1. Educational Training Program ESC European Heart House, Nice, April 19 th –21st, 2007 CORONARY PHYSIOLOGY IN THE CATHLAB LONG-TERM CLINICAL OUTCOME OF MILD CORONARY STENOSIS Nico H.J. Pijls, MD, PhD, Catharina Hospital, Eindhoven, The Netherlands

2. Any treatment in health care should be directed either to Releave symptoms ( improve functional class ) or to Improve outcome ( prognosis, longevity) No other justification for any treatment is possible ! NOTE

3. In patients with coronary artery disease, the most important factor with respect to both functional class (symptoms) and prognosis (outcome) Is the presence and extent of inducible ischemia (many invasive & non-invasive studies in > 100,000 patients) If a stenosis is responsible for reversible ischemia, revascularization improves symptoms (if present) and outcome….. DEFER study: background (1)

4. Davies et al, Circulation, 1997 0 4 8 12 16 20 24 mos 0 4 8 12 16 20 24 mos 0 2 4 6 8 % 6.6% Cumulative Mortality 1.1% Revascularization 4.1% Medical treatment No treatment 558 patients, functionally significant stenosis without symptoms: randomization in 3 treatments strategies Is it useful to revascularize hemodynamically significant stenosis ? (ACIP study) P < 0.05

5. DEFER study: background (2) If a stenosis is responsible for reversible ischemia, revascularization is justified…… ……But what if a stenosis or “plaque” is NOT responsible for reversible ischemia ? (functionally “non-significant”, “non-culprit”) PCI is often performed in such lesions, yet the benefit of such treatment is not clear

6. 158 vb38/interm.RCA/Buddem (1) female, 58-y-old underwent PCI of severe LCX lesion a minute before 50 % stenosis in mid RCA Should this lesion be stented ??

7. The DEFER Study: Background (3) The incidence of coronary lesions The incidence of coronary lesions increases with age. About 40% of increases with age. About 40% of all 60-year-old “healthy” persons all 60-year-old “healthy” persons have one or more plaques, have one or more plaques, “non-significant”, or equivocal stenoses “non-significant”, or equivocal stenoses (50-70 % by angiography) in (50-70 % by angiography) in their coronary arteries. their coronary arteries.

8. Cardiac Death + Myocardial Infarction Rates at 9-12 Months after (DES)-stenting 02468 % 4.1 4.7 4.9 4.9 3.7 3.8 SIRIUS TAXUS IV ENDEAVOR DES – stenting is not harmless !! DES BMS DES BMS DES BMS

9. Fractional Flow Reserve, calculated from Fractional Flow Reserve, calculated from coronary pressure measurement, is an accurate, coronary pressure measurement, is an accurate, invasive, and lesion-specific index to demonstrate invasive, and lesion-specific index to demonstrate or exclude whether a particular coronary stenosis or exclude whether a particular coronary stenosis can cause reversible ischemia. can cause reversible ischemia. FFR can be determined easily, in the cath-lab, FFR can be determined easily, in the cath-lab, immediately prior to a planned intervention immediately prior to a planned intervention DEFER study: background (4) FFR based strategy for PCI in equivocal stenosis ( DEFER – Study)

10. 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 data collection & analysis: Jan Willem Bech, MD, PhD Pepijn van Schaardenburgh, MD

11. The DEFER Study: Objectives to test safety of deferring PCI of stenoses to test safety of deferring PCI of stenoses not responsible for inducible ischemia as not responsible for inducible ischemia as indicated by FFR > 0.75 ( “outcome” ) indicated by FFR > 0.75 ( “outcome” ) Secondary objective Secondary objective to compare quality of life in such patients, to compare quality of life in such patients, whether or not treated by PCI whether or not treated by PCI (CCS-class, need for anti-anginal drugs) (CCS-class, need for anti-anginal drugs) (“symptoms”) (“symptoms”) Primary objective

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

13. THE DEFER STUDY: RANDOMIZATION 1 : 1 randomization deferral of PCI performance of PCI If FFR < 0.75 performance anyway reference group If FFR > 0.75 randomization followed defer PCI perform PCI

14. The DEFER Study: Catheterization 6 or 7 F guiding catheter for measurement of aortic pressure ( P a) QCA from 2 orthogonal views Coronary pressure measurement ( P d ) by 0.014” pressure wire (Radi Medical Systems) Maximum hyperemia by i.v. adenosine (140 ug/kg/min) Calculation of Fractional Flow Reserve by: FFR = P d / P a

15. The DEFER Study: Base line data Randomized toRandomized to Deferral of PTCA Performance of PTCA N=167 N=158 Diabetes (%) 13 12 Hypertension (%) 41 35 Hyperlipidemia(%) 47 48 Current Smoker (%) 30 25 Family History CAD (%) 50 49 Age, (yr) 62  9 63  10 Female sex (%) 29 29 Ejection Fraction (%)67  10 68  9

16. The DEFER Study: Baseline QCA and FFR Ref. diam. (mm) 2.96  0.63 2.98  0.57 MLD (mm) 1.42  0.40 DS (%) 52  10 1.42  0.38 52  11 Randomized to Randomized to Deferral of PTCA Performance of PTCA N=167 N=158 FFR 0.72  0.19 0.73  0.19 All baseline characteristics were identical between both groups

17. The DEFER Study: Diameter Stenosis versus FFR

18. No. at risk Defer group90 85 82 74 73 72 Perform group88 78 73 70 67 65 Reference gr135 105 103 96 90 88 78.8 72.7 64.4 012345 0 25 50 75 100 Defer Perform Reference (FFR < 0.75) p=0.52 p=0.17 p=0.03 Years of Follow-up event – free survival (%)

19. 72 % 58 % 58 % 68 % Pts free of angina(%) 52 (39 %) 24 (27 %) 19 (21 %) Patients ≥1 event (%) 702921 Total events 2 (1.5) 1 (1.1) 0 Other (%) 11 (8.2) 6 (6.8) 6 (6.7) Non-TLR(%) 14 (10.4) 4 (4.5) 1 (1.1) CABG(%) 7 (5.2) 1 (1.1) 0 Non-Q wave MI(%) 6 (4.5) 4 (4.5) 0 Q wave MI (%) 4 (3.0) 3 (3.4) 3 (3.3) Non Cardiac Death(%) 8 (6.0) 2 (2.3) 3 (3.3) Cardiac Death(%) 1449091 Number of patients ReferencePerformDefer FFR<0.75 FFR ≥0.75 18 (13.4) 8 (9.1) 8 (8.9) TLR(%) DEFER: Clinical Outcome at 5 Years Lost to follow-up 1 2 10 Lost to follow-up 1 2 10

20. Cardiac Death And Acute MI After 5 Years 3.3 7.9 15.7 0 5 10 15 20 % P=0.20 P< 0.03 P< 0.005 DEFER PERFORM REFERENCE FFR > 0.75 FFR < 0.75

21. 0% 20% 40% 60% 80% 100% baseline1month1 year2 year5 year Defer groupPerform groupReference group freedom from chest pain FFR > 0.75 FFR > 0.75 FFR < 0.75 * * *

22. DEFER: Summary and Conclusions (1) 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 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

23. DEFER: Summary and Conclusions (2) Message Stenting an ischemic lesion makes sense because Stenting an ischemic lesion makes sense because it improves symptoms and often also outcome. it improves symptoms and often also outcome. Stenting a “non-ischemic” stenosis has no benefit compared to medical treatment, neither in prognostic nor symptomatic respect. Stenting a “non-ischemic” stenosis has no benefit compared to medical treatment, neither in prognostic nor symptomatic respect. Importance of FFR programm of tomorrow

25. What was wrong the wrong concept in the (mostly retrospective) studies performed so far ?! e.g. ARTS-studies: 30% incomplete revascularization, but…. “arbitrary” choice of no revascularization, or even worse: no revascularization because of technical difficulties  considerable number of the non-revascularized lesions were ischemic lesions Whereas among the treated lesions, quite a bit of non-ischemic lesions must have been stented Complete vs Incomplete Revascularization:

26. What was wrong the wrong concept in the (mostly retrospective) studies performed so far ?! e.g. ARTS-studies: 30% incomplete revascularization, but…. “arbitrary” choice of no revascularization, or even worse: no revascularization because of technical difficulties  considerable number of the non-revascularized lesions were ischemic lesions Whereas among the treated lesions, quite a bit of non-ischemic lesions must have been stented Complete vs Incomplete Revascularization:

27. DEFER: Summary and Conclusions 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 these patients, clinical outcome of such “ischemic” stenosis, even when treated by PCI, is much worse than that of a even when treated by PCI, is much worse than that of a functionally “non-significant” stenosis. 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 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 Conclusion Stenting a “non-significant” stenosis does not benefit patients with stable chest pain, neither in prognostic nor symptomatic respect

28. No. at risk FFR ≥ 0.75178162154143138136 FFR < 0.75135105103969088 75.8 64.4 012345 0 25 50 75 100 FFR  0.75 FFR < 0.75 p=0.03 Years of Follow-up event – free survival (%)

29. 7.4 0.6 0 1 2 3 4 5 6 7 8 12000 Patients ( 2 x 6000) similar stenosis severity by coronary angio The risk for death or acute myocardial infarction in the next five years is 20 times higher for an ischemic lesion compared to a non-ischemic lesion !!! Iskander S, Iskandrian A E JACC 1998 % death or Acute MI no ischemia ischemia

30. Simply stated: Ischemia - guided PCI strategy versus “stent ‘m all strategy” In single vessel disease With respect to: outcome (adeverse events), quality of life cost-efectiveness The DEFER Study: Objectives

32. DEFER: Clinical Outcome at 5 Years Cardiac death and Acute Myoc Infarction ReferencePerformDefer FFR < 0.75 FFR ≥ 0.75 FFR ≥ 0.75 3.3 % 7.9 % 15.7 % P = 0.20 P < 0.005 P < 0.003

33. Death + Myocardial Infarction Rates at 9-12 Months 02468 % 4.1 4.7 4.9 4.9 3.7 3.8 SIRIUS DES BMS TAXUS IV DES BMS ENDEAVORDES BMS DEFER ALL PCI (BMS) (BMS) (9 months) (12 months) 5.1

34. Death + Myocardial Infarction Rates at 9-12 Months 02468 % 2.7 7.6 4.1 4.7 4.9 4.9 3.7 3.8 SIRIUS DES BMS TAXUS IV DES BMS ENDEAVORDES BMS DEFER FFR<0.75 FFR≥0.75 FFR≥0.75 (9 months) (12 months) perform 1.1 defer