FRACTIONAL FLOW RESERVE versus ANGIOGRAPHY FAME compares for the first time in a prospective, randomised study the outcomes between an FFR guided stenting strategy to an angio alone guided stenting strategy in those patients with intermediate MVD. FRACTIONAL FLOW RESERVE versus ANGIOGRAPHY FOR GUIDING PCI IN PATIENTS WITH MULTIVESSEL CORONARY ARTERY DISEASE

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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 under- or overestimation of functional stenosis severity We know from Defer that the stenting of a non-ischaemic lesions has no benefit whereas outcome by medial treatment is excellent with combined death/MI <1% year However Defer also shows that the stenting of ischaemic single vesselintermediate lesions improves both patient symptoms and outcome therefore such stenting is justified. Cardiologists recognise that especially in MVD, present in the majority of cases, it is difficult to distinguish between those lesions which are ischaemic and those that are not, simply by looking at the angio Nevertheless, current angiography is still the main tool for most interventionalists in daily practice to decide whether or not to stent…. This means that in every day practice many stenoses > 50% are stented, irrespective of the fact whether they cause ischemia or not.

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 cathlab just prior to stenting Therefore: FFR guidance of PCI in patients with multivessel disease may improve outcome FFR’s ability to easily discriminate between ischaemic and nonischaemic lesions has been well validated and documented. However the use of FFR in guiding MV revascularisation by identifying ischaemic lesions and optimising the use of DES has not been prospectively studied before.

FFR guided Percutaneous Coronary Intervention (PCI) FAME study: HYPOTHESIS FFR guided Percutaneous Coronary Intervention (PCI) in multivessel disease, is superior to current angiography guided PCI Consequently is was essential to test the The main hypothesis FFR guided PCI in MVD is superior to angiography guided PCI.

FAME study: DESIGN Randomized multicenter study in 1000 patients undergoing DES-stenting for multivessel disease in 20 US and European centers 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 is a well designed and structured study. 1005 pts recruited over a period of 18 months. 20 international centres 4 in UK - Belfast, Bristol, Glasgow and London. An independent core lab, independent data analysis and blinded adverse event committee were used. MVD was defined as >50% stenoses in at least 2 major epicardial coronary arteries. In order to remove the gray zone as most cardiologists ignore it anyway and to simplify decision making, an FFR cut-off value of 0.80 was used to guide intervention. This increases sensitivity to 95% but a slight decrease in specificity. FFR Cut-off: 0.80

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 ST-elevation MI with CK > 1000 U/l within last 5 days extremely tortuous or calcified coronary arteries Note: patients with previous PCI were not excluded In order to make sure that FAME reflected routine cathlab practise, a very liberal inclusion criteria was adopted and only few exclusion criteria were used. CTO

FLOW CHART Patient with stenoses ≥ 50% in at least 2 of the 3 major epicardial vessels Indicate all stenoses ≥ 50% considered for stenting Randomization Angiography-guided PCI FFR-guided PCI Measure FFR in all indicated stenoses Patients were selected on the basis of the coronary angiogram where at least 2 of the major epcardial vessels had lesions >50% stenosis. Following randomisation patients entered either the FFR guided treatment arm of the angio alone guided treatment arm. In the angio arm all indicated lesions where stented - in the FFR arm all lesions with FFR< or = to 0.80 were stented except in diffuse disease. All stented patients were prescribed Plaxix for 12 months. CTOS were included if crossed and given default value of 0.75. In the patients randomized to FFR measurement, FFR could be measured succesfully in 98 % of the lesions. This is exluded the 58 total occlusions where FFR cannot be performed by definition and to which a default value of 0.50 was assigned. So, all the TO were considered hemod sign and attempted to treat. Stent only those stenoses with FFR ≤ 0.80 Stent all indicated stenoses 1-year follow-up 8

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 An average of approximately 3 lesions were indicated per patient.

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 The stenosis severity of indicated lesions ranged from 44% - 78% Av stenosis severity> taxus

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) 90-99% narrowing, No (%) 207 (15) 202(14) Total occlusion, No (%) 40 (3) 58 (4) Patients with ≥1 total occlusion (%) 7.5 10.6 0.08 60% of all lesions indicated were over 70% stenosed - highlighting the fact that the majority of lesions looked significant.

FAME study: Procedural Results ANGIO-group N=496 FFR-group N=509 P-value # indicated lesions per patient 2.7 ± 0.9 2.8 ± 1.0 0.34 FFR results 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 PROCEDURAL RESULTS FFR was measured successfully in 98 % of the lesions in those patients randomised to the FFR arm. In 63% of all lesions, i.e. 2/3 of the lesions were ishchaemic as determined by FFR. Data correlating FFR result and size of lesion have not yet been released.

FAME study: Procedural Results ANGIO-group N=496 FFR-group N=509 P-value # indicated lesions per patient 2.7 ± 0.9 2.8 ± 1.0 0.34 FFR results Lesions succesfully measured, No (%) - 1329 (98%) Lesions with FFR ≤ 0.80 ,No (%) 874 (63%) Lesions with FFR > 0.80 ,No (%) 513 (37%) stents per patient 2.7 ± 1.2 1.9 ± 1.3 <0.001 Lesions succesfully stented (%) 92% 94% DES, total, No 1359 980 Number of Stents The first dramatic result is that the mean number of stents placed in the FFR arm was one less per patient than the angio guided arm - indicating there was a 30% lower stent implant rate in the FFR arm - this is statistically significant with a p value of .001. However whilst the number of stents is reduced the number of patients treated does not decrease - lesions may be deferred but not patients! Defer the lesion not the patient

FAME study: Adverse Events at 1 year ANGIO-group N=496 FFR-group N=509 P-value Events at 1 year, No (%) Death, MI, CABG, or repeat-PCI 91 (18.4) 67 (13.2) 0.02 Let’s go then to the adverse events at one year. First the primary endpoint - there were significantly lower rates of the composite of death, mi and revascularisation rates in the FFR group. 13.2 v 18.4% - this is again statistically significant with a p value of 0.02. This relates to a reduction of primary endpoint mace rates of some 30% over standard angiography - an achievement which is dramatic and seldom seen in comparitive studies in patients with coronary artery disease. Dramatic and seldom seen

FAME study: Adverse Events at 1 year ANGIO-group N=496 FFR-group N=509 P-value Events at 1 year, No (%) Death, MI, CABG, or repeat-PCI 91 (18.4) 67 (13.2) 0.02 Death 15 (3.0) 9 (1.8) 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 Also for all types of individual events, there was a very consistent decrease by approximately 30-40% Death rates were lower by some 34% and whilst not statistically significant the difference is extremely important not least to those surviving patients!! A snap analysis in Sweden and Belgium shows that potentially this could result in a saving of over 300 lives per year. The hard endpoint of death and MI is also lower in the FFR arm. Again this difference of 7.3 compared to 11.1 (which compares favourably with the Syntax 3VD group) is statistically significant and reflects a reduction of some 35%!!!

FAME study: Adverse Events at 1 year ANGIO-group N=496 FFR-group N=509 P-value Events at 1 year, No (%) Death, MI, CABG, or repeat-PCI 91 (18.4) 67 (13.2) 0.02 Death 15 (3.0) 9 (1.8) 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 Total no. of MACE 113 76 Revascularisation rates, which were a major concern in Syntax, where lower in the FFR group and whilst not statistically significant we will see that the trend is towards a greater divergence as time goes on. These numbers compare favourably with those patients in the cabg arm of the Syntax trial. Also total number of was was strikingly lower for patients undergoing PCI guided by Fract Flow Res These MACE rates are comparable with those of the 3 VSD cabg subgroup group in the Syntax trial. In real life terms what impact does this have on patient populations? Recent data extrapolations in both Sweden and in Belgium showed that 300 deaths can be prevented in the FAME cohort of patients. These are indeed dramatic figures.

FAME study: Adverse Events at 1 year ANGIO-group N=496 FFR-group N=509 P-value Events at 1 year, No (%) Death, MI, CABG, or repeat-PCI 91 (18.4) 67 (13.2) 0.02 Death 15 (3.0) 9 (1.8) 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 Total no. of MACE 113 76 Myocardial infarction, specified All myocardial infarctions 43 (8.7) 29 (5.7) 0.07 Small periprocedural CK-MB 3-5 x N 16 12 Other infarctions (“late or large”) 27 17 You could ask if this difference was mightbe caused by overrepresentation of small periprocedural MI, but that was not the case either:

absolute difference in MACE-free survival FAME study: Event-free Survival FFR-guided absolute difference in MACE-free survival 30 days 2.9% Angio-guided 90 days 3.8% 180 days 4.9% This Kaplan Meier graph shows that at 30 days, there is already a absolute diff of 2.9 %, but this is steadily increasing over the year and reaches a value of 5.3% at 1 year. If will be extremely interesting to see how this trend continues in subsequent follow-up. 360 days 5.3% The benefits of ffr do not diminish/ vulnerable plaque and better to stent

FAME study: Procedural Results ANGIO-group N=496 FFR-group N=509 P-value Procedure time (min) 70 ± 44 71 ± 43 0.51 PROCEDURAL RESULTS There was no difference between both arms in procedure time (counted from introduction of the first guiding catheter to removal of the last one).

FAME study: Procedural Results ANGIO-group N=496 FFR-group N=509 P-value Procedure time (min) 70 ± 44 71 ± 43 0.51 Contrast agent used (ml) 302 ± 127 272 ± 133 <0.001 The amount of contrast agent used was significantly lower in the FFR arm.

FAME study: Procedural Results ANGIO-group N=496 FFR-group N=509 P-value Procedure time (min) 70 ± 44 71 ± 43 0.51 Contrast agent used (ml) 302 ± 127 272 ± 133 <0.001 Materials used at procedure (US $) 6007 5332 Cost per procedure based on materials used was significantly lower. Staging and revascularation costs were also counted.

FAME study: Procedural Results ANGIO-group N=496 FFR-group N=509 P-value Procedure time (min) 70 ± 44 71 ± 43 0.51 Contrast agent used (ml) 302 ± 127 272 ± 133 <0.001 Materials used at procedure (US $) 6007 5332 Length of hospital stay (days) 3.7 ± 3.5 3.4 ± 3.3 0.05 Lenght of hospital stay tends to be shorter. In consideration of all these factors the cost savings associated with an FFR guided treatment strategy could potentially be even greater.

FAME study: Functional Class at 1 Year ANGIO-group N=496 FFR-group N=509 P-value Patients without event and free from angina 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 FUNCTIONAL CLASS So far the adverse events, but what about functional class, subjective well-being, and freedom from angina? That was also favorable to the FFR-guided patients. If we look at the percentage of ……, so those who did not experience any cardiac problem anymore during the next year. Patients free from angina is over 80% in the FFR group which is a high number in such a population especially considering the fact that their treatment strategy was less complex and 30% fewer stnets were used. In the Courage trail only 60% of patients were free from angina and those patients had less complex disease - indicating that ont only is PCI FFR guided strategy superior to angio but also to an optimised medical only treatment strategy. Courage 60%

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 % CONCLUSION From whatever standpoint you look at the FAME study, it is good news for interventional cardiology: The FAME study shows that Routine measurement of FFR to guide interventional treatment strategy….reduces the composite endpoint by approx 30%. Hard enpoints of death and MI is reduced by approx 35% …where 3 patients die in the 12 months post PCI using angio guided strategy, only 2 will die if an FFR guided strategy is used. ...where 3 patients experience MI with an angio guided strategy, only 2 patients will experience MI with an FFR strategy.

FAME study: CONCLUSIONS (2) Routine measurement of FFR during PCI with DES in patients with multivessel disease, when compared to current angiography guided strategy, furthermore: 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 Furthermore, routine FFR measurement reduces number of stens used significantly; it decreases the amount of contrast used; it is cost-saving without adding any additional time to the procedure and it results in simliar if not better functional class.

FAME study: CONCLUSIONS (3) 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 “Functionally Complete Revascularization”, i.e. stenting of ischemic lesions and medical treatment of non-ischemic ones. Therefore,…., in ALL ASPECTS…. 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 “Functionally Complete Revascularization”, i.e. stenting of ischemic lesions and medical treatment of non-ischemic ones.

FAME study: CONCLUSIONS (3) 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 “Functionally Complete Revascularization”, i.e. stenting of ischemic lesions and medical treatment of non-ischemic ones. Therefore,…., in ALL ASPECTS….

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