Fractional Flow Reserve–Guided PCI versus Medical Therapy in Stable Coronary Disease FAME 2 Clinicaltrials.gov NCT 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

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

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

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

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

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

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

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%

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

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

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

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± ± ± Male sex - (%) BMI 28.3± ± ± Risk factors for CAD Positive family history CAD - (%) Smoking - (%) Hypertension - (%) Hypercholesterolemia - (%) Diabetes mellitus - (%) Insulin requiring diabetes - (%) *P value compares all RCT patients with patients in registry FAME 2 : FFR-Guided PCI versus Medical Therapy in Stable CAD

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) - (%) History of stroke or TIA - (%) Peripheral vascular disease - (%) Cardiac History History of MI - (%) History of PCI in target vessel -(%) Angina - (%)0.64 Asymptomatic CCS class I CCS class II CCS class III CCS class IV, stabilized Silent ischemia- (%) LVEF < 50% - (%) FAME 2 : FFR-Guided PCI versus Medical Therapy in Stable CAD *P value compares all RCT patients with patients in registry

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± ± ±0.59<0.001 No of vessels with ≥ 1 significant stenoses - (%) < Prox- or mid- LAD stenoses - (%) < FAME 2 : FFR-Guided PCI versus Medical Therapy in Stable CAD *P value compares all RCT patients with patients in registry

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± ± ±0.17<0.001 No of vessels with ≥ 1 significant stenoses (by FFR) - (%) Prox- or mid- LAD stenoses - (%) <0.001 Lesions with FFR ≤ (%) ** <0.001 Mean FFR in stenoses with FFR ≤ ± ± ± * 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 These patients also had another lesion >50% with an FFR >0.80.

FAME 2 : FFR-Guided PCI versus Medical Therapy in Stable CAD Primary Outcomes Cumulative incidence (%) Registry PCI+MT MT No. at risk Months after randomization MT vs. Registry: HR 4.32 ( ); p<0.001 PCI+MT vs. Registry: HR 1.29 ( ); p=0.61 PCI+MT vs. MT: HR 0.32 ( ); p<0.001

FAME 2 : FFR-Guided PCI versus Medical Therapy in Stable CAD Death from any Cause Cumulative incidence (%) Registry PCI+MT MT No. at risk Months after randomization MT vs. Registry: HR 2.66 ( ); p=0.30 PCI+MT vs. Registry:HR 1.12 ( ); p=0.54 PCI+MT vs. MT: HR 0.33 ( ); p=0.31

FAME 2 : FFR-Guided PCI versus Medical Therapy in Stable CAD Myocardial Infarction Cumulative incidence (%) Registry PCI+MT MT No. at risk Months after randomization MT vs. Registry: HR 1.65 ( ); p=0.41 PCI+MT vs. Registry:HR 1.61 ( ); p=0.41 PCI+MT vs. MT: HR 1.05 ( ); p=0.89

FAME 2 : FFR-Guided PCI versus Medical Therapy in Stable CAD Urgent Revascularization Cumulative incidence (%) Registry PCI+MT MT No. at risk Months after randomization MT vs. Registry: HR 4.65 ( ); p=0.009 PCI+MT vs. Registry: HR 0.63 ( ); p=0.43 PCI+MT vs. MT: HR 0.13 ( ); p<0.001

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%

Kaplan-Meier plots of Landmark Analysis of Death or MI FAME 2 : FFR-Guided PCI versus Medical Therapy in Stable CAD Cumulative incidence (%) 0 7days Months after randomization p-interaction: p=0.003 > 8 days: HR 0.42 ( ); p=0.053 ≤7 days: HR 7.99 ( ); p=0.038 MT alone PCI plus MT MT alone PCI plus MT ≤7 days >8 days

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

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

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

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