Chun & McGee Am J Med 2004;117:334

Chun & McGee Am J Med 2004;117:334

Tests non invasifs et vie réelle 398.978 patients Pas d ATCD coronaire non invasive test before 83.9% Sténose >70% = 37.6% multivessel disease 53% Un test non invasif positif augmente modérément la probabilité de coronaropathie par rapport à l absence de test (41% vs 35%; OR 1.28) Patel et al. NEJM 2010; 362:886

Capacité d informations avant coronarographie Patel et al. NEJM 2010; 362:886 + results non invasive tests + symptoms + Clinical risk factors Framingham risk score

La cascade ischémique Sténose Perfusion Métabolisme Contraction Electrogénèse Angor Coronarographie (QCA) Échographie endocoronaire (IVUS) Scanner coronaire Guide de pression (FFR) Isotopes (TEPS TEP) IRM Tomographie d émission de positons (TEP) Écho IRM de repos et de stress ECG de repos et d effort

La sténose coronaire: significativité chez l Homme Gould KL. JACC Cardiovasc Imaging: 2009;2:1009

QCA

Limits of visual estimation Subjective interpretation of what the stenosis should be: Before PTCA, stenosis are found more severe After PTCA, stenosis are found less severe Dichotomous analysis High inter-observer variability Can be trained/perform QCA Not suitable for multicentric trials/+++

Caliper Methods Calibration: Guiding catheter Use magnified images High interobserver variability (r=0.6 to 0.7) Used in the BARI trial

Quantitative angiographic methods Calibration: Guiding catheter Use magnified images Orthogonal views or worst view Automated edge detection algorithms Process : film digitization, image calibration, arterial contour detection Interobserver variability 3.1% for diameter stenosis 0.1 to 0.18 mm for MLD

QCA techniques

QCA techniques

QCA techniques

QCA techniques

Quantitative angiographic systems ARTREK Quinton imaging, Ann Arbor, MI Edges = 75% weighted thresh. between 1st and 2nd derivative User defined Average reference diameter Interobserver variability: MLD : 0.2 mm, Percent stenosis : 8% CAAS : Cardiovascular Angiography Analysis System Pie Data Medical, Maastricht, The Netherlands Edges = 50% weighted threshold Interpolated reference diameter CMS : Cardiovascular Measurement System MEDIS, The Netherlands Edges = 50% weighted threshold Interpolated reference diameter Interobserver variability: MLD : 0.15 mm, Percent stenosis : 4%

Correctable sources of imaging error during acquisition Biologic variation in lumen diameter Cardiac cycle : end-diastolic diastolic frames Vasomotor tone : nitroglycerin : 0.2 mg Image acquisition : single study Respiration : Breath holding Vessel foreshortening : Multiple angiographic projections Insufficient contrast injection : use 6-French catheters Branch vessel overlap : Multiple angiographic projections Pincushion distortion : Image objects in center of image Image acquisition : Sequential studies X-ray generator, X-ray X tube, Image intensif. : use same Cath Lab Differences in angle and gantry height = Record gantry height/angle/skew on worksheet Image calibration : use the same catheter diameter

QCA techniques

Correctable sources of errors during image analysis Electronic noise Recurzing digitization and frame averaging Quantum noise Spatial filtering of digital image data Automated edge detection Selection of reference positions Identification of lesion length : use of side branches, oth. landmarks Frame selection : End-diastolic diastolic frame Use of worst view (or orthognal views)

On-line QCA Several systems are available: Automated coronary analysis (ACA) :Philips CMS CAAS-II Infrequently used: Quality of data recording Analysis performed by a technician Limited ability to check for the quality of the analysis Use of QCA: Allow to train for qualitative assessment of vessel diameter and % stenosis

Methodologic limitations of QCA Limited ability to detect the presence and the severity of coronary atherosclerosis and its evolution overtime : Progression/regression studies Definition of Vessel reference diameter when using stents Use of radiopaque stents decrease reliability of QCA : Accuracy of MLD falling from 0.07 mm to 0.12 mm Accuracy of RVD not affected Modified algorithms have been designed (e.g. CMS- GFT)

Reference vessel diameter

Radiopaque stents

Radiopaque stents outside stent Within stent - no stenosis

Radiopaque stents

Radiopaque stents outside stent Within stent stenosis

Analyse angiographique L angiographie coronaire reste l outil l d évaluation de routine de l arbre l coronaire Il est important d en d connaître les limites (techniques, analyse qualitative) pour l utiliser à bon escient L analyse quantitative n est n pas indispensable en routine (intérêt dans la formation des médecins, m dans la réalisation des études multicentrique)

FFR

La sténose coronaire: significativité chez l Homme Gould KL. JACC Cardiovasc Imaging: 2009;2:1009

Aorta coronary artery Myocardium 100 0 P a P d Q normal Max. hyperemia Normal perfusion pressure 100 P d 0 P a Q stenosis Stenotic perfusion pressure Q stenosis Stenotic perfusion press. P d FFR = = = Q normal Normal perfusion press. P a

Characteristics of FFR FFR is not influenced by changes in blood pressure, heart rate, or contractility FFR has a unique normal value of 1.0 in every patient and every coronary artery FFR incorporates the contribution of collateral flow to myocardial perfusion

FFR threshold for ischemia No ischemia Yes ischemia FFR 1.00 0.75 0.00 FFR < 0.75 inducible ischemia (spec. 100 % ) FFR > 0.75 no inducible ischemia (sens. 90 % ) Pijls, De Bruyne et al, NEJM 1996

Angiography and functional significance DEFER Study FAME Study 325 lesions 1329 lesions Bech et al. Circulation 2001 Tonino et al. TCT 2009

Lésion du tronc coronaire gauche 213 pts Hamilos et al. Circulation 2009; 120:1505

Predictors of FFR: A multivariate model T β 95% CI β P Decrease LAD location -7.41-0.05-0.64- - 0.37 0.0001 Num. of diseased vessels -5.79-0.16-0.21--0.10 0.0001 Length, mm -5.00-0.02-0.03- - 0.01 0.0001 ACC/AHA -3.12-0.1-0.2--0.04 0.002 % stenosis, % -2.50-0.01-0.02- - 0.01 0.01 Increase Age, years 3.32 0.01 0.003-0.01 0.0009 Ejection fraction 2.75-0.04-7.01--0.25 0.006 Other variables in the model: Center, gender, diabetes, previous MACE, symptoms, stability, non-invasive testing, proximal lesion, Reference diameter, MLD. E van Belle, et al. Circulation 2013

évaluation morphologique CT scan Quantitative coronary angiography 65% Diagnosis accuracy Quantitative CT angiography 67% 79 pts stable angina 89 stenosis (18% FFR 0.75, 34% FFR 0.80) Meijboom et al. JACC 2008;52:636

Multivessel disease and diagnosis Spect performances vs FFR Concordance 42% Sur estimation 22% Sous estimation 36% 67 pts 2 ou 3 vx disease Melikian et al. JACC Intv 2010;3:307

Dobutamine stress echography performances vs FFR accuracy 62% accuracy 77% 70 pts single vessel disease Jung et al. Eur Heart J 2008;29:2536

Stress (adenosine) MRI performances vs FFR 37 pts 103 pts Valeur prédictive positive 97% valeur prédictive négative 84% Costa et al. JACC 2007;50:514 Watkins et al. circulation 2009;120:2207

Decision making based on FFR 0.75 FFR < 0.75 ischaemia inducible: revascularization is justified. FFR > 0.75 ischaemia highly unlikely:? is it justified to DEFER revascularization, even when the lesion is angiographically serious? DEFER STUDY: 325 pat. all accepted for elective PTCA of a single lesion. Just prior to PTCA FFR was determined. Bech et al, Circulation 2001

DEFER study 325 patients 181 patients FFR > 0.75 => No ischaemia Randomisation 144 patients FFR < 0.75 => Ischaemia PTCA 144 patients Performance of PTCA 90 patients 2 yr follow-up Deferral of PTCA 91 patients 2 yr follow-up Bech et al, Circulation 2001

Pijls et al. JACC 2007

Cardiac Death And Acute MI After 5 Years 20 % 15 10 P=0.20 P< 0.03 7.9 P< 0.005 15.7 5 3.3 0 DEFER PERFORM REFERENCE FFR > 0.75 FFR < 0.75

Compliance with FFR Non Compliance group n= 71 No Revasc n=34 Revasc n=37 Clinical events 7/34(21%) 4/37(11%) Death 2/34(6%) 1/ 37(3%) Acute Coronary syndromes Vessel revascularization 2/34(6%) 1/31(3%) 3/34(9%) 2/37(5)

Compliance with FFR Non Compliance group n= 71 Compliance group n = 336 No Revasc n=34 Revasc n=37 No Revasc n=237 Revasc n=99 Clinical events 7/34(21%) 4/37(11%) 14/237(7%) 6/99(6%) Death 2/34(6%) 1/ 37(3%) 3/237(1%) 0/99 Acute Coronary syndromes Vessel revascularization 2/34(6%) 1/31(3%) 2/237(1%) 0/99 3/34(9%) 2/37(5) 9/237(4%) 6/99(6%)

FLOW CHART Patient with stenoses 50% in at least 2 of the 3 major epicardial vessels Indicate all stenoses 50% coansidered for stenting Randomization Angiography-guided PCI FFR-guided PCI Measure FFR in all indicated stenoses Stent all indicated stenoses Stent only those stenoses with FFR 0.80 1-year follow-up

Procedural Characteristics Angio- Guided n = 496 FFR- Guided n = 509 P Value Indicated lesions / patient 2.7 0.9 2.8 1.0 0.34 Stents / patient 2.7 1.2 1.9 1.3 <0.001 Procedure time (min) 70 44 71 43 0.51 Contrast agent used (ml) 302 127 272 133 <0.001 Equipment cost (US $) 6007 5332 <0.001 Length of hospital stay (days) 3.7 3.5 3.4 3.3 0.05

FAME study: Event-free Survival absolute difference in MACE-free survival FFR-guided Angio-guided 30 days 2.9% 90 days 3.8% 180 days 4.9% 360 days 5.3%

Adverse Events at 2 Years Angio- Guided n = 496 FFR- Guided n = 509 P Value Total no. of MACE 139 105 Individual Endpoints Death 19 (3.8) 13 (2.6) 0.25 Myocardial Infarction 48 (9.7) 31 (6.1) 0.03 CABG or repeat PCI 61 (12.3) 53 (10.4) 0.35 Composite Endpoints Death or Myocardial Infarction 63 (12.7) 43 (8.4) 0.03 Death, MI, CABG, or re-pci 110 (22.2) 90 (17.7) 0.07

1 Year Economic Evaluation Bootstrap Simulation Angio Less Costly Angio Better FFR Better QALY FFR Less Costly USD

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 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

FAME 2 : FFR-Guided PCI versus Medical Therapy in Stable CAD Primary Outcomes 25 20 15 10 5 Cumulative incidence (%)30 No. at risk MT PCI+MT Registry 0 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 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

FAME 2 : FFR-Guided PCI versus Medical Therapy in Stable CAD Death from any Cause Cumulative incidence (%) No. at risk MT PCI+MT Registry 30 25 20 15 10 5 0 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 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

FAME 2 : FFR-Guided PCI versus Medical Therapy in Stable CAD Myocardial Infarction Cumulative incidence (%) No. at risk MT PCI+MT Registry 30 25 20 15 10 5 0 PCI+MT vs. MT: MT vs. Registry: HR 1.05 (0.51-2.19); p=0.89 PCI+MT vs. Registry: HR 1.61 (0.48-5.37); p=0.41 HR 1.65 (0.50-5.47); p=0.41 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

FAME 2 : FFR-Guided PCI versus Medical Therapy in Stable CAD Urgent Revascularization Cumulative incidence (%) No. at risk MT PCI+MT Registry 30 25 20 15 10 5 0 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 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

FAME 2 : FFR-Guided PCI versus Medical Therapy in Stable CAD Kaplan-Meier plots of Landmark Analysis of Death or MI Cumulative incidence (%) 30 25 20 15 10 5 0 Cumulative incidence (%) 2.5 2.0 1.5 1.0 0.5 0 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 0 1 2 3 4 5 6 7 Days after randomization >8 days PCI plus MT MT alone 7 days 07days 1 2 3 4 5 6 7 8 9 10 11 12 Months after randomization MT alone PCI plus MT

FFR and the change of strategy Revascularization A Global view strategy 100% 80% 60% 40% 20% 11 11 37 31 52 58 P=0.02 CABG PCI Conservative 0% A priori Final E van Belle, et al. Circulation 2013

FFR: Change of strategy in 47% of individuals 100% 80% 60% 40% 20% 11 37 52 7 5 21 16 19 33 P=0.0001 Modified CABG PCI Conservative 0% A priori Final E van Belle, et al. Circulation 2013

Change of Revascularization strategy according to the «a priori» strategy group 100% 80% 60% 40% 20% 10 8 26 42 64 50 32 4 64 Final strategy CABG PCI Conservative 0% Conserv. PCI CABG n=491 n=350 n=104 «A priori» strategy E van Belle, et al. Circulation 2013

FFR result and impact on the revascularization strategy FFR 1 0,9 0,8 Conservative PCI CABG 0,7 0,6 Conserv. PCI CABG n=491 n=350 n=104 «A priori» strategy E van Belle, et al. Circulation 2013

procédure -Heparine 1000-2000 UI IV -Aspirine 250 mg IV -1 mg risordan IC -Egalisation des pressions -Franchissement de la sténose -Stimulus hyper-hémique Adénosine - ATP- Papavérine / IC - IV Krénosin 1 amp/500 ml NaCl 9% = 12 µg/ml -Mesure en continu du ratio Pd/Pa

Guide wire - 0.14 straight or J tip pressure sensor - 3 cm proximal to the end of the wire

Pressure sensor Tip

blood pressure distal to the lesion being assessed - Pressure distal (Pd) conventional pressure transducer - measures arterial/aortic pressure - Pressure arterial (Pa)

Pa Pd

mean pressures of Pd and Pa are used assuming there is no lesion present = no difference in pressure The difference between these two pressures taken at rest determines if there is a resting gradient across a lesion Gradient calculation = Pd/Pa.

no lesion, the pressures will be the same and therefore the gradient value will be 1 E.g. Pa = 150 mmhg Pd = 150mmHg Then Pd/Pa = 1

Fractional Flow Reserve The Fractional Flow Reserve (FFR) is a ratio which is measured in a state of Hyperemia

Hyperemia Hyperemia state of myocardial vasculature dilatation Myocardial bed - pharmacologically dilated with an agent Adenosine occurs naturally in the body in small quantities and is produced during exercise to assist in the dilatation of the myocardial bed.

Dilation of micro-vasculature increases oxygen demand a flow limiting lesion will cause the blood pressure distal to the lesion to fall FFR will fall The extent of this reduction gives an indication as to the degree of flow limitation and hence degree of severity of stenosis

Adenosine Pa Decreased Pd Decrease FFR

Legalery et al. Am J Cardiol 2003

8% 6 dogs 30sec occ. 40 µg ado vs 140 µg IV 15% 26% Rioufol Eurointerv 2005 Lopez-Palop Heart 2004 Jeremias circulation 2000 Jeremias Am Heart J 2000

procédure -Heparine 1000-2000 UI IV -Aspirine 250 mg IV -1 mg risordan IC - guiding au choix -Egalisation des pressions -Franchissement de la sténose - hémodynamique stable -Stimulus hyper-hémique Adénosine - ATP- Papavérine / IC - IV Krénosin 1 amp/500 ml NaCl 9% = 12 µg/ml 100 µg IC (12-15 cc) ou 140 µg/kg/min PSE - catheter extubé -Mesure en continu du ratio Pd/Pa - éliminer toute dérive Verifier en fin de procédure