Is FFR a Substitute For Sound Clinical Judgement ?

Jeffrey W. Moses, MDColumbia University Medical Center/

NY-Presbyterian Hospital

Conflicts of Interest

• Consultant /SAB: BSC,Abbott

74 y/o woman with effort and rest angina ETT ; ex time 3’ with ST changes.

Anterior reversible perfusion defect

FFR of LAD 0.9 ......... Med Rx

Continued Sx on Med Rx

MLA=2.7mm2

PB=72%Vessel size=3.5mm

Repeat FFR 0.91

Complete symptomatic relief !

POST STENTMLA=5.9 mm2

Correllation Slide

• If FFR is validated by MPI…

• …how can it overrule an unequivocal MPI?

15 Studies:FFR and MPI (0.75 Cutoff)

n=996

Christou et al. Am. J Cardiol 2007;99:450

TP FN FP TN

331 100 143 422

FFR and the “Grey Zone”

De Bruyne, et al. Circulation 2001;104:157-62

FFR

Specificity

100

80

60

40

20

00.2 0.3 0.4 0.5 0.6 0.7 0.8 0.9 1.0

Sensitivity

FFR=0.75 0.80Specificity

Sensitivity

FFR=0.75 0.80

“Grey Zone”

FFR Test Retest Reproducibility

Petraco et al., J Am Coll Cardiol Intv 2013;6:222-5

What is Our Basis for Deferral?

DEFER: Patients with Intermediate Lesions with Equivocal or Negative Stress Tests: No Data With

Unequivocal Ischemia

Bech et al, Circ 2001;103:2928-34

Ste

nosi

s S

ever

ity (

%)

DeferGroup

PerformGroup

ReferenceGroup

FFR >0.75 FFR <0.75

20

30

40

50

3060

70

80

90

100

N=90N=91

N=144

3.3

7.9

15.7

0

5

10

15

20

%

P=0.20

P< 0.003

P< 0.005

DEFER PERFORM REFERENCE

FFR ≥ 0.75 FFR < 0.75

5 Year Cardiac Death and MI rate in DEFER Trial

Safety of Deferring PCI Based on FFR

Pijls, et al. J Am Coll Cardiol 2007;49:2105-11

Primary Endpoint: Death, MI, Urgent Revascularization at 2 years

FAME 2 : Trial DesignStable patients with 1, 2, or 3 vessel CAD evaluated for PCI with DES

n=1220

FFR in all target lesions

At least 1 stenosis with FFR ≤ 0.80 (n=888)

Randomization 1:1

PCI + MT MT

Randomized Trial

All FFR > 0.80(n=322)

MT

Registry

50% randomly assigned to follow-up

0

5

10

15

20

25

30

Cum

ulat

ive

inci

denc

e (%

)

166 156 145 133 117 106 93 74 64 52 41 25 13Registry447 414 388 351 308 277 243 212 175 155 117 92 53PCI+MT441 414 370 322 283 253 220 192 162 127 100 70 37MT

No. at risk

0 1 2 3 4 5 6 7 8 9 10 11 12

FAME 2: Primary Outcomes

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

Months after randomization

De Bruyne B et al. NEJM 2012:on-line

What a Difference a Decade Makes: 1 Year Outcomes

Deferral Perform

Non ischemic Ischemic

DEFER2001

20%

DEFER2001

8%

FAME II2011

3.0

FAME II2011

4.3

Circ 2012;201:2928

Possible Problems with FRR

• The flow impediment specific to the interrogated stenosis is underestimated as an opposite stenosis becomes more severe because maximal hyperemic flow is not achieved Branches between serial stenoses may inhibit

maximal hyperemia because of “branch steal.” Left ventricular hypertrophy causes inadequate

flow reserve because of a mismatch between the vasculature and myocardial mass

Exercise induced vasoconstriction not accounted for

Old Myocardial Infarction

Irreversible Microvascular Damage

Maximum Achievable Flow is Less

Smaller Gradient and Higher FFR across Any Given Stenosis

Chronic Microvascular Damage and FFR

Systemic Adenosine Infusion and Maximum Hyperemia: Variable Responses

• Routine set up for FFR measurement in my lab: venous sheath in the groin for adenosine infusion 140 μg/kg/min :FFR .98

• Repeat assessment by bolus injection of 100μg into RCA: short total AV block, then FFR 0.78 repeated with 50μg without AV block, then FFR 0.80

• Some patients may metabolize adenosine faster than others -> use a multipurpose catheter to deliver adenosine into the right atrium

FFR Gets Complex in Serial Stenosis

Pijls et al. Circulation. 2000;102:2371-2377

FFR in MI/ACS

• NOT in acute INFARCT or ACS lesion These lesions ALL need treatment

• May use in chronic infarct lesion Does not predict viability Does correlate with residual ischemia

• May use in non-culprit ACS lesions Avoid “over-treatment” Avoid need for subsequent stress testing

PCI in ACS : Angiographically Driven PCI Saves Lives

Fox et al, JACC 2010;55:435-45

Selective invasiveRoutine Invasive

High

Follow-up time (years)

Intermediate

LowCu

mu

lati

ve d

eath

an

d M

I

0 1 2 3 4 5

0%

5%

10%

15%

20%

25%

30%

35%

50%

45%

40%

Primary endpoint: Cardiac death, MI or refractory angina

Wald DS et al. NEJM 2013:on-line

91%

77%

Fre

edo

m f

rom

Pri

mar

y O

utc

om

e (%

)

Months

HR 0.35 (95%CI 0.21-0.58)P<0.001

No. at RiskPreventive PCINo Preventive PCI

0

231

6

234

12 18 24 30 36

168196

144166

122146

96118

7489

5067

0

20

40

60

80

100

PRAMI: “Preventative” PCI of Non-culprit Lsns after Culprit Lesion Primary PCI in STEMI

465 non-shock pts at 5 UK sites with MVD; after successful primary PCI randomized to NCL PCI of non-LM DS 50-99% stenoses vs. conservative care600 pts planned; DSMB stopped trial early after 465 pts enrolled (2008-2013)

Complete revasc

Culprit PCI only

Complete revasc

(N=234)

Culprit PCI only

(N=231)HR

(95%CI) P value

Pre-specified outcomes

Cardiac death, MI, or refractory angina 21 53 0.35 (0.21-0.58) <0.001

Cardiac death or MI 11 27 0.36 (0.18-0.73) 0.004

Cardiac death 4 10 0.34 (0.11-1.08) 0.07

Nonfatal MI 7 20 0.32 (0.13-0.75) 0.009

Refractory angina w/o CD or MI 12 30 0.35 (0.18-0.69) 0.002

Secondary outcomes

Noncardiac death 8 6 1.10 (0.38-3.18) 0.86

Repeat revascularization 16 46 0.30 (0.17-0.56) <0.001

Median FU 2.3 Years

Wald DS et al. NEJM 2013:on-line

PRAMI: “Preventative” PCI of Non-culprit Lsns after Culprit Lesion Primary PCI in STEMI

465 non-shock pts at 5 UK sites with MVD; after successful primary PCI randomized to NCL PCI of non-LM DS 50-99% stenoses vs. conservative care600 pts planned; DSMB stopped trial early after 465 pts enrolled (2008-2013)

How Do Patients End up on the Cath Table?

• ACS• Symptoms• Significant ischemia• Left ventricle dysfunction• Atypical symptoms and equivocal

non-invasives• Anatomically driven (ie abnormal CTA)

How Do Patients End up on the Cath Table?

• ACS• Symptoms• Significant ischemia• Left ventricle dysfunction• Atypical symptoms and equivocal

non-invasives• Anatomically driven (ie abnormal CTA)

VD 4.8x5.0 VA 19.5 mm2

LD 1.4x2.3LA 2.6 mm2

Recurrent Angina 9 Months Post Stent

FFR = 0.83

Are you going to Defer?

102

83

Recurrent Symptoms Post BMS

How Do Patients End up on the Cath Table?

• ACS• Symptoms• Significant ischemia• Left ventricle dysfunction• Atypical symptoms and equivocal

non-invasives• Anatomically driven (ie abnormal CTA)

Cardiac Mortality in Medically Treated Patients According to Ischemic Risk – CSMC Database

Hachamovitch et al Circulation. 2003;107:2900-07

% Total Myocardial Ischemia

0% 1- 5% 5-10% 11-20% >20%

Car

dia

c D

eath

Rat

e (%

)(1

.9 y

r F

U)

N=7110 N=1331 N=718 N=545 N=252

N=9,956 pts

0.0%

15.6%

22.3%

39.3%

0%

10%

20%

30%

40%

Dea

th o

r M

I R

ate

(%)

Rates of Death or MI by ResidualIschemia on 6-18m MPS

p=0.002

0%(n=23)

p=0.023

p=0.063

1%-4.9% (n=141)

5%-9.9%(n=88)

>10%(n=62)

Shaw LA et al. Circulation 2008;117:1283-91

How to Treat

ACS

“Classic” Symptoms

Significant ischemia

Left ventricle dysfunction

Atypical symptoms

+/- equivocal NI

Anatomic (culprit)

Anatomic

Anatomic

Anatomic +/- viability FFR

Location + severity+ / - FFR

FFR for ILMultivessel disease

Anatomically driven

Conclusions

• FFR needs to be put into the context of our overall understanding of coronary physiology , the prognosis of CAD and the influence of revascularization in various clinical and anatomic situations

• It has been validated in limited clinical trials and extending it to areas where other modalities (e.g., MPI , angiography ,viability studies) have demonstrated improvement of outcomes is simply not “evidence based”