Percutaneous Coronary Interventions of Bifurcation Lesions · We therefore investigated how the use of dif-ferent modalities (visual estimation, ‘straight vessel’ QCA, and bifurcation

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Percutaneous coronary interventions of bifurcation lesions

Grundeken, M.J.D.

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Citation for published version (APA):Grundeken, M. J. D. (2016). Percutaneous coronary interventions of bifurcation lesions.

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Chapter 14Visual estimation versus different quantitative coronary angiography methods to assess lesion severity in bifurcation lesions

Maik J. GrundekenCarlos ColletYuki IshibashiPhilippe GénéreuxTakashi MuramatsuLaura LaSalleAaron V. KaplanMarie-angèle MorelJan G.P. TijssenYoshinobu OnumaMartin B. LeonJoanna J. WykrzykowskaRobbert J. de WinterPatrick W.J.C. Serruys

Submitted

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ABSTRACT

Objectives

Investigating how the use of different modalities (visual estimation, ‘straight vessel’ quantitative coronary angiography [QCA], and bifurcation QCA) affected the classifica-tion of bifurcation lesion severity and extent of disease.

Background

QCA has been introduced to overcome the acknowledged limitations of visual esti-mation. Conventional QCA however, developed in ‘straight vessels’, has proved to be inaccurate in bifurcation lesions. Therefore, bifurcation QCA was developed. However, the impact of the different modalities in bifurcation lesion severity classification is yet unknown

Methods

From a randomized controlled trial investigating a novel dedicated bifurcation stent, pa-tients with baseline assessment of lesion severity by means of visual estimation, single vessel QCA, 2D bifurcation QCA and 3D bifurcation QCA were included. The primary end-point was to compare how the use of different modalities affected the classification of bifurcation lesion severity and extent of disease.

Results

Overall, we included 114 bifurcations lesions in which all 5 modalities were assessed. On visual estimation, 100% of lesions had side-branch diameter stenosis (DS%) >50%, whereas in 83% with single-vessel QCA, 16% with 2D bifurcation QCA and 15% with 3D bifurcation QCA a side branch DS% >50% was found (P<0.0001). With regard to the per-centage of “true” bifurcation lesions, there was a significant difference between visual estimate (100%), single-vessel QCA (75%) and bifurcation QCA (17% with 2D bifurcation software and 13% with 3D bifurcation software, p<0.0001).

Conclusions

Our study showed that bifurcation lesion complexity was significantly affected when more advanced bifurcation QCA software were used. “True” bifurcation lesion rate was 100% on visual estimation, but as low as 13% when analyzed with dedicated bifurcation QCA software.

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INTRODUCTION

Ever since the introduction of coronary angiography it has been recognized that visual estimation is inaccurate to quantify coronary stenosis severity 1, 2. This seems to be par-ticular true for the side branch stenosis in bifurcation lesions, where even experts in the field of bifurcations have difficulties to deal with the differences in reference vessel diameters between the three different segments of the bifurcation  3. Conventional QCA software, developed to objectively quantify lesion severity in ‘straight’ vessels, also have been shown to be inaccurate in bifurcation lesions due to the natural ‘step-down’ in diameter at each branching point (i.e. coronary bifurcation), overestimating the reference vessel diameter (and thus diameter stenosis) of the distal main branch and side branch 4-6. Dedicated bifurcation QCA software packages were developed and have proved, in a bifurcation phantom model, to be accurate and reproducible for the quantification of bifurcation stenosis severity 4.

However, until to date no studies have been performed to investigate the impact of the use of bifurcation QCA when compared to conventional ‘straight-vessel’ QCA or visual estimation in patients with coronary artery disease involving a bifurcation. This is of particular importance because side branch involvement (i.e. presence or absence of side branch stenosis) is not only a major inclusion criterion for clinical trials 7, it is also associated with a worse prognosis 8, and it is used by operators as treatment guidance with a tendency to treat with more complex (2-stent) treatment strategies when there is extensive disease in the side branch 9-11. We therefore investigated how the use of dif-ferent modalities (visual estimation, ‘straight vessel’ QCA, and bifurcation QCA) affected the classification of bifurcation lesion severity and extent of disease.

METHODS

Setting

For this study, coronary angiographies were used from a randomized controlled trial investigating a novel dedicated bifurcation stent 7. Angiographic inclusion criteria were based on visual estimation. The most important angiographic inclusion criteria were the presence of >50% stenosis in both the main branch and side branch in a native coronary artery with side branch diameters from ≥2.5mm to ≤3.5mm and main branch diameters from ≥2.5mm to ≤4.0mm 7. All baseline angiographies were collected and send to two independent core labs (The Cardiovascular Research Foundation [CRF, New York, US] and Cardialysis B.V. [Rotterdam, The Netherlands]) for further offline QCA analysis 5.

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Modalities to assess bifurcation lesion severity

Visual estimation of lesion severity were reported by the investigators in the electronic case report form (eCRF) using the Medina score. The Medina score indicates for each of the three bifurcation segments separately whether a ≥50% stenosis is present (as ‘1’) or absent (as ‘0’) in the following order: proximal main branch -distal main branch - side branch, resulting in scores ranging from Medina 0.0.0 to Medina 1.1.1 12.

Baseline QCA were performed by both core labs using different methodologies 5. CRF core lab applied a conventional single vessel QCA algorithm for their analyses (QAngio XA, version 7.2.34, Medis Medical Imaging Systems, Leiden, The Netherlands) 5. For each bifurcation, two separate analyses were performed: one for the main branch and one for the side branch (figure 1) 5. First, calibration was performed before each analyses. Then, for the main branch the ‘region of interest’ was determined manually from the proximal to the distal main branch  5. For the side branch, the region of interest was set in two different ways. In the first method, the region of interest was set from the proximal main branch to the side branch (see figure 1). In the alternative method, the region of interest

A BB C

D EFigure 1. Different modalities to assess bifurcation lesion severity. A: Coronary bifurcation lesion of the left anterior descending and diagonal branch. Panel A represents the visual estimation of lesion severity, with-out additional help from software. B: single-vessel QCA applied to a bifurcation lesion. The left panel rep-resents QCA of the (proximal and distal) main branch, whereas the right panel represents QCA of the side branch with the region of interest taken from the proximal main branch to the side branch. C: single-vessel QCA applied to a bifurcation lesion. The left panel again represents QCA of the main branch, similar to the left panel in B. The right panel represents QCA of the side branch with the region of interest taken from the side branch ostium to distally in the side branch. D: 2D bifurcation QCA in which the region of interest includes all three segments (proximal main branch, distal main branch and side branch) of the bifurcation. E: 3D bifurcation QCA in which a 3D image was reconstructed from two different angiographic views.

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for the side branch was set from the side branch ostium to distally in the side branch (see figure 1). Then, the QCA software automatically detected the vessel contours 13. The main branch reference vessel diameter (RVD), used to calculate diameter stenosis, was determined by the average between the proximal main branch and distal main branch reference diameter. For the side branch, the RVD was determined in two different ways. In the first methodology, the average between the proximal main branch diameter and the side branch diameter was chosen (in case the region of interest was set from the proximal main branch to the side branch). Alternatively, the diameter of a ‘healthy’ part distally in the side branch was taken as reference diameter (in case the region of interest was from the side branch ostium to distally in the side branch). Diameter stenoses were calculated as follows: (RVD – minimal lumen diameter [MLD]) / RVD) 5.

Cardialysis core lab used a bifurcation QCA software package for their analyses (Coronary Angiography Analysis System [CAAS], version 5.10, Pie Medical Imaging, Maastricht, the Netherlands)  5. For each bifurcation, only one analysis was performed in which the ‘region of interest’ included all three bifurcation segments: the proximal main branch, distal main branch and side branch. The software automatically detected the vessel contours and the percentage diameter stenosis was automatically calculated using a ninterpolated RVD at the MLD site of each of the three bifurcation segments separately  5. The analyses were performed both in a two-dimensional (2D) as in a three-dimensional (3D) fashion, as previously described  14. Two angiographic images separated by a viewing angle of ≥30° were selected for the 3D analysis 14. After contour detection of two angiographic images, a common image point (CIP) was defined to cor-rect for the distortion introduced by the isocenter offset. Subsequently, the centre line of the main branch and the side branch were reconstructed based on the adaptive 3D epipolar geometry algorithm. A 3D model of the bifurcated vessel assuming elliptical cross-section was constructed. In the central bifurcation area, defined as the polygon of confluence (POC), the cross sectional area was defined by using the “minimum energy” cross-section, i.e., the smoothest possible surface that spans the lumen at each centre line position. MLD was derived from the absolute minimal lumen area using the previ-ously described “equivalent diameters” methodology 14, 15.

Statistical analysis

For the current analysis, only those baseline angiograms were used in which all used modalities (i.e. visual estimation, single-vessel QCA [two different methodologies for the side branch], 2D bifurcation QCA and 3D bifurcation QCA) were available. Presence of a stenosis on QCA was defined as a percentage diameter stenosis of ≥50%. For the 2D and 3D bifurcation QCA analysis, Medina scores were derived using the calculated percentage diameter stenosis of each bifurcation segment, in a similar fashion as the Medina scores assessed by visual estimate by the investigators. This was not possible for

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the single-vessel QCA because there was only one value calculated for the main branch (i.e. not for the proximal and distal main branch separately).

Furthermore, bifurcation lesions were divided according to the following categories:• ‘true’ bifurcation lesions, with ≥50% stenosis in both the main branch and the side

branch;• ‘non-true’ bifurcation lesions, with ≥50% stenosis in the main branch, but <50%

stenosis in the side branch;• ‘side branch lesion only’, with ≥50% stenosis in the side branch, but <50% stenosis in

the main branch;• ‘no lesion’, defined as <50% stenosis in the main branch and side branch.Finally, bifurcation lesions were dichotomized according to ‘side branch involvement’ (i.e. all bifurcation lesions with ≥50% stenosis of side branch) or ‘no side branch involve-ment’ (i.e. all the remainder bifurcation lesions with <50% stenosis of the side branch).

Categorical variables were presented as frequencies and percentages, and compari-sons were made using chi-square. All statistical analysis were performed using the SPSS software package (version 19.0, IBM, Chicago, IL, USA).

RESULTS

There were in total 114 baseline angiographies in which all 5 modalities were available. Table 1 shows the extent of disease in the bifurcation lesions according to the different modalities. On visual estimate all lesions were scored as either Medina 0,1,1, 1,0,1 or 1,1,1.

With regard to the percentage of ‘true bifurcation lesions’ (i.e. bifurcations in which both main and side branch had ≥50% stenosis), there was a significant difference between visual estimate (100%), single-vessel QCA (75% or 56%, depending on the methodology) and bifurcation QCA (17% with 2D bifurcation software and 13% with 3D bifurcation soft-ware, p<0.0001). Moreover, there was a significant difference in percentage of bifurcations without any stenosis >50%: 0% with visual estimation, 1% or 4% with single vessel QCA, 33% with 2D bifurcation QCA, and even 46% with 3D bifurcation QCA (table 1).

The percentage of bifurcation lesions with side branch involvement (i.e. the presence of >50% stenosis in the side branch) was 100% on visual estimate. However, this per-centage was significantly lower when single-vessel QCA was used, and further reduced when bifurcation QCA was used (only 26% [2D bifurcation QCA] and 25% [3D bifurcation QCA] of lesions had side branch involvement with bifurcation QCA) (table 1).

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Tabl

e 1.

Visu

al e

stim

ate

by in

vest

igat

ors

QCA

with

sin

gle-

vess

el s

oftw

are

(SB

RVD

bas

ed o

n pr

ox.

and

dist

. ref

.)

QCA

with

sin

gle-

vess

el s

oftw

are

(SB

RVD

bas

ed

on d

ista

l ref

.)

QCA

w

ith 2

D

bifu

rcat

ion

soft

war

e

QCA

w

ith 3

D

bifu

rcat

ion

soft

war

eP-

valu

e

(n=1

13)

(n=1

13)

(n=1

13)

(n=1

13)

(n=1

13)

Med

ina

scor

e<0

.000

1

1,1,

177

(68%

)N

AN

A6

(5%

)0

(-)

1,0,

112

(11%

)N

AN

A5

(4%

)7

(6%

)

0,1,

124

(21%

)N

AN

A8

(7%

)8

(7%

)

1,1,

00

(-)N

AN

A5

(4%

)4

(4%

)

1,0,

00

(-)N

AN

A24

(21%

)14

(12%

)

0,1,

00

(-)N

AN

A17

(15%

)15

(13%

)

0,0,

10

(-)N

AN

A11

(10%

)14

(12%

)

0,0,

00

(-)N

AN

A37

(33%

)51

(45%

)

Bifu

rcat

ion

type

<0.0

001

‘true

’ (>5

0% s

teno

sis

in b

oth

MB

and

SB)

113

(100

%)

85 (7

5%)

63 (5

6%)

19 (1

7%)

15 (1

3%)

‘non

-tru

e’ (M

B st

enos

is >

50%

, SB

sten

osis

<50

%)

0 (-)

18 (1

6%)

40 (3

5%)

46 (4

1%)

33 (2

9%)

‘SB

only

’ (M

B st

enos

is <

50%

, SB

sten

osis

>50

%)

0 (-)

9 (8

%)

5 (4

%)

11 (1

0%)

14 (1

2%)

‘no

lesi

on’ (

<50%

ste

nosi

s in

bot

h M

B an

d SB

)0

(-)1

(1%

)5

(4%

)37

(33%

)51

(45%

)

SB in

volv

emen

t<0

.000

1

SB in

volv

emen

t11

3 (1

00%

)94

(83%

)68

(60%

)30

(27%

)29

(26%

)

No

SB in

volv

emen

t0

(-)16

(17%

)32

(40%

)83

(73%

)84

(74%

)

Dia

met

er st

enos

is si

de b

ranc

h (%

)73

.5±1

3.5

60.2

±11.

053

.2±1

2.7

38.5

±14.

940

.0±1

5.6

<0.0

001

MB:

mai

n br

anch

. NA

: not

ava

ilabl

e. R

VD: r

efer

ence

ves

sel d

iam

eter

. SB:

sid

e br

anch

.

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DISCUSSION

The main findings of our study are: (1) the rate of ‘true bifurcation lesions’(i.e. bifurcation lesions with ≥50% stenosis in both main and side branch), the major inclusion criterion of the trial, was 100% on visual estimation, and 13% when dedicated bifurcation QCA software was used; (2) When dedicated bifurcation software was used, 33% (2D bifurca-tion QCA) or even 45% (3D bifurcation QCA) of the bifurcation lesions did not have any stenosis ≥50% in any of the bifurcation segments.

This is the first study with a head-to-head comparison between visual estimation, single-vessel QCA and bifurcation QCA to assess coronary bifurcation lesions. Within this study no ‘true value’ could be established. However, previous studies on precision phantom bifurcation models, made from Plexiglas with a tolerance <10µm, have shown that visual estimates of diameter stenoses by experts in the field of bifurcations were inaccurate and highly variable 3. This seemed to be particularly true for the side branch ostium. An explanation for this might be that the experienced interventional cardiolo-gists intuitively interpreted the side branch stenosis by using the reference diameter of the proximal main branch. However, due to the fractal geometry of the coronary tree with its natural step-down in diameter at each branching point, the reference diameter of the side branch is per definition smaller than the reference diameter of the proximal main branch, hence overestimating diameter stenosis of the side branch 3, 6, 16, 17.

Another study on the same precision phantom bifurcation models, comparing single-vessel QCA with 2D bifurcation QCA, have shown that the accuracy and precision of single-vessel QCA was very poor 4. Single-vessel QCA systematically overestimated the RVD (and thus percent diameter stenosis) of the side branch 4. The same study showed that dedicated bifurcation QCA, either CAAS software (Coronary Angiography Analysis System, Pie Medical Imaging, Maastricht, the Netherlands) or QAngio XA software (Me-dis Medical Imaging Systems, Leiden, The Netherlands), were both accurate and precise and therefore suitable for quantification of stenosis in bifurcation lesions 4.

The data from the current study, together with the previous work on the precision phantom models, suggests that the human eye is unreliable to quantify bifurcation lesions, overestimating side branch stenosis. On visual estimate, all bifurcation lesions included had a ≥50% side branch stenosis, while with the more sophisticated 2D bifur-cation QCA methodology, 27% of bifurcations had side branch involvement. Our study also showed that single-vessel QCA, especially when the side branch reference diameter was derived based on the proximal main branch and side branch reference diameters, does not overcome the limitations of the human eye. These findings might have impor-tant implications for the following reasons:

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1. First, when inclusion criteria of trials are based on visual estimation of side branch stenosis, this will lead to over exaggeration of side branch lesion severity and over-treatment of insignificant stenosis. This is important because more complex lesion treatment strategies, including the use of two stents with or without the use of dedicated bifurcation stents, are not expected to result in superior clinical outcomes compared with provisional single stent strategy when used in less complex bifurca-tion lesions without significant side branch stenosis. The use of single-vessel QCA will not overcome this problem because it will still lead to overestimation of side branch stenosis as has been shown in the phantom study 4. Major bifurcation randomized trials such as BBC ONE, CACTUS, the Thueringer bifurcation study and the Tryton IDE trial in which two-stent techniques (with or without a bifurcation stent) were compared with the provisional single-stent approach have used single-vessel QCA analysis for their baseline analysis 7, 18-20. Mandatory preprocedural lesion assessment with bifurcation QCA might have resulted in inclusion of truly significant side branch stenosis which could have showed the clinical benefit of the two-stent approach. The European Bifurcation Club (EBC) recommends the use of bifurcation QCA 10, 21.

2. Second, in trials with a repeat angiography, overestimation of side branch stenosis during repeat angiography might result in increased rates of clinically-indicated target lesion revascularization. As defined by the Academic Research Consortium, revascularizations are considered clinically indicated if the lesion is >70% stenosed, or >50% stenosis with additional evidence of ischemia 22. Use of single-vessel QCA during repeat angiographic follow-up might therefore influence event adjudication.

The additional advantage of 3D bifurcation software over 2D bifurcation software in terms of assessing stenosis severity are yet to be determined. A validation study using the above mentioned precision phantom bifurcation models have showed that 3D bi-furcation software being accurate, precise and reproducible 23. However, a head-to-head study comparing 2D with 3D bifurcation software in this phantom model is lacking. The potential benefits of 3D over 2D bifurcation software is difficult to demonstrate in this model for the following reasons: 1) in the phantom model, stenoses are shaped concentric, while advantage of 3D are expected to be more pronounced when steno-ses are elliptically shaped; 2) the phantom model is constructed in a horizontal plane, while in-vivo the coronary arteries are curved around the heart, which would result in an expected benefit of 3D QCA over 2D QCA in terms of less foreshortening of the curved arteries; 3) in the bifurcation model the most optimal view, perpendicular to the bifurcation, is easily to obtain, while it has been shown in-vivo that the optimal viewing angle for bifurcation lesions cannot be obtained in almost half of the cases, hampering accurate 2D bifurcation QCA assessment while this optimal view can be reconstructed with 3D bifurcation QCA software 24.

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A previous study by Sarno et al comparing single vessel versus 2D bifurcation QCA against invasive fractional flow reserve (FFR) in bifurcation lesions has shown a higher cor-relation between anatomic severity (i.e., diameter stenosis) and functional significance (FFR < 0.80) with dedicated bifurcation software. These finding seem to be particularly more pronounced when assessing side-branch stenosis, which can be overestimated when using single vessel QCA 25. In addition, Yong et al has shown that 3D QCA luminal measurements had a better correlation with invasive FFR measurements than 2D QCA derived parameters 26. This suggests a more accurate assessment of luminal dimensions with 3D than with 2D QCA, although this needs further research including a head-to-head comparison in an appropriate phantom model. In addition to luminal dimensions measurements, the true advantage of 3D bifurcation QCA seems to be the superiority of 3D QCA modalities to assess (lesion) length, overcoming the disadvantage of length measurements in 2D caused by foreshortening  27. Another potential advantage of 3D over 2D bifurcation software is its ability to perform analysis in the (reconstructed) most optimal viewing angle, even when it is not possible to obtain this viewing angle during angiography 24.

Limitations

A true ‘gold standard’ was lacking in this study. However, previous studies have shown the superiority of bifurcation QCA over visual estimate and over single-vessel QCA in as-sessing lesion severity in bifurcation lesions. The potential benefit of 3D bifurcation QCA compared to 2D bifurcation QCA software in terms of assessment of luminal dimensions is still uncertain. Nevertheless, we showed that the assessment of bifurcation lesion complexity (i.e. involvement with >50% stenosis of the different bifurcation segments) is strongly affected when more advanced bifurcation QCA techniques were used. 3D QCA analysis depend on the acquisition of two obtained views, more than 30 degrees apart. If only 1 view was available 3D QCA analyses could not be performed, which might have introduced a selection bias.

CONCLUSIONS

Our study showed that bifurcation lesion complexity was significantly affected when more advanced bifurcation QCA software were used. ‘True bifurcation lesion’ (i.e. bifur-cation lesions with ≥50% stenosis in both main and side branch) rate was 100% on visual estimation, but as low as 13% when dedicated bifurcation QCA software was used. Side branch involvement (defined as >50% stenosis of the side branch) was found in 100% of the cases on visual estimation and in only 27% of the cases when 2D bifurcation QCA software was used. Furthermore, when dedicated bifurcation software was used, 33%

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(2D bifurcation QCA) or even 45% (3D bifurcation QCA) of the bifurcation lesions did not have any stenosis ≥50% in any of the bifurcation segments.

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