Fractional Flow Reserve–Guided PCI for Stable Coronary Disease

FAME 2Report of the Primary Endpoint

Clinicaltrials.gov NCT01132495

Bernard De Bruyne, William F Fearon, Nico HJ Pijls, Emanuele Barbato, Pim AL Tonino, Peter Juni

for the FFR vs Angiography for Multivessel Evaluation 2 (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

FAME 2 Background

• In patients with stable coronary artery disease (CAD), PCI has not been shown to improve ‘hard endpoints’.

• In previous trials comparing PCI and Medical Therapy (MT), neither FFR-guidance nor DES were used. (‘contemporary PCI’).

FAME 2 Objective

To compare the rate of death, myocardial infarction, or urgent revascularization 2 years after contemporary PCI+MT to MT alone in stable CAD

FAME 2 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 Exclusion Criteria

1. Prior CABG

2. LVEF < 30%

3. LM disease

FAME 2 Primary End Point

Composite of

• all cause death • myocardial infarction• unplanned hospitalization with urgent revascularization

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FAME 2 Study Centers (n=28)

Investigators Centers # of PatientsPiroth 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

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Investigators Centers # of PatientsVer 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 3Schampaert Hopital du Sacre Coeur- Canada 2

FAME 2 Study Centers (n=28)

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On recommendation of the independent Data and Safety Monitoring Board* recruitment was halted on January 15th, 2012 after inclusion of 1220 patients (± 54% of the initially planned number of randomized patients)

DSMB Recommendation

*DSMB: Stephan Windecker, Chairman, Stuart Pocock, Bernard Gersh

FAME 2 Flow Chart

Stable CAD patients scheduled for 1, 2 or 3 vessel DES-PCIN = 1220

When all FFR > 0.80 (n=332)

MT

At least 1 stenosiswith FFR ≤ 0.80 (n=888)

Randomization 1:1

PCI + MT MT

Follow-up after 1, 6 months, 1, 2, 3, 4, and 5 years

FFR in all target lesions

Registry

50% randomly assigned to FU27%

Randomized Trial

73%

FAME 2 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) 64±9 64±10 64±10 0.89 Male sex - (%) 79.6 76.6 68.1 0.006 BMI 28.3±4.3 28.4±4.6 27.8±3.9 0.14

Risk factors for CAD

Positive family history CAD - (%) 49 47 46 0.60 Smoking - (%) 20 20 21 0.79 Hypertension - (%) 78 78 83 0.21 Hypercholesterolemia - (%) 74 80 73 0.15 Diabetes mellitus - (%) 28 27 25 0.65

11*P value compares all RCT patients with patients in registry

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) - (%) 2 3 3 0.14 History of stroke or TIA - (%) 8 7 6 0.52 Peripheral vascular disease - (%) 10 11 5 0.03Cardiac History History of MI - (%) 38 39 38 0.92 History of PCI in target vessel -(%) 18 17 21 0.36Angina - (%) 0.60 Asymptomatic 12 10 10 CCS class I 18 22 25 CCS class II 46 45 45 CCS class III 18 15 14 CCS class IV, stabilized 6 8 6Silent ischemia- (%) 16 17 16 0.93LVEF < 50% - (%) 20 14 18 0.70

12*P value compares all RCT patients with patients in registry

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 1.76±0.98 1.34±0.60 <0.001

No of vessels with ≥ 1 significant stenoses - (%)

<0.001

1 56 59 782 35 33 183 9 8 3

Prox- or mid- LAD stenoses - (%) 65 63 45 <0.001

13*P value compares all RCT patients with patients in registry

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 1.51±0.78 1.43±0.73 0.03±0.17 <0.001

No of vessels with ≥ 1 significant stenoses (by FFR) - (%)

1 74 78 3.02 23 19 03 3 3 0

Prox- or mid- LAD stenoses - (%) 62 59 0 <0.001

Lesions with FFR ≤ 0.80 - (%) 76 76 2 ** <0.001

Mean FFR in stenoses with FFR ≤ 0.80 0.64±0.13 0.64±0.14 0.50±0.00 0.01

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* 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.

FAME 2 Primary Outcomes

0

5

10

15

20

Cum

ula

tive

inci

denc

e (%

)

166 164 162 160 157 157 156 153 151 150 150 150 122Registry447 434 429 426 425 420 416 414 410 408 405 403 344PCI+MT441 417 398 389 379 369 362 360 359 355 353 351 297MT

No. at risk

0 2 4 6 8 10 12 14 16 18 20 22 24Months after randomization

MT vs. Registry: HR 2.34 (95% CI 1.35-4.05) P=0.002

PCI+MT vs. Registry: HR 0.90 (95% CI 0.49-1.64) P=0.72

PCI+MT vs. MT: HR 0.39 (95% CI 0.26-0.57) P<0.001

MT alone

Registry

PCI+MT

0

5

10

15

20

Cu

mu

lativ

e in

cid

en

ce (

%)

0 2 4 6 8 10 12 14 16 18 20 22 24

Months after randomisation

0

.5

1

1.5

2

2.5C

umul

ativ

e in

cide

nce

(%)

0 1 2 3 4 5 6 7

Days after randomisation

0-7days: HR 0.49 (95%CI 0.09-2.70) 8 days-2years: HR 0.21 (95%CI 0.12-0.37)

P for interaction=0.34PCI+MT vs MT

PCI+MT

MT alone

FAME 2Landmark Analysis for Urgent Revascularization

0

5

10

15

20

Cu

mu

lativ

e in

cid

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%)

0 2 4 6 8 10 12 14 16 18 20 22 24

Months after randomisation

0

.5

1

1.5

2

2.5C

umul

ativ

e in

cide

nce

(%)

0 1 2 3 4 5 6 7Days after randomisation

0-7days: HR 9.01 (95%CI 1.13-72.0) 8 days-2years: HR 0.56 (95%CI 0.32-0.97)

P for interaction 0.002PCI+MT vs MT

PCI+MT

MT alone

FAME 2 Landmark Analysis for Death or Myocardial Infarction

0

5

10

15

20

25

30

35

40

Cum

ulat

ive

inci

denc

e (%

)

447 440 434 429 427 422 417 410 407 406 402 399 343PCI+MT441 389 360 337 315 302 290 277 272 268 260 254 218MT

No. at risk

0 2 4 6 8 10 12 14 16 18 20 22 24Months after randomization

PCI+MT vs. MT: HR 0.16 (95% CI 0.11-0.22) P<0.001

MT alone

PCI+MT

FAME 2 Urgent AND Non-Urgent Revascularizations

After 2 years, > 40% of patients treated by MT had crossed over i.e. had undergo any revascularisation

FAME 2Urgent revascularisations according to

different triggers for the revascularisation

Months after Revascularisation0 4 8 12 16 20 24

Months after Revascularisation0 4 8 12 16 20 24

0

4

8

12

16

20

24 PCI + MT MT alone

Cum

ulati

ve U

rgen

t Rev

ascu

lariz

ation

Ev

ents

per

100

pati

ents

-yea

rs

Urgent revascularisation was triggered in > 80% by an MI, by dynamic ST changes, or by resting angina

BaselinePCI+MT

MT alone

Registry

30 DaysPCI+MT

MT alone

Registry

6 MonthsPCI+MT

MT alone

Registry

12 MonthsPCI+MT

MT alone

Registry

24 MonthsPCI+MT

MT alone

Registry

0 20 40Patients with CCS II to IV (%)

FAME 2 Symptoms

0

5

10

15

20

25

30

35

40

Cum

ulat

ive

inci

denc

e (%

)

166 165 162 160 157 156 153 149 144 142 141 141 116Registry

447 440 434 429 427 422 417 410 407 406 402 399 343PCI+MT

441 389 360 337 315 302 290 277 272 268 260 254 218MT

No. at risk

0 2 4 6 8 10 12 14 16 18 20 22 24Months after randomization

MT vs. Registry: HR 4.26 (95% CI 2.66-6.81) P<0.001

PCI+MT vs. Registry: HR 0.66 (95% CI 0.38-1.14) P=0.13

PCI+MT vs. MT: HR 0.16 (95% CI 0.11-0.22) P<0.001

Total Revascularisations

FAME 2 Conclusions

1. More than 25% of stable CAD patients scheduled for PCI on the basis of clinical and angiographic data, have no stenosis with an FFR<0.80. These patients have a favorable outcome with MT alone. 2. The rate of death, MI, or urgent revascularization at 2 years in patients with stable CAD treated with FFR-guided PCI with new generation drug-eluting stents was less than half than in patients treated with MT alone.

3. Beyond 7 days from randomisation, PCI plus MT significantly reduces the rate of death or MI when compared to MT alone.

FAME 2

Accepted for publication in the NEJM, September 2, 2014