FFR Going Beyond
Angiography
By
Amr El Nagar
•Should this lesion be stented ??
Back to the Basic
Coronary Physiology
• Coronary blood flow = 3-5% of C.O.
• Resting myocardial O2 demand is
extremely high (20 x skeletal O2 demand)
• Myocardium extracts maximum O2
from blood (80% versus 30-40% skeletal muscle)
• Myocardium has high capillary density
(3000-4000/mm2 versus 500-2000/mm2 skeletal muscle)
• Therefore, only way to meet increasing
demand is to increase blood flow
Coronary Blood Flow vs Percent
Diameter Stenosis
Autoregulation
Autoregulation
Hyperemia



Hyperemia is a state of myocardial vasculature
dilatation
Myocardial bed can be pharmacologically dilated
with an agent eg:Adenosine
occurs naturally in the body in small quantities
and is produced during exercise to assist in the
dilatation of the myocardial bed.
Physiology to Address Clinical
Questions in the Cath Lab…
FFR





What ??????????????
Why???????????????
How??????????????
When?????????????
$$$$$$$$$$$$$$$$
What is FFR?
It is a
Ratio
Maximum flow down a vessel in the
presence of a stenosis…
…and
maximum flow in the hypothetical
absence of the stenosis
between
Derivation of FFR

FFR = Coronary Flow(Stenosis)
Coronary Flow (Normal)

Coronary Flow =

Pressure
Resistance
at maximal hyperemia Coronary Flow ≈Pressure
So, FFR =
Coronary Pressure(Stenosis)
Coronary Pressure (Normal)
FFR threshold for ischemia
No
ischemia
Yes
ischemia
FFR
1.00
0.75
0.00
FFR < 0.75  inducible ischemia (spec. 100 % )
FFR > 0.75  no inducible ischemia (sens. 90 % )
Pijls, De Bruyne et al, NEJM 1996
Why FFR(is it superior)????
*Stenting of non-ischemic stenoses has no benefit
compared to medical treatment only.
*Stenting of ischemia-related stenoses improves
symptoms and outcome.
*In multivessel coronary disease (MVD), identifying
which stenoses cause ischemia is difficult.
*Non-invasive tests are often unreliable in MVD
and coronary angiography often results in both
under or overestimation of functional stenosis
severity.
Limitations of Anatomic
Techniques:
- Underestimates diffuse disease
- Large Intra- and inter-observer variability
- Not designed to assesses physiologic
lesion significance
Limitations of Non-Invasive Studies
SPECT Imaging
- SPECT imaging 70%
sensitivity for single vessel
disease
- SPECT imaging has 85-90%
sensitivity for detecting
disease in patients with
MVD, but only 50%
sensitivity for detecting
MVD ischemia pattern
But FFR !!!!
• FFR is not influenced by changes in blood pressure,
heart rate, or contractility
• FFR has a unique normal value of 1.0 in every patient
and every coronary artery
• FFR incorporates the contribution of collateral flow
to myocardial perfusion
How????
Technique!!!!
Pressure Wire
Tip
Guide wire - 0.014
straight or ‘J’ tip
pressure sensor - 3 cm
proximal to the end of the wire
Pressure sensor
Equipments
RADI ANALYZER
PRESSURE WIRE
Myocardium
Aorta
coronary
artery
100
Pa
0
Pd
Max. hyperemia
100
Pa
Qnormal
Normal perfusion pressure
0
Pd
Qstenosis
Stenotic perfusion pressure
Qstenosis
FFR =
Stenotic perfusion press.
=
Qnormal
Pd
=
Normal perfusion press.
Pa

blood pressure distal to the lesion being
assessed - Pressure distal (Pd)

conventional pressure transducer - measures
arterial/aortic pressure - Pressure arterial (Pa)




mean pressures of Pd and Pa are used
assuming there is no lesion present = no
difference in pressure
The difference between these two
pressures taken at rest determines if there
is a resting gradient across a lesion
Gradient calculation = Pd/Pa.

no lesion, the pressures will be the same
and therefore the gradient value will be 1

e.g. Pa = 150 mmHg Pd = 150mmHg

So,
Pd/Pa = 1




Dilation of micro-vasculature increases
oxygen demand
a flow limiting lesion will cause the blood
pressure distal to the lesion to fall
FFR will fall
The extent of this reduction gives an
indication as to the degree of flow
limitation and hence degree of severity of
stenosis
Vasodilatory Agents for Hyperemia
Where to Administer Adenosine?
Examples of coronary pressure
gradient
Coronary pressure measuremnts
Pitfalls and Artifacts
Technical:

loose connection

leak in guide connections

improper zero

Inadequate hyperemia
Anatomic/Theoretical:

Ostial, diffuse disease

microvascular disease

Extreme tortuosity

Serial lesions
Mechanical/Hemodynamic:

Guide catheter obstruction

Low drug delivery
Insufficient Hyperemia
IV Adenosine:


Check infusion, pump system and lines
Infuse through central vein
Avoid Valsalva maneuver during infusion
For Intracoronary route:


Guiding catheter failure to seat
flow obstruction-incorrect dose mix or dilution
incorrect dose mix or dilution
Reasons of Non-ischemic FFR Despite an
Apparently Tight Stenosis
Physiologic explanations:




Stenosis hemodynamically nonsignificant despite
angiographic appearance
Small perfusion territory, old MI, little viable tissue, small
vessel
Abundant collaterals
Severe microvascular disease (rarely affecting FFR)
Interpretable explanations:


Other culprit lesion, diffuse disease not focal stenosis
Chest pain of noncardiac origin
Technical explanations:



Insufficient hyperemia
Guiding catheter related pitfall (deep engagement,
small ostium,sideholes)
Electrical drift
Actual false negative FFR:



Acute phase of ST elevation myocardial infarction
Severe left ventricular hypertrophy
Exercise-induced spasm
When FFR???(value)
Borderline lesions
 Evaluation of PCI
FFR after coronary intervention should preferably be
higher than 0.90

Multicenter registry Europe-USA-Asia
750 pat. post-STENT FFR
% death, infarction, or re-intervention at 6 mnths.
40%
30%
20%
10%
37%
After stenting: Inverse correlation
between FFR and event rate.
28%
19%
7%
4%
0%
0.76-0.80 0.81-0.85 0.86-0.90 0.91-0.95
Post-STENT FFR
0.96-1.00
How does FFR works in complex coronary
disease?
•
difficult anatomy, poorly visible lesions, overlap
•
multiple stenoses within one artery
•
diffuse disease
left main disease
multivessel disease
•
•
Male, 67, stable angina, positive exercise test
LCX
RCA
2 intermediate stenoses mid RCA
LAD
D1
D2
Complex lesion proximal LAD
LAD, hyperemia
Pa
Pa
100
Pd
Pd
FFR = 92/98 = 0.94
0
DIAG 2, hyperemia
Pa
Pa
100
Pd
Pd
0
FFR = 87/97 = 0.89
DIAG 1, hyperemia
Pa
Pd
100
Pd
0
Pa
FFR = 87/96 = 0.90
RCA, hyperemia
100
0
FFR = 38/92 = 0.41
Pa
Pd
Balloon 3.0 mm
After balloon inflation
3.0 balloon 12 atm
Pa
100
FFR = 55/82 = 0.67
0
Pd
Stent 3.5 mm(mid-RCA)
Stent 3.5 mm(mid-RCA)
Pa
100
Pd
0
FFR = 76/95 = 0.80
Pressure drop
Pull back pressure wire
Additional Stent
3.5 mm (prox-RCA)
Stent 3.5 mm(mid-RCA) +
Stent 3.5 mm(prox-RCA)
Pa
100
Pd
FFR = 88/94 = 0.94
0
In this patient with complex coronary artery disease,
coronary pressure measurement:
• confirmed the appropriateness of stenting the RCA
while avoiding a riskful intervention of the LAD
or bypass surgery
• Selected the correct spots in the RCA where to stent
• evaluated the result of stenting.
How does FFR works in complex coronary
disease?
•
difficult anatomy, poorly visible lesions, overlap
•
multiple stenoses within one artery
•
diffuse disease
left main disease
multi vessel disease
•
•
A
B
Coronary Pressure & FFR: Pull-Back Curve
Focal disease: sudden changes in pressure
Coronary Pressure & FFR: Pull-Back Curve
Diffuse coronary disease: gradual increase of pressure.
FFR: The Pressure Pull-back Curve
•
By slowly retrieving the pressure wire under
fluoroscopy and sustained hyperemia
•
the individual contribution of every segment of the
coronary system to the extent of disease can be
studied and such spatial information cannot be
obtained by any other method
How does FFR works in complex coronary
disease?
•
difficult anatomy, poorly visible lesions, overlap
•
multiple stenoses within one artery
•
•
diffuse disease
long and ostial lesions
•
left main disease
•
multivessel disease
Decision making in
equivocal left main coronary artery
disease
by Fractional Flow Reserve
Bech et al, Heart 2001
•The presence of angiographic clearly significant
LMCA stenosis is often decisive in the choice for
invasive strategy.
•However, often patients are encountered with
angiographically an intermediate LMCA stenosis of
unclear physiological significance.
•It is unclear whether bypass surgery should be
performed.
Aim of the study
•To investigate the usefulness of pressure derived FFR
to decide between medical versus surgical therapy
in patients with equivocal LMCA disease.
follow-up
54 patients
FFR > 0.75
N=24
Medical Group
FFR < 0.75
N=30
Surgical Group
28 15
2914
Death
0
1
MI
0
1
Early re-operation
--
3
CABG
3
0
PTCA
2
0
Total
5 (21%)
5 (17%)
Mean follow-up (mths)
Conclusion
•FFR is useful in equivocal left main coronary artery disease.
•If LM FFR  0.75, a conservative medical of the LM lesion
approach seems to be safe.
•If LM FFR < 0.75, the stenosis bears physiologic significance
which justifies bypass surgery of the LM lesion.
How does FFR works in complex coronary
disease?
•
difficult anatomy, poorly visible lesions, overlap
•
multiple stenoses within one artery
•
•
diffuse disease
long and ostial lesions
left main disease
•
multivessel disease (FAME Study)
•
Evidence Based
DEFER STUDY:

A Multicenter Randomized Study to
Compare Deferral Versus Performance of
PCI of Non-Ischemia-Producing Stenoses
The DEFER Study: Design
prospective randomized multicentric trial
(14 centers) in 325 patients with stable
chest pain and an intermediate stenosis
without objective evidence of ischemia
Aalst
Amsterdam
Eindhoven
Essen
Gothenborg
Hamburg
Liège
Maastricht
Madrid
Osaka
Rotterdam
Seoul
Utrecht
Zwolle
The DEFER Study: Objectives
Primary objective
• to test safety of deferring PCI of stenoses
not responsible for inducible ischemia as
indicated by FFR > 0.75 ( “outcome” )
Secondary objective
• to compare quality of life in such patients,
whether or not treated by PCI
(CCS-class, need for anti-anginal drugs)
(“symptoms”)
The DEFER Study: Flow Chart
Patients scheduled for PCI
without Proof of Ischemia
(n=325)
Randomization
performance of PTCA
(158)
deferral of PTCA
(167)
FFR  0.75
(91)
No PTCA
DEFER
Group
FFR < 0.75
(76)
PTCA
FFR < 0.75
(68)
PTCA
REFERENCE Group
FFR  0.75
(90)
PTCA
PERFORM
Group
event – free survival (%)
100
75
78.8
72.7
64.4
Defer
50
p=0.52
p=0.03
Perform
25
p=0.17
Reference
(FFR < 0.75)
0
0
1
2
3
4
5
Years of Follow-up
No. at risk
Defer group
90
85
82
74
73
72
Perform group
88
78
73
70
67
65
Reference gr
135
105
103
96
90
88
Cardiac Death And Acute MI After 5 Years
P< 0.03
20
%
P< 0.005
15.7
15
P=0.20
10
5
0
7.9
3.3
DEFER
PERFORM
FFR > 0.75
REFERENCE
FFR < 0.75
Freedom From Chest Pain
100%
*
**
**
80%
**
*
60%
40%
20%
0%
baseline
1month
1 year
Defer group
Perform group
FFR > 0.75
FFR > 0.75
2 year
5 year
Reference group
FFR < 0.75
DEFER: Summary
1. In patients with stable chest pain, the most important
prognostic factor of a given coronary artery stenosis,
is its ability of inducing myocardial ischemia (as
reflected by FFR < 0.75)
2. In those patients, clinical outcome of such “ischemic”
stenosis, even when treated by PCI, is much worse
than that of a functionally “non-significant” stenosis.
3. The prognosis of “non-ischemic” stenosis (FFR > 0.75)
is excellent and the risk of such “non-significant”
stenosis or plaque to cause death or AMI is < 1% per
year, and not decreased by stenting
DEFER:
Conclusion
Stenting a “non-ischemic” stenosis does not
benefit patients with stable chest pain, neither
in prognostic nor symptomatic respect.
FAME study:
Study Population
The FAME study was designed to reflect daily practice in performing PCI
in patients with multivessel disease
Inclusion criteria:


ALL patients with multivessel disease
Stenoses ≥ 50% in 2 or 3 major epicardial coronary arteries,
which are amenable for stenting.
Exclusion criteria:



Left main disease or previous bypass surgery
Acute STEMI
Extremely tortuous or calcified coronary arteries
PRIMARY ENDPOINT:

Composite of death, myocardial infarction,
or repeat revascularization (“MACE”) at 1
year
SECONDARY ENDPOINTS:







Individual components of MACE at 1 year
Functional class
Use of anti-anginal drugs
Health-related quality of life (EuroQOL-5D)
Procedure time
Amount of contrast agent used during
procedure
Cost of the procedure
CONCLUSIONS (1):
*Routine measurement of FFR during PCI with
DES in patients with multivessel disease, when
compared to current angiography guided
strategy:
 Reduces the rate of the composite endpoint of
death, myocardial infarction, re-PCI and CABG at
1 year by ~ 30%
 Reduces mortality and myocardial infarction at 1
year by ~ 35 %
CONCLUSIONS (2):




Routine measurement of FFR during PCI with
DES in patients with multivessel disease, when
compared to current angiography guided
strategy:
Is cost-saving and does not prolong the
procedure.
Reduces the number of stents used.
Decreases the amount of contrast agent used.
Results in a similar, if not better, functional
status.
Routine measurement of FFR during PCI
with DES supports the evolving paradigm
of:
“Functionally Complete Revascularization”
i.e. revascularization of ischemic lesions and
medical treatment of non-ischemic ones.
FFR and Viability :

Hibernating myocardium is defined as chronic, reversible
left ventricular dysfunction due to CAD.

Several animal and human studies have shown that
hibernating myocardium was characterized by a
mismatch between flow and function: a dyssynergy in
the presence of a normal (or near normal) myocardial
flow. Explaining the apparent paradox between severe
contractile dysfunction in presence of normal flow.

Lee et al,. showed that dyssynergic myocardial segments with a
contractile reserve had a lower flow reserve than normal segments
but a significantly higher flow reserve than dyssynergic segments
without contractile reserve.
The relationship between hibernating myocardium and fraction flow
reserve can be summarized as follows:
(a) resting flow is normal,
(b) flow reserve is reduced,
(c) the higher flow reserve (but within the abnormal range), the
higher the likelyhood and the extent of viability.

Practically, in a patient with an epicardial stenosis and a
dyssynergy at left ventricular angiogram, it is reasonable
to state that:
“a high FFR suggest the absence of reversible ischemia.”
Cost-effectiveness issue:
*compare
the long-term costs and benefits of 3 strategies for treating
patients with an intermediate coronary lesion and no prior functional
study:

1) deferring the decision for (PCI) to obtain a nuclear
stress imaging study (NUC strategy)

2) measuring fractional flow reserve (FFR) at the time of
angiography to help guide the decision for PCI (FFR
strategy)

3) stenting all intermediate lesions (STENT strategy).

*Division of Cardiovascular Medicine, Stanford University Medical Center, Stanford, Calif 94305-5406, USA.
wfearon@stanford.edu

RESULTS:
The FFR strategy saved 1795 $ per patient
compared with the NUC strategy and 3830 $
compared with the STENT strategy.
Quality-adjusted life expectancy was similar
among the 3 strategies .
CONCLUSION:
In patients with an intermediate coronary
lesion and no prior functional study,
measuring FFR to guide the decision to
perform PCI may lead to
significant cost savings
compared with performing nuclear stress
imaging or with simply stenting lesions in
all patients.

•Again.......Should this lesion be
stented ??
FFR
IVUS
Thank You
“If you want to treat a lesion, use IVUS;
if you want to treat it correctly, use FFR.”