1. FFR Going Beyond AngiographyBy
Amr El Nagar

2. Should this lesion be stented ??

3. 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
( /mm2 versus /mm2 skeletal muscle)
• Therefore, only way to meet increasing
demand is to increase blood flow

4. Coronary Blood Flow vs Percent Diameter Stenosis Autoregulation Autoregulation

5. 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.

6. Physiology to Address Clinical Questions in the Cath Lab…

7. FFR
What ??????????????
Why???????????????
How??????????????
When?????????????
$$$$$$$$$$$$$$$$

8. What is FFR? It is a Ratio between
Maximum flow down a vessel in the presence of a stenosis…
…and
maximum flow in the hypothetical absence of the stenosis

9. 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)

10. FFR threshold for ischemiaNo
ischemia
Yes
ischemia
FFR
1.00
0.75
0.00
Bovendien is er een drempewaarde van 0.75 die onderscheid maakt tussen wel of geen induceerbare ischaemie.
FFR <  inducible ischemia (spec. 100 % )
FFR >  no inducible ischemia (sens. 90 % )
Pijls, De Bruyne et al, NEJM 1996

11. 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.

12. Limitations of Anatomic Techniques:
- Underestimates diffuse disease
- Large Intra- and inter-observer variability
- Not designed to assesses physiologic lesion significance

13. 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

14. 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

15. How???? Technique!!!!

16. Pressure Wire Tip Pressure sensor Guide wire - 0.014
straight or ‘J’ tip
pressure sensor - 3 cm proximal to the end of the wire
Pressure sensor

18. Equipments
RADI ANALYZER
PRESSURE WIRE

19. 100 Qnormal 100 Qstenosis Myocardium Aorta coronary artery Pa Pd
Qnormal
Max. hyperemia
Normal perfusion pressure
100 Pa Pd
Qstenosis
U ziet hier een schema van de aorta, een normale kransslagader en het myocard. Veronderstel nu een toestand na toediening van een maximaal hyperaemische prikkel. Met andere woorden: de bloedstroom is maximaal en de weerstand derhalve minimaal en constant. De perfusiedruk over het myocard is nu 100 mm kwik.
Stel nu verder dat er een stenose ontstaat met een maximale gradient van 30mm kwik. Dan resteert achter de vernauwing nog een perfusiedruk van slechts 70mm kwik.
Omdat bij maximale hyperaemie de bloedstroom door het myocard recht evenredig is met de perfusiedruk in de kransslagader voorbij de vernauwing betekent dit dat de maximale bloedstroom in aanwezigheid van de vernauwing geindexeerd voor de bloedstroom zoals deze had moeten zijn gelijk is aan de stenotische perfusiedruk in dit geval 70 gedeeld door de normale perfusiedruk van 100mm kwik waardoor de FFR nog 70% is van wat deze had moeten zijn.
We zeggen dan dat de FFR 0,70 0f 70% is.
Deze metingen kunnen worden gedaan met dunne PTCA voerdraden waarmee de druk kan worden gemeten.
Stenotic perfusion pressure
Qstenosis Stenotic perfusion press Pd
FFR = = =
Qnormal Normal perfusion press Pa

20. blood pressure distal to the lesion being assessed - Pressure distal (Pd)
conventional pressure transducer - measures arterial/aortic pressure - Pressure arterial (Pa)

21. 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.

22. 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

23. 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

24. Vasodilatory Agents for Hyperemia

25. Where to Administer Adenosine?

26. Examples of coronary pressure gradient

27. Coronary pressure measuremnts

28. Pitfalls and Artifacts

29. Anatomic/Theoretical:
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

30. 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

31. 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

32. 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

33. When FFR???(value) Borderline lesions Evaluation of PCI
FFR after coronary intervention should preferably be higher than 0.90

34. Multicenter registry Europe-USA-Asia 750 pat. post-STENT FFR
% death, infarction, or re-intervention at 6 mnths.
40%
37%
After stenting: Inverse correlation between FFR and event rate.
30%
28%
19%
20%
Na stenten is dit nog veel meer uitgesproken het geval. Bij een groep van 750 patienten bij wie na stent implantatie met angiografisch optimaal resultaat de FFR werd gemeten hebben bleek bij de patienten met een FFR groter dan 0.90 dat de kans op dood infacrt of reinterventie na 6 maanden ongeveer 5% was terwijl bij hen met een FFR minder dan 0.90 dit 4 maal zo hoog lag.
10% 7% 4% 0%
Post-STENT FFR

35. difficult anatomy, poorly visible lesions, overlap
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

36. Male, 67, stable angina, positive exercise test
LCX
D 2
RCA
LAD
D 1
Laten we nu eens kijken hoe deze kennis in de praktijk kan worden toegepast bij onze voorbeelden uit het begin van mijn presentatie. Bij deze patient hebben we zowel in de LAD, de diagonalen, als in de RCA de FFR bepaalt.
2 intermediate stenoses mid RCA Complex lesion proximal LAD

37. LAD, hyperemia Pa Pa
100 Pd Pd
FFR = 92/98 = 0.94

38. DIAG 2, hyperemia Pa Pa
100 Pd Pd
FFR = 87/97 = 0.89

39. DIAG 1, hyperemia Pa Pa Pd
100 Pd
FFR = 87/96 = 0.90

40. RCA, hyperemia Pa
100 Pd
FFR = 38/92 = 0.41

41. Balloon 3.0 mm

42. Pa Pd After balloon inflation 3.0 balloon 12 atm FFR = 55/82 = 0.67
100 Pd
FFR = 55/82 = 0.67

43. Stent 3.5 mm(mid-RCA)

44. Stent 3.5 mm(mid-RCA) Pa
100 Pd
FFR = 76/95 = 0.80

45. Pressure drop
Pull back pressure wire

46. Additional Stent
3.5 mm (prox-RCA)

47. Pa Pd Stent 3.5 mm(mid-RCA) + Stent 3.5 mm(prox-RCA)
100 Pd
FFR = 88/94 = 0.94

48. while avoiding a riskful intervention of the LAD or bypass surgery
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.

49. difficult anatomy, poorly visible lesions, overlap
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

50. A B

51. Coronary Pressure & FFR: Pull-Back Curve
Focal disease: sudden changes in pressure

52. Coronary Pressure & FFR: Pull-Back Curve
Diffuse coronary disease: gradual increase of pressure.

53. 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

54. difficult anatomy, poorly visible lesions, overlap
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

55. equivocal left main coronary artery disease by Fractional Flow Reserve
Decision making in
equivocal left main coronary artery disease
by Fractional Flow Reserve
Bech et al, Heart 2001

56. 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.

57. 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.

58. follow-up 54 patients FFR > 0.75 N=24 Medical Group FFR < 0.75
Surgical Group
Mean follow-up (mths) 28  14
Death MI
Early re-operation
CABG
PTCA
Total (21%) (17%)

59. 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.

60. difficult anatomy, poorly visible lesions, overlap
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)

61. Evidence Based DEFER STUDY:
A Multicenter Randomized Study to Compare Deferral Versus Performance of PCI of Non-Ischemia-Producing Stenoses

62. prospective randomized multicentric trial
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

63. 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”)

64. Patients scheduled for PCI without Proof of Ischemia (n=325)
The DEFER Study: Flow Chart
Patients scheduled for PCI without Proof of Ischemia (n=325)
Randomization
deferral of PTCA
(167)
deferral of PTCA
(167)
performance of PTCA (158)
performance of PTCA (158)
FFR < 0.75
(68)
PTCA
FFR  0.75
(91)
FFR < 0.75
(76)
FFR  0.75
(90)
No PTCA
PTCA
PTCA
DEFER Group
REFERENCE Group
PERFORM Group

65. event – free survival (%)
100 75
78.8
72.7
64.4 50
Defer
p=0.52
Perform
p=0.03
p=0.17 25
Reference
(FFR < 0.75) 1 2 3 4 5
Years of Follow-up
No. at risk
Defer group 90 85 82 74 73 72
Perform group 88 78 70 67 65
Reference gr
135
105
103 96

66. Cardiac Death And Acute MI After 5 Years
P< 0.03 % 20
P< 0.005
15.7 15
P=0.20 10
7.9 5
3.3
DEFER PERFORM REFERENCE
FFR > FFR < 0.75

67. Freedom From Chest Pain
100% *
* *
* *
80%
* * *
60%
40%
20% 0%
baseline
1month
1 year
2 year
5 year
Defer group
Perform group
Reference group
FFR > FFR > FFR < 0.75

68. DEFER: Summary
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)
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

69. DEFER:
Conclusion
Stenting a “non-ischemic” stenosis does not benefit patients with stable chest pain, neither
in prognostic nor symptomatic respect.

70. FAME study:

72. Study Population Inclusion criteria: Exclusion criteria:
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

74. PRIMARY ENDPOINT:
Composite of death, myocardial infarction, or repeat revascularization (“MACE”) at 1 year

75. 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

83. 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 %

84. 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.

85. “Functionally Complete Revascularization”
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.

86. 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.

87. 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.

88. 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.”

89. 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 , USA.

90. 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 .

91. significant cost savings
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.

92. Again.......Should this lesion be stented ??

93. Thank You FFR IVUS “If you want to treat a lesion, use IVUS;
if you want to treat it correctly, use FFR.”