New strategies in the work-up of chronic coronary syndromes

Carlos Collet Bortone MD, PhDInterventional Cardiologist

Cardiovascular Center OLV-Aalst, Belgium

Introduction

• The current understanding of the pathophysiology of coronary

artery disease relies on the potential adverse effect of myocardial

ischemia.

log

Haz

ard

Rat

io

01

23

45

% Ischemic Myocardium0 12.5% 25% 32.5% 50%

Medical Rx*

Revasc*

*p<0.001

N=10,627 no known CAD

146 Cardiac Deaths

Hachamovitch Circulation 2003;107:2900-2907.

Observational study: Revascularization was associated with lower risk of

cardiac death only in those with >10% ischemia on perfusion imaging

Ischemia

Angio-Based

Invasive physiology

Symptoms

Non-invasive

Test

FFR

iFR

Pd/Pa

RFR

dPR

DFR

2020

Introduction

• The current understanding of the pathophysiology of coronary

artery disease relies on the potential adverse effect of myocardial

ischemia.

• No clear evidence supporting the benefit of revascularization in

terms of hard clinical endpoints namely myocardial infarction

and death.

1. Tonino P et al. FAME NEJM (2009) 360:213-24

COURAGE 10 years FU

Sedlis SP et al. NEJM 2015

0%

5%

10%

15%

20%

25%

30%

0 1 2 3 4 5

Cu

mu

lati

ve I

ncid

en

ce (

%)

Follow-up (years)

CON

INV

Adjusted Hazard Ratio = 0.93 (0.80, 1.08), p-value = 0.34

Subjects at Risk

CON 2591 2431 1907 1300 733 293

INV 2588 2364 1908 1291 730 271

ISCHEMIA Primary OutcomeCV Death, MI, hospitalization for UA, HF or resuscitated cardiac arrest

15.5%

13.3%

Introduction

• The current understanding of the pathophysiology of coronaryartery disease relies on the potential adverse effect of myocardialischemia.

• No clear evidence supporting the benefit of revascularization interms of hard clinical endpoints namely myocardial infarctionand death.

• Patients selection based on functional non-invasive methods wasunable to identify which patients may benefit fromrevascularization using percutaneous based therapies.

Sedlis SP et al. NEJM 2015

Introduction

• Patient selection for PCI using FFR, epicardial vessel level metrichas been associated with improved clinical outcomes. 1

2. Xaplanteris et al. FAME 2 NEJM 2018

1. Tonino P et al. FAME NEJM 2009

Fractional Flow Reserve in MVD

Tonino P et al. FAME NEJM (2009) 360:213-24

RR 0.72 (95% CI 0.54 -0.96), p=0.02

Introduction

• Patient selection using FFR at the vessel level is associated withimproved clinical outcomes. 1

• FFR-guided PCI strategy was associated with a significantlylower rate of MACE than medical therapy alone. 2

2. Xaplanteris et al. FAME 2 NEJM 2018

1. Tonino P et al. FAME NEJM 2009

PCI vs. OMT in patients with FFR ≤ 0.80

Xaplanteris et al. NEJM 2018

Introduction

• Patient selection using FFR at the vessel level is associated withimproved clinical outcomes. 1

• FFR-guided PCI strategy was associated with a significantlylower rate of MACE than medical therapy alone. 2

• Randomized controlled trials have confirmed clinical benefit ofinvasive functional assessment for decision-making aboutrevascularization in patients with chronic coronary syndromes.

2. Xaplanteris et al. FAME 2 NEJM 2018

1. Tonino P et al. FAME NEJM 2009

Revascularization in patients with multivessel CAD

c With documented ischaemia or a haemodynamically relevant lesion defined by FFR ≤0.80 or iwFR ≤0.89, or >90% stenosis in a major coronary vessel.

ESC/EACTS Guidelines 2018

Improving outcomes in patients undergoing PCI

Effective therapies PCI

Thin strut biodegradable

or biocompatible

polymer

Physiology guided-PCI

IVUS/OCT for sizing and

optimisation

DAPT, PCSK9…

PCI Patient Selection

Focal CAD Diffuse CAD

Microvascular CAD Others

The current approach is limited in differentiating CAD endotypes

Personalised approach

Focal CAD Diffuse CAD

Microvascular CAD Others

PCIOMTCABG

OMTRevalidation

Tailored MT

Personalised approach

Goal = Complete “functional” myocardial revascularization

Focal CAD Diffuse CAD

Epicardial Coronary Artery Disease

Incomplete anatomical revascularisation: Residual SYNTAX score (RSS)

Farooq et al. Circulation 2013

Impact of residual angiographic disease after functionally complete revascularisation

Kobayashi et al. JACC 2016 RSS Residual SYNTAX score

Choi et al. JACC Cardiovasc Interv. 2018

Clinical Implication of Functional Incomplete Revascularization

Clinical risk factors: age, sex, HTN, DLP, DM, PMI, prior revasc, and ACS

3-vessel FFR performed after PCI Residual functional SYNTAX score (rFSS) defined as rSS in vessels with

FFR ≤0.80)

Risk scores 2 years clinical outcomes in 358 pts

Choi et al. JACC Cardiovasc Interv. 2018

How often do we achieve functional revascularisation

after PCI?

Toth et al. Circ Cardiovasc Interv. 2017.

Clinical outcomes stratified by FFR Post-PCI in the FAME trial

One-third of the vessel remained with FFR <0.88

Jeremias A et al. JACC Card Interv 2020

Post PCI iFR

Case # 17 Case # 5

Pullback vs. single FFR

Confidential information Cardiovascular Center OLV Aalst

FFR

FFR

gra

die

nt

0.78

Motorized FFR with n=12800 values

FFR 0.78

Male, 51 years old. Post PCI for RCA (STEMI, 2 month ago). BMI 31.8kg/m2. CrCl 152ml/min (Cr 0.75 mg/dL). LVEF 60%. Elective PCI for LAD

Focal Functional CAD

Length(mm)

FFR

FFR

gra

die

nt

0.78

ΔFFR lesion = 0.19 units

PCI DES 3.0 x 23 mm

Focal Functional CAD

Length(mm)

FFR

FFR

gra

die

nt

0.88

Focal Functional CAD Post-PCI

Length(mm)

0.78

FFR

FFR

gra

die

nt

Length(mm)

Male, 61 years old. Hypertension, Hyperlipidemia. BMI 27.7kg/m2. CrCl 115ml/min (Cr 0.86 mg/dL). LVEF 60%. Stable typical chest pain.

Motorized FFR with n=12500 values

Diffuse Functional CAD

0.78FFR

FFR

gra

die

nt

ΔFFR = 0.10

PCI DES 3.5 x 33 mm

Diffuse Functional CAD

Length(mm)

0.80

FFR

FFR

gra

die

nt

Diffuse Functional CAD Post-PCI

Length(mm)

PCI in Focal and Difusse CAD

Pre PCI Post PCI

Functional Focal CAD

Functional Diffuse CAD

Refining patient selection and predicting functional

revascularisation

PPG index calculation

PPGindex =Maximal PPG over 20 mm

Vessel FFR gradient

Length with functional disease

Vessel length+( )1-

2

PPGindex = Magnitude of pressure drop

Extent of functional CAD

Confidential information Cardiovascular Center OLV Aalst

PPG index calculation

PPGindex =Maximal PPG over 20 mm

Vessel FFR gradient

Length with functional disease

Vessel length+( )1-

2

PPGindex = Magnitude of pressure drop

Extent of functional CAD

Confidential information Cardiovascular Center OLV Aalst

PPG index calculation

PPGindex =Maximal PPG over 20 mm

Vessel FFR gradient

Length with functional disease

Vessel length+( )1-

2

PPGindex = Magnitude of pressure drop

Extent of functional CAD

Confidential information Cardiovascular Center OLV Aalst

PPGindex =Maximal PPG over 20 mm

Vessel FFR gradient

Length with functional disease

Vessel length+

Maximal PPG over 20 mm: Maximum FFR gradient over 20 mm.

Vessel FFR: Difference between FFR values obtained at the ostium of the

vessel and the most distal anatomical location.

Length with functional disease: Length of coronary artery in millimetres

with FFR drop ≥0.0015 FFR units.

Vessel length: Length from the ostium to the most distal pressure wire

location.

( )1-

2

PPG index calculation

Functional Patterns of CAD

Confidential information Cardiovascular Center OLV Aalst

PPGindex 0.86PPGindex 0.45PPGindex 0.28

Focal CADCombined CADDiffuse CAD

Collet et al. JACC 2019 in press

Epicardial Resistance and PCI

PPGindex 0.95 Post-PCI FFR 0.97

PPGindex 0.36 Post-PCI FFR 0.83

Pre PCI

Pre PCI Post PCI

Post PCI

Foca

l CA

DD

iffu

se C

AD

17%

12% 9%

0.4%

Reduction of epicaldial resistance

97%

Reduction of epicaldial resistance

23%

Epicardial Resistance and PCI

PPGindex 0.95 Post-PCI FFR 0.97

PPGindex 0.36 Post-PCI FFR 0.83

Pre PCI

Pre PCI Post PCI

Post PCI

Foca

l CA

DD

iffu

se C

AD

17%

12% 9%

0.4%

Reduction of epicaldial resistance

97%

Reduction of epicaldial resistance

23%

PPG index and post-PCI FFR

PPG Index and FFR post PCI

N = 53

Slope = 0.21

Intercept = 0.76

r = 0.69 (95%CI 0.51 to 0.81)

P < 0.001

PPG Index and Functional Gain

N = 53

Adjusted R2 = 0.72 (95%CI 0.50

to 0.86)

P < 0.001

Mizukami T, Collet C et al. Under revision

iFR Pullback

Kikuta JACC Intv2018

Stent

Collet et al. Nature Reviews 2018.

Baseline LM PCI Mid LAD PCI Mid + distal LAD PCI

FFRCT Revascularization Planner in MVD

Macro-circulation Macro and Micro-circulation

Patel MR et al. N Engl J Med. 2010.

398,9

78 p

atients

Noninvasive testing 83.9%

Diagnostic Yield of Elective Coronary Angiography

Macro-circulation Macro and Micro-circulation

Methods to diagnose MVD

Non-invasive Invasive

Thermodilution

Doppler

Spasm provocation test

PET/SPECT

Doppler LAD

MRI

CT Perfusion

0

10

20

30

40

50

60

70

80

90

100Invasive-CFR Invasive-IMR Non-Invasive

Prevalence of Microvascular Dysfucntion

Pro

po

rtio

n (

%)

Prevalence of Microvascular Dysfunction 47% (CI 95% 34 to 59%)

Comprising 14073 patients included in 24 studies undergoing invasive and

non-invasive assessment

I2 99.5%

4,22

4,11

4,18

4,16

4,17

4,15

4,17

4,22

4,2

3,99

4,14

4,16

4,12

4,22

4,11

4,15

4,22

4,22

4,23

4,22

4,18

4,17

4,18

4,1

Collet et al. Under revision

14% of the screened patients had moderate to severe

ischemia and NOCAD

Approx. 40% of the patients in the invasive arm remained

symptomatic (diffuse disease?, MVD?)

Prevalence of Microvascular Dysfunction

Lee et al. Circulation 2015.

PET derived CRF and MBF

Gupta A et al. Circulation. 2017 Dec 12;136(24):2325-2336.

CFR independent predictor of cardiovascular mortality

CMD PathwaysMicrovascular Dysfunction

Macrovascular Dysfunction

Non-endothelium dependentCFR in response to adenosine

< 2.5

Change in coronary artery diameter in response to

nitroglycerine < 20%

Endothelium dependentChange in CBF in response to

acetylcholine < 50%

Change in coronary artery diameter in response to

acetylcholine ≤ 0%

Coronary spasmChest pain + ECG change + Change in coronary artery diameter

in response to acetylcholine < 90%

Methods to diagnose MVD

Bolus thermodilution Continuous thermodilution

Index of Microvascular Resistance Absolute Microvascular Resistance and Flow

Ford TJ et al. JACC 2018

Ford TJ et al. JACC 2018

Conclusions

• The evaluation of patients with chronic coronary syndromes is

advancing to better identify patients that benefit from

revascularization.

• For patients considered for PCI, the characterization of the

pattern of CAD (PPG index) predicts functional complete

revascularization.

• The evaluation of the microvascular compartment can further

personalise medical management and improve symptoms.

Conclusions

An epicardial ‘luminogram’ as tool to diagnose, decide

upon and treat CAD is sub-optimal. A functional

evaluation of both epicardial and microvascular

compartments is required to understand identify disease

endotypes and individualize therapies.