1. PRIMARY Results of ADVISE ADenosine Vasodilation Independent Stenosis Evaluation Dr Justin Davies MD, PhD Imperial College London on behalf of the ADVISE investigators

2. Disclosure Statement of Financial Interest Research Support/ Intellectual Property Rights Consulting Fees/Honoraria Volcano Corporation Medtronic, Volcano Corporation Within the past 12 months, I or my spouse/partner have had a financial interest/arrangement or affiliation with the organization(s) listed below. Affiliation/Financial RelationshipCompany

3. FFR is established in clinical practice At best it is only used in 6% of PCI in USA 1 One barrier is the current requirement for vasodilator drugs such as adenosine Contraindicated or disliked by patients Adds to procedural time Adds to procedural costs 1 Kleiman NS. J Am Coll Cardiol 2011; 58:1291-21

4. When coronary resistance is stable – pressure can be used as as a surrogate for flow to assess a coronary stenosis 150 75 Time (s) 24 Resistance (mm Hg s/m) Pressure (mm Hg) Velocity (m/s)

5. If we can identify a period of naturally occurring stable resistance Why do we give drugs such as adenosine to calculate fractional flow reserve (FFR)?

6. Pa Pd De Bruyne et al. JACC Vol. 22, No.1 July 1993:119-26 Marked damping of coronary pressure – necessitated the use of mean pressure in the development of FFR

7. Pa Pd Marked damping of coronary pressure – necessitated the use of mean pressure in the development of FFR De Bruyne et al. JACC Vol. 22, No.1 July 1993:119-26

8. Phasic resistance during the cardiac cycle ADVISE study 150 75 Resistance (mm Hg s/m) Pressure (mm Hg) Velocity (m/s) Time (s) 24

9. ADVISE study Phasic resistance during the cardiac cycle 150 75 Resistance (mm Hg s/m) Pressure (mm Hg) Velocity (m/s) Time (s) 24

10. 150 75 Resistance (mm Hg s/m) Pressure (mm Hg) Velocity (m/s) Time (s) 24

11. Fully automated algorithms Identification of naturally low resistance period Uses pressure only Wave-free period Sen S, Escaned J, Davies JE et al. JACC (in press 2011) Davies JE et al. Circulation 2006;113:1767-1778 Davies JE et al. Circulation 2011;124:1565-1572 Identification of wave-free period

12. Hypothesis 1 Resistance measured at rest during the resting wave- free period is similar to mean resistance during hyperaemia. Hyperaemic mean resistanceResting wave-free resistance ADVISE study

13. Wave-free period Hypothesis 2 The Pd/Pa ratio (iFR) during the resting wave-free period was similar to FFR. ADVISE study

14. Resting wave-free resistance vs. mean hyperaemic resistance n=39 Intra-coronary pressure and flow velocity measurements Baseline resistance assessment Resistance assessment under pharmacological vasodilatation iFR vs. FFR n=157 Intra-coronary pressure measurements iFR & FFR assessment ADVISE Study ADenosine Vasodilation Independent Stenosis Evaluation Part 1 Proof of concept Part 2 Validation study

15. ADVISE study demographics n=156 lesions age = 63 years RISK FACTORS VESSEL CHARACTERISTICS ADVISE study

16. Test stability and magnitude of resistance during wave-free period in comparison to during adenosine hyperaemia Hypothesis 1

17. Resting wave-free resistance Hyperaemic mean resistance Stability of resistance is similar over the wave- free period and during hyperaemia Coefficient of Variation of resistance Sen S, Escaned J, Davies JE et al. JACC (in press 2011) ADVISE study

18. Resting wave-free resistance Hyperaemic mean resistance p=0.96 Stability of resistance is similar over the wave- free period and during hyperaemia Coefficient of Variation of resistance Sen S, Escaned J, Davies JE et al. JACC (in press 2011) ADVISE study

19. Resting mean resistance Resistance (mm Hg s/m) Magnitude of resistance is similar over the wave-free period and during hyperaemia 0 800 Resting wave-free resistance Hyperaemic mean resistance ADVISE study

20. Resting wave-free resistance Hyperaemic mean resistance Resting mean resistance Resistance (mm Hg s/m) p<0.001 p=0.70 Magnitude of resistance is similar over the wave-free period and during hyperaemia 0 800 ADVISE study

21. Resistance measured at rest during the wave-free period… Hypothesis 1

22. Resistance measured at rest during the wave-free period… is similar in both stability and magnitude to values achieved under adenosine hyperaemia. Hypothesis 1

23. Assess whether iFR was numerically similar to Fractional flow reserve. Hypothesis 2

24. Definition: Instantaneous pressure gradient, across a stenosis during the wave-free period, when resistance is constant and minimised in the cardiac cycle iFR = instantaneous wave-free ratio Pa Pd Wave-free period

25. Close relationship between iFR and FFR y=1.022x + 0.03 Regression coefficient FFR iFR Sen S, Escaned J, Davies JE et al. JACC (in press 2011) ADVISE study

26. Close relationship between iFR and FFR r = 0.90 y=1.022x + 0.03 Regression coefficient FFR iFR Sen S, Escaned J, Davies JE et al. JACC (in press 2011) ADVISE study

27. Close relationship between iFR and FFR y=1.022x + 0.03 Regression coefficient Left coronary artery Right coronary artery FFR iFR r = 0.90 Sen S, Escaned J, Davies JE et al. JACC (in press 2011) ADVISE study

28. Magnitude of hyperaemia does not explain the small difference between iFR and FFR Δ Abs Hyperaemic – wave-free resistance (mmHg s/m) ΔFFR - iFR

29. ADVISE study Diagnostic efficiency of iFR Sen S, Escaned J, Davies JE et al. JACC (in press 2011)

30. iFR positive iFR negative FFR False (+) False (-) Assessment of diagnostic efficiency of iFR Left coronary artery Right coronary artery Diagnostic accuracy (+) predictive value (-) predictive value Sensitivity Specificity 88% 91% 85% 91% Sen S, Escaned J, Davies JE et al. JACC (in press 2011) ADVISE study

31. FFR False (+) False (-) 95% CI variability in FFR* Left coronary artery Right coronary artery Assessment of diagnostic efficiency of iFR after adjustment for inherent variability in FFR *De Bruyne B et al. Circulation. 1996;94:1842-1849 Circulation 2006;114;1321-1341 iFR positive iFR negative Diagnostic accuracy (+) predictive value (-) predictive value Sensitivity Specificity 95% 97% 93% 97% 88% 91% 85% 91% Adjusting for variability in FFR ADVISE study

32. Summary Identified a wave-free period in cardiac cycle when resistance is naturally stabilized and minimal avoiding the need for administration of adenosine Wave-free period

33. Summary iFR measured during this wave-free period gives a measure of stenosis severity similar to FFR

34. Clinical implications of iFR Removes barriers to adoption of physiological assessment Increased applicability Improved work-flow in catheter lab Improves patient experience

35. ADVISE team Hospital Clínico San Carlos Javier Escaned, Rafael Mila Royal Brompton Hospital Carlo Di Mario Imperial College Sayan Sen Iqbal Malik, Jamil Mayet, Alun Hughes, Darrel Francis, Ghada W Mikhail, Rodney A Foale, Jason Tarkin, Ricardo Petraco, Christopher Broyd, Richard Jabbour, Amarjit Sethi, Christopher Baker, Michael Bellamy, Mahmud Al-Bustami, David Hackett, Masood Khan, David Lefroy, and Kim H Parker.

36. ADVISE team Wave-free period Hospital Clínico San Carlos Javier Escaned, Rafael Mila Royal Brompton Hospital Carlo Di Mario Imperial College Sayan Sen Iqbal Malik, Jamil Mayet, Alun Hughes, Darrel Francis, Ghada W Mikhail, Rodney A Foale, Jason Tarkin, Ricardo Petraco, Christopher Broyd, Richard Jabbour, Amarjit Sethi, Christopher S Baker, Micheal Bellamy, Mahmud Al-Bustami, David Hackett, Masood Khan, David Lefroy, and Kim H Parker. advisestudy.org justindavies@heart123.com