1. When IVUS? When FFR? Assessing Intermediate Lesions
Itsik Ben-Dor, MD
Washington Hospital Center

2. I/we have no real or apparent conflicts of interest to report.
Itsik Ben-Dor, MD
I/we have no real or apparent conflicts of interest to report.

3. Case Would you treat this lesion ? Need more information?
58-year-old male with new onset of chest pain with exercise
Would you treat this lesion ?
Need more information?
IVUS?
FFR?

4. FFR

12. Intravascular Ultrasound
IVUS

13. Mechanical Transducer Solid State Transducer
IVUS – Catheters
Mechanical Transducer
Solid State Transducer

14. Lumen area (mm2) Plaque area (mm2) Plaque burden (%) Remodeling Index
1 slide
stenosis
2 slides R S
stenosis
reference
Remodeling Index
(total area/ref total area)
Lumen area (mm2)
Plaque area (mm2)
Plaque burden (%)
(total area-lumen)/total area

15. MLA 2.9mm2
MLA 4.3mm2 ?

16. Clinical data on outcome-based IVUS
No prospective randomized study has ever shown better PCI outcome by using IVUS in DES era

17. WHC: Abizaid et al. Circ 1999; 100:256-261
IVUS final lumen area determines prognosis
Where did the number 4 mm2 come from?
Clinical follow up in 357 intermediate lesions in 300 patients deferred intervention after IVUS imaging
Death/MI/TLR
TLR DM
no-DM
2-3
3-4
4-5 5
2-3
3-4
4-5 ≥5
IVUS MLA (mm2)
IVUS MLA (mm2)
Death/MI/TLR at mean 13 months = 8%
Death/MI/TLR at mean 13 months = 4.4% in lesion with MLA >4 mm2
Only independent predictor of death/MI/TLR was IVUS MLA
WHC: Abizaid et al. Circ 1999; 100:

18. PROSPECT Study

19. Stone et al. N Engl J Med 2011;361:226-35
PROSPECT Study
Stone et al. N Engl J Med 2011;361:226-35

20. PROSPECT: Predictors of Non Culprit Lesion Events
Stone et al. N Engl J Med 2011;361:226-35

21. Clinical data on
outcome-based FFR

22. DEFER 5-Year Results N=325 Event-Free Survival Cardiac Death and MI
(Pijls et al. J am Coll Cardiol 2007;49: )

23. Fractional Flow Reserve Versus Angiography for Guiding Percutaneous Coronary Intervention in Patients With Multivessel Coronary Artery Disease (FAME I)
Lesions warranting
PCI identified
FFR-Guided
Angio-Guided
PCI performed on
indicated lesions
only if FFR <0.80
PCI performed on
indicated lesions
Randomized
Primary Endpoint
Composite of death,
MI and repeat revasc.
(MACE) at 1 year
Key Secondary Endpoints
Individual rates of death, MI,
and repeat revasc., MACE,
and functional status at 2 years
Pijls N. et al. J Am Coll Cardiol 2010;56:177–84

24. Pijls N. et al. J Am Coll Cardiol 2010;56:177–84
Fractional Flow Reserve Versus Angiography for Guiding Percutaneous Coronary Intervention in Patients With Multivessel Coronary Artery Disease (FAME 2years)
Absolute Difference in MACE-Free Survival
2-Year Follow-Up of the FAME ,,Fractional Flow Reserve Versus Angiography for Multivessel Evaluation’’
Angio guided
FFR guided
1 month
2.9% 6
months
4.9%
12 months
5.1%
24 months
4.7%
Conclusion: In pts with multivessel CAD undergoing PCI, routine measurement of FFR as compared with PCI guided by angiography alone results in a significant reduction of the rate of mortality and myocardial infarction
Pijls N. et al. J Am Coll Cardiol 2010;56:177–84

25. At least 1 stenosis with FFR ≤ 0.80 (n=888)
FAME II
Trial Design
Stable patients with 1, 2, or 3 vessel CAD evaluated for PCI with DES
n=1220
FFR in all target lesions
At least 1 stenosis with FFR ≤ 0.80 (n=888)
Randomization 1:1
PCI + MT MT
Randomized Trial
All FFR > 0.80
(n=322) MT
Registry
50% randomly assigned to follow-up
The FAME 2 trial included stable patients with single, double or triple vessel coronary disease being evaluated for PCI with DES. This study was different from previous trials evaluating PCI in patients with stable CAD in that FFR was first measured across all lesions. By doing this, patients with angiographically significant CAD, but not hemodynamically significant (and therefore unlikely to be responsible for symptoms or to cause a future event) were not included in the randomized study. On the other hand, patients who did have at least one lesion in a major epicardial vessel with an FFR ≤0.80 were included, ensuring a significant ischemic burden in those randomized to FFR-Guided PCI or to MT. The primary endpoint was D, MI, or urgent revasc at 2 years.
Primary Endpoint: Death, MI, Urgent Revascularization at 2 years

26. Trial Results % FFR-Guided PCI (n=447) MT (n=441) P-Value
Primary Endpoint
4.3
12.7
<0.001
Death
0.2
0.7
0.31
Myocardial Infarction
3.4
3.2
0.89
Urgent Revascularization
1.6
11.1
Free from Angina (1 month) 71 48 %
The study was stopped early after 888 patients were included and after a mean follow-up of 7 months. There was a highly significant difference in the primary endpoint with 12.7% of the MT patients reaching it and 4.3% of the FFR-Guided PCI patients reaching it. There was no difference in death or MI, but a highly significant difference in urgent revascularization and freedom from angina favoring the FFR-guided PCI group. This raises the question of whether this benefit is worth the cost of up front FFR-guided PCI in all patients with stable coronary disease.
De Bruyne, et al. New Engl J Med 2012;367:

27. Assessment of intermediate coronary lesions

28. QCA

29. FAME Study 37% FFR >0.80 1329 lesions in the FFR-guided arm 65% 20%4%
(44%)
(37%)
(18%)
50-70%
71-90%
91-100%
Angiographic Diameter Stenosis
Tonino et al., JACC 2009

30. Inappropriate decision
Correlation of FFR with % QCA Diameter Stenosis left main coronary artery
Inappropriate decision
Based on angiography
= 29%
Hamilos M, et al. Circulation 2009;120:

31. Ben-Dor EuroIntervention. 2011 Jun;7(2):225-33.
Correlation between Fractional Flow Reserve and Intravascular Ultrasound Lumen Area in Intermediate Coronary Artery Stenosis
205 intermediate lesions in 185 patients were studied consecutively by QCA, IVUS, and FFR during diagnostic coronary angiography between July 2007 and January 2011
Intermediate coronary stenosis was defined by QCA as a stenosis 40-70%
Excluded: Patients with acute myocardial infarction, lesions in small vessels <2.5 mm reference vessel diameter, or with more than one lesion in the studied vessel
Ben-Dor EuroIntervention Jun;7(2):

32. IVUS vs. FFR 193 lesions (excluding 12 LM)
41 (53.2%) with MLA <3 mm2 had non ischemic FFR ≥0.8
92 (65.7%) with MLA <4mm2 had non ischemic FFR ≥0.8
15 (12.9%) with MLA >3 mm2 had ischemic FFR <0.8
3 (5.6%) with MLA >4mm2 had ischemic FFR <0.8
Ben-Dor EuroIntervention Jun;7(2):

33. IVUS cut-off for ischemic FFR
3.09 mm2
(sensitivity 69.2%, specificity 71.5%)
Percentage
Ben-Dor EuroIntervention Jun;7(2):

34. Ben-Dor EuroIntervention. 2011 Jun;7(2):225-33.
IVUS vs. FFR for intermediate coronary stenosis (n=205 lesions, 185 patients)
r= 0.36, p<0.001
r= 0.25, p<0.001
r= -0.43, p<0.001
r= -0.33, p<0.001
Ben-Dor EuroIntervention Jun;7(2):

35. Ben-Dor EuroIntervention. 2011 Jun;7(2):225-33.
Correlation of FFR with MLA by reference vessel diameter
r= 0.2, p=0.11
r= 0.44, p<0.001
MLA
MLA
N=50
FFR
N=76
FFR
r= 0.43, p<0.001
MLA
N=79
FFR
Ben-Dor EuroIntervention Jun;7(2):

36. Ben-Dor EuroIntervention. 2011 Jun;7(2):225-33.
IVUS cut-off for ischemic FFR <0.8 by reference vessel diameter
2.4 mm2
2.7 mm2
C=0.74
C=0.77
Percentage
Percentage
3.6 mm2
C=0.70
Percentage
Ben-Dor EuroIntervention Jun;7(2):

37. All lesion with MLA<3mm2
FFR <0.8
N=38
FFR >0.8
N=39
P value
Lesion characteristics
LAD
22(57.9%)
14(35.9%)
0.05
Circumflex
3(7.9%)
4(10.3%)
0.9
RCA
10(26.3%)
11(28.2%)
0.85
Diagonal/Ramus/Marginal
10(25.6%)
0.03
Proximal
19(50.0%)
25(64.1%)
0.21
Mild
17(44.7%)
0.07
Distal
2(5.3%)
0.67
Lesion length (mm)
19.2±8.5
12.5±6.4
0.01
Area stenosis (%)
65.6±7.8
57.8±15.6
Reference diameter (mm)
7.5±1.9
6.6±2.5
0.17
Reference diameter 2.5-3mm
14(36.8%)
18(46.2%)
0.4
Reference diameter 3-3.5mm
16(41.0%)
0.42
Reference diameter >3.5mm
5(13.2%)
5(12.8%)
Pressure drops across stenosis:
Luminal area MLA
Lesion length Length
Flow Reference vessel
Ben-Dor EuroIntervention Jun;7(2):

38. Study participating Sites
THE F1RST TRIAL Results
Study participating Sites
Site Name
City, State Country
Principal Investigators
# Enrolled
Washington Hospital Center
Washington, DC USA
Ron Waksman, MD 91
University Hospital Krakow
Krakow, Poland
Jacek Legutko, MD 59
Barnes Jewish Hospital
St. Louis, MO USA
Jasvindar Singh, MD 49
Hamot Medical Center
Erie, PA USA
Quentin Orlando, MD 33
St. Luke’s Health Center
Kansas City, MO USA
Steven Marso, MD 27
Patients First
Washington, MO USA
Timothy Schloss, MD 26
Ohio Heart Research
Columbus, OH USA
John Tugaoen, MD 7
Dartmouth Medical Center
Lebanon, NH USA
James DeVries, MD 6
Liverpool Heart and Chest
Liverpool, United Kingdom
Nicholas Palmer, MD 5
Städtische Kliniken Neuss
Neuss, Germany
Michael Haude, MD 1
350 patients with 369

39. Overall Population Analyses
F1RST
MLA: 3.07 mm2
Sensitivity 0.64
Specificity 0.65
C= 0.65

40. RVD < 3.0 mm
RVD 3.0 to 3.5 mm
RVD > 3.5 mm
MLA

41. Optimal MLA Cut-off Values
F1RST N
MLA Cut-off mm2
C-Statistic
Accuracy
Vessel Size
RVD <3.0 mm
175
2.68
0.64
65.7%
RVD mm 92
3.16
0.69
70.7%
RVD >3.5 mm 62
3.74
67.7%
LV Functional Status
Normal LV
245
2.92
0.66
67.8%
Reduced LV (<50%
/ Prior MI) 85
3.07
68.2%

42. Diameter stenosis >50%
Reference vessel size ?
Reference diameter
Area
Area % stenosis for 4mm2
2.5 mm
4.9 mm2
18%
3 mm
7.1 mm2
44%
3.5 mm
9.6 mm2
58%
4 mm
12.5 mm2
68%
Area stenosis >70%
Diameter stenosis >50%

43. Reference vessel size ?

45. Conclusions
Anatomic measure of intermediate coronary lesion obtained by IVUS show only a moderate correlation to FFR values.
The MLA is vessel size dependent and better correlated in large diameter vessels.
The optimal MLA cutoff that corresponds with an FFR < 0.8 is ~3.0mm2
The optimal MLA cutoff varied with regards to vessel location, vessel size and, lesion severity
However, the utility of IVUS MLA as an alternative to FFR for guidance of intervention of intermediate lesions may be limited and should be tested clinically