Contrast as an easy vasodilatory agent? - Nils Johnson

1. Contrast FFR (cFFR)
An easy vasodilatory agent!
Nils P. Johnson, MD, MS, FACC
Associate Professor of Medicine
Weatherhead Distinguished Chair of Heart Disease
Division of Cardiology, Department of Medicine
and the Weatherhead PET Imaging Center
McGovern Medical School at UTHealth
Memorial Hermann Hospital – Texas Medical Center
United States of America
Weatherhead
PET Imaging
Center

2. Disclosure Statement of Financial InterestDisclosure Statement of Financial Interest
• Grant/research support
(to institution)
• Licensing and associated consulting
(to institution)
• Educational organizations
(travel support for academic meetings)
• St Jude Medical (for CONTRAST study)
• Volcano/Philips (for DEFINE-FLOW study)
• Boston Scientific
(for smart-minimum FFR algorithm)
• ASNC (travel award 2007)
• Canadian CPI (Montréal 2013-15)
• CRF (TCT 2012-15, CPIIS 2014)
• CVIT (Tokyo 2016)
• CVRF (IPS 2015)
• Emory (EPIC-SEC 2015)
• ESC (ETP physiology courses 2013-15)
• KSIC (annual meeting & IPOP 2015)
• Norwegian Society of Cardiology
• PCR (EuroPCR 2015)
• SCAI (travel award 2010)
• SJM (various 2015-16)
Within the past 12+ months, Nils Johnson has had a financial
interest/arrangement or affiliation with the organization(s) listed below.
Affiliation/Financial Relationship Organizations (alphabetical)

3. Pyramid of diagnostic accuracy
Johnson NP, JACC Cardiovasc Interv. 2016 Apr 25;9(8):757-67. (Based on Figure 1)
100% = gold standard
50% = coin flip

4. Coronary angiography
Ryan TJ, JACC. 1998 Mar 15;31(4 Suppl B):89B-96B. (Figure 1)
Frame from 1st
ever selective coronary angiogram
Mason Sones, October 30, 1958, Cleveland Clinic

5. Angiogram <70% accuracy
top = Toth G, Eur Heart J. 2014 Oct 21;35(40):2831-8 (Figure 1A)
bottom = Park SJ, JACC Cardiovasc Interv. 2012 Oct;5(10):1029-36 (Figure 1A)
4,086 lesions with QCA
Compared to FFR≤0.8
•50%DS threshold
– 0.64 AUC
1,066 lesions with QCA
Compared to FFR≤0.8
•52%DS threshold
– 66% accuracy
– 0.66 AUC

6. Pyramid of diagnostic accuracy
100% = gold standard
50% = coin flip
65% ≈ angiogram alone
Sones, 1958

7. Resting physiology

8. RESOLVE = Jeremias A, JACC. 2014 Apr 8;63(13):1253-61
ADVISE 2 = Escaned J, JACC Cardiovasc Interv. 2015 May;8(6):824-33 and 834-6
VERIFY 2 = Hennigan B, manuscript under review
CONTRAST = Johnson NP, JACC Cardiovasc Interv. 2016 Apr 25;9(8):757-67
50%
60%
70%
80%
90%
100% = FFR with adenosine
RESOLVE
n=1,593
ADVISE 2
n=690
VERIFY 2
n=257
CONTRAST
n=763
p=0.78
Pd/Pa
iFR
Key conclusions
•80% accuracy
•Pd/Pa ≈ iFR
•3,300+ lesions
•multiple studies
•Volcano iFR
p=1.00
Resting physiology ≈ 80% accuracy

9. Pyramid of diagnostic accuracy
100% = gold standard
50% = coin flip
65% ≈ angiogram alone
80% ≈ rest physiology
(Pd/Pa or iFR)
Grüntzig, 1979
Sones, 1958

10. Clinical importance of hyperemia
Composite of slides presented by Pijls NH, TCT lecture on September 14, 2014
Pd/Pa = 0.96
iFR = 0.97
normal ECGRest
Rest no defect
59 year-old man with
mild & long LAD lesion
and no rest symptoms

11. Clinical importance of hyperemia
Composite of slides presented by Pijls NH, TCT lecture on September 14, 2014
59 year-old man with
mild & long LAD lesion
and no rest symptoms
but classic angina
Pd/Pa = 0.96
iFR = 0.97
FFR = 0.73
normal ECG
+ECG
Rest
Treadmill
Rest
Stress
no defect
LAD defect

12. • FFR<0.75
– all 21 had 1+ test positive (often 2 or 3)
– all positive tests return to normal
– all FFR increased to >0.75 after PCI
Multi-test, pre/post validation of FFR
Pijls NH, N Engl J Med. 1996 Jun 27;334(26):1703-8 (Figure 2 and quotes from text with emphasis added)
– “composite information from sequentially
performed noninvasive tests has a
diagnostic accuracy of almost 100%”

13. Pyramid of diagnostic accuracy
100% = gold standard
50% = coin flip
65% ≈ angiogram alone
80% ≈ rest physiology
(Pd/Pa or iFR)
95+% ≈ FFR
hyperemia
Grüntzig, 1979
Sones, 1958

14. Vasodilators in human physiology
• contrast medium (1974, Gould KL, Am J Cardiology)
• dipyridamole (1978, Gould KL, Am J Cardiology)
• coronary occlusion (1984, Marcus ML, NEJM)
• papaverine (1986, Wilson RF, Circulation)
• adenosine (1990, Wilson RF, Circulation)
• ATP (2003, De Bruyne B, Circulation)
• nitroprusside (2004, Kern MJ, Circulation)
• nicorandil (2006, Kang JC, Int J Cardiology)
• regadenoson (2011, Nair PK, JACC Interventions)

15. 1959 paper on contrast hyperemia
Guzman SV, Am Heart J. 1959 Oct;58(4):597-607 (taken from results, page 602)
70 kg * (0.025 to 0.25 cc/kg) =
1.8 to 18cc ≈ 10cc of IC contrast
gave 60% increase in flow

16. 2003 contrast FFR
De Bruyne B, Circulation. 2003 Apr 15;107(14):1877-83 (Figure 2, data from Table 2 and results)
“intracoronary bolus
administration of 6 mL of
iohexol did produce a
significantly weaker effect
than all other stimuli”
•10 seconds to effect
•2 second plateau
(vs 22 for papaverine,
or 5-7 for adenosine)

17. CONTRAST study hypothesis
• Contrast FFR provides superior agreement with FFR
than resting metrics (rest Pd/Pa or iFR)
• Primary endpoint: diagnostic accuracy vs FFR≤0.8
• Secondary endpoints: AUC by ROC, repeatability

18. • Unique features of the CONTRAST study
– Larger sample size (improves precision)
– International and multicenter (widely applicable)
– Blinded core lab analysis (minimizes bias)
– Pragmatic protocol (real-world scenarios)
– Two measurements (test/retest stability)
– IC and IV adenosine (route of hyperemia)
– Rest Pd/Pa and iFR (both resting metrics)
CONTRAST design

19. Pyramid of diagnostic accuracy
100% = gold standard
50% = coin flip
65% ≈ angiogram alone
80% ≈ rest physiology
(Pd/Pa or iFR)
95+% ≈ FFR
Where does contrast fit?

20. Methods
• 763 subjects (prospective) with 1 lesion/patient
– Any lesion fulfilling a clinical indication for FFR
• Hyperemic drugs
– IC contrast: medium and volume per local practice
– IC adenosine: recommended dose 100-200 μg
– IV adenosine: standard infusion rate (140 μg/kg/min)
• Cutoffs for comparison with FFR
– iFR<0.90 (DEFINE-FLAIR), Pd/Pa<0.92 (RESOLVE)

21. Belgium (Aalst)
•B De Bruyne
•E Barbato
Korea
•BK Koo (SNUH)
•SJ Park (Asan)
Scotland (Glasgow)
•C Berry
•K Oldroyd
•B Hennigan
USA
•W Fearon (Palo Alto)
•G Chrysant (OKC)
France (Lyon)
•G Rioufol
Netherlands (Eindhoven)
•N Pijls
•F Zimmermann
Sweden (Stockholm)
•N Witt
CRF (physiology core lab)
•A Jeremias
•A Maehara
•M Matsumura
Italy (Naples, Rome)
•G Esposito
•B Trimarco
•A Leone
Portugal (Lisbon)
•S Baptista
UT-Houston (sponsor)
•N Johnson
•R Kirkeeide
•KL Gould
CONTRAST: participating centers

22. CONTRAST example: rest #1
Johnson NP, JACC Cardiovasc Interv. 2016 Apr 25;9(8):757-67. (Figure 2, annotated)
coronary
aortic
Pd/Pa

23. CONTRAST example: IC contrast #1
Johnson NP, JACC Cardiovasc Interv. 2016 Apr 25;9(8):757-67. (Figure 2, annotated)

24. CONTRAST example: IC contrast #2
Johnson NP, JACC Cardiovasc Interv. 2016 Apr 25;9(8):757-67. (Figure 2, annotated)

25. CONTRAST example: IC adeno #1
Johnson NP, JACC Cardiovasc Interv. 2016 Apr 25;9(8):757-67. (Figure 2, annotated)

26. CONTRAST example: IC adeno #2
Johnson NP, JACC Cardiovasc Interv. 2016 Apr 25;9(8):757-67. (Figure 2, annotated)

27. CONTRAST example: rest #2
Johnson NP, JACC Cardiovasc Interv. 2016 Apr 25;9(8):757-67. (Figure 2, annotated)

28. CONTRAST example: IV adeno #1
Johnson NP, JACC Cardiovasc Interv. 2016 Apr 25;9(8):757-67. (Figure 2, annotated)
140μg/kg/min of
IV adenosine

29. CONTRAST example: IV adeno #2
Johnson NP, JACC Cardiovasc Interv. 2016 Apr 25;9(8):757-67. (Figure 2, annotated)

30. CONTRAST example: drift check
Johnson NP, JACC Cardiovasc Interv. 2016 Apr 25;9(8):757-67. (Figure 2, annotated)

31. CONTRAST example: summary
• Rest
– Pd/Pa = 0.93 and 0.92
– iFR = 0.91 and 0.91
• IC contrast
– cFFR = 0.77 and 0.76
• IC adenosine
– FFR = 0.69 and 0.69
• IV adenosine
– FFR = 0.68 and 0.69
• Drift check
– 1.01 at guide

32. CONTRAST example: summary
• Rest
– Pd/Pa = 0.93 and 0.92
– iFR = 0.91 and 0.91
• IC contrast
– cFFR = 0.77 and 0.76
• IC adenosine
– FFR = 0.69 and 0.69
• IV adenosine
– FFR = 0.68 and 0.69
• Drift check
– 1.01 at guide
Both Pd/Pa and iFR miss low FFR,
but contrast FFR gets it right!

33. Results: Baseline characteristics
• Age 66±10 years, 72% male
• 10% with renal insufficiency (eGFR<60)
• Average 8±2 mL of IC contrast, 8 different agents:
– iomeprol (30%)
– iodixanol (25%)
• Exclusions by core lab
– 10% of pressure tracings
– 15% of ECG tracings
– iohexol (14%)
– iopromide (9%)
– ioversol (9%)

34. Results: Lesion physiology
Rest
iFR
Contrast
Adenosine
0.7 0.8 0.9 1.0
Pd/Pa
0.92
0.85
0.81
(shows median and interquartile range)
0.90
49.2% with FFR≤0.8

35. Results: Lesion physiology
Rest
iFR
Contrast
Adenosine
0.7 0.8 0.9 1.0
Pd/Pa
0.92
0.85
0.81
(shows median and interquartile range)
0.90
9.4% with Pd/Pa≤0.8
28.8% with cFFR≤0.8

36. Johnson NP, JACC Cardiovasc Interv. 2016 Apr 25;9(8):757-67. (Figure 4, left+modified)
Pd/Pa = 78.5% accuracy
Results: Diagnostic accuracy

37. Johnson NP, JACC Cardiovasc Interv. 2016 Apr 25;9(8):757-67. (Figure 4, left+modified)
iFR = 79.9% accuracy
Pd/Pa = 78.5% accuracy
 no difference (p=0.78)
Results: Diagnostic accuracy
• AUC = area under ROC curve (DeLong comparison)
• Accuracy uses FFR≤0.8 (McNemar comparison)

38. Johnson NP, JACC Cardiovasc Interv. 2016 Apr 25;9(8):757-67. (Figure 4, left)
contrast = 85.8% accuracy
iFR = 79.9% accuracy
Pd/Pa = 78.5% accuracy
 superior accuracy (p<0.001)
Results: Diagnostic accuracy
Optimal binary cutoff for contrast FFR ≤0.83
(accuracy >84% for 0.83-0.85)

39. Results: Binary versus hybrid
Binary = never adenosine
 contrast best
Johnson NP, JACC Cardiovasc Interv. 2016 Apr 25;9(8):757-67. (Figure 4, left)

40. Results: Binary versus hybrid
Binary = never adenosine
 contrast best
Hybrid = selective adenosine
 contrast best
Johnson NP, JACC Cardiovasc Interv. 2016 Apr 25;9(8):757-67. (Figure 4)

41. Results: Test/retest stability
Average contrast FFR
0.2
-0.2
-0.1
0.0
+0.1
+0.2
-0.2
-0.1
0.0
+0.1
+0.2
Average iFR
0.4 0.6 0.8 1.0 0.2 0.4 0.6 0.8 1.0
Δ < 0.01
SD = 0.017
(less scatter)
Δ < 0.01
SD = 0.033
(more scatter)

42. Limitations
• Contrast hyperemia too short for pull-back tracings
– Applies to IC adenosine too
– Can perform serial IC bolus measurements
• No data collected on contrast-induced nephropathy
– Average dose 8 mL of IC contrast for single vessel
– Used to document pressure wire position anyway
– Clinical impact negligible
• Further details in substudies
– Contrast medium and volume dose/response

43. Conclusions
• Contrast FFR is superior to rest Pd/Pa and iFR for
predicting FFR (using binary or hybrid approach)
• iFR and rest Pd/Pa provide equivalent diagnostic
accuracy
• FFR with strong hyperemia (adenosine) remains the
reference standard for diagnostic certainty (even
contrast FFR only reached ≈85% accuracy)

44. Pyramid of diagnostic accuracy
Johnson NP, JACC Cardiovasc Interv. 2016 Apr 25;9(8):757-67. (Figure 1)

45. Clinical impact
• Contrast FFR was ≤0.8 in ≈30% of cohort, thus
confirming functional significance “for free”
• In healthcare systems in which adenosine is
prohibitively expensive or in the rare cases when
adenosine is contraindicated, contrast FFR:
– Is easy, inexpensive, and safe
– Displays excellent test/retest stability
– Does not depend on a specific software platform
(available on all pressure-wire systems) or ECG gating (core lab
excluded 15% of ECG tracings)

46. cFFR better than resting physiology
CONTRAST = Johnson NP, JACC Cardiovasc Interv. 2016 Apr 25;9(8):757-67.
MEMENTO = Leone AM, EuroIntervention. 2016 Aug 20;12(6):708-15.
Kanaji = Kanaji Y, Int J Cardiol. 2016 Jan 1;202:207-13.
50% 0.5
60%
70%
80%
90%
100% = FFR with adenosine
CONTRAST
n=763
MEMENTO
n=1026
Kanaji
n=91
0.6
0.7
0.8
0.9
1.0 = FFR with adenosine
Pd/Pa
cFFR
CONTRAST MEMENTO Kanaji
p<0.001
87%
p<0.0001
Pd/Pa
cFFRp<0.001
p<0.001

47. Practical algorithm
Pd/Pa
≤0.8
PCI reasonable
>0.8
Based on discussion with Keith Oldroyd, March 27, 2016.

48. Practical algorithm
Pd/Pa
≤0.8
PCI reasonable
(10% of lesions)
>0.8
• less information about depth of ischemia!
• pullback less sensitive (smaller pressure jumps)
Approximate percentages from CONTRAST

49. Practical algorithm
Pd/Pa
≤0.8
PCI reasonable
(10% of lesions)
>0.8
contrast FFR
≤0.8
PCI reasonable
(20% of lesions)
>0.8
• maintains 100% accuracy
• reduces adenosine use by 30%

50. Practical algorithm
Pd/Pa
≤0.8
PCI reasonable
(10% of lesions)
>0.8
contrast FFR
≤0.8 >0.8
PCI reasonable
(20% of lesions) adenosine FFR
>0.8≤0.8
PCI reasonable
(20% of lesions)
medical therapy
(50% of lesions)