CLINICAL RESEARCH

CORONARY INTERVENTIONS
EuroIntervention 2018;14:798-805 published online

Clinical significance of concordance or discordance between

fractional flow reserve and coronary flow reserve for coronary
physiological indices, microvascular resistance, and
prognosis after elective percutaneous coronary intervention
January 2018

Eisuke Usui, MD; Tadashi Murai, MD; Yoshihisa Kanaji, MD; Masahiro Hoshino, MD;
Masao Yamaguchi, MD; Masahiro Hada, MD; Rikuta Hamaya, MD; Yoshinori Kanno, MD;
Tetsumin Lee, MD; Taishi Yonetsu, MD; Tsunekazu Kakuta*, MD

Department of Cardiovascular Medicine, Tsuchiura Kyodo General Hospital, Tsuchiura, Ibaraki, Japan

KEYWORDS
Abstract
Aims: We aimed to investigate the impact of concordance or discordance of fractional flow reserve (FFR)
and coronary flow reserve (CFR) on coronary flow profiles and microvascular resistance after percutaneous
• clinical research
coronary intervention (PCI), and the prognostic impact of the periprocedural physiological indices.
• fractional flow
reserve
Methods and results: A total of 249 de novo physiologically significant coronary lesions from 231 patients
• other technique
who underwent FFR, CFR, and index of microcirculatory resistance (IMR) examinations before and after
• QCA
PCI were included. Baseline characteristics and physiological indices were compared between the con-
cordant (FFR ≤0.80 and CFR <2.0, n=114) and discordant (FFR ≤0.80 and CFR ≥2.0, n=135) groups.
Follow-up data were collected to determine predictors of cardiac events. Shortening of the mean transit
time, CFR improvement, and decrease in the hyperaemic IMR were all significantly greater in the concord-
ant territories. Cox proportional hazards analysis showed that a lower pre-PCI CFR was an independent
predictor of adverse events at a median follow-up of 26.5 months, whereas neither the pre- nor post-PCI
FFR was predictive of events. Event-free survival was significantly worse in patients with a lower pre-PCI
CFR.
DOI: 10.4244/EIJ-D-17-00449

Conclusions: FFR/CFR concordantly abnormal territories provide a favourable benefit as assessed by

coronary physiological indices after elective PCI. The pre-PCI CFR may predict adverse cardiac events.

*Corresponding author: Department of Cardiovascular Medicine, Tsuchiura Kyodo General Hospital, 4-1-1, Otsuno, Tsuchiura,
Ibaraki, 300-0028, Japan. E-mail: [email protected]

© Europa Digital & Publishing 2018. All rights reserved. SUBMITTED ON 02/06/2017 - REVISION RECEIVED ON 1st 11/09/2017 / 2 nd 19/10/2017 - ACCEPTED ON 08/01/2018

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Abbreviations of acute coronary syndrome, and lesions with FFR values >0.80
CABG coronary artery bypass grafting were also excluded. All patients received antiplatelet treatment with
CFR coronary flow reserve aspirin (200 mg/d) and clopidogrel (75 mg/d; loading dose, 300 mg)
FFR fractional flow reserve ≥24 hours before cardiac catheterisation. Of the 260 lesions from
IMR index of microcirculatory resistance the 242 patients, 11 lesions fulfilled the definition of type 4a myo-
PCI percutaneous coronary intervention cardial infarction7 in the present cohort and were excluded from the
Tmn mean transit time final analysis, since significant microvascular injury in these cases
would result in impaired physiological profiles. Therefore, the final
Introduction data set included 249 lesions from 231 patients. Baseline patient
Coronary flow reserve (CFR) has been identified as a measure characteristics and follow-up data were collected by reviewing the
of coronary artery dysfunction that integrates the haemodynamic medical charts and by telephone interviews. The study protocol was
effects of epicardial coronary stenosis, diffuse atherosclerosis, and approved by the institutional review board, and all patients provided
microvascular dysfunction on myocardial perfusion1,2 and car- written informed consent for institutional database registration and
ries an excellent prognostic value3,4. Current guidelines recom- future clinical research prior to catheterisation.
mend a fractional flow reserve (FFR) cut-off value of 0.80 for
revascularisation decision making5 irrespective of the CFR value. CARDIAC CATHETERISATION
However, the clinical implications of the difference between FFR/ Each patient initially underwent standard selective coronary angio-
CFR concordantly abnormal territories (FFR ≤0.80 and CFR <2.0) graphy to assess the coronary anatomy via the radial artery using
and FFR/CFR discordant territories (FFR ≤0.80 and CFR ≥2.0) a 6 Fr system. Coronary angiograms were analysed quantitatively
for percutaneous coronary intervention (PCI) decision making using the CMS-MEDIS system (Medis medical imaging systems,
remain unclear. Although the potential aim of PCI is to increase Leiden, the Netherlands) to measure the lesion length, minimum
the coronary blood flow by targeting epicardial coronary steno- lumen diameter, reference lumen diameter, and percent diameter
sis, an increase in the hyperaemic coronary flow after PCI may stenosis at the target lesion. All patients underwent coronary stent
not be determined solely by modifying the epicardial stenosis6. We implantation (drug-eluting stent, 94%; bare metal stent, 6%; no
hypothesised that epicardial stenosis with ischaemic FFR and pre- bioresorbable vascular scaffolds) with predilatation. The type of
served CFR may not exhibit favourable changes in the coronary stent was selected at the operator’s discretion. To avoid aggres-
flow profiles and that pre-PCI CFR may carry prognostic informa- sive stent expansion, online quantitative coronary angiography
tion. To test this hypothesis, we compared changes in physiological was used to help determine the proper stent size. Successful PCI
indices, including FFR, CFR, and the index of microcirculatory was defined as <20% residual stenosis with Thrombolysis In
resistance (IMR), before and after successful PCI between terri- Myocardial Infarction (TIMI) grade 3 flow. After the angiographic
tories with concordantly abnormal FFR/CFR and those with an endpoint was achieved, intravascular ultrasound examination was
ischaemic FFR and preserved CFR to elucidate the impact of PCI performed to confirm optimal stent deployment, and additional
on coronary flow profiles. Furthermore, we assessed whether pre- PCI was performed in cases with suboptimal results.
PCI physiological indices predicted event-free survival after PCI.
INTRACORONARY PHYSIOLOGICAL INDICES
Methods Before and after PCI, the FFR, mean Tmn, CFR, and IMR val-
STUDY POPULATION ues were determined using the RadiAnalyzer™ Xpress instrument
The institutional database of cardiac catheterisation at Tsuchiura with the coronary PressureWire™ Certus™ (both St. Jude Medical,
Kyodo General Hospital was searched for the period between St. Paul, MN, USA) as described previously8-10. The post-PCI
January 2013 and September 2016 to identify patients treated with physiological assessment was performed approximately 10 min-
elective PCI who underwent FFR, CFR, mean transit time (Tmn), utes after completion of PCI. After administration of nitroglycerine,
and IMR measurements before and after PCI. Patients were elig- a pressure monitoring guidewire was advanced distal to a steno-
ible for the analysis if they satisfied the following criteria: physio- sis. Hyperaemia was induced by intravenous infusion of adenosine
logical assessment by pressure temperature sensor-tipped wire for (140 μg/kg/min through a central vein). The FFR was calculated
a de novo single coronary lesion at the proximal or mid segment by dividing the mean distal pressure (Pd ) by the mean aortic pres-
exhibiting intermediate to obstructive stenosis (estimated as 30-90% sure (Pa ) during stable hyperaemia. For the IMR measurements,
diameter stenosis on an angiogram by visual estimation). A total of hyperaemic thermodilution curves were obtained (three times each
349 patients with 382 lesions were identified for the analysis. We using a 3 ml saline bolus injection) and the mean hyperaemic Tmn
excluded patients with left main disease, a history of coronary artery were documented. IMR was calculated as the product of the mean
bypass grafting surgery (CABG), lesions requiring balloon angio- Pd and the Tmn during stable hyperaemia10. CFR was calculated as
plasty prior to pressure wire crossing, tandem lesions, and lesions the mean basal Tmn divided by the mean hyperaemic Tmn. In the
with insufficient physiological data acquisition. Patients with presence of significant epicardial stenosis and/or collateral flow,
a severely impaired systolic ejection fraction (<35%), culprit lesions accurate determination of the IMR has been reported to require

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measurement of the coronary wedge pressure11. In the present study, p<0.10 level in the univariate analysis were tested in a stepwise
both corrected pre-PCI IMR values using wedge pressure during multivariable Cox regression analysis. Differences in combined
balloon predilatation and uncorrected pre-PCI IMR values were adverse events according to the pre-PCI CFR value were analysed
analysed. Since the inverse value of the mean hyperaemic Tmn has using the Kaplan-Meier method. Event-free survival curves were
been validated to correlate with the absolute coronary blood flow6,9 compared using the Mantel-Cox test. P<0.05 indicated statistical
and the Tmn can be used as a surrogate of the coronary flow veloc- significance. The statistical analyses were performed using SPSS,
ity, a shorter Tmn suggests a higher coronary flow velocity with Version 23.0 (IBM Corp., Armonk, NY, USA) and R version 3.0.2
a greater hyperaemic coronary flow. A positive value calculated by (R Foundation for Statistical Computing, Vienna, Austria).
subtracting the post-PCI Tmn from the pre-PCI Tmn might be inter-
preted as a shortening of the Tmn, suggesting improved coronary Results
flow profiles after PCI and an increase in the hyperaemic coronary PATIENT CHARACTERISTICS, ANGIOGRAPHIC DATA, AND
flow. Changes in the physiological indices were also studied and PHYSIOLOGICAL INDICES
compared between territories with CFR <2.0 and CFR ≥2.0. The baseline patient characteristics are summarised in Table 1.
A significant, albeit modest, relationship was found between the
STATISTICAL ANALYSIS pre-PCI FFR and CFR (r=0.41; p<0.01) (Figure 1A). Figure 1B
Patient demographics are presented as n (%) where appropriate. shows the distribution of the FFR values of the concordant and
Categorical data are expressed as absolute frequencies and per- discordant groups. The concordant group comprised 114 territories
centages and were compared using the χ2 or Fisher’s exact test as (FFR 0.66 [0.57-0.74], CFR 1.36 [1.12-1.73]), and 135 territories
appropriate. The data were analysed on a per-patient and per-lesion were included in the discordant group (FFR 0.75 [0.69-0.78], CFR
basis. Continuous variables are expressed as the mean±standard 3.00 [2.36-3.76]). The FFR and CFR were both significantly lower
deviation for normally distributed variables or as the median (25th- (p<0.01 for both comparisons) in the concordant group than those
75th percentiles) for non-normally distributed variables and were in the discordant group, and the IMR was significantly greater
compared using the Student’s t-test or the Mann-Whitney U test, (p<0.01) in the concordant group. In the total cohort, both the
respectively. Receiver operating characteristic curves were ana- FFR and CFR increased significantly after PCI (p<0.01), although
lysed to assess the best cut-off values of the pre-PCI physiological the changes in the FFR and CFR were significantly greater in the
indices for predictions based on the Cox proportional hazards concordant group than those in the discordant group (p<0.01 for
regression analyses. The pre- and post-PCI physiological vari- both comparisons). The post-PCI CFR was significantly lower in
ables were analysed separately, and all significant variables were the concordant group than that in the discordant group (p<0.01),
tested to identify predictors of adverse events during the follow-up whereas no significant differences in the post-PCI FFR and IMR
period. Hazard ratios with corresponding 95% confidence intervals were detected (p=0.11 and p=0.17, respectively). These results
are reported. All variables associated with adverse events at the were consistent regardless of whether the IMR correction was

A B 45
Concordant group (N=114)

40
35
0.80
30
Frequency

Total cohort (N=249) 25

60 20
0.70 15
50 10
R=0.410 5
p<0.01 40
0.60 0
Pre-PCI FFR

Frequency

0.3 0.4 0.5 0.6 0.7 0.8 0.9

30
Pre-PCI FFR

0.50 Discordant group (N=135)

20 45
40
10 35
0.40
30
Frequency

0 25
0.3 0.4 0.5 0.6 0.7 0.8 0.9
20
0.30
Pre-PCI FFR
15
0.00 2.00 4.00 6.00 8.00
10
Pre-PCI CFR 5
0
0.3 0.4 0.5 0.6 0.7 0.8 0.9
Pre-PCI FFR

Figure 1. Distribution of lesions. A) Frequency distribution of lesions as a function of the FFR and CFR. A modest correlation was found
between the FFR and CFR (r=0.41, p<0.01). B) Lesion-level histograms of the pre-PCI FFR in two groups divided by the CFR value of 2.0.

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EuroIntervention 2018;14:798-805
Table 1. Baseline patient characteristics, angiographic and physiological parameters according to FFR/CFR concordance or discordance.
Total Concordance Discordance p-value
Per-patient analysis 231 (100) 104 (45.0) 127 (55.0)
Age, yrs 66.7±9.9 68.4±10.1 65.3±9.5 0.02
Female sex, n (%) 35 (15.2) 20 (19.2) 15 (11.8) 0.12
Hypertension, n (%) 171 (74.0) 78 (75.0) 93 (73.2) 0.76
Dyslipidaemia, n (%) 138 (59.7) 59 (56.7) 79 (62.2) 0.40
Diabetes, n (%) 100 (43.3) 49 (47.1) 51 (40.2) 0.29
Acute coronary syndrome, n (%) 33 (14.3) 16 (15.4) 17 (13.4) 0.67
Previous myocardial infarction site, n (%) 22 (9.5) 14 (13.5) 8 (6.3) 0.07
Total cholesterol, mg/dL 161 (143-192) 164 (143-188) 164 (141-193) 0.84
LDL cholesterol, mg/dL 94 (74-117) 95 (75-116) 91 (74-118) 0.54
HDL cholesterol, mg/dL 45 (37-52) 44 (36-50) 46 (38-54) 0.06
Triglycerides, mg/dL 125 (89-185) 123 (87-171) 129 (92-191) 0.42
Medication, n (%) ACE-I or ARB 148 (64.1) 62 (59.6) 86 (67.7) 0.20
Statin 147 (63.6) 63 (60.6) 84 (66.1) 0.38
β-blocker 102 (44.5) 43 (41.3) 59 (47.2) 0.42
Echocardiographic LVEF, % 65 (57-70) 65 (56-70) 64 (57-70) 0.97
Per-vessel analysis 249 (100) 114 (45.8) 135 (54.2)
Lesion location, Left anterior descending artery 172 (69.1) 74 (64.9) 98 (72.6)
n (%)
Right coronary artery 44 (17.7) 23 (20.2) 21 (15.6) 0.43
Left circumflex artery 33 (13.3) 17 (14.9) 16 (11.9)
Angiographic findings before PCI
Minimal lumen diameter, mm 1.13±0.33 1.03±0.32 1.20±0.32 <0.01
Reference diameter, mm 2.61 (2.29-3.00) 2.63 (2.24-3.08) 2.60 (2.33-2.97) 0.87
Stenosis, % 56.9±12.0 60.6±11.7 53.7±11.3 <0.01
Lesion length, mm 13.2 (9.43-17.5) 13.4 (9.59-20.9) 12.7 (9.33-17.1) 0.33
Angiographic findings after PCI
Minimal lumen diameter, mm 2.90±0.48 2.90±0.53 2.90±0.43 0.96
Reference diameter, mm 3.19±0.46 3.20±0.48 3.19±0.43 0.80
Stent total length, mm 28 (20-38) 28 (18-38) 26 (20-33) 0.17
Drug-eluting stent 234 (94.0) 106 (93.0) 128 (94.8) 0.55
Physiological parameters before PCI
Pre-PCI FFR 0.72 (0.63-0.77) 0.66 (0.57-0.74) 0.75 (0.69-0.78) <0.01
Pre-PCI CFR 2.08 (1.42-3.06) 1.36 (1.12-1.73) 3.00 (2.36-3.76) <0.01
Pre-PCI IMR with correction 19.5 (12.2-29.3) 25.7 (14.4-36.6) 16.5 (11.0-21.6) <0.01
Pre-PCI IMR without correction 22.0 (14.3-35.2) 32.4 (21.8-45.0) 18.3 (12.2-24.0) <0.01
Tmn at rest, seconds 0.87 (0.60-1.23) 0.83 (0.51-1.20) 0.89 (0.67-1.24) 0.07
Tmn at hyperaemia, seconds 0.39 (0.24-0.63) 0.61 (0.42-0.95) 0.29 (0.20-0.40) <0.01
Physiological parameters after PCI
Post-PCI FFR 0.87 (0.84-0.92) 0.88 (0.84-0.94) 0.87 (0.83-0.91) 0.11
Post-PCI CFR 3.26 (2.00-5.07) 2.54 (1.63-3.83) 3.73 (2.57-5.57) <0.01
Post-PCI IMR 16.3 (11.9-23.0) 17.1 (12.2-24.0) 15.2 (10.8-21.6) 0.17
Tmn at rest, seconds 0.80 (0.56-1.07) 0.72 (0.41-0.98) 0.86 (0.62-1.10) <0.01
Tmn at hyperaemia, seconds 0.23 (0.16-0.32) 0.24 (0.16-0.36) 0.22 (0.15-0.30) 0.05
ΔTmn (pre-post at hyperaemia) 0.14 (0.01-0.35) 0.32 (0.12-0.62) 0.07 (-0.01 to 0.18) <0.01
ΔFFR (post-pre) 0.16 (0.11-0.24) 0.22 (0.14-0.32) 0.13 (0.08-0.18) <0.01
ΔCFR (post-pre) 0.97 (-0.15 to 2.40) 1.32 (0.34-2.42) 0.68 (-0.60 to 2.38) <0.01
ΔIMR (pre-post) 1.89 (-4.04 to 10.6) 6.80 (-2.43 to 16.1) -0.10 (-6.74 to 5.75) <0.01
Values are shown as n (%), mean±standard deviation, or median (25 -75th percentiles). ACE-I: angiotensin-converting enzyme inhibitor;
th

ARB: angiotensin receptor blocker; CFR: coronary flow reserve; FFR: fractional flow reserve; HDL: high-density lipoprotein; IMR: index of
microcirculatory resistance; LDL: low-density lipoprotein; LVEF: left ventricular ejection fraction; PCI: percutaneous coronary intervention; Tmn: mean
transit time

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applied or if the values were corrected only when the FFR values ratio [HR] 0.764, 95% confidence interval [CI]: 0.592-0.986,
showed severe stenosis (FFR ≤0.65). Shortening of the Tmn was p=0.039) was an independent predictor of adverse events dur-
significantly greater in the concordant territories (p<0.01). ing follow-up (Table 4). Receiver operating characteristic curve

LONG-TERM FOLLOW-UP AFTER PCI Table 2. Incidence of adverse events.

Four patients were lost at a median follow-up of 26.5 months
All lesions
(interquartile range 9.30-52.4 months). Therefore, the follow- (n=245)
up data were analysed for 245 (98.4%) lesions. The cumulative All adverse events 48 (19.6)
event rate of adverse events was 19.6% (48/245) (Table 2). No
Cardiac death 0 (0.0)
significant differences in coronary anatomy, angiographic find-
Myocardial infarction 2 (0.8)
ings, and elevation of cTnI after PCI were observed between
Target vessel revascularisation 8 (3.3)
the patients with and without adverse events. The pre-PCI CFR
Non-target vessel revascularisation 25 (10.2)
(p=0.06), post-PCI CFR (p=0.05), and post-PCI Tmn at baseline
Hospitalisation for heart failure 10 (4.1)
(p=0.04) tended to be different between lesions in patients with
Arrhythmia 3 (1.2)
and without adverse events (Table 3). The stepwise multivariate
Values are shown as n (%).
Cox regression analysis showed that a low pre-PCI CFR (hazard

Table 3. Angiographic findings and physiological indices with and without adverse events.
Adverse events No adverse events
Total (n=245) p-value
(n=48) (n=197)
Lesion location, n (%) Left anterior descending artery 170 (69.4) 30 (62.5) 140 (71.1)
Right coronary artery 43 (17.6) 11 (22.9) 32 (16.2) 0.48
Left circumflex artery 32 (13.1) 7 (14.6) 25 (12.7)
Angiographic findings before PCI
Minimal lumen diameter, mm 1.13±0.33 1.18±0.37 1.11±0.32 0.25
Reference diameter, mm 2.61 (2.29-3.01) 2.70 (2.41-3.09) 2.58 (2.27-3.00) 0.10
Stenosis, % 56.9±12.0 56.3±13.1 57.1±11.7 0.70
Lesion length, mm 13.2 (9.49-17.5) 13.4 (11.0-18.4) 13.0 (9.17-17.5) 0.45
Angiographic findings after PCI
Minimal lumen diameter, mm2 2.90±0.48 3.01±0.49 2.88±0.48 0.08
Reference diameter, mm 3.20±0.46 3.26±0.44 3.18±0.46 0.26
Stent total length, mm 28 (20-38) 28 (22-40) 26 (20-36) 0.13
Drug-eluting stent 230 (93.9) 44 (91.7) 186 (94.4) 0.50
Periprocedural myocardial injury 58 (23.7) 13 (27.1) 45 (22.8) 0.54
Physiological parameters before PCI
Pre-PCI FFR 0.72 (0.63-0.76) 0.69 (0.62-0.76) 0.73 (0.63-0.77) 0.13
Pre-PCI CFR 2.08 (1.42-3.05) 1.96 (1.19-2.80) 2.17 (1.48-3.07) 0.06
Concordance or discordance, Concordant group (CFR <2.0) 113 (46.1) 24 (50.0) 89 (45.2)
n (%) 0.55
Discordant group (CFR ≥2.0) 134 (53.9) 24 (50.0) 110 (54.8)
Pre-PCI IMR with correction 19.6 (12.5-30.0) 17.9 (12.0-28.0) 19.6 (12.6-29.9) 0.71
Pre-PCI IMR without correction 22.4 (14.6-35.3) 22.4 (14.8-35.4) 22.0 (14.6-35.3) 0.91
Tmn at rest, seconds 0.87 (0.60-1.24) 0.75 (0.52-1.11) 0.89 (0.62-1.28) 0.12
Tmn at hyperaemia, seconds 0.40 (0.25-0.64) 0.41 (0.27-0.64) 0.39 (0.24-0.64) 0.66
Physiological parameters after PCI
Post-PCI FFR 0.87 (0.84-0.92) 0.87 (0.83-0.92) 0.87 (0.84-0.92) 0.83
Post-PCI CFR 3.26 (2.01-5.07) 2.74 (1.62-3.93) 3.32 (2.11-5.29) 0.05
Post-PCI IMR 16.3 (11.9-23.0) 15.5 (11.3-23.1) 16.3 (11.9-23.0) 0.82
Tmn at rest, seconds 0.80 (0.56-1.07) 0.71 (0.43-1.03) 0.82 (0.58-1.09) 0.04
Tmn at hyperaemia, seconds 0.23 (0.16-0.32) 0.23 (0.16-0.33) 0.22 (0.16-0.32) 0.81
ΔTmn (pre-post at hyperaemia) 0.14 (0.02-0.36) 0.20 (0.03-0.33) 0.14 (0.02-0.37) 0.60
Values are shown as n (%), mean±standard deviation, or median (25th-75th percentiles). CFR: coronary flow reserve; FFR: fractional flow reserve;
IMR: index of microcirculatory resistance; PCI: percutaneous coronary intervention; Tmn: mean transit time

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EuroIntervention 2018;14:798-805
Table 4. Cox regression analysis for the prediction of adverse events.
Univariate analysis Multivariate analysis
HR 95% CI p-value HR 95% CI p-value
Pre-PCI FFR 0.180 0.013-2.474 0.200
Pre-PCI CFR 0.764 0.592-0.986 0.039 0.764 0.592-0.986 0.039
Concordant group 1.481 0.841-2.609 0.174
Pre-PCI IMR with correction 1.011 0.992-1.030 0.247
Pre-PCI IMR without correction 1.009 0.995-1.024 0.209
Pre-PCI Tmn at rest, seconds 0.836 0.464-1.507 0.552
Pre-PCI Tmn at hyperaemia, seconds 1.415 0.751-2.668 0.283
Post-PCI FFR 0.100 0.001-7.438 0.295
Post-PCI CFR 0.877 0.757-1.017 0.082
Post-PCI IMR 0.993 0.965-1.021 0.620
Post-PCI Tmn at rest, seconds 0.563 0.273-1.160 0.119
Post-PCI Tmn at hyperaemia, seconds 1.436 0.244-8.460 0.689
ΔTmn (pre-post at hyperaemia) 1.472 0.712-3.043 0.297
ΔFFR 2.280 0.175-29.79 0.530
CFR: coronary flow reserve; CI: confidence interval; FFR: fractional flow reserve; HR: hazard ratio; IMR: index of microcirculatory resistance;
PCI: percutaneous coronary intervention; Tmn: mean transit time

analysis showed that the optimal cut-off value of the pre-PCI CFR CFR, although no significant difference in the IMR was observed
to predict adverse events was 2.26 (area under the curve 0.586; between the two groups after PCI; and (3) a lower pre-PCI CFR
95% CI: 0.494-0.679). Event-free survival was significantly worse was an independent predictor of adverse cardiac events during
in patients with a lower pre-PCI CFR (log-rank test χ2=9.011; long-term follow-up after PCI.
p=0.003) (Figure 2).
DETERMINANTS OF CORONARY FLOW AFTER PCI
1.0 This study is the first to demonstrate that FFR/CFR concordance or
Pre-PCI CFR >2.26 discordance has an impact on coronary physiological indices after
0.8
successful elective PCI. Pre-PCI CFR and FFR determinations may
Adverse event-free rate

incrementally provide functional information. CFR provides impor-

0.6
tant information that represents the effects of various circulatory sta-
0.4 Pre-PCI CFR ≤2.26 tus and is considered as a marker of the integrity of coronary artery
Log-rank χ =9.011
2 function12,13. In territories with ischaemic FFR and preserved CFR,
p=0.003
0.2 an FFR below the diagnostic cut-off value may reflect the potential
to accommodate high hyperaemic coronary flow and not the pres-
0.0
0 500 1,000 1,500 2,000 2,500 ence of significantly flow-limiting stenosis14. Our results suggested
Follow-up duration (days) that coronary flow improvement assessed by the surrogate marker
No. at risk
Pre-PCI CFR >2.26 110 65 45 23 5 of flow velocity after PCI for territories with ischaemic FFR and
Pre-PCI CFR ≤2.26 135 58 41 18 4
preserved CFR might be less than that in the territories with con-
cordantly abnormal FFR and CFR. This concept might be supported
Figure 2. Kaplan-Meier curves according to the CFR cut-off values
by a study by van de Hoef et al which showed that the long-term
>2.26 and ≤2.26.
outcomes of patients with non-flow-limiting stenosis were favour-
able after deferral of revascularisation3. FFR/CFR interrogation may
Discussion clarify the existence of a differentiated pattern of ischaemic heart
The main findings of the present study are as follows. In patients disease that harbours epicardial and microvascular dysfunction; this
undergoing elective PCI with lesions showing an ischaemic FFR, pattern may potentially benefit revascularisation decision making
(1) territories with concordantly abnormal FFR/CFR showed signi- for individual lesion levels.
ficantly greater shortening of the mean transit time and improve- Our results also support those of a recent study suggesting that
ment of the CFR when compared to the territories with a preserved post-PCI changes in hyperaemic coronary blood flow velocity are
CFR; (2) pre-PCI hyperaemic microvascular resistance was signi- associated with the baseline lesion physiological indices15. The
ficantly higher in the group with concordantly abnormal FFR and lesions with a high pre-PCI IMR tended to decrease after PCI.

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This phenomenon was in line with the findings in our recent pro- values were significantly associated with these adverse events.
spective study16, which showed that the magnitude and direction of Our results may indicate an association between a lower regional
change in the IMR immediately after PCI significantly correlated CFR and impaired global cardiovascular function. Our results also
with the pre-PCI IMR and that decrease in the IMR was signi- strongly support the concept of an ongoing clinical trial (DEFINE-
ficantly associated with a favourable change in the coronary physio- FLOW; NCT02328820). A prospective large clinical study is
logical index represented by Tmn shortening. The documentation needed to investigate the efficacy of increases in the CFR relative
of different outcomes by territories with different combinations to the FFR.
or measures of these physiological indices has great importance
and supports the feasibility of improving the invasive diagnosis of Study limitations
ischaemic coronary heart disease beyond FFR assessment. This study has several limitations that warrant consideration in the
interpretation of the results. First, this study included subjects from
EFFECTS OF CORONARY HAEMODYNAMIC INDICES ON THE a single centre and was retrospective; consequently, selection bias
CLINICAL OUTCOME was unavoidable. Second, the decision to perform the FFR meas-
Although no significant relationship was found between FFR/ urement was at the discretion of the operator. Third, we measured
CFR concordance/discordance and the occurrence of adverse car- a vali­dated surrogate of absolute coronary flow (Tmn). Fourth,
diac events in the present study, the multivariate Cox regression because the injection of saline can cause submaximal hyperaemia
analysis revealed that the pre-PCI CFR was an independent pre- to some extent, thermodilution method-derived CFR values may
dictor of adverse cardiac events in the FFR-positive lesions. Our be different from conventional velocity-derived CFR values. Fifth,
results indicated that no physiological indices after PCI or changes there is no solid scientific basis for defining a biomarker threshold
in these parameters were associated with event-free survival after to diagnose periprocedural myocardial injury. Sixth, because analy-
PCI and that pre-PCI CFR, but not pre- or post-PCI FFR, may sis of non-culprit vessels was not performed, the results might have
carry prognostic information. been biased by a focal, single vessel assessment of flow. Finally,
In a recent prospective study, Barbato et al reported that the because the extent of post-PCI improvement of coronary physio-
stenosis severity assessed by FFR was a major and independent logical indices capable of improving symptoms or producing a prog-
predictor of lesion-related outcomes after treatment with medical nostic benefit is unknown, the clinical significance and findings of
therapy alone17. Conversely, numerous studies have demonstrated the present study should be considered hypothesis-generating and
the capacity of CFR to predict future cardiovascular events in should be tested in future large, prospective studies.
a wide range of the subset population3,4,18. These results were in
line with our study, which indicated that CFR was a significant Conclusions
predictor of future adverse events, including culprit and non- FFR/CFR concordance or discordance influenced coronary
culprit lesion-related events, heart failure, and other composite physiological indices after elective PCI for lesions showing an
adverse events. Taqueti et al reported that the CFR was associated ischaemic FFR. Compared with territories showing an ischaemic
with adverse cardiac outcomes independent of revascularisation4. FFR and preserved CFR, FFR/CFR concordantly abnormal terri-
These authors also reported a significant interaction between the tories showed a favourable impact on Tmn shortening and CFR
CFR and early revascularisation via CABG; as a result, patients improvement after elective PCI. Impairment of the pre-PCI CFR
with a low CFR who underwent CABG but not PCI experienced may predict adverse cardiac events after a successful PCI.
event rates comparable to patients with a preserved CFR inde-
pendent of revascularisation. CFR may play an important role in
diagnosing pathophysiological abnormalities that lead to adverse
Impact on daily practice
Current guidelines recommend an FFR cut-off value of 0.80 for
cardiac events in patients undergoing PCI. Although revascular-
revascularisation decision making in the absence of prior objec-
isation should be considered for severely impaired FFR lesions
tive evidence of myocardial ischaemia in patients with angina,
because their lesion-related outcomes by medical therapy alone
irrespective of the CFR value. In patients undergoing an elective
may not be favourable17, PCI may not alter the natural his-
PCI, territories in the FFR/CFR concordantly abnormal group
tory of the total atherosclerotic disease burden of these patients.
showed significantly favourable changes in the coronary physio-
Compared with FFR, which represents the epicardial focal steno-
logical indices after PCI when compared with those exhibiting
sis severity, CFR includes focal epicardial stenosis, diffuse arte-
an ischaemic FFR and preserved CFR; during long-term fol-
rial disease, and microvascular dysfunction, suggesting that CFR
low-up after PCI, event-free survival was significantly worse in
may be a better surrogate marker of integrated vascular function.
the patients with a lower pre-PCI CFR. The documentation of
Coronary arterial dysfunction may exist diffusely in addition to
different outcomes by territories with different combinations of
local isolated stenosis and microvascular dysfunction, and thus
physiological indices supports the feasibility of improving the
localised mechanical intervention may fail to alter long-term dis-
functional diagnosis of ischaemic coronary heart disease beyond
ease outcomes. In the present study, more than half of the events
FFR assessment.
were non-target vessel revascularisation, and lower pre-PCI CFR

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 FFR/CFR relationships and outcomes after PCI

EuroIntervention 2018;14:798-805
Conflict of interest statement 7. Yang X, Tamez H, Lai C, Ho K, Cutlip D. Type 4a myocardial
The authors have no conflicts of interest to declare. infarction: Incidence, risk factors, and long-term outcomes.
Catheter Cardiovasc Interv. 2017;89:849-56.
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