Long-term clinical outcome after fractional flow reserve– versus angio-guided percutaneous coronary intervention in patients with intermediate stenosis of coronary artery bypass grafts

Long-term clinical outcome after fractional flow reserve– versus angio-guided percutaneous coronary intervention in patients with intermediate stenosis of coronary artery bypass grafts Luigi Di Serafino, MD, PhD, a Bernard De Bruyne, MD, PhD, a Fabio Mangiacapra, MD, PhD, a Jozef Bartunek, MD, PhD, a Pierfrancesco Agostoni, MD, PhD, b Marc Vanderheyden, MD, PhD, a Gabriella Scognamiglio, MD, a Guy R. Heyndrickx, MD, PhD, a William Wijns, MD, PhD, a and Emanuele Barbato, MD, PhD a Aalst, Belgium; and Utrecht, The Netherlands

Background Fractional flow reserve (FFR)–guided percutaneous revascularization (percutaneous coronary intervention [PCI]) of intermediate stenosis in native coronary artery is safe and associated with better clinical outcomes as compared with an angiography-guided PCI. It is unknown whether this applies to coronary artery bypass grafts (CABGs). Methods We included 223 patients with CABG and with stable or unstable angina and an intermediate stenosis involving an arterial or a venous graft. Patients were divided into 2 groups: FFR guided (n = 65, PCI performed in case of FFR ≤0.80) and angio guided (n = 158, PCI performed based on angiographic evaluation). Primary end point was major adverse cardiac and cerebrovascular event, defined as death, myocardial infarction, target vessel failure, and cerebrovascular accident (CVA). Results

The 2 groups were similar in terms of demographic and clinical characteristics. Percutaneous coronary intervention was performed in 23 patients (35%) of the FFR-guided group and 90 patients (57%) of the angio-guided group (P b .01). In the FFR-guided group, PCI was more often performed in arterial grafts as compared with the angio-guided group (16 [70%] vs 12 [13%], respectively; P b .01). Follow-up was obtained in 96% of patients at a median of 3.8 years (1.6-4.0 years). At multivariate analysis, major adverse cardiac and cerebrovascular event rate was significantly lower in the FFRguided group as compared with the angio-guided group (18 [28%] vs 77 [51%], hazard ratio 0.33 [0.11-0.96], P = .043]. Procedure costs were overall reduced in the FFR-guided group (€2240 ± €652 vs €2416 ± €522, P = .03).

Conclusions An FFR-guided PCI of intermediate stenosis in bypass grafts is safe and results in better clinical outcomes as compared with an angio-guided PCI. This clinical benefit is achieved with a significant overall reduction in procedural costs. (Am Heart J 2013;166:110-8.)

Percutaneous coronary interventions (PCI) in patients with previous coronary artery bypass graft surgery (CABG) are ever increasing in the catheterization laboratory. 1 In fact, PCI of bypass grafts is usually preferred to redo-surgery, 2 although it is associated with higher rates of acute and long-term events as compared with PCI of native vessels. 3 Bypass grafts From the aCardiovascular Center Aalst OLV Clinic, Aalst, Belgium, and bDepartment of Cardiology, University Medical Center Utrecht, Utrecht, The Netherlands. Submitted January 17, 2013; accepted April 17, 2013. Reprint requests: Emanuele Barbato, MD, PhD, Cardiovascular Center Aalst OLV Clinic, Moorselbaan, n. 164, B-9300 Aalst, Belgium. E-mail: [email protected] 0002-8703/$ - see front matter © 2013, Mosby, Inc. All rights reserved. http://dx.doi.org/10.1016/j.ahj.2013.04.007

intervention still represents a challenge because patients are usually older with several comorbidities. 1 Stenoses are usually complex and often thrombotic. 4 In addition, the angiographic evaluation of stenosis severity is more difficult in bypass conduits than in native arteries. Therefore, appropriateness of PCI in bypass grafts is crucial, especially in intermediate equivocal stenosis, to avoid exposing patients to unacceptable higher procedural risks without significant clinical benefit. Fractional flow reserve (FFR) guidance of PCI has been adopted in the catheterization laboratory to overcome the limited spatial resolution and poor specificity of noninvasive functional tests, especially in the context of multivessel disease. 5 In addition, an FFR-guided PCI of native coronary stenosis has been associated with an improved long-term clinical outcome. 6-8 In the present

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retrospective registry, we evaluated the long-term clinical outcome of patients undergoing FFR-guided PCI versus contemporary patients undergoing angio-guided PCI of intermediate stenosis in bypass grafts.

Methods Patient population All patients referred to coronary angiography for stable or unstable angina from January 2000 until June 2011 with at least 1 intermediate stenosis of an arterial or a venous bypass graft measured with FFR were included. Contemporary patients with previous CABG undergoing coronary angiography and with intermediate stenosis of an arterial or a venous bypass graft were used as a reference group. Intermediate stenosis was defined as percent diameter stenosis (%DS) at a visual estimation between 40% and 70%. Exclusion criteria were as follows: (1) patients presenting with ST-segment elevation myocardial infarction (MI) or non–ST-segment elevation MI, (2) patients in whom revascularization has been deferred because of serious comorbidities, (3) the presence of serial stenosis located in bypass graft or in both bypass graft and its subtended native vessel, and (4) the presence of sequential anastomosis in the target bypass graft. Patients were grouped into the following: (a) angio-guided PCI strategy, where PCI of an angiographically intermediate stenosis was performed or deferred based on the angiographic appearance of the coronary lesion (angio-guided group) and (b) FFR-guided PCI strategy, where patients underwent PCI in case of FFR ≤0.80 and deferred to optimal medical therapy in case of FFR N0.80 (FFR-guided group). Patients were divided according to the respective treatment strategy group regardless of whether they underwent PCI or not.

Pressure measurements Fractional flow reserve was measured using a 0.014-in. miniaturized pressure monitoring guidewire system (RADI PressureWire; St Jude Medical Systems, Plymouth, MN), as previously described. 9-11 In case the native vessel upstream to the anastomosis was not completely occluded, and therefore, the bypass graft was not the only donor vessel, the pressure wire was advanced further down to exactly position the pressure sensor 2 to 3 mm beyond the anastomosis (Figure 1). Maximal hyperemia was induced with intravenous adenosine infusion (140 μg kg −1 min −1), intragraft adenosine (N100 μg), or papaverine (using 12-20 mg) bolus injection. 12 An FFR ≤0.80 was used to define functionally significant stenosis. 10,13

Coronary angiography and percutaneous intervention Coronary angiography and PCI with stent implantation were performed as clinically indicated. 14 Minimal lumen diameter, %DS, reference diameter, and lesion length were measured by quantitative coronary angiography (QCA) on end-diastolic images performed by 2 independent operators.

Data collection and follow-up This study complied with the Declaration of Helsinki and was approved by the local ethical committee. All patients provided written informed consent. No extramural funding was used to support this work. Clinical follow-up was performed using

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hospital records and telephone interviews, and it was conducted up to 4 years. All events were classified and adjudicated by a physician not aware of the chosen strategy. Primary end point was major adverse cardiac and cerebrovascular events (MACCEs) defined as the composite end point of all-cause death, nonfatal MI, target vessel failure (TVF), and cerebrovascular accidents (CVA). Target vessel failure was defined as repeated PCI of the target graft, redo-CABG involving the target graft territory, and target graft found occluded at the occasion of a repeated angiography. Secondary end points were as follows: all-cause death, nonfatal MI, TVF, CVA, inhospital outcome (periprocedural MI [PMI], acute kidney injury [AKIN], and major bleedings), and freedom from chest pain at the follow-up. Periprocedural MI and AKIN were defined as previously described. 15-17 Costs of the equipment used during the index procedure (ie, balloons, stents, etc) were also evaluated.

Statistical analysis All analyses were performed with SPSS version 16 (SPSS Inc, Chicago, IL). Continuous variables are expressed as mean ± SD. Categorical variables are reported as frequencies and percentages. Normal distribution was assessed by the KolmogorovSmirnov test. The Student t test was used to compare continuous variables. Comparisons between categorical variables were evaluated using the 2-tailed Fisher exact test or Pearson χ 2 test, as appropriate. A propensity score was built with a nonparsimonious method to account for potential differences in treatment allocation and then entered into a logistic regression model. In particular, all variables listed in Tables I and II were incorporated into the model, and the score was then used in proportional hazards analyses as a covariate. Clinical end points were evaluated by Kaplan-Meier method and Cox proportional hazard analysis. A probability value of b.05 was considered statistically significant. The authors are solely responsible for the design and conduct of this study, all study analyses, the drafting and editing of the manuscript, and its final contents.

Results Clinical characteristics of the patients A total of 223 patients were included: 65 in the FFRguided group and 158 in the angio-guided group. No significant differences were found between the 2 groups in terms of clinical and demographic characteristics (Table I). In patients with unstable angina, all PCI procedures were performed within 48 hours from symptoms onset, similarly in the FFR-guided and angioguided groups (27.5 ± 3.5 hours vs 28.1 ± 3.9 hours [P = .65], respectively). Angiographic and procedural characteristics Angiographic characteristics are reported in Table II. No differences were found between the 2 groups in terms of total bypass grafts and number of occluded grafts (at baseline). In the FFR-guided group, the index stenosis was more frequently located on arterial grafts. Angiographic severity of the index stenosis was higher in the angio-guided group both by visual estimation and QCA. In

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Figure 1

Schematic representation of FFR measurement in stenosis of bypass grafts. After the equalization at the tip of the guiding catheter (1), pressure wire was advanced 2 to 3 mm beyond the anastomosis in case the native vessel upstream the anastomosis was not completely occluded (A). If the native vessel upstream to the anastomosis was completely occluded, the pressure wire was advanced and positioned at least 10 mm beyond the stenosis (B). In this case, in fact, the bypass graft is the only donor vessel, and FFR assessment of bypass graft stenosis is similar to the native circulation. The green arrow shows the induction of maximal hyperemia; the blue arrow shows the position of the sensor of the pressure wire.

the FFR-guided group, overall FFR value was 0.84 ± 0.13. An FFR value ≤0.80 was found in 23 patients. Procedural characteristics are reported in Table III. In the FFR-guided group, 23 (35%) patients underwent PCI (FFR 0.68 ± 0.09), whereas 42 (65%) patients (FFR 0.92 ± 0.05, P b .01 vs treated patients) were deferred to optimal medical therapy. In the angio-guided group, 90 (57%) patients (%DS at QCA: 56.8 ± 13.7) underwent PCI, whereas 68 (43%) patients (%DS at QCA 41.7 ± 9, P b .01 vs treated patients) were deferred to optimal medical therapy. In the FFR-guided group, PCI was more frequently performed on arterial grafts as compared with the angio-guided group. Percutaneous coronary

intervention–related myocardial territory was also different between the 2 groups, with higher rate of PCI performed on graft perfusing the left anterior descending artery (LAD) territory in the FFR-guided group as compared with the angio-guided group. The average number of stents used per patient was significantly lower in the FFR-guided group as compared with angio-guided group, with no significant differences in terms of the proportion of DES implanted and stent size. Inhospital outcome was comparable between the 2 groups, with the exception of higher rate of PMI in the angio-guided group (overall PMI 1 [1%] in the FFR-guided group vs 18 [11%] in the angio-guided group, P b .01) (Table III), mostly

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Table I. Clinical characteristics

Age (y) Male, n (%) BMI (kg/m2) EF (%) SBP (mm Hg) DBP (mm Hg) Smoker, n (%) Hypertension, n (%) Hyperlipidemia, n (%) Diabetes, n (%) Previous MI, n (%) PVD, n (%) CVD, n (%) Previous PCI, n (%) Redo-CABG, n (%) CABG to angio Time (mo) Clinical presentation, n (%) Stable angina Unstable angina

Table II. Angiographic characteristics

FFR guided (n = 65)

Angio guided (n = 158)

69 ± 9.3 50 (77) 27 ± 4 63 ± 16 144 ± 30 67 ± 13 30 (46) 37 (57) 43 (66) 15 (21) 23 (35) 12 (18) 6 (9) 30 (46) 12 (18) 118 ± 78

71 ± 8.9 121 (77) 27 ± 4 63 ± 17 149 ± 33 67 ± 10 65 (41) 90 (57) 97 (61) 46 (29) 56 (35) 31 (20) 19 (12) 64 (40) 19 (12) 126 ± 82

53 (81) 12 (18)

117 (74) 41 (26)

P .15 1.00 .24 .84 .40 .87 .55 1.00 .54 .41 1.00 1.00 .64 .46 .21 .19 .30

BMI, Body mass index; EF, ejection fraction; SBP, systolic blood pressure; DBP, diastolic blood pressure; PVD, peripheral vascular disease; CVD, cerebrovascular disease.

occurring in saphenous vein grafts (SVGs; PMI in SVGs 1 [2%] vs 16 [12%], respectively; P = .02). Acute kidney injury occurred only in 5 patients of the angio-guided group, and no differences were observed in clinical, angiographic, and procedural characteristics between patients with and without AKIN (data not shown).

Clinical outcomes Clinical follow-up was obtained in 215 (96%) of 223 patients at a median of 3.8 years (1.6-4.0 years). KaplanMeier survival curves and Cox proportional hazard analysis are shown in Table IV and in Figures 2 and 3. Fractional flow reserve–guided PCI was associated with a significantly lower MACCE rate at 4-year follow-up. This association remained significant after propensity score adjustment. Fractional flow reserve–guided PCI was also associated with a strong reduction in secondary end points like combined death or nonfatal MI, nonfatal MI, and TVF, with no significant differences in death and CVA. At the follow-up, 34 (68%) patients in the FFRguided group were free from chest pain as compared with 55 (52%) patients (risk ratio 1.31 [1.01-1.71], P = .08 vs FFR-guided group) in the angio-guided group. Of note, among the deferred patients, freedom from chest pain was significantly more frequent in the FFR-guided group as compared with the angio-guided group (24 [77%] vs 20 [50%], risk ratio 1.55 [1.08-2.23], P = .03). For patients with arterial graft stenosis, the rate of MACCE and TVF was lower, and survival free from MACCE and TVF was higher in the FFR-guided group. For patients with SVG stenosis, no significant differences were observed for both MACCE and TVF between the 2 groups.

Bypass grafts, n (%) 1 2 ≥3 Occluded grafts, n (%) 0 1 2 ≥3 Index graft stenosis Location on arterial graft, n (%) Visual DS (%) QCA DS (%) RD (mm) MLD (mm) FFR Arterial graft type LIMA RIMA Free RIMA Radial Stenosis location on arterial graft Proximal anastomosis Body Distal anastomosis Stenosis location on vein graft Proximal anastomosis Body Distal anastomosis Previous MI territory supplied by the index graft LAD LCX RCA Native artery perfused by index stenotic graft, n (%) LAD LCX RCA

FFR guided

Angio guided

7 (11) 16 (25) 42 (65)

7 (4) 38 (24) 113 (71)

38 21 3 3

94 (59) 48 (30) 12 (8) 4 (2)

P .45

.67 (58) (32) (5) (5)

27 (41) 49 ± 17 45 ± 17 2.8 ± 0.8 1.6 ± 0.7 0.84 ± 0.13

26 (16) 58 ± 13 52 ± 14 3.0 ± 0.8 1.4 ± 0.5 –

17 (63) 6 (22) 1 (3) 3 (11)

15 (58) 6 (23) 5 (19) 0 (0)

3 (11) 8 (30) 16 (59)

2 (7) 5 (19) 19 (73)

4 (10) 26 (68) 8 (21)

19 (14) 82 (62) 31 (23)

b.01 b.01 b.01 .09 .23 .12

.57

.74

.88 2 (3) 1 (1) 3 (4)

7 (4) 2 (1) 12 (7) .26

24 (37) 20 (31) 21 (32)

41 (26) 58 (37) 59 (37)

RD, Reference diameter; MLD, minimal lumen diameter; LCX, left circumflex; RCA, right coronary artery.

Discussion Our findings demonstrate that FFR-guided PCI of intermediate stenosis in bypass grafts is safe and results in a better clinical outcome as compared with an angio-guided PCI. This clinical benefit was more pronounced in arterial grafts, whereas it was limited to a reduced incidence of PMI in SVGs. In addition, a significant overall reduction in procedural costs has also been observed.

Percutaneous coronary intervention in CABGs Percutaneous coronary intervention of bypass grafts is associated with higher rates of acute and long-term adverse events as compared with PCI of native vessels, 3 mainly because of the higher rate of PMI and repeat

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Table III. Procedural characteristics

PCI performed, n (%) PCI on arterial grafts, n (%) PCI-related myocardial territory, n (%) LAD LCx RCA Embolic protection device, n (%) Stent per patient, n (%) DES, n (%) Stent diameter (mm) Stent length (mm) PCI deferred, n (%) Myocardial deferred territory, n (%) LAD LCx RCA Procedural time (min) X-ray time (min) Contrast medium (mL) Cost of procedure (€) Inhospital outcome PMI, n (%) TIMI major bleedings, n (%) AKIN, n (%)

FFR guided

Angio guided

P

23 (35) 16 (70)

90 (57) 12 (13)

b.01 b.01 b.01

14 (61) 5 (22) 4 (17) 0 (0) 0.3 ± 0.5 9 (14) 3.0 ± 0.3 16.9 ± 5.2 42 (65)

19 (21) 32 (36) 39 (43) 3 (3) 0.7 ± 0.8 21 (13) 3.5 ± 0.6 21.1 ± 12.2 68 (43)

10 (24) 16 (38) 16 (38) 68 ± 26 19 ± 14 277 ± 110 2240 ± 652

22 (32) 27 (40) 19 (28) 62 ± 33 17 ± 11 294 ± 112 2416 ± 522

.23 .37 .44 .03

1 (1) 1 (1) 0 (0)

18 (11) 3 (1) 5 (3)

b.01 1.00 .32

.26 b.01 .83 .06 .12 b.01 .47

LCX, Left circumflex; RCA, right coronary artery.

Table IV. Clinical events at follow-up Overall Death, n (%) Death or nonfatal MI, n (%) Nonfatal MI, n (%) CVA, n (%) TVR, n (%) TVF, n (%) MACCE, n (%) Arterial grafts TVF, n (%) MACCE, n (%) Venous grafts TVF, n (%) MACCE, n (%)

FFR guided

Angio guided

Unadjusted HR (95% CI)

P

10 (15) 12 (18)

29 (19) 50 (33)

0.81 (0.39-1.66) 0.52 (0.28-0.97)

.566 .041

– –

– –

3 (5) 0 (0) 9 (14) 10 (15) 18 (28)

24 5 33 41 77

0.28 0.03 0.60 0.52 0.46

(0.08-0.93) (0.0-87.76) (0.29-1.25) (0.26-1.03) (0.28-0.77)

.037 .384 .17 .061 .003

– –

– –

– 0.47 (0.30-0.75)

– .001

(16) (3) (22) (27) (51)

P

PS-adjusted HR (95% CI)

3 (11) 4 (15)

7 (30) 13 (56)

0.11 (0.01-0.90) 0.22 (0.07-0.66)

.04 .008

– –

– –

7 (18) 14 (37)

34 (27) 64 (50)

0.68 (0.30-1.53) 0.67 (0.37-1.19)

.35 .17

– –

– –

HR, Hazard ratio; PS, Propensity score.

revascularizations. Stenoses in bypass grafts, in fact, are often represented by degenerated and thrombotic plaques, with a higher risk of atherothrombotic embolization into the downstream native coronary circulation. Hence, several strategies have been adopted to reduce distal embolization, including both proximal and distal embolic protection devices able to significantly reduce the rate of PMI. 18 In our patients treated with angioguided revascularization, PCI was more often performed in venous grafts as compared with the FFR-guided group, and only in few cases (b10%) distal protection devices

were used. Similarly to previous reports, 19 this reflected the local practice at the time of the registry and might have been responsible for the higher PMI rate in the angio-guided group. However, this does not undermine the importance of our findings because it should be rather considered as a failure of the treatment strategy adopted: (a) use of protection device is not always feasible and it does not eliminate the risk of distal embolization, and (b) FFR guidance of revascularization by reducing the number of PCI performed in venous grafts prevented the possibility of PMIs.

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Figure 2

Survival curves in the overall population. Top left, Kaplan-Meier curve for survival (log rank 2.65, P = .56). Top right, Kaplan-Meier curve for survival free from nonfatal MI (log rank 5.3, P = .02). Bottom left, Kaplan-Meier curve for TVF-free survival (log rank 3.67, P = .05). Bottom right: Kaplan-Meier curve for MACCE-free survival (log rank 9.42, P = .002).

Fractional flow reserve–guided strategy of intermediate stenosis in bypass grafts In the FFR-guided group, stenoses were more frequently located and PCI was more often performed in arterial bypass graft. This is not surprising considering that arterial grafts are often supplying larger myocardial territories as compared with venous bypass grafts. Importantly, the rate of PCI performed in the FFR-guided group was reduced by nearly one-third as compared with the angio-guided group. If we consider that PCI in the

angio-guided group was performed more frequently in venous grafts, it allows to speculate that a significant number of these revascularizations might have been avoided, had the indication to PCI been taken on the basis of the functional significance of the stenosis. In addition, our findings do not support the common attitude of lowering the threshold to revascularization of even “angiographically nonsignificant stenosis,” especially in venous bypass grafts, in the belief that a faster atherosclerotic progression might occur as compared with

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Figure 3

Survival curves for patients with index stenosis on arterial grafts and SVGs. Top left, Kaplan-Meier curve for MACCE-free survival in arterial grafts (log rank 8.71, P = .003). Bottom left, Kaplan-Meier curve for TVF-free survival in arterial grafts (log rank 5.01, P = .02). Top right, Kaplan-Meier curve for MACCE-free survival in SVG (log rank 1.98, P = .11). Bottom right: Kaplan-Meier curve for TVF-free survival in SVG (log rank 0.90, P = .34).

stenosis located in native vessels. 20-22 In fact we observed the following: (1) no significant excess hazard in patients presenting with SVG stenosis in terms of TVF in the FFRguided group (despite the higher rate of PCI deferral) as compared with the angio-guided group and (2) patients deferred on the basis of FFR measurements were even more frequently free from chest pain at the follow-up as compared with patients deferred solely on the basis of angiography. At this regard, we can hypothesize that a number of functionally significant stenoses in the angioguided group went undetected and therefore left

untreated, underscoring the limited diagnostic accuracy of the angiographic evaluation also in bypass grafts.

Clinical implications Fractional flow reserve–guided PCI has been associated with favorable outcome in different clinical and angiographic settings, 6-8,23-25 but never in the presence of intermediate stenosis of bypass grafts. Our findings, extending these previous evidences, present important clinical implications considering that assessment of residual myocardial ischemia in stable patients with

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previous CABG is usually difficult. Fractional flow reserve with its unequal spatial resolution allows to overcome the common limitations of noninvasive functional tests in multivessel disease. 5,10,13,24,26-29 However, a number of technical aspects when performing FFR assessment in bypass grafts should be taken into account (Figure 1). Notwithstanding all the technical pitfalls, we showed that deferring PCI of intermediate stenosis of bypass graft on the basis of a negative FFR value is safe, and it results in a better clinical outcome as compared with an angio-guided strategy. This beneficial effect of the FFR-guided strategy was particularly evident in arterial grafts, whereas it was mainly limited to a robust reduction in PMI in the SVGs.

Study limitations This study might be affected by the limitations inherent to all retrospective registries: that is, events underreporting and bias related to the operator's decision as to the revascularization strategy to be adopted. Percutaneous coronary intervention of a stenosis, deemed angiographically mild, could have been dictated by the clinical syndrome (ie, unstable angina) or by the unstable angiographic aspect of the lesion/vessel. This might have occurred in the angio-guided group. In fact, PCI in the FFR-guided group was strictly dictated by the functional significance of the stenosis: that is, no PCI was performed in patients with nonsignificant FFR measurement. In addition, the worse clinical outcome in the angio-guided group might have been also partly the consequence of a greater atherosclerosis burden, as suggested by higher angiographic stenosis severity. These limitations remain, although we tried to minimize their impact by performing a propensity score adjusted Cox regression analysis to assess the clinical outcome. The sample size is limited, reflecting the low adoption of FFR assessment in bypass grafts. The latter is related to the paucity of the available data. Only patients with stable and unstable angina were included; thereby, our results cannot be extended to patients with non–ST- and STelevation MI. Noninvasive functional testing was available only in a few patients. We are unable to discriminate whether they have been used for PCI guidance. There was no difference in CABG to angio time between the 2 groups, yet we cannot exclude that the age of bypass grafts might have represented an additional confounder.

Conclusions An FFR-guided revascularization strategy in CABGs is safe and results in better clinical outcomes as compared with an angio-guided strategy in arterial grafts. In SVGs, the FFR-guided strategy was associated with a significant reduction in PCI rate and procedural-related MI, with no excess risk up to 4-year clinical follow-up. This clinical benefit is achieved with a significant overall reduction in procedural costs.

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Disclosures None.

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