyafford enhanced ef-
ficiency and safety. Recently, a non-invasive method to determine
the haemodynamic significance of coronary stenoses has been de-
veloped that computes the fractional flow reserve by computed
tomographic angiography (FFR
CT
) based on computational fluid dy-
namics and simulated maximal coronary hyperaemia.
6
Fractional
flow reserve by computed tomographic angiography has been vali-
dated against invasively measured FFR as a reference standard,
7–9
but there are no data on the clinical utility of this new method
and how its use may affect patient care and clinical outcomes.
The present study was designed to test the hypotheses that patients
with suspected CAD evaluated using a CTA/FFR
CT
-guided strategy
would have fewer invasive angiograms that showed no obstructive
CAD than would patients who were evaluated based on standard
practice, and would have similar and low rates of major cardiac events.
Methods
Study design
PLATFORM is a prospective, consecutive cohort study utilizing a
comparative effectiveness observational design (ClinicalTrials.gov num-
ber NCT01943903).
10
The study was conducted with fidelity to the
protocol (see Supplementary material online). Local or central institu-
tional review boards approved the study at the 11 enrolling European
sites and at Duke Clinical Research Institute (DCRI); all subjects pro-
vided written informed consent.
Study participants
PLATFORM subjects were symptomatic outpatients ≥18 years old
without known CAD, but with an intermediate likelihood of obstructive
CAD, whose physician had planned non-emergent, non-invasive, or
invasive cardiovascular testing to evaluate suspected CAD. Exclusion
criteria were (i) acute coronary syndrome or clinical instability, (ii) pre-
viously documented CAD, (iii) contraindications to CTA, and (iv)
needed emergent or urgent procedure. Additional exclusion criteria in-
cluded recent cardiovascular testing (,90 days) (see Supplementary
material online, Table S1 for full inclusion and exclusion criteria).
Study procedures
Subjects were enrolled in two consecutive cohorts assigned to receive
the planned usual care testing or CTA/FFR
CT
testing. All sites enrolled
patients into both cohorts, and each site had to complete enrolment of
the planned number of usual care subjects before enrolling any CTA/
FFR
CT
subjects. Each cohort was subdivided into two groups based
on the evaluation plan decided upon before enrolment in the study:
non-invasive testing (any form of stress testing or CTA without FFR
CT
)
or invasive coronary angiography (ICA) (Figure 1). For balance, no cen-
tre could enrol .30 subjects in either planned non-invasive group or
.145 subjects in the trial.
In the CTA/FFR
CT
cohort, all subjects underwent CTA instead of the
planned non-invasive or invasive evaluation. Fractional flow reserve by
computed tomographic angiography analyses were performed centrally
when requested by the site (recommended if the CTA revealed ≥30%
stenosis or if the patient was referred to ICA).
Optimal medical therapy was encouraged in all groups, and local phy-
sicians made all subsequent clinical decisions following standard prac-
tice,
2
including cancelling or ordering additional testing or procedures.
Follow-up visits were performed at 90 days, 6 months, and 12 months
from study entry. Enrolment began on 10 September 2013 and was
completed on 26 November 2014. There were no major protocol
amendments. This article reports 90-day clinical results.
Diagnostic non-invasive and invasive testing
All usual care testing, including CTA, was performed and interpreted lo-
cally according to standard practices at the enrolling site. All CTAs uti-
lized a ≥64-slice multi-detector, single- or dual-source CT scanner and
followed scanning protocols satisfying Society of Cardiac Computed
Tomography quality standards.
11
An independent angiographic core la-
boratory (DCRI) performed all quantitative coronary angiography
(QCA) measurements using QAngio software (Medis, the Netherlands)
according to standard procedures.
12,13
P.S. Douglas et al.Page 2 of 9
Fractional flow reserve by computed tomographic angiography ana-
lysis was performed centrally (HeartFlow) as previously described.
6–8
Briefly, three-dimensional blood flow simulations in the coronary vascu-
lature were performed using proprietary software, with quantitative im-
age quality analysis, image segmentation, and physiological modelling
using computational fluid dynamics. Coronary blood flow was simulated
under conditions that modelled intravenous adenosine to mirror pres-
sure and flow data and the FFR numeric values that would have been ob-
tained during an invasive evaluation. Data provided to the clinical site
included the lowest FFR
CT
numeric value in each coronary distribution,
and colour-scale representations of the coronary tree showing FFR
CT
values in all vessels .1.8 mm in diameter (see Supplementary material
online for a sample FFR
CT
report).
Effectiveness and safety endpoints
The primary endpoint was the rate of ICA within 90 days that showed no
obstructive CAD in patients who had invasive testing planned before en-
rolment, comparing those receiving usual care to those allocated to
CTA/FFR
CT
. Obstructive disease was defined as either (i) an invasively
measured FFR ≤0.80 in any segment, regardless of degree of stenosis,
or (ii) QCA stenosis ≥50% in a vessel ≥2.0 mm diameter without an
invasively measured FFR .0.80 in the same distribution (see Supple-
mentary material online, Table S2 for endpoint definitions). A secondary
endpoint was the comparison of the rate of ICA with no obstructive
CAD in those with planned non-invasive testing. The major safety end-
point was a composite of major adverse cardiovascular events (MACE)
at 90 days: all-cause mortality, myocardial infarction (MI), and unplanned
hospitalization for chest pain leading to urgent revascularization. An in-
dependent clinical events committee (DCRI) adjudicated all MACE in a
blinded fashion based on standard, prospectively determined
definitions.
14
Cumulative radiation exposure within 90 days of study entry included
all cardiovascular tests and invasive procedures, including CTA, myocar-
dial perfusion imaging, and ICA. Radiation exposure for study CTAs was
calculated from dose length product measured in mGY ×cm using the
formula mSv ¼(dose length product) ×0.014, or was imputed using
the median measured value; other exposures were imputed using stand-
ard published doses of 7 mSv for ICA, 15 mSv for percutaneous coron-
ary intervention, and 14 mSv for myocardial perfusion imaging.
15
Statistical analysis
The primary endpoint (rate of ICA showing no obstructive CAD in pa-
tients with invasive testing planned prior to enrolment) was compared
between the usual care invasive testing vs. CTA/FFR
CT
-guided care
arms. The risk difference and 95% confidence interval (CI) were deter-
mined, and a one-sided Wald test (
a
error ¼0.025) for a risk difference
,0 was used to evaluate whether CTA/FFR
CT
was superior to usual
testing. Enrolment of 380 subjects in the planned invasive care arm
(190 usual care and 190 CTA/FFR
CT
guided) was estimated to provide
the study with 90% power to detect a 50% reduction in the frequency of
ICA documenting non-obstructive CAD at a one-sided 0.025 level of
significance, assuming an event rate of 30% in the usual care arm and
15% in the CTA/FFR
CT
-guided arm, and a dropout rate of 10%.
Figure 1 Enrolment, allocation, and follow-up of the study patients. NI, non-invasive; ICA, invasive coronary angiography; FFR
CT
, computation
of fractional flow reserve from coronary computed tomographic angiography data; CTA, computed tomographic angiography; PCI, percutaneous
coronary intervention; CABG, coronary artery bypass grafting. *One subject withdrew consent for use of any of his/her data. In keeping with
relevant national law, this subject is not included in any data listing or analysis.
FFR
CT
-guided diagnostic strategies vs. usual care Page 3 of 9
All statistical assessments were independently confirmed by DCRI.
All analyses were performed comparing patients as allocated, either in
aggregate or within the planned non-invasive or invasive test groups. Ex-
ceptions to this include four additional analyses of the primary endpoint:
(i) reanalysis in propensity score matched subpopulations of subjects
using age, sex, diabetes, smoking status, and type of angina (see below);
(ii) assessment in pre-specified subgroups: age, sex, race/ethnicity,
diabetes status, pre-test probability of obstructive CAD (updated Dia-
mond and Forrester score),
16
and country of enrolment; (iii) acceptable
image quality population excluding subjects in the CTA/FFR
CT
arm with
unavailable or uninterpretable CTA images; and (iv) best practices per
protocol analysis as determined by independent central adjudication,
excluding those CTA/FFR
CT
subjects who underwent ICA but for
whom CTA/FFR
CT
did not support the need for ICA and those who
did not undergo ICA but for whom CTA/FFR
CT
did support the need
for ICA.
Baseline characteristics were summarized and compared across usual
care and CTA/FFR
CT
-guided care cohorts. Continuous variables are
presented as mean +SDandwerecomparedusingStudent’st-test
or the Wilcoxon rank-sum test. Categorical variables are presented
as counts (percentages) and were compared using the Pearson
x
2
test, or with Fisher’s exact test if cell frequencies were not sufficient.
The level of statistical significance was set to 0.0025 using the Bonferroni
correction to adjust for multiple comparisons.
Although extensive analysis of baseline characteristics indicated no
significant differences between the cohorts, since group assignment
was not randomized, a sensitivity analysis of the primary endpoint was
performed using propensity score matching (see Supplemental material
online for propensity scoring methods used). The propensity score was
estimated based on age, sex, diabetes, smoking status, and type of angina
using multivariable logistic regression, and subjects were matched using
a greedy algorithm.
17
All analyses were performed using SAS version 9.3 (Cary, NC, USA),
and a P-value of ,0.05 was considered statistically significant, unless
otherwise specified. No interim analyses were performed.
Results
Study population
The study population (Figure 1) consisted of 584 enrolled and con-
sented patients followed for 90 days. Complete 12-month follow-up
is planned; 90-day data were obtained in 563 subjects (96.4%).
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Table 1 Baseline characteristics of the study participants, according to study group
Variable Planned non-invasive test (N5204) Planned invasive test (N5380)
Usual care strategy
(n5100)
FFR
CT
-guided
strategy (n5104)
P-value Usual care strategy
(n5187)
FFR
CT
-guided strategy
(n5193)
P-value
Demographics
Age, mean +SD (years) 57.9 +10.7 59.5 +9.3 0.25 63.4 +10.9 60.7 +10.2 0.02
Female sex, no. (%) 34 (34.0) 44 (42.3) 0.22 79 (42.2) 74 (38.3) 0.44
Racial/ethnic minority
(self-reported), no. (%)
5 (5.0) 0 (0.0) 0.06 2 (1.1) 1 (0.5) 0.60
Cardiac risk factors
BMI, mean +SD (kg/m
2
) 26.0 +3.0 27.3+3.9 0.01 27.2 +3.8 27.1 +3.9 0.62
Hypertension, no. (%) 38 (38.0) 57 (54.8) 0.02 111 (59.4) 111 (57.5) 0.72
Diabetes, no. (%) 8 (8.0) 6 (5.8) 0.52 36 (19.3) 30 (15.5) 0.33
Dyslipidaemia, no. (%) 22 (22.0) 28 (26.9) 0.49 76 (40.6) 77 (39.9) 0.81
Current or past tobacco use,
no. (%)
52 (52.0) 59 (56.7) 0.50 103 (55.1) 101 (52.3) 0.59
Mean number of risk
factors +SD
a
1.2 +0.93 1.4+0.92 0.92 1.7 +1.02 1.7 +1.09 0.41
Pre-test probability of
obstructive CAD +SD
b
(%)
44.5 +15.3 45.3 +16.8 0.89 51.7 +16.7 49.4 +17.2 0.26
Relevant medications, no. (%)
Aspirin 29 (29.0) 45 (43.3) 0.039 115 (61.5) 90 (46.6) 0.004
Statin 24 (24.0) 29 (27.9) 0.58 83 (44.4) 77 (39.9) 0.37
Anginal type, no. (%) 0.018 0.09
Typical angina 8 (8.0) 18 (17.3) 52 (27.8) 45 (23.3)
Atypical angina 91 (91.0) 80 (76.9) 122 (65.2) 142 (73.6)
Non-cardiac chest pain 1 (1.0) 6 (5.8) 13 (7.0) 5 (2.6)
BMI, body mass index (weight in kilograms divided by the square of the height in metres); CAD, coronary artery disease; CT, computed tomographic angiography; SD, standard
deviation.
a
Includes hypertension, diabetes, dyslipidaemia, and tobacco use.
b
Mean pre-test probability of obstructive CAD +SD calculated by updated Diamond and Forrester score.
16
P.S. Douglas et al.Page 4 of 9
Baseline characteristics
Patient age averaged 60.9 years and 231 (39.6%) were women
(Table 1). Diabetes was present in 13.7%, hypertension in 54.3%, his-
tory of smoking in 53.9%, and dyslipidaemia in 34.8% (Table 1). Typ-
ical chest pain was the presenting symptom in 123 (21.1%) and
atypical pain in 435 (74.5%). The mean pre-test probability of ob-
structive CAD was 49 +17%. All baseline characteristics were simi-
lar between the usual care and FFR
CT
-guided care cohorts and
within the planned non-invasive and invasive test groups.
Allocation and testing
Among the 204 participants who had a non-invasive test planned for
cardiac evaluation, 100 were allocated to usual care (Figure 1). The
non-invasive tests performed are listed in Supplementary material
online, Table S3. One hundred and four patients were allocated to
CTA/FFR
CT
, and 39 patients (37.5%) had at least one site inter-
preted stenosis ≥50%. Fractional flow reserve by computed tomo-
graphic angiography was requested in 67 patients (64.4%), but was
not completed in 7 (10.4%), due to poor image quality or inadequate
acquisition.
Among the 380 participants who had an invasive catheterization
(ICA) planned, 187 were allocated to and received ICA (usual care)
and 193 patients were allocated to and received a CTA/FFR
CT
; 118
patients (61%) had a stenosis ≥50%. Fractional flow reserve by
computed tomographic angiography was requested in 134
(69.4%) but was not completed in 17 (12.7%). Overall, there was
one reported adverse event from CTA testing, a mild contrast
reaction.
Outcome measures
Rates of ICA and findings of no obstructive disease by QCA and/or
FFR in the planned non-invasive testing group are shown in Table 2.
There was no difference in the secondary endpoint of the cohort
rate of ICA which did not show obstructive CAD according to
QCA: 6.0% usual care vs. 12.5% CTA/FFR
CT
;P¼0.95 (Table 2).
Among patients in the planned invasive testing groups, 187 pa-
tients (100%) underwent an ICA within 90 days in the usual care co-
hort, and 137 (73.3%) catheterizations did not show obstructive
disease by QCA and/or FFR (Figure 2,Table 2). In the CTA/FFR
CT
cohort, 76 (39.4%) underwent ICA, with 24 (31.6%) catheteriza-
tions showing no obstructive CAD. The primary endpoint of the
rate of ICA which did not show obstructive CAD in the planned in-
vasive testing group was found in substantially more subjects in the
usual care arm at 137 (73.3%) of 187 compared with 24 (12.4%) of
193intheCTA/FFR
CT
arm (risk difference 60.8%, 95% CI 53.0 –
68.7%, P,0.0001). Propensity score matching resulted in inclusion
of 148 patients in each group and yielded similar results (72% usual
care vs. 12% CTA/FFR
CT
,P,0.0001; see Supplementary material
online, Table S4), as did analysis of acceptable CTA image quality
(CAD was not found in 11.4% of the CTA/FFR
CT
arm), and a best
practices/per protocol analysis (obstructive CAD was not found
in 7.2%). Results were also similar in all subgroups examined (see
Supplementary material online, Table S5).
Only two MACE events occurred in the planned ICA group as-
signed to CTA/FFR
CT
-guided care. One was a peri-procedural MI
in a subject whose CTA was of insufficient quality for FFR
CT
analysis,
and the other was hospitalization for urgent revascularization
............................................................... ................................................................
...............................................................................................................................................................................
Table 2 Ninety-day outcomes according to study group
Planned non-invasive test (n5204) Planned invasive test (n5380)
Usual care
strategy (n5100)
FFR
CT
-guided
strategy (n5104)
P-value Usual care
strategy (n5187)
FFR
CT
-guided
strategy (n5193)
P-value
Invasive catheterization without obstructive CAD by core lab quantitative coronary angiography
No. (%) 6 (6.0) 13 (12.5) 0.95 137 (73.3) 24 (12.4) ,0.0001
Risk difference, % (95% CI) 26.5 (214.4 to 1.4) 60.8 (53.0–68.7)
Invasive catheterization without obstructive CAD by site interpretation
No. (%) 5 (5.0) 8 (7.7) 0.79 106 (56.7) 18 (9.3) ,0.0001
Risk difference (95% CI) 22.7 (29.4 to 4.0) 47.4 (39.2–55.6)
Secondary endpoint composite,
MACE, no. (%)
0 0 0 2 (1.0)
All-cause death 0 0 0 0
Non-fatal MI 0 0 0 1 (0.5)
Hospitalization with urgent
revascularization
0 0 0 1 (0.5)
MACE or vascular complications,
no. (%)
0 1 (1.0) 2 (1.1) 7 (3.6)
Cumulative radiation exposure
(enrolment to 90 days)
0.0002 0.20
Mean +SD (mSv) 5.8 +7.1 8.8 +9.9 9.4 +4.9 9.9+8.7
Median (IQR) (mSv) 2.3 (0 – 9.3) 3.9 (2.4– 11.6) 7.0 (7.0 –7.0) 7.9 (2.6–16.3)
CAD, coronary artery disease; CTA, computed tomographic angiography; MI, myocardial infarction; MACE, major adverse cardiovascular events; CI, confidence interval; IQR,
inter-quartile range; SD, standard deviation.
FFR
CT
-guided diagnostic strategies vs. usual care Page 5 of 9
following a CTA/FFR
CT
showing severe CAD. There were no events
in the 61% of CTA/FFR
CT
patients in whom ICA was cancelled. Vas-
cular complications were similarly rare (Table 2). Rates of MACE and
vascular complications were too low to assess non-inferiority.
Cumulative radiation exposure in patients with an intended non-
invasive evaluation is shown in Table 2. In patients with an intended
invasive evaluation, cumulative radiation exposure to 90 days was
similar in the usual care cohort (9.4 mSv) and the CTA/FFR
CT
co-
hort (9.9 mSv, P¼0.2). Across both CTA/FFR
CT
cohorts, CTA ra-
diatio n ave raged 5 .2 +5.4 mSv (9.0 +6.7 mSv for retrospective
scans, 3.0 +1.6 mSv for prospectively gated scans).
There were no differences in rates of revascularization in subjects
allocated to CTA/FFR
CT
vs. usual care in either the planned non-
invasive or planned invasive testing arms; P¼0.29 and 0.58.
Information available for invasive
catheterization and revascularization
In subjects in the planned non-invasive group proceeding to ICA or
revascularization, there were no differences between the two arms
in the proportion with functional data available (see Supplementary
material online, Table S6).
In subjects in the planned invasive group proceeding to ICA, func-
tional information was available in 83 of the 187 (44.4%) usual care
subjects compared with 74 of 76 (97.4%) in the CTA/FFR
CT
group;
P,0.0001. Among those proceeding to revascularization, function-
al information was available in 30 of 59 (50.8%) in the usual care
cohort vs. 53 of 55 (96.3%) patients in the CTA/FFR
CT
;P,0.0001.
Discussion
Current guidelines recommend that stable chest pain patients be
evaluated with non-invasive stress testing, yet the rates of invasive
angiograms showing no obstructive CAD remain high.
18,19
The
PLATFORM study showed that, in patients with planned ICA, a
diagnostic strategy based on CTA/FFR
CT
yielded a significantly low-
er rate of ICA showing no obstructive CAD. In patients with
planned non-invasive testing, there was no difference between use
of CTA/FFR
CT
and usual care. Clinical events through 90 days were
rare with either strategy.
The goals of the diagnostic evaluation of patients with stable
chest pain include identifying those individuals needing catheteriza-
tion as well as those who cannot benefit, and providing optimal
guidance for subsequent care. Two recent trials provide evidence
that non-invasive visualization of the coronary arteries using CTA
enhances diagnostic certainty and appropriately alters diagnostic
and therapeutic plans, with comparable clinical outcomes.
3,4
How-
ever, CTA increased the rate of referral to ICA and revasculariza-
tion by up to 50%.
3
Because the use of adjunctive invasive measures
such as FFR to assess haemodynamic significance was rare, in keep-
ing with current practice,
20
a CTA-only strategy resulted in revas-
cularization with little understanding of the ischaemia-producing
potential of coronary lesions, as recommended for appropriate
revascularization and optimal outcomes.
5,21,22
Our data demon-
strate that it is possible to obtain both anatomic and functional
information non-invasively, and that doing so reduces the rate of
finding no obstructive CAD at catheterization among those with
planned ICA.
The low adverse clinical event rate in PLATFORM is similar to re-
cent trials
3,4
and indicates that studies of non-invasive testing in a
contemporary chest pain population should, in addition to clinical
events, consider use of endpoints such as changes in care plans, ef-
ficiency of diagnosis, and quality of information guiding care. To this
end, the remarkable reduction in the primary endpoint of not finding
obstructive CAD at ICA, and the lower overall rate of ICA, coupled
with the higher rate of revascularizations informed by haemo-
dynamic significance or ischaemia, suggest that use of CTA/FFR
CT
more effectively triages patients for invasive procedures than usual
care strategies.
Figure 2 Determination of the rate of invasive catheterization without obstructive coronary artery disease. NI, non-invasive; ICA, invasive
coronary angiography; Obs CAD, obstructive coronary artery disease; FFR
CT
, computation of fractional flow reserve from coronary computed
tomographic angiography data.
P.S. Douglas et al.Page 6 of 9
The rate of finding no obstructive CAD in our usual care ICA pa-
tients was high, but was determined by core laboratory QCA. The
corresponding rate using site visual readings was lower (57%), iden-
tical to population studies
19,20
reporting that 54 – 62% of elective
catheterizations do not have obstructive disease. The higher rate
by QCA is consistent with known differences between the two
assessment techniques.
23
Although FFR
CT
is a relatively new technique, PLATFORM de-
monstrates that it is feasible and safe in busy clinical settings. Overall,
90% of CTAs had acceptable image quality for analysis, and radiation
averaged 5.2 +5.4 mSv, less than the average level of 14 mSv noted
in the literature for nuclear stress testing.
15
Use of FFR
CT
improved
the availability of functional data available in those referred to ICA
(96% CTA/FFR
CT
vs. 45% usual care), and those referred to revas-
cularization (95% CTA/FFR
CT
vs. 55% usual care), allowing compli-
ance with current recommendations supporting use of both
anatomic and functional data in decision-making.
5
While still high,
the rate of revascularization performed without functional data in
usual care patients is improved from previous reports of 55%.
24
PLATFORM adds substantially to both the PROMISE and
SCOT-HEART trials.
3,4
Compared with PROMISE, the addition of
FFR
CT
functional information in PLATFORM to the anatomic CTA
information prevented the reported 50% increase in catheteriza-
tions and revascularizations. PLATFORM builds on SCOT-HEART’s
finding of increased diagnostic certainty with CTA by noting cancel-
lation of ICA in 61% of the CTA/FFR
CT
arm and a dramatically lower
rate of finding no obstructive CAD. Like these studies, PLATFORM
provides prospective data essential to evaluating and optimizing the
role of non-invasive testing as a gatekeeper to catheterization.
While PLATFORM has many strengths, it is important to note
that the sample size and follow-up duration are insufficient to detect
an impact on clinical outcomes. Although not randomized, PLAT-
FORM differs substantially from most observational studies by re-
quiring a carefully controlled ‘experimental’ intervention in the
CTA/FFR
CT
groups, and core lab angiographic reading. The study’s
rigour is further enhanced by basing all analyses on the prospective
allocation of patients into cohorts regardless of actual care. Use of
an initial roll-in group of usual care ‘control’ patients provided a de-
tailed, real-time snapshot of contemporaneous practice at enrolling
centres, rather than using historical controls. Even in a randomized
trial it would have been impossible to blind investigators to the re-
sults of testing since they are needed for clinicians to determine
downstream care. Further, the current approach reflects clinical re-
search trends favouring pragmatic design and effectiveness (vs. effi-
cacy) evaluations. The multiple sensitivity analyses of the primary
endpoint, yielding similar results, document that our findings are ro-
bust and free of significant verification bias.
In conclusion, when used as an alternative diagnostic strategy to
guide care in those with planned invasive catheterization, CTA/
FFR
CT
was associated with a significantly lower rate of angiography
showing no obstructive CAD.
Authors’ contributions
K.C., D.C., A.W., and F.W.: performed statistical analysis. P.S.D., G.P.,
M.A.H., M.R.P., B.L.N., C.R., and B.D.B.: handled funding and super-
vision. G.P., B.L.N., R.A.B., N.C., I.P., M.G., G.R., U.H., H.W.S., G.F.,
M.G., D.A., J.M.J., and M.H.: acquired the data. P.S.D., G.P., M.A.H.,
M.R.P., B.L.N., C.R., and B.D.B.: conceived and designed the re-
search. P.S.D.: drafted the manuscript. P.S.D., G.P., M.A.H., M.R.P.,
K.C., D.C., A.W., C.R., and B.D.B.: made critical revision of the
manuscript for key intellectual content.
Supplementary material
Supplementary material is available at European Heart Journal online.
Acknowledgements
We thank the patients who participated in the PLATFORM trial and
Auben Debus, Peter Hoffmann, Judith Jaeger, and Beth Martinez for
their contributions to the study.
Funding
This work was supported by HeartFlow, Inc., Redwood City, CA, USA.
Duke Clinical Research Institute independently performed QCA, adju-
dicated clinical events, and verified the primary and secondary endpoint
determinations. There were no data confidentiality agreements. An Ex-
ecutive Committee oversaw trial design and study conduct, final data re-
view, and presentation and publication of results, independently making
the decision to publish. The investigators independently drafted the
manuscript and take full responsibility for the accuracy and complete-
ness of data analyses.
Conflict of interest: P.S.D. has received grants from HeartFlow during
the conduct of the study and other support from GE Medical Systems
outside the submitted work; M.A.H. has received grants from Heart-
Flow during the conduct of the study; M.R.P. has received grants from
HeartFlow during the conduct of the study, and grants from Jansen,
Johnson & Johnson, Astra Zeneca, NHLBI, and AHRQ, and personal
fees from Astra Zeneca, Bayer, and Otsuka outside the submitted
work; R.A.B. has received grants from HeartFlow during the conduct
of the study and personal fees from B. Braun, Biotronik, and Boston Sci-
entific outside the submitted work; N.C. has received grants from Bos-
ton Scientific and Medtronic, and grants and personal fees from
HeartFlow, Haemonectics, and St Jude Medical outside the submitted
work; G.R. has received grants from HeartFlow during the conduct of
the study, and personal fees from Saint Jude Medical and Boston Scien-
tific outside the submitted work; D.A. has received grants and personal
fees from GE Healthcare, outside the submitted work; M.H. has re-
ceived grants from Siemens Healthcare outside the submitted work;
K.C. has received support from HeartFlow during the conduct of the
study; F.W. and C.R. have received personal fees and other support
from HeartFlow during the conduct of the study and outside the submit-
ted work; B.D.B. has received grants from Abbott, St. Jude Medical, and
Medtronic, and other support from St. Jude Medical, Boston Scientific,
Opsens, Omega Pharma, Siemens, Edwards, GE, Sanofi, HeartFlow, and
Bayer outside the submitted work.
Appendix
PLATFORM trial organization
Sites, principal/site investigators, and staff
Milan, Italy: Principal Investigator: Gianluca Pontone; Site Investiga-
tors: Antonio Bartorelli, Daniele Andreini, Maurio Pepi, Francesco
Alamanni; Staff: Erika Bertella, Saima Mushtaq, Virginia Beltrama,
FFR
CT
-guided diagnostic strategies vs. usual care Page 7 of 9
Andrea Baggiano; Aarhus, Denmark: Principal Investigator: Bjarne
Norgaard; Site Investigators: Sara Gaur, Jesper Moller Jensen; Staff:
Lone Romby, Jette R Broderson, Lene Hjelm; Munich, Germany:
Principal Investigator: Robert Byrne; Site Investigators: Elena Guer-
ra, Oliver Husser, Tobias Koppara, Jonathan Nadjiri, Martin Hada-
mitzky, Janina Winogradow, Janika Repp, Severin Weigand, Fritz
Wimbaur, Raphazza Lohaus, Philipp Montz Rumpf, Elke Lorenz;
Staff: Gisela Schoemig, Karin Hosl, Judith Ruf, Marco Valenski Ines
Zenullahi; Southampton, UK: Principal Investigator: Nick Curzen;
Site Investigators: James Shambrook, Simon Corbett, Iain Simpson,
Alison Calver, James Wilkinson; Staff: Zoe Nicholas, Judith Ann Rad-
more, Bryony Tyrell, Claire Elridge, Rayner Lacoste; Newcastle, UK:
Principal Investigator: Ian Purcell, Site Investigators: Rajiv Das, Ifti-
khar Haq, Azfar Ghaus Zaman, I Spyridopoulos, Alan Bagnall, J
Ahmed; Staff: Alla Narytnyk, Jennifer Adams-Hall, Leslie Bremner,
Susan Hetherington, Sarah Lamb, Angela Phillipson, Rebecca Wil-
son, Kathryn Procter, Samantha Jones, Victoria Andrianna Richard-
son, Louise Quinn, Vera Wealleans, Sarah Rowling, Chris Price;
Leipzig, Germany: Principal Investigator: Matthias Gutberlet, Site In-
vestigators: Lukas Lehmkuhl, Michael Woinke, Gerhard Schuler,
Daniel Urban, Christian Lu¨cke; Staff: Fabian Juhrich, Kathrin Luderer,
Jacqueline Fohlisch, Carola Dohnert; Lyon, France: Principal Investi-
gator: Gilles Rioufol; Site Investigators: Ge
´rard Finet, Philippe
Douek; Staff: Yvonne Varillon, Delphine Laval, Adeline Mansuy,
Pauline Renaudin, Muriel Rageade; Mainz, Germany: Principal Inves-
tigator: Ulrich Hink; Site Investigators: Karl Kreitner, Alexander Jabs,
Yang Yang, Tommaso Gori; Staff: Ba¨rbel Kaesberger; Graz, Austria:
Principal Investigator: Herwig Schuchlenz; Site Investigators: Dieter
Botegal, Martin Genger, Peter Zechner, Wolfgang Weihs, Peter
Kullnig, Walter Kau; Staff: Stefan Weikl; Innsbruck, Austria: Principal
Investigator: Gudrun Feuchtner; Site Investigator: Guy Friedrich;
Staff: Fabian Plank; Brest, France: Principal Investigator: Martine
Gilard, Site Investigators: Jacques Boschat, Philippe Castellant,
Romain Didier; Staff: Franc¸oise Martin.
Executive committee
Pamela S. Douglas, Duke Clinical Research Institute, Durham, NC,
USA
Bernard De Bruyne, OLV Hospital, Aalst, Cardiovascular Centre,
Aalst, Belgium
Mark Hlatky, Stanford University, Department of Health Research
and Policy, Stanford, CA, USA
B.L. Norgaard, Aarhus University Hospital Aarhus Skejby, Denmark
Manesh Patel, Duke Clinical Research Institute, Durham, NC, USA
Gianluca Pontone, Centro Cardiologico Monzino, IRCCS, Milan,
Italy
Campbell Rogers, HeartFlow, Redwood City, CA, USA
Clinical events committee
Duke Clinical Research Institute, Durham, NC, USA
Manesh Patel, Christopher Fordyce, Joni O’Briant
Quantitative coronary angiography
laboratory
Duke Clinical Research Institute, Durham, NC, USA
Manesh Patel, W. Schuyler Jones, Rohan Shah, Gary Dunn, Alicia
Lowe
Clinical operations
Duke Clinical Research Institute, Durham, NC, USA
Beth Martinez
HeartFlow, Redwood City, CA, USA
Auben Debus, Judi Jaeger, Furong Wang, Alan Wilk
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FFR
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EDITORIAL
FFR
CT
:anewtechnologyinsearchofaclinical
application
Troy M. LaBounty*and Brahmajee K. Nallamothu
Department of Medicine, University of Michigan Health System, Ann Arbor, MI, USA
This editorial refers to ‘Clinical outcomes of fractional flow
reserve by computed tomographic angiography-guided
diagnostic strategies vs. usual care in patients with sus-
pected coronary artery disease: the prospective longitudin-
al trial of FFR
CT
: outcome and resource impacts study’, by
P.S. Douglas et al., doi:10.1093/eurheartj/ehv444.
Our general approach to grading coronary lesions—by percentage
of diameter stenosis—is overly simplistic and ignores important
laws of fluid haemodynamics. As a result, stenosis assessment by in-
vasive coronary angiography (ICA) often underestimates or overes-
timates the physiological significance of lesions as compared with
functional testing, such as fractional flow reserve (FFR).
1
Indeed,
the use of FFR to guide revascularization in patients with coronary
artery disease (CAD) reduces the rate of revascularization and ad-
verse cardiac events,
2
which has prompted interest in developing
non-invasive alternatives to it such as coronary CT angiography
(CTA)-derived fractional flow reserve (FFR
CT
).
FFR
CT
is a novel technique that applies computational fluid
haemodynamics to standard CTA images. This models the resting
and hyperaemic pressure of coronary arteries to estimate the
physiological significance of lesions, and may identify myocardial ter-
ritories expected to experience ischaemia.
3
By identifying anatomic
stenosis on coronary CTA plus ischaemia based on computational
modelling by FFR
CT
, this non-invasive approach could improve
our ability to determine which patients may benefit from ICA and
revascularization.
The potential benefits of this approach are clear; however, previ-
ous studies of FFR
CT
have focused largely on its diagnostic accuracy
rather than clinical outcomes. In a multicentre study of 252 patients,
the diagnostic sensitivity and specificity of FFR
CT
to identify an inva-
sive FFR ≤0.80 were 90% and 54%, respectively
3
. In a subsequent
multicentre study of 254 patients using a refined FFR
CT
version
and an emphasis on improved CTA image quality, the reported
sensitivity was 86% while the specificity was improved at 79%.
4
What this level of diagnostic performance of FFR
CT
means for
patients being evaluated for CAD remains unclear.
In this context, Douglas et al. report in this journal the results of
the important PLATFORM study—an initial attempt to examine
how incorporation of FFR
CT
into clinical decision-making may
impact on clinical outcomes. This multicentre trial was non-
randomized and assigned consecutive chest pain patients at 11 sites
initially to usual testing (n¼287) and subsequently to a FFR
CT
ap-
proach (n¼297) over two time periods.
5
The clinical care team in-
dicated an initial plan for either non-invasive testing or ICA prior to
subject enrolment, and clinical care teams made management deci-
sions after receiving test results. This is a complex study design, per-
haps in an effort to explore different clinical applications for FFR
CT
.
Its primary endpoint also is not truly clinical, but an angiographic
endpoint of the percentage of patients between usual care and
FFR
CT
cohorts with ICA without obstructive CAD, in patients
with invasive testing planned before enrolment. It also was exam-
ined only in a subset of the overall study cohort with an initial
plan for ICA. The secondary endpoint was a similar angiographic
endpoint but compared the percentage of patients with ICA without
obstructive CAD in patients with non-invasive testing planned be-
fore study enrolment.
In reality, this study really represents two separate studies in two
distinct populations; one examines subjects planned for non-
invasive testing, while the other evaluates individuals planned for
ICA. In the cohort planned for non-invasive testing (n¼204), there
was no difference in the proportion of ICA procedures without ob-
structive CAD between usual care and FFR
CT
. It is notable that 60%
of subjects in the usual care strategy underwent coronary CTA,
which largely makes this a comparison between coronary CTA
alone and FFR
CT
with CTA. The FFR
CT
cohort received higher radi-
ation doses than the usual care cohort, which may be attributed to
some patients in the usual care group having no tests or tests with-
out radiation. There were no adverse cardiac events at 90 days in
either cohort; however, this study was not powered to detect differ-
ences in this endpoint. Larger studies and longer follow-up
(as planned in the PLATFORM study) will be helpful to better
understand its role. Overall, this portion of the study fails to find a
clinical advantage for FFR
CT
over usual care, and in fact finds a small
potential for harm with the observed increase in radiation exposure.
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
*Corresponding author: University of Michigan Medical Center, 1500 E Medical Center Dr., SPC 5853, Room 2365, Ann Arbor, MI 48109-5853, USA. Tel: +1 734 764 7440,
Fax: +1 734 232 4132, Email: labt@med.umich.edu
Published on behalf of the European Society of Cardiology. All rights reserved. &The Author 2015. For permissions please email: journals.permissions@oup.com.
European Heart Journal
doi:10.1093/eurheartj/ehv534
European Heart Journal Advance Access published October 7, 2015
at ESC Member on October 9, 2015http://eurheartj.oxfordjournals.org/Downloaded from
Further, as new technology is often associated with increased cost, it
is likely that FFR
CT
will be more expensive than CTA or stress test-
ing alone. Given the lack of benefit, and the potential for increased
radiation and uncertain costs, this application of FFT
CT
does not ap-
pear clinically useful in this setting.
The second study in this paper compares strategies in patients ini-
tially planned for ICA. The low yield of ICA as currently performed
represents an important opportunity for improvement.
6
In the initial
cohort assigned to ICA (n¼187) in the PLATFORM study, all indi-
viduals underwent a standard ICA (100%); in the subsequent cohort
assigned to FFR
CT
(n¼193), only 39% (76/193) proceeded to ICA
after the results of the CTA and FFR
CT
were made available to clin-
icians. Further, there was a marked decrease in the proportion of
patients undergoing ICA without obstructive CAD between CTA/
FFR
CT
and direct ICA cohorts (12% vs. 73%, P,0.001). These find-
ings have important implications, as they suggest that CTA/FFR
CT
as
a ‘gatekeeper’ to ICA could markedly reduce unnecessary invasive
testing and improve the ‘yield’ of ICA, which may be associated
with significant cost and a small risk of adverse complications.
However, some unanswered questions remain. First, we do not
know if CTA/FFR
CT
is a safe alternative in patients planned for
ICA. Based on the reported diagnostic accuracy of FFR
CT
,
3,4
it is pos-
sible that this approach may have underestimated and overesti-
mated disease. The clinical care teams used these results to
inform their subsequent management, and frequently cancelled
ICA procedures that had been planned based on the initial strategy.
While the effect of this on clinical safety outcomes could be small or
even negligible, this remains unknown. This study is not powered
to detect differences in clinical outcomes. Given the low rates of
observed events at 90 days, planned future analyses at 12 months
may also be underpowered and are unlikely to clarify this further
as this was a stable cohort of patients with suspected CAD. While
a reduced rate of ICA procedures with non-obstructive CAD is an
important endpoint, it does not establish the clinical safety of CTA/
FFR
CT
as a ‘gatekeeper’ to ICA.
Further, it is possible that coronary CTA alone in patients as-
signed to an invasive approach would reduce the number of ICA
procedures and the frequency of ICA with non-obstructive CAD.
In the Prospective Multicenter Imaging Study for Evaluation of Chest
Pain (PROMISE) Trial, which randomized 10 003 symptomatic pa-
tients planned for non-invasive testing to functional stress testing
vs. coronary CTA, patients randomized to the coronary CTA co-
hort experienced a lower rate of ICA with non-obstructive CAD
(3.4% vs. 4.3%, P¼0.02)
7
. Given the comparable diagnostic accur-
acy of coronary CTA in relation to ICA,
8
a similar study that pro-
vided the care team with the coronary CTA results alone may
have also resulted in fewer ICA procedures and ICA studies demon-
strating non-obstructive CAD. The incremental clinical utility of
FFR
CT
findings over coronary CTA findings alone to reduce ICA
procedures without obstructive CAD cannot be determined from
this study, and needs to be further elucidated.
There are other limitations with this study. First, instead of using a
randomized study design, all patients were initially treated with usual
care, and only after completing this enrolment were patients as-
signed to CTA/FFR
CT
. This study design can introduce bias, and sig-
nificant differences were observed between groups in age, type of
chest pain, risk factors, and medications, although no difference
was observed in the primary endpoint on sensitivity analysis. In add-
ition, poor CTA image quality prevented measurement of FFR
CT
in
11.9% (21/201) of subjects when it was requested. This suggests that
improvements in CTA acquisition, FFR
CT
application, and/or patient
selection are needed, as this represents a non-trivial rate of non-
diagnostic studies.
FFR
CT
is a highly promising new technology, but it is still in search
of a clinical application. This study examines the role of FFR
CT
in two
settings with divergent findings. In patients with suspected CAD
planned for non-invasive testing, results from the PLATFORM study
do not support an immediate clinical role for FFR
CT
. In contrast, the
performance of coronary CTA/FFR
CT
in patients planned for ICA in
the PLATFORM study markedly reduced the number of ICA proce-
dures and subsequent ICA procedures without obstructive CAD.
If validated, this latter approach could reduce healthcare costs
(depending on FFR
CT
costs) as well as the risks associated with these
invasive procedures. However, as the PLATFORM study was not
powered to detect a difference in clinical safety outcomes, its overall
cost-effectiveness remains uncertain. We still need more evidence
in more patients before FFR
CT
is ready for clinical use, but its poten-
tial is exciting.
Conflict of interest: none declared.
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