1. Fractional Flow Reserve–Guided PCI versus Medical Therapy in Stable Coronary Disease FAME 2 Clinicaltrials.gov NCT01132495 Bernard De Bruyne, Nico H.J. Pijls, William F Fearon, Peter Juni, Emanuele Barbato, Pim Tonino, for the FAME 2 study group FAME 2 : FFR-Guided PCI versus Medical Therapy in Stable CAD

2. Potential conflicts of interest Speaker’s name: Bernard De Bruyne  I have the following potential conflicts of interest to report:  Research contracts  Consulting  Employment in industry  Stockholder of a healthcare company  Owner of a healthcare company  Other(s)  I do not have any potential conflict of interest Study Supported by St. Jude Medical FAME 2 : FFR-Guided PCI versus Medical Therapy in Stable CAD

3. Background In patients with stable coronary disease, PCI has not been shown to improve prognosis FAME 1 demonstrated the superiority of FFR-guided over angiography-guided PCI In previous trials, revascularization has been guided by the angiographic appearance of the lesions It is likely that in previous trials a sizable proportion of patients had no or little ischemia FAME 2 : FFR-Guided PCI versus Medical Therapy in Stable CAD

4. Objective To compare clinical outcomes of FFR- guided contemporary PCI plus the best available medical therapy (MT) versus MT alone in patients with stable coronary disease FAME 2 : FFR-Guided PCI versus Medical Therapy in Stable CAD

5. Inclusion Criteria Referred for PCI because of Stable angina pectoris (CCS 1, 2, 3) Stabilized angina pectoris CCS class 4 Atypical or no chest pain with documented ischemia And Angiographic 1, 2, or 3 vessel disease FAME 2 : FFR-Guided PCI versus Medical Therapy in Stable CAD

6. Exclusion Criteria 1. Prior CABG 2. LVEF < 30% 3. LM disease

7. Primary End Point FAME 2 : FFR-Guided PCI versus Medical Therapy in Stable CAD Composite of all cause death myocardial infarction unplanned hospitalization with urgent revascularization

8. Flow Chart Stable CAD patients scheduled for 1, 2 or 3 vessel DES-PCI N = 1220 FFR in all target lesions When all FFR > 0.80 (n=332) MT At least 1 stenosis with FFR ≤ 0.80 (n=888) Randomization 1:1 PCI + MT MT Follow-up after 1, 6 months, 1, 2, 3, 4, and 5 years Registry 50% randomly assigned to FU 27% FAME 2 : FFR-Guided PCI versus Medical Therapy in Stable CAD Randomized Trial 73%

9. Study Centers (n=28) InvestigatorsCenters# of Patients PirothHungarian Institute of Cardiology- Hungary145 JagicClinical Center Kragujevac- Serbia132 Mobius-WinklerHeart Center Leipzig- Germany131 PijlsCatherina-Ziekenhuis- The Netherlands89 RioufolHospices Civil de Lyon- France86 WittSodersjukhuset- Sweden85 De BruyneCardiovascular Center Aalst- Belgium82 KalaUniversity Hospital Brno- Czech Republic75 FearonStanford Univ/VA Med Center Palo Alto- USA50 MacCarthyKings College Hospital- UK42 EngstroemRigshospitalet University Hospital- Denmark42 OldroydGolden Jubilee National Hospital- UK37 MavromatisAtlanta VA Medical Center- USA34 ManoharanRoyal Victoria Hospital- Ireland27 9 FAME 2 : FFR-Guided PCI versus Medical Therapy in Stable CAD

10. InvestigatorsCenters# of Patients Ver LeeNortheast Cardiology Associates- USA25 FrobertOrebro University Hospital- Sweden25 CurzenSouthampton General Hospital- UK18 SohnKlinikum der Universitat Munchen- Germany18 UrenEdinburgh Heart Center- Scotland12 SamadyEmory University- USA12 DambrinkIsala Klinieken- Netherlands12 MansourCHUM - Hotel Dieu- Canada11 ArainTulane University- USA8 MatesNemocnice Na Homolce- Czech Republic8 RensingSt. Antonius Ziekenhuis- Netherlands5 ValgimigliUniversitaria de Ferrara- Italy4 RieberHeart Center Munich- Germany3 SchampaertHopital du Sacre Coeur- Canada2 10 Study Centers (n=28) FAME 2 : FFR-Guided PCI versus Medical Therapy in Stable CAD

11. On recommendation of the independent Data and Safety Monitoring Board* recruitment was halted on January 15 th, 2012 after inclusion of 1220 patients (± 54% of the initially planned number of randomized patients) 11 DSMB Recommendation FAME 2 : FFR-Guided PCI versus Medical Therapy in Stable CAD *DSMB: Stephan Windecker, Chairman, Stuart Pocock, Bernard Gersh

12. Baseline Clinical Characteristics (1) Randomized trial N=888 Registry N=322 P* Patients, N PCI+MT=447MT=441with FU=166 Demographic Age (y)63.5±9.3 63.9±9.663.6±9.8 0.90 Male sex - (%) 79.676.668.10.005 BMI 28.3±4.328.4±4.627.8±3.90.14 Risk factors for CAD Positive family history CAD - (%) 48.346.9 45.80.65 Smoking - (%) 19.920.4 21.1 0.79 Hypertension - (%) 77.677.881.90.23 Hypercholesterolemia - (%) 73.978.971.10.15 Diabetes mellitus - (%) 27.526.525.30.65 Insulin requiring diabetes - (%)8.78.86.00.24 12 *P value compares all RCT patients with patients in registry FAME 2 : FFR-Guided PCI versus Medical Therapy in Stable CAD

13. Baseline Clinical Characteristics (2) Randomized trial N=888 Registry N=322 P* Patients, NPCI+MT=447MT=441with FU=166 Non-Cardiac Co-Morbidity Renal Failure (Cr > 2.0 mg/dL) - (%)1.82.74.20.14 History of stroke or TIA - (%)7.46.36.00.69 Peripheral vascular disease - (%)9.610.74.80.03 Cardiac History History of MI - (%)37.237.836.60.83 History of PCI in target vessel -(%)17.917.220.50.37 Angina - (%)0.64 Asymptomatic11.910.510.2 CCS class I18.322.325.3 CCS class II45.644.844.6 CCS class III17.914.813.9 CCS class IV, stabilized6.37.76.0 Silent ischemia- (%)16.316.616.30.96 LVEF < 50% - (%)19.613.718.00.69 13 FAME 2 : FFR-Guided PCI versus Medical Therapy in Stable CAD *P value compares all RCT patients with patients in registry

14. Angiographic Characteristics Randomized trial N=888 Registry N=322 P* Patients, N PCI+MT=447MT=441with FU=166 Angiographically significant stenoses - no. per patient 1.87±1.051.73±0.941.32±0.59<0.001 No of vessels with ≥ 1 significant stenoses - (%) <0.001 1 56.259.281.9 2 34.933.115.7 3 8.97.72.4 Prox- or mid- LAD stenoses - (%) 65.162.644.6<0.001 14 FAME 2 : FFR-Guided PCI versus Medical Therapy in Stable CAD *P value compares all RCT patients with patients in registry

15. FFR Measurements Randomized trial N=888 Registry N=322 P* Patients, NPCI+MT=447MT=441with FU=166 FFR significant stenoses - no. per patient 1.52±0.781.42±0.730.03±0.17<0.001 No of vessels with ≥ 1 significant stenoses (by FFR) - (%) 1 74.077.83.0 2 22.819.30 3 3.12.90 Prox- or mid- LAD stenoses - (%) 62.459.60.6<0.001 Lesions with FFR ≤ 0.80 - (%) 76.376.72.1 ** <0.001 Mean FFR in stenoses with FFR ≤ 0.80 0.68±0.100.68±0.150.50±0.000.01 15 * P value compares all RCT patients with patients in registry FAME 2 : FFR-Guided PCI versus Medical Therapy in Stable CAD ** Chronic occlusions in the registry patients were arbitrarily assigned an FFR value of 0.50. These patients also had another lesion >50% with an FFR >0.80.

16. FAME 2 : FFR-Guided PCI versus Medical Therapy in Stable CAD Primary Outcomes 0 5 10 15 20 25 30 Cumulative incidence (%) 16615614513311710693746452412513Registry 4474143883513082772432121751551179253PCI+MT 4414143703222832532201921621271007037MT No. at risk 0123456789101112 Months after randomization MT vs. Registry: HR 4.32 (1.75-10.7); p<0.001 PCI+MT vs. Registry: HR 1.29 (0.49-3.39); p=0.61 PCI+MT vs. MT: HR 0.32 (0.19-0.53); p<0.001

17. FAME 2 : FFR-Guided PCI versus Medical Therapy in Stable CAD Death from any Cause 0 5 10 15 20 25 30 Cumulative incidence (%) 16615614513411810796766755432713Registry 4474233963593182882502201831631229554PCI+MT 4414233903503122812472191881541229054MT No. at risk 0123456789101112 Months after randomization MT vs. Registry: HR 2.66 (0.14-51.18); p=0.30 PCI+MT vs. Registry:HR 1.12 (0.05-27.33); p=0.54 PCI+MT vs. MT: HR 0.33 (0.03-3.17); p=0.31

18. FAME 2 : FFR-Guided PCI versus Medical Therapy in Stable CAD Myocardial Infarction 0 5 10 15 20 25 30 Cumulative incidence (%) 16615614513411810795756553422613Registry 4474143883523092782442141771571199454PCI+MT 4414213863413042732392121821481178548MT No. at risk 0123456789101112 Months after randomization MT vs. Registry: HR 1.65 (0.50-5.47); p=0.41 PCI+MT vs. Registry:HR 1.61 (0.48-5.37); p=0.41 PCI+MT vs. MT: HR 1.05 (0.51-2.19); p=0.89

19. FAME 2 : FFR-Guided PCI versus Medical Therapy in Stable CAD Urgent Revascularization 0 5 10 15 20 25 30 Cumulative incidence (%) 16615614513311710694756553422613Registry 4474213953563152852482171801601199353PCI+MT 4414143713252862562231951641291017138MT No. at risk 0123456789101112 Months after randomization MT vs. Registry: HR 4.65 (1.72-12.62); p=0.009 PCI+MT vs. Registry: HR 0.63 (0.19-2.03); p=0.43 PCI+MT vs. MT: HR 0.13 (0.06-0.30); p<0.001

20. FAME 2 : FFR-Guided PCI versus Medical Therapy in Stable CAD Patients with urgent revascularization Myocardial Infarction Unstable angina +evidence of ischemia on ECG 51.8% 26.8% 21.4%

21. Kaplan-Meier plots of Landmark Analysis of Death or MI FAME 2 : FFR-Guided PCI versus Medical Therapy in Stable CAD 0 5 10 15 20 25 30 Cumulative incidence (%) 0 7days123456789101112 Months after randomization p-interaction: p=0.003 > 8 days: HR 0.42 (0.17-1.04); p=0.053 ≤7 days: HR 7.99 (0.99-64.6); p=0.038 MT alone PCI plus MT MT alone PCI plus MT ≤7 days >8 days

22. FAME 2 : FFR-Guided PCI versus Medical Therapy in Stable CAD Medications at 6 Months of Follow-up

23. 020406080 Percentage of patients with CCS II to IV, % Baseline 30 days 6 months 12 months PCI+MT MT Registry PCI+MT MT Registry PCI+MT MT Registry PCI+MT MT Registry FAME 2 : FFR-Guided PCI versus Medical Therapy in Stable CAD Patients with Angina Class II to IV P<0.001 P=0.002 P=0.073 P=0.002

24. Conclusions FAME 2 : FFR-Guided PCI versus Medical Therapy in Stable CAD In patients with stable coronary artery disease, FFR-guided PCI, improves patient outcome as compared with medical therapy alone This improvement is driven by a dramatic decrease in the need for urgent revascularization for ACS In patients with functionally non-significant stenoses medical therapy alone resulted in an excellent outcome, regardless of the angiographic appearance of the stenoses

25. FAME 2: FFR-Guided PCI versus Medical Therapy in Stable CAD Available on-line on Aug 28, 2012 on www.nejm.org www.nejm.org