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

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 !

and prognosis (outcome) 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…..

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

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 ?? 158 vb38/interm.RCA/Buddem (1)

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)

prospective randomized multicentric trial 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

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”)

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

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

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

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 Diabetes (%) 13 12 Hypertension (%) 41 35 Hyperlipidemia (%) 47 48 Current Smoker (%) 30 25 Family History CAD (%) 50 49

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

Diameter Stenosis versus FFR The DEFER Study: Diameter Stenosis versus FFR

event – free survival (%) 100 75 78.8 72.7 64.4 50 Defer p=0.52 Perform p=0.03 p=0.17 25 Reference (FFR < 0.75) 1 2 3 4 5 Years of Follow-up No. at risk Defer group 90 85 82 74 73 72 Perform group 88 78 70 67 65 Reference gr 135 105 103 96

DEFER: Clinical Outcome at 5 Years 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) Non Cardiac Death(%) 3 (3.3) 3 (3.4) 4 (3.0) Q wave MI (%) 4 (4.5) 6 (4.5) Non-Q wave MI(%) 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) 11 (8.2) 6 (6.8) 6 (6.7) Non-TLR(%) Other (%) 1 (1.1) 2 (1.5) Total events 21 29 70 52 (39 %) 24 (27 %) 19 (21 %) Patients ≥1 event (%) Pts free of angina(%) 68 % 58 % 72 %

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 DEFER PERFORM REFERENCE FFR > 0.75 FFR < 0.75

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

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

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

event – free survival (%) 100 75.8 75 64.4 50 FFR ³ 0.75 p=0.03 FFR < 0.75 25 1 2 3 4 5 Years of Follow-up No. at risk FFR ≥ 0.75 178 162 154 143 138 136 FFR < 0.75 135 105 103 96 90 88