DEFER STUDY: 5-YEAR FOLLOW-UP

1. DEFER STUDY: 5-YEAR FOLLOW-UP A Multicenter Randomized Study to Compare Deferral Versus Performance of PCI of Non-Ischemia-Producing Stenoses Principal investigators Nico H.J. Pijls, MD, PhD Catharina Hospital Eindhoven, The Netherlands Bernard De Bruyne, MD, PhD Cardiovascular Center Aalst Aalst, Belgium

2. NOTE • 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 !

3. DEFER study: background (1) • 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…..

4. 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

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

6. DEFER study: background (3) • Fractional Flow Reserve, calculated from • coronary pressure measurement, is an accurate, • invasive, and lesion-specific index to demonstrate • or exclude whether a particular coronary stenosis • can cause reversible ischemia. • FFR can be determined easily, in the cath-lab, • immediately prior to a planned intervention FFR based strategy for PCI in equivocal stenosis ( DEFER – Study)

7. 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

8. 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”)

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

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

11. The DEFER Study: Catheterization • 6 or 7 F guiding catheter for measurement of • aortic pressure(Pa) • QCA from 2 orthogonal views • Coronary pressure measurement (Pd)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 = Pd / Pa

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

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

14. The DEFER Study: Diameter Stenosis versus FFR

15. event – free survival (%) 100 75 78.8 72.7 64.4 Defer 50 p=0.52 p=0.03 Perform p=0.17 25 Reference (FFR < 0.75) 0 0 1 2 3 4 5 Years of Follow-up

16. DEFER: Clinical Outcome at 5 Years Non-TLR(%) 6 (6.7) 6 (6.8) 11 (8.2) Patients ≥1 event (%) 24 (27 %) 52 (39 %) 19 (21 %) FFR ≥0.75 FFR<0.75 Defer Perform Reference Number of patients 91 90 144 Lost to follow-up 1 2 10 Cardiac Death(%) 3 (3.3) 2 (2.3) 8 (6.0) 4 (3.0) Non Cardiac Death(%) 3 (3.3) 3 (3.4) Q wave MI (%) 0 4 (4.5) 6 (4.5) Non-Q wave MI(%) 0 1 (1.1) 7 (5.2) CABG(%) 1 (1.1) 4 (4.5) 14 (10.4) TLR(%) 8 (8.9) 8 (9.1) 18 (13.4) Other (%) 0 1 (1.1) 2 (1.5) Total events 21 29 70 Pts free of angina(%) 68 % 58 % 72 %

17. 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 0 DEFER PERFORM REFERENCE FFR > 0.75 FFR < 0.75

18. Defer group Perform group Reference group freedom from chest pain 100% * * * * * 80% * * * 60% 40% 20% 0% baseline 1month 1 year 2 year 5 year FFR > 0.75 FFR > 0.75 FFR < 0.75

19. DEFER: Summary and Conclusions (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) • 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

20. DEFER: Summary and Conclusions (2) • Conclusion • Stenting a “non-ischemic” stenosis does not benefit patients with stable chest pain, neither • in prognostic nor symptomatic respect.

21. event – free survival (%) 100 75.8 75 64.4 50 ³ FFR 0.75 p=0.03 FFR < 0.75 25 0 0 1 2 3 4 5 Years of Follow-up