Fractional Flow Reserve Guided PCI versus Medical Therapy in Stable Coronary Disease FAME 2 Trial 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
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
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
Objective To compare clinical outcomes of FFRguided contemporary PCI plus the best available medical therapy (MT) versus MT alone in patients with stable coronary disease
Inclusion Criteria Referred for PCI because of And Stable angina pectoris (CCS 1, 2, 3) Stabilized angina pectoris CCS class 4 Atypical or no chest pain with documented ischemia Angiographic 1, 2, or 3 vessel disease
Exclusion Criteria 1. Prior CABG 2. LVEF < 30% 3. LM disease
Primary End Point 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 Randomized Trial FFR in all target lesions Registry At least 1 stenosis with FFR 0.80 (n=888) When all FFR > 0.80 (n=332) Randomization 1:1 PCI + MT 73% MT 27% MT 50% randomly assigned to FU Follow-up after 1, 6 months, 1, 2, 3, 4, and 5 years
Study Centers (n=28) Investigators Centers # of Patients Piroth Hungarian Institute of Cardiology- Hungary 145 Jagic Clinical Center Kragujevac- Serbia 132 Mobius-Winkler Heart Center Leipzig- Germany 131 Pijls Catherina-Ziekenhuis- The Netherlands 89 Rioufol Hospices Civil de Lyon- France 86 Witt Sodersjukhuset- Sweden 85 De Bruyne Cardiovascular Center Aalst- Belgium 82 Kala University Hospital Brno- Czech Republic 75 Fearon Stanford Univ/VA Med Center Palo Alto- USA 50 MacCarthy Kings College Hospital- UK 42 Engstroem Rigshospitalet University Hospital- Denmark 42 Oldroyd Golden Jubilee National Hospital- UK 37 Mavromatis Atlanta VA Medical Center- USA 34 Manoharan Royal Victoria Hospital- Ireland 27 9
Study Centers (n=28) Investigators Centers # of Patients Ver Lee Northeast Cardiology Associates- USA 25 Frobert Orebro University Hospital- Sweden 25 Curzen Southampton General Hospital- UK 18 Sohn Klinikum der Universitat Munchen- Germany 18 Uren Edinburgh Heart Center- Scotland 12 Samady Emory University- USA 12 Dambrink Isala Klinieken- Netherlands 12 Mansour CHUM - Hotel Dieu- Canada 11 Arain Tulane University- USA 8 Mates Nemocnice Na Homolce- Czech Republic 8 Rensing St. Antonius Ziekenhuis- Netherlands 5 Valgimigli Universitaria de Ferrara- Italy 4 Rieber Heart Center Munich- Germany 3 Schampaert Hopital du Sacre Coeur- Canada 2 10
DSMB Recommendation 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) *DSMB: Stephan Windecker, Chairman, Stuart Pocock, Bernard Gersh 11
Baseline Clinical Characteristics (1) Randomized trial N=888 Registry N=322 P* Patients, N PCI+MT=447 MT=441 with FU=166 Demographic Age (y) 63.5±9.3 63.9±9.6 63.6±9.8 0.90 Male sex - (%) 79.6 76.6 68.1 0.005 BMI 28.3±4.3 28.4±4.6 27.8±3.9 0.14 Risk factors for CAD Positive family history CAD - (%) 48.3 46.9 45.8 0.65 Smoking - (%) 19.9 20.4 21.1 0.79 Hypertension - (%) 77.6 77.8 81.9 0.23 Hypercholesterolemia - (%) 73.9 78.9 71.1 0.15 Diabetes mellitus - (%) 27.5 26.5 25.3 0.65 Insulin requiring diabetes - (%) 8.7 8.8 6.0 0.24 *P value compares all RCT patients with patients in registry 12
Baseline Clinical Characteristics (2) Randomized trial N=888 Registry N=322 P* Patients, N PCI+MT=447 MT=441 with FU=166 Non-Cardiac Co-Morbidity Renal Failure (Cr > 2.0 mg/dl) - (%) 1.8 2.7 4.2 0.14 History of stroke or TIA - (%) 7.4 6.3 6.0 0.69 Peripheral vascular disease - (%) 9.6 10.7 4.8 0.03 Cardiac History History of MI - (%) 37.2 37.8 36.6 0.83 History of PCI in target vessel -(%) 17.9 17.2 20.5 0.37 Angina - (%) 0.64 Asymptomatic 11.9 10.5 10.2 CCS class I 18.3 22.3 25.3 CCS class II 45.6 44.8 44.6 CCS class III 17.9 14.8 13.9 CCS class IV, stabilized 6.3 7.7 6.0 Silent ischemia- (%) 16.3 16.6 16.3 0.96 LVEF < 50% - (%) 19.6 13.7 18.0 0.69 *P value compares all RCT patients with patients in registry 13
Angiographic Characteristics Randomized trial N=888 Registry N=322 P* Patients, N PCI+MT=447 MT=441 with FU=166 Angiographically significant stenoses - no. per patient 1.87±1.05 1.73±0.94 1.32±0.59 <0.001 No of vessels with 1 significant stenoses - (%) 1 56.2 59.2 81.9 2 34.9 33.1 15.7 3 8.9 7.7 2.4 <0.001 Prox- or mid- LAD stenoses - (%) 65.1 62.6 44.6 <0.001 *P value compares all RCT patients with patients in registry 14
FFR Measurements Randomized trial N=888 Registry N=322 P* Patients, N PCI+MT=447 MT=441 with FU=166 FFR significant stenoses - no. per patient 1.52±0.78 1.42±0.73 0.03±0.17 <0.001 No of vessels with 1 significant stenoses (by FFR) - (%) 1 74.0 77.8 3.0 2 22.8 19.3 0 3 3.1 2.9 0 Prox- or mid- LAD stenoses - (%) 62.4 59.6 0.6 <0.001 Lesions with FFR 0.80 - (%) 76.3 76.7 2.1 ** <0.001 Mean FFR in stenoses with FFR 0.80 0.68±0.10 0.68±0.15 0.50±0.00 0.01 * P value compares all RCT patients with patients in registry ** 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. 15
Cumulative incidence (%) FAME 2 : FFR-Guided PCI versus Medical Therapy in Stable CAD Primary Outcomes 30 25 PCI+MT vs. MT: HR 0.32 (0.19-0.53); p<0.001 PCI+MT vs. Registry: HR 1.29 (0.49-3.39); p=0.61 MT vs. Registry: HR 4.32 (1.75-10.7); p<0.001 20 15 10 5 No. at risk MT PCI+MT Registry 0 0 1 2 3 4 5 6 7 8 9 10 11 12 Months after randomization 441 414 370 322 283 253 220 192 162 127 100 70 37 447 414 388 351 308 277 243 212 175 155 117 92 53 166 156 145 133 117 106 93 74 64 52 41 25 13
Cumulative incidence (%) FAME 2 : FFR-Guided PCI versus Medical Therapy in Stable CAD Death from any Cause 30 25 PCI+MT vs. MT: HR 0.33 (0.03-3.17); p=0.31 PCI+MT vs. Registry: HR 1.12 (0.05-27.33); p=0.54 MT vs. Registry: HR 2.66 (0.14-51.18); p=0.30 20 15 10 5 0 No. at risk MT PCI+MT Registry 0 1 2 3 4 5 6 7 8 9 10 11 12 Months after randomization 441 423 390 350 312 281 247 219 188 154 122 90 54 447 423 396 359 318 288 250 220 183 163 122 95 54 166 156 145 134 118 107 96 76 67 55 43 27 13
Cumulative incidence (%) FAME 2 : FFR-Guided PCI versus Medical Therapy in Stable CAD Myocardial Infarction 30 25 PCI+MT vs. MT: HR 1.05 (0.51-2.19); p=0.89 PCI+MT vs. Registry: HR 1.61 (0.48-5.37); p=0.41 MT vs. Registry: HR 1.65 (0.50-5.47); p=0.41 20 15 10 5 No. at risk MT PCI+MT Registry 0 0 1 2 3 4 5 6 7 8 9 10 11 12 Months after randomization 441 421 386 341 304 273 239 212 182 148 117 85 48 447 414 388 352 309 278 244 214 177 157 119 94 54 166 156 145 134 118 107 95 75 65 53 42 26 13
Cumulative incidence (%) FAME 2 : FFR-Guided PCI versus Medical Therapy in Stable CAD Urgent Revascularization 30 25 PCI+MT vs. MT: HR 0.13 (0.06-0.30); p<0.001 PCI+MT vs. Registry: HR 0.63 (0.19-2.03); p=0.43 MT vs. Registry: HR 4.65 (1.72-12.62); p=0.009 20 15 10 5 No. at risk MT PCI+MT Registry 0 0 1 2 3 4 5 6 7 8 9 10 11 12 Months after randomization 441 414 371 325 286 256 223 195 164 129 101 71 38 447 421 395 356 315 285 248 217 180 160 119 93 53 166 156 145 133 117 106 94 75 65 53 42 26 13
Patients with urgent revascularization Unstable angina only 51.8% 21.4% 26.8% Myocardial Infarction Unstable angina +evidence of ischemia on ECG
Cumulative incidence (%) Cumulative (%) FAME 2 : FFR-Guided PCI versus Medical Therapy in Stable CAD Kaplan-Meier plots of Landmark Analysis of Death or MI 30 25 7 days: HR 7.99 (0.99-64.6); p=0.038 > 8 days: HR 0.42 (0.17-1.04); p=0.053 p-interaction: p=0.003 20 15 10 5 0 2.5 2.0 1.5 1.0 0.5 0 0 1 2 3 4 5 6 7 Days after randomization >8 days PCI plus MT MT alone 7 days 0 7days 1 2 3 4 5 6 7 8 9 10 11 12 Months after randomization MT alone PCI plus MT
Proportion of patients (%) Medications at 6 Months of Follow-up 100 90 80 70 60 50 40 30 20 10 0 PCI + MT MT alone Registry
Patients with Angina Class II to IV Baseline PCI+MT MT Registry 30 days PCI+MT MT Registry P<0.001 P=0.002 6 months PCI+MT MT Registry P=0.002 12 months PCI+MT MT Registry P=0.073 0 20 40 60 80 Percentage of patients with CCS II to IV, %
Conclusions 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 www.nejm.org