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DECISION MAKING IN MULTIVESSEL DISEASE: CLINICAL PRACTICE BASED UPON THE FAME TRIALS Saudi Heart Association Rhyadh, February 13th, 2013

Nico H.J.Pijls, MD, PhD Catharina Hospital, Eindhoven The Netherlands,

Fractional Flow Reserve versus

Angiography for Multivessel Evaluation FRACTIONAL FLOW RESERVE versus ANGIOGRAPHY FOR GUIDING PCI IN PATIENTS WITH MULTIVESSEL CORONARY ARTERY DISEASE

FAME study: BACKGROUND (1) • Stenting of non-ischemic stenoses has no benefit compared to medical treatment only • Stenting of ischemia-related stenoses improves symptoms and outcome • In multivessel coronary disease (MVD), identifying which stenoses cause ischemia is difficult: Non-invasive tests are often unreliable in MVD and coronary angiography often results in both underor overestimation of functional stenosis severity

FAME study: BACKGROUND (2) • Fractional Flow Reserve (FFR), is the most accurate and selective index to indicate whether a particular stenosis is responsible for inducible ischemia • FFR can be easily determined in the cath lab just prior to stenting Therefore: • FFR guidance of PCI in patients with multivessel disease may improve outcome

FAME - 1 study: HYPOTHESIS FFR – guided Percutaneous Coronary Intervention (PCI) in multivessel disease, is superior to current angiography – guided PCI

FAME study: DESIGN Randomized multicenter study in 1005 patients undergoing DES-stenting for multivessel disease in 20 US and European centers â&#x20AC;˘ â&#x20AC;˘ â&#x20AC;˘

independent core-lab independent data analysis blinded adverse event committee

Multivessel disease: Stenoses of > 50% in at least 2 of the 3 major coronary arteries

FAME study: Study Population The FAME study was designed to reflect daily practice in performing PCI in patients with multivessel disease Inclusion criteria: • ALL patients with multivessel disease • At least 2 stenoses ≥ 50% in 2 or 3 major epicardial coronary artery disease, amenable for stenting Exclusion criteria: • Left main disease or previous bypass surgery • Acute STEMI • Extremely tortuous or calcified coronary arteries Note: patients with previous PCI were not excluded

FLOW CHART

Patient with stenoses ≥ 50% in at least 2 of the 3 major epicardial vessels Indicate all stenoses ≥ 50% considered for stenting Randomization FFR-guided PCI

Angiography-guided PCI

Measure FFR in all indicated stenoses Stent only those stenoses with FFR ≤ 0.80

Stent all indicated stenoses 1-year follow-up

FAME study: PRIMARY ENDPOINT Composite of death, myocardial infarction, or repeat revascularization (“MACE”) at 1 year

FAME study: SECONDARY ENDPOINTS • • • •

Individual components of MACE at 1 year Functional class Use of anti-anginal drugs Health-related quality of life (EuroQOL-5D)

• Procedure time • Amount of contrast agent used during procedure • Cost of the procedure

FAME study: Treatment • PCI according to local routine • Only drug-eluting stents (DES) • FFR measured by Pressure Wire (Certus wire, RADI Medical Systems) • Hyperemia induced by i.v. adenosine 140 µg/kg/min in femoral vein • EKG, CK, CK-MB, etc during hospital stay • Follow-up at 1 month, 6 months, 1 year

FAME study: Baseline Characteristics (1) ANGIO-group N=496

FFR-group N=509

Pvalue

64±10

65±10

0.47

Male, %

0.30

Diabetes, %

0.65

Hypertension, %

0.10

Current smoker, %

0.12

Hyperlipidemia, %

0.62

Previous MI, %

0.84

Unstable angina, %

0.11

Previous PCI , %

0.34

57±12

57±11

0.92

0.47

Age, mean±SD

LVEF,

mean±SD

LVEF < 50% , %

FAME study: Baseline Characteristics (2) ANGIO-group N=496

FFR-group N=509

P-value

# indicated lesions per patient

2.7±0.9

2.8±1.0

0.34

50-70% narrowing, No (%)

550 (41)

624 (44)

70-90% narrowing, No (%)

553 (41)

530 (37)

90-99% narrowing, No (%)

207 (15)

202(14)

40 (3)

58 (4)

7.5

10.6

0.08

Patients with prox LAD involved,

186 (38)

210 (41)

0.39

% lesions in segment 1,2,6,7,or 11

960 (71)

1032 (73)

0.42

Total occlusion, No (%) Patients with ≥1 total occlusion (%)

No (%)

FAME study: Procedural Results (1) ANGIOgroup N=496

FFR-group N=509

P-value

2.7 ± 0.9

2.8 ± 1.0

0.34

Lesions succesfully measured, No

1329 (98%)

Lesions with FFR ≤ 0.80 ,No (%)

874 (63%)

Lesions with FFR > 0.80 ,No (%)

513 (37%)

FFR in ischemic lesions

0.60 ± 0.14

FFR in non-ischemic lesions

0.88 ± 0.05

# indicated lesions per patient

FFR results (%)

FAME study: Procedural Results (1) ANGIOgroup N=496

FFR-group N=509

P-value

2.7 ± 0.9

2.8 ± 1.0

0.34

Lesions succesfully measured, No

1329 (98%)

Lesions with FFR ≤ 0.80 ,No (%)

874 (63%)

Lesions with FFR > 0.80 ,No (%)

513 (37%)

2.7 ± 1.2

1.9 ± 1.3

<0.001

Lesions succesfully stented (%)

92%

94%

DES, total,

1359

980

# indicated lesions per patient

FFR results (%)

Stents per patient No

FAME study: Procedural Results (2)

Procedure time (min)

ANGIO-group N=496

FFR-group N=509

P-value

70 ± 44

71 ± 43

0.51

FAME study: Procedural Results (2)

Procedure time (min)

Contrast agent used (ml)

ANGIO-group N=496

FFR-group N=509

P-value

70 ± 44

71 ± 43

0.51

302 ± 127

272 ± 133

<0.001

FAME study: Procedural Results (2)

Procedure time (min)

Contrast agent used (ml)

Materials used at procedure (US $)

ANGIO-group N=496

FFR-group N=509

P-value

70 ± 44

71 ± 43

0.51

302 ± 127

272 ± 133

<0.001

6007

5332

<0.001

FAME study: Procedural Results (2)

Procedure time (min)

Contrast agent used (ml)

Materials used at procedure (US $) Length of hospital stay (days)

ANGIO-group N=496

FFR-group N=509

P-value

70 ± 44

71 ± 43

0.51

302 ± 127

272 ± 133

<0.001

6007

5332

<0.001

3.7 ± 3.5

3.4 ± 3.3

0.05

FAME study: Adverse Events at 1 year ANGIO-group N=496 Events at 1 year, No (%) Death, MI, CABG, or repeat-PCI

FFR-group N=509

P-value

FAME study: Adverse Events at 1 year ANGIO-group N=496

FFR-group N=509

P-value

91 (18.4)

67 (13.2)

0.02

Events at 1 year, No (%) Death, MI, CABG, or repeat-PCI

FAME study: Adverse Events at 1 year ANGIO-group N=496

FFR-group N=509

Death, MI, CABG, or repeat-PCI Death

91 (18.4)

67 (13.2)

15 (3.0)

9 (1.8)

0.02 0.19

Death or myocardial infarction

55 (11.1)

37 (7.3)

0.04

CABG or repeat PCI

47 (9.5)

33 (6.5)

0.08

P-value

Events at 1 year, No (%)

FAME study: Adverse Events at 1 year ANGIO-group N=496

FFR-group N=509

Death, MI, CABG, or repeat-PCI Death

91 (18.4)

67 (13.2)

15 (3.0)

9 (1.8)

0.02 0.19

Death or myocardial infarction

55 (11.1)

37 (7.3)

0.04

CABG or repeat PCI

47 (9.5)

33 (6.5)

0.08

113

0.02

P-value

Events at 1 year, No (%)

Total no. of MACE

FAME study: Adverse Events at 1 year ANGIO-group N=496

FFR-group N=509

Death, MI, CABG, or repeat-PCI Death

91 (18.4)

67 (13.2)

15 (3.0)

9 (1.8)

0.02 0.19

Death or myocardial infarction

55 (11.1)

37 (7.3)

0.04

CABG or repeat PCI

47 (9.5)

33 (6.5)

0.08

113

0.02

43 (8.7)

29 (5.7)

0.07

Small periprocedural CK-MB 3-5 x N

Other infarctions (“late or large”)

P-value

Events at 1 year, No (%)

Total no. of MACE Myocardial infarction, specified All myocardial infarctions

FAME study: Event-free Survival Absolute Difference in MACE-Free Survival

FFR-guided 30 days 2.9% 90 days 3.8%

Angio-guided 180 days 4.9%

360 days 5.3%

FAME study: CONCLUSIONS (1) Routine measurement of FFR during PCI with DES in patients with multivessel disease, when compared to current angiography guided strategy • Reduces the rate of the composite endpoint of death, myocardial infarction, re-PCI and CABG at 1 year by ~ 30% • Reduces mortality and myocardial infarction at 1 year by ~ 35 %

FAME study: CONCLUSIONS (2) Routine measurement of FFR during PCI with DES in patients with multivessel disease, when compared to current angiography guided strategy • Is cost-saving and does not prolong the procedure • Reduces the number of stents used • Decreases the amount of contrast agent used • Results in a similar, if not better, functional status

FAME study: CONCLUSIONS Routine measurement of FFR during DES-stenting in patients with multivessel disease is superior to current angiography guided treatment. It improves outcome of PCI significantly It supports the evolving paradigm of â&#x20AC;&#x153;Functionally Complete Revascularizationâ&#x20AC;?, i.e. stenting of ischemic lesions and medical treatment of non-ischemic ones.

OPTIMUM TREATMENT OF MULTIVESSEL DISEASE FAME showed that PCI becomes a better and more effective treatment by FFR guidance……..but what about PCI vs Medical treatment vs CABG ? Perspectives from COURAGE, SYNTAX, and FAME

(the 3 large randomized trials in MVD in the last years) COURAGE: Boden et al, NEJM 2007;356:1503-1516 SYNTAX: Serruys et al, NEJM (under review) FAME: Tonino et al, NEJM 2008 (in press)

REVASCULARIZATION IN MULTIVESSEL DISEASE: Multivessel PCI vs Medical Treatment ?? • COURAGE study: - multivessel PCI only better in patients with inducible ischemia - relatively simple patients, mainly BMS stenting - high rate of recurrent angina with R/x only Multivessel PCI by DES vs CABG ?? • SYNTAX study: - multivessel PCI by DES ( and using standard angiography !) is inferior to CABG: more MACE, but similar mortality/ myocardial infarction

But…….

REVASCULARIZATION IN MULTIVESSEL DISEASE:

But……… PCI in COURAGE and SYNTAX was

angiography-guided !! This means that • a number of non-ischemic lesions was unnecesarily stented… • …and some ischemic lesions were not stented So: PCI in those studies might have been better by FFR guidance !! FAME-2 and FAME-3

MACE in COURAGE, SYNTAX–3VD, and FAME STUDY

% 20

L A IC I D PC ME >20 >20

I C P

G B CA

19.1

io g n FR a F I I PC PC 18.4

10 11.2

COURAGE

SYNTAX

13.2

FAME

FAME -2 study:

FAME 2:

De Bruyne et al, NEJM 2012

FAME -2 study: OBJECTIVE

To compare clinical outcomes of FFRguided contemporary PCI plus the best available medical therapy (OMT) versus OMT alone in patients with stable coronary disease

FAME -2 study: INCLUSION CRITERIA Patients, referred for PCI because of

Angiographic 1, 2, or 3 vessel disease

FAME -2 study: EXCLUSION CRITERIA

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

FAME -2 study: PRIMARY ENDPOINT

Composite of • all cause death • myocardial infarction • unplanned hospitalization with urgent revascularization because of ACS

FAME 2 : FFR-Guided PCI versus Medical Therapy in Stable CAD

Flow Chart Stable CAD patients scheduled for 1, 2 or 3 vessel DES-PCI N = 1220

Randomized Trial

FFR in all target lesions

At least 1 stenosis with FFR â&#x2030;¤ 0.80 (n=888)

Registry

When all FFR > 0.80 (n=332)

Randomization 1:1

PCI + MT

73%

27%

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

50% randomly assigned to FU

FAME -2 study: KEY ISSUE The key issue in the FAME 2 study is , that the total study population of patients with CAD classifying for PCI on the basis of angiography is divided into 2 groups, based upon FFR: Group A, the randomized trial, in which ALL patients have inducible ischemia (from 1 or more lesions) (“the bad guys”, more severely diseased, a priori worse prognosis)  FFR-guided PCI vs OMT Group B, the Registry, consisting of patients WITHOUT inducible ischemia. (“the good guys”, less severely diseased, a priori favourable prognosis)  OMT

FAME -2 study: DSMB RECOMMENDATION

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

*DSMB: Stephan Windecker, Chairman, Stuart Pocock, Bernard Gersh 40

FAME 2 : FFR-Guided PCI versus Medical Therapy in Stable CAD

Cumulative incidence (%)

Primary Outcomes

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 HR 4.32 (1.75-10.7); p<0.001 25 MT vs. Registry: 30

20 15

ischemia, OMT

ischemia, PCI

no ischemic

No. at risk MT PCI+MT Registry

441 447 166

414 414 156

370 388 145

322 351 133

283 308 117

253 277 106

220 243 93

192 212 74

162 175 64

127 155 52

100 117 41

70 92 25

37 53 13

Months after randomization

FAME 2 : FFR-Guided PCI versus Medical Therapy in Stable CAD

Urgent Revascularization

Cumulative incidence (%)

No. at risk MT PCI+MT Registry

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

ischemia, OMT

10 5

ischemia, PCI

no ischemic 0

441 447 166

414 421 156

371 395 145

325 356 133

286 315 117

256 285 106

223 248 94

195 217 75

164 180 65

129 160 53

101 119 42

71 93 26

38 53 13

Months after randomization

FAME 2 : FFR-Guided PCI versus Medical Therapy in Stable CAD

Patients with urgent revascularization

21.4%

Myocardial Infarction

51.8% 26.8% Unstable angina +evidence of ischemia on ECG

FAME 2 : FFR-Guided PCI versus Medical Therapy in Stable CAD

Patients with urgent revascularization

21.4%

Myocardial Infarction

26.8% Unstable angina +evidence of ischemia on ECG

Primary Outcomes (with only the urgent revascularizations based on positive biomarkers or EKG changes) Cumulative incidence (%)

PCI+OMT vs. OMT:

HR 0.49 (0.27-0.90, p=0.019)

Biomarkers

21.4%

P = 0.019

ECG +

51.8%

26.8%

No. at risk OMT PCI+OMT

441 447

418 414

379 388

332 352

295 309

5 6 7 8 Months after randomization 263 278

229 244

202 213

172 176

140 156

110 118

77 93

41 54

FAME 2 : FFR-Guided PCI versus Medical Therapy in Stable CAD

Kaplan-Meier plots of Landmark Analysis of

Death or MI â&#x2030;¤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

25 2.5

Cumulative incidence (%)

2.0

PCI plus MT

1.5

â&#x2030;¤7 days

1.0 0.5

MT alone

0 0

2 3 4 5 Days after randomization

MT alone 5

>8 days

PCI plus MT

0 07days 1

Months after randomization

FAME 2 : FFR-Guided PCI versus Medical Therapy in Stable CAD

Kaplan-Meier plots of Landmark Analysis of

Death or MI â&#x2030;¤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

25 2.5

Cumulative incidence (%)

2.0

PCI plus MT

1.5

â&#x2030;¤7 days

1.0 0.5

MT alone

0 0

2 3 4 5 Days after randomization

MT alone 5

>8 days

PCI plus MT

0 07days 1

Months after randomization

FAME -2 study: CONCLUSIONS • In patients with stable (or stabilized) 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, a condition leading without PCI to increased rate of AMI and negative influence on survival • In patients with functionally non-significant stenoses medical therapy alone resulted in an excellent outcome, regardless of the angiographic appearance of the stenoses

FAME : CLINICAL CONSEQUENCES

R/x

PCI

CABG

FAME : CLINICAL CONSEQUENCES

R/x

PCI

CABG

• FFR –guidance makes PCI and Stenting a better treatment for more patients • It improves the quality of interventional treatment and makes PCI the treatment of choice for more – and better selected - patients

IMPACT OF FAME-studies ON USE OF PRESSURE WIRE

• worldwide use of Pressure Wire increased from 90.000 end of 2008 to 300.000 in 2012 (= 12% of all PCI) and expected to be 700.000 in 2016 ( = 25% of all PCI at that time)

• integration of FFR with regular cathlab equipment (General Electric & SJM) and wireless sensors will have further positive impact

Catharina Hospital, Eindhoven, The Netherlands

FAME study: Baseline Characteristics (2) ANGIO-group N=496

FFR-group N=509

P-value

# indicated lesions per patient

2.7±0.9

2.8±1.0

0.34

Reference diameter (mm)

2.5±0.6

2.5±0.7

0.81

% stenosis severity

61±17

60±18

0.24

MLD (mm)

1.0±0.4

1.0±0.5

0.35

50-70% narrowing, No (%)

550 (41)

624 (44)

70-90% narrowing, No (%)

553 (41)

530 (37)

> 90% narrowing, No (%)

247 (18)

260 (18)

7.5

10.6

0.08

Patients with ≥1 total occlusion (%)

FAME 2 : FFR-Guided PCI versus Medical Therapy in Stable CAD

Baseline Clinical Characteristics (1)

Patients, N

Randomized trial N=888

Registry N=322

PCI+MT=447

MT=441

with FU=166

63.5±9.3 79.6 28.3±4.3

63.9±9.6 76.6 28.4±4.6

63.6±9.8 68.1 27.8±3.9

0.90 0.005 0.14

45.8

0.65

21.1 81.9 71.1 25.3 6.0

0.79 0.23 0.15 0.65 0.24

Demographic Age (y) Male sex - (%) BMI

Risk factors for CAD

Positive family history CAD - 48.3 46.9 (%) Smoking - (%) 19.9 20.4 Hypertension - (%) 77.6 77.8 Hypercholesterolemia - (%) 73.9 78.9 Diabetes mellitus - (%) 27.5 26.5 Insulin requiring diabetes - 8.7 8.8 (%) *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)

Patients, N

Randomized trial N=888 PCI+MT=447

MT=441

Non-Cardiac Co-Morbidity Renal Failure (Cr > 2.0 mg/dL) - 1.8 2.7 (%) History of stroke or TIA - (%) 7.4 6.3 Peripheral vascular disease - 9.6 10.7 (%) Cardiac History History of MI - (%) 37.2 37.8 History of PCI in target vessel 17.9 17.2 (%) Angina - (%) Asymptomatic 11.9 10.5 CCS class I 18.3 22.3 CCS class II 45.6 44.8 *P value compares all RCT patients with 17.9 patients in registry CCS class III 14.8

Registry N=322

with FU=166

4.2

0.14

6.0 4.8

0.69 0.03

36.6 20.5

0.83 0.37 0.64

10.2 25.3 44.6 13.9

FAME 2 : FFR-Guided PCI versus Medical Therapy in Stable CAD

Angiographic Characteristics

Randomized trial N=888

Patients, N

Angiographically significant stenoses - no. per patient No of vessels with ≥ 1 significant stenoses - (%) 1 2 3 Prox- or mid- LAD stenoses - (%)

PCI+MT= 447

OMT= 441

1.87±1.05

1.73±0.94

Registry N=322 with FU=166

1.32±0.59

<0.001 <0.001

56.2 34.9 8.9

59.2 33.1 7.7

81.9 15.7 2.4

65.1

62.6

44.6

*P value compares all RCT patients with patients in registry

<0.001 56

FAME 2 : FFR-Guided PCI versus Medical Therapy in Stable CAD

FFR Measurements Randomized trial N=888 PCI+MT=447 OMT=44

Patients, N

Registry N=322 with FU=166

1 FFR significant stenoses no. per

1.52±0.78

1.42±0.7 3

0.03±0.17

<0.00 1

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

1 2 3

Prox- or mid- LAD stenoses (%)

74.0 22.8 3.1

77.8 19.3 2.9

3.0 0 0

62.4

59.6

0.6

<0.00 1

FAME 2 : FFR-Guided PCI versus Medical Therapy in Stable CAD

Death from any Cause

Cumulative incidence (%)

30 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 25 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

441 447 166

423 423 156

390 396 145

350 359 134

312 318 118

281 288 107

247 250 96

219 220 76

188 183 67

154 163 55

122 122 43

90 95 27

54 54 13

Months after randomization

FAME 2 : FFR-Guided PCI versus Medical Therapy in Stable CAD

Myocardial Infarction

Cumulative incidence (%)

30 PCI+MT vs. MT: 25

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

441 447 166

421 414 156

386 388 145

341 352 134

304 309 118

20 15 10 5 0

No. at risk MT PCI+MT Registry

273 278 107

239 244 95

212 214 75

182 177 65

148 157 53

117 119 42

85 94 26

48 54 13

Months after randomization

FAME -2 study: INCLUSION CRITERIA Patients, 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

CONSORT-E CHART

Not eligible N= 900 Left main stenosis N= 157 Extreme coronary tortuosity

Assessed for eligibility N=1905

or calcification N= 217 No informed consent N= 105 Contra-indication for DES N= 86 Participation in other study N= 94 Logistic reasons N= 210 Other reasons N= 31

Randomized N=1005 Angiographyguided PCI N=496

FFR-guided PCI N=509

Lost to follow-up N=11

Lost to follow-up N=8

Analyzed N=496

Analyzed N=509

FAME study: Functional Class at 1 Year ANGIOgroup N=496

FFR-group N=509

P-value

326 (68)

360 (73)

0.07

Patients free from angina, No. (%)

374 (78)

399 (81)

0.20

Number of anti-anginal meds, No.

1.2 ± 0.7

1.2 ± 0.8

0.48

EQ-5D visual analogue scale

74 ± 16

75 ± 16

0.65

Patients without event and free from angina

Relationship between Stenosis Severity and Clinical Outcome

Event Rates(%)

FAME 2: Patients with angiographically significant stenoses and treated with the best available medical therapy

R/X

FFR N=117 n=43 n=447

n=112

n=173

n=129

Stenosis Severity (FFR)

n=33

Relationship between Stenosis Severity and Clinical Outcome

Event Rates(%)

FAME 2: Patients with angiographically significant stenoses and treated with the best available medical therapy

R/X

FFR N=117 n=43 n=447

n=112

n=173

n=129

Stenosis Severity (FFR)

n=33