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Contents
Section 4. Coronary Bifurcation Interventions: Bench Testing and Dedicated
Bifurcation Stents
9. Bench Testing of Coronary Bifurcation Stenting Techniques: How Is It Done?
Does It Help Technical Decision Making? 193
Yoshinobu Murasato
10. Current Status and Future of Dedicated Bifurcation Stent Systems 211
Azeem Latib, Giuseppe M. Sangiorgi, and Antonio Colombo
Index .... 251
Contributors
Remo Albiero Cath Lab, Clinica San Rocco di Franciacorta, Ome (Brescia), Italy
Emiliano Boldi Cath Lab, Clinica San Rocco di Franciacorta, Ome (Brescia), Italy
Alaide Chieffo Interventional Cardiology Unit, San Raffaele Scientific Institute, and
Interventional Cardiology Unit, EMO-GVM Centro Cuore Columbus, Milan, Italy
Antonio Colombo Interventional Cardiology Unit, San Raffaele Scientific Institute, and
Interventional Cardiology Unit, EMO-GVM Centro Cuore Columbus, Milan, Italy
Marco Costa Harrington-McLaughlin Heart and Vascular Institute, University Hospitals,
Case Western Reserve University, Cleveland, Ohio, U.S.A.
Ricardo A. Costa Instituto Dante Pazzanese de Cardiologia & Cardiovascular Research
Center, S˜ao Paulo, Brazil
Luca Favero Department of Cardiology, Mirano Hospital, Mirano, Italy
Ted Feldman Cardiac Catheterization Laboratory, Cardiology Division, Evanston Hospital,
Evanston, Illinois, U.S.A.
Young-Hak Kim University of Ulsan College of Medicine, Asan Medical Center, Seoul,
South Korea
Bon-Kwon Koo Seoul National University Hospital, Seoul, South Korea
Hiroyuki Kyono Harrington-McLaughlin Heart and Vascular Institute, University
Hospitals, Case Western Reserve University, Cleveland, Ohio, U.S.A.
Azeem Latib Interventional Cardiology Unit, San Raffaele Scientific Institute, and
Interventional Cardiology Unit, EMO-GVM Centro Cuore Columbus, Milan, Italy
Michael J. Lim Saint Louis University, St. Louis, Missouri, U.S.A.
Issam D. Moussa Cardiac Catheterization Laboratory, New York Presbyterian
Hospital–Weill Medical College of Cornell University, New York, New York, U.S.A.
Yoshinobu Murasato Department of Cardiovascular Medicine, Heart Center, New
Yukuhashi Hospital, Yukuhashi, Japan
Andrea Pacchioni Department of Cardiology, Mirano Hospital, Mirano, Italy
Seung-Jung Park University of Ulsan College of Medicine, Asan Medical Center, Seoul,
South Korea
Bernhard Reimers Department of Cardiology, Mirano Hospital, Mirano, Italy
Mary E. Russell Ascent Translational Sciences, Inc., Carlisle, Massachusetts, U.S.A.
Giuseppe M. Sangiorgi Interventional Cardiology Unit, San Raffaele Scientific Institute, and
International Cardiology Unit, EMO-GVM Centro Cuore Columbus, Milan, Italy
1
Coronary Artery Bifurcation Interventions:
Bridging the Gap Between Research
and Practice
Issam D. Moussa
Cardiac Catheterization Laboratory, New York Presbyterian Hospital–Weill Medical College of Cornell University,
New York, New York, U.S.A.
Antonio Colombo
Interventional Cardiology Unit, San Raffaele Scientific Institute, and Interventional Cardiology Unit, EMO-GVM
Centro Cuore Columbus, Milan, Italy
INTRODUCTION
The mark of mediocrity in written material, whether it is literature, politics, or medicine, is
to rely heavily on precedents; so whatever is previously written about a certain topic gets
written again, propagating the same narratives over and over. Of course, this statement may
initially seem irrelevant to our topic, and to medical writing in general, because we are in
the era of “evidence-based medicine” and written medical literature need to be supported by
“evidence” and not merely reflect opinions and anecdotal experience. In reality, however, what
is occasionally presented as“evidence” does not qualify as anundisputable guidefor clinical or
technical decision making. There is no topic in interventional Cardiovascular Medicine where
this “disconnect” is more relevant than that of interventional treatment of coronary bifurcation
lesions.
The narrative that has been propagated in the literature is that provisional stenting (PS)
[stenting the main vessel (MV), with additional stenting of the side branch (SB) only in the
case of an unsatisfactory result] is better than elective double stenting (EDS) of both branches.
This narrative declares no exceptions to the rule and some perceive it as if it applies to “all”
patients with coronary bifurcation lesions. Proponents of this narrative base their conclusion on the results of several retrospective registries (1–7) and randomized controlled trials
(RCTs) (8–12).
The purpose of this chapter is to present a counter perspective to this dominant narrative;
namely, that neither approach should be the default strategy in all patients with bifurcation
lesions and that a decision as to which approach to use should be based on the patient’s
bifurcation anatomy. The majority of patients with bifurcation lesions will have anatomy that
can be safely treated with PS (see chap. 3); however, some patients have “at risk” bifurcation
anatomy where PS may be associated with high risk of side branch occlusion (see chap. 2). In
this chapter, we will
I. Critically appraise the “evidence-base” with regard to PCI of bifurcation lesions:
1. Review the evidence-base
2. Discuss the questions that clinicians should ask of the evidence-base to make an
informed decision:
A. Does the design of the RCTs appropriately address the questions that need to be
answered?
B. Are the current bifurcation classifications reliable vehicles to tell us what we need
to know about bifurcation anatomy?
C. How do we apply the results of the RCTs to patient-centered decision making?
II. Discuss the “cost” of inappropriate generalizabilty of the results of the RCTs to all patients
III. Summary
2
MOUSSA AND COLOMBO
CRITICAL APPRAISAL OF THE EVIDENCE-BASE
Review of the Evidence-Base
Retrospective Studies
Over the last decade, numerous retrospective studies compared PS with EDS using bare metal
stents (BMS) and drug-eluting stents (DES) (1–7). Although a detailed discussion on this topic
is beyond the scope of this chapter, all these studies were limited by the systematic bias,
favoring the use of PS in less complex bifurcations and EDS in more complex bifurcations. This
bias rendered the findings of these studies, namely, lower restenosis and thrombosis with PS,
misleading. Despite the obvious limitations of these studies, the debate concerning the role of
PS versus EDS has been errounously framed in a manner that ignores the importance of the
specific bifurcation anatomy in determining technique choice.
RCTs of PS Vs. EDS
The conclusions of the above retrospective studies shaped the underlying hypothesis of the
subsequent RCTs (8–12). The basic hypothesis was that one technique is better than the other
technique in all patients with bifurcation lesions. This chapter addresses the largest RCTs that
have been published in peer-reviewed journals, namely, the NORDIC, BBK, and CACATUS
trials (10–12). As shown in Tables 1 and 2, these trials demonstrated the following:
r
There is nostatistical differencebetween PS andEDS in mainvessel (MV) restenosis or target
vessel revascualrization (TVR).
Tab le 1 Clinical and Angiographic Outcomes in the RCTs of EDS Vs. PS
NORDIC BBK CACTUS
Elective Provisional Elective Provisional Elective Provisional
(
N
= 206) (N= 207) (N= 101) (N= 101) (N= 177) (N= 173)
Clinical outcome 6 mo 1 yr 6 mo
Death (%) 1.5 1 1 2 0.0 0.5
Nonfatal MI (%) 0.5 0.0 2 1 10.7 8.6
Q-wave 0.5 0.0 NA NA 1.7 1.1
Non–Q-wave 18 8 NA NA 9.0 7.4
TVR (%) 1.9 1.9 8.9 10.9 7.3 6.3
Any MACE (%) 3.4 2.9 11.9 12.9 15.8 15.0
Stent thrombosis (%) 0.0 0.5 2 1 1.7 1.1
Angiographic outcome 8mo 9mo 6mo
Restenosis (%)
MV 5.1 4.6 3.1 7.3 4.6 6.7
SB 11.5 19.2 10.4 5.2 13.2 14.7
Tab le 2 Procedural Details: RCTs of ES Vs. PS
NORDIC BBK CACTUS
Elective Provisional Elective Provisional Elective Provisional
(
N
= 206) (N= 207) (N= 101) (N= 101) (N= 177) (N= 173)
Cross over (%) 5 4 3 18.8 1 31
Final kissing (%) 74 32 100 100 92 90
Contrast volume (mL) 283 + 117 233 + 93 203 + 109 204 + 86 NA NA
Procedure time (min) 76 + 40 62 + 51 51 + 23 56 + 25 NA NA
Fluoroscopy time (min) 21 + 10 15 + 915+ 913+ 7NA NA
CORONARY ARTERY BIFURCATION INTERVENTIONS
r
There is no statistical difference between PS and EDS in SB restenosis or TVR (10) [although
in the NORDIC trial there was a trend towards higher SB restenosis in the PS arm (19% vs.
11%; p =0.06)].
r
There is no statistical difference between PS and EDS in stent thrombosis.
r
The NORDIC trial showed increased procedure time and contrast use with EDS compared
to PS (10), while other trials did not (11,12).
r
The NORDIC trial showed higher rate of postprocedure cardiac biomarker elevation in the
EDS arm but showed no difference in MI at follow-up (10).
These RCTs confirmedthat theconclusions drawnfrom theretrospectivestudies—namely,
that a one stent approach is associated with lower restenosis and thrombosis—are erroneous.
Nonetheless, one canfairly proposethat althoughboth approachesare equally safeand effective,
PS stenting should be the preferred startegy in patients with bifurcation lesions because it is
simpler than EDS and uses less resources. Indeed, these were the conclusions made by the
authors of the NORDIC study. So, are these conclusions consistent with the application of
evidence-based medicine? We propose that they are not!
Questions Clinicians Should Ask of the Evidence-Base to Make an Informed Decision?
The applicationof evidence-basedmedicine findingsto clinicalpractice does notimply theliteral
adaptation of the conclusionsof agiven study(s).Evidence-based medicine should be a dynamic
process of intelligent decision making that involves critical appraisal of the “evidence” before
adapting its results to treat patients. The disconnect between clinical research methodology
and patient-centered decision making is undeniable and may even be unavoidable given the
logistical difficulty and potential monetary cost involved if we attempt to tackle the complex
clinical/technical questions facing the practice of Interventional Cardiology. As caregivers we
should always aim to understand the reasons for this disconnect, how to narrow the gap in
future evidence collection, and above all how to make sound clinical/technical decisions in the
absence of absolute certainty. Inthat regard, the following are keyquestions that we need to ask
of the RCTs before using them as basis for decision making regarding the treatment of coronary
bifurcation lesions.
3
Does the Design of the RCTs Appropriately Address the Questions that Need to be Answered?
The answer is absolutely not. The hypothesis underpinning the design of the RCTs was determined in isolation from clinical reality. The most effective approach to rationalize this answeris
to compare the hypothesis underlying the relevant RCTs to the question(s) a physician would
ask before making a decision on how to treat a bifurcation lesion:
1. What is the hypothesis underlying the design of the relevant RCTs?
The hypothesisof these clinicaltrials states thatone technique shouldbe the preferred,
compared to other technique(s), approach in all patients with bifurcation lesions? So what
is wrong with this hypothesis? This hypothesis is disconnected from the clinical reality in
that no physician would use EDS in all patients with bifurcation lesions but typically select
this technique for more complex bifurcations. This hypothesis does not specify “which”
bifurcations to be evaluated with the assumption that all bifurcations should similarly
respond to various techniques, irrespective of individual variations in SB lesion severity and
bifurcation morphology. The study designbased on this hypothesis would allow, for example,
a patient with a bifurcation lesion 1,1,0 (no SB disease) to be a candidate for randomization.
This patient may end up with EDS, even though in clinical practice no rational physician
would elect to use EDS in the absence of SB disease. This is just a simple example that
illustrate the over simplistic study design underlying some of these clinical trials.
2. What are the question(s) a physician would ask before making a decision how to treat a
bifurcation lesion?
When a physician is planning to treat an individual patient with a bifurcation lesion,
he orshe would determine thevarious anatomic attributes ofthe bifurcation before deciding
which technique to use:
(a) How large is the SB (diameter, vessel length, and myocardial territory supplied)?
(b) Is the SB ostium diseased? If yes, what is the severity and length of the lesion?
4
Medina
MOUSSA AND COLOMBO
Duke
(modified)
Sanborn - - IIIIIVIIIV
Lefevre 2 -1434a4b
Safian IA IB IIA IIIA IIB IIIB IV
Movahed S 2L1m1sVT
Staico-Feres 3 2A 2B 2C 1A 1B 1C
Figure 1 Coronary bifurcation classifications.
DCFGABE
(c) Is there severe disease in the SB beyond the ostium?
(d) What is the angle of the SB takeoff? Is it difficult to wire/rewire?
(e) What is the severity and distribution of the MV lesion?
(f) What will happen to theSB after stenting (mild orsignificant compromise orocclusion)?
And what are the consequences of SB occlusion (depend on the territory supplied)?
The answer to these questions would determine whether an operator uses PS or EDS
(this topic will be extensively covered in the forthcoming chapters). The above discussion
clarifying the gap between the design of the RCTs and the process of patient-centered
decision making clearly illustrates that the available evidence-base is not sufficient to fill
the current knowledge gap. Clinical research can only answer the questions that we pose
to it. If we pose the wrong questions we cannot expect to get the right answers!
Are the Current Bifurcation Classifications Schemes Reliable Vehicles to Tell Us What We Need
to Know About Bifurcation Anatomy?
Unlike non-bifurcation lesions that can be fairly characterized by reference vessel diameter and
lesion length, coronary bifurcationshave complexanatomic attributes both in the MV and theSB
that donot lend itself to simpleclassifications (see chap. 2). There have beenmultiple bifurcation
classification schemes in an attempt to standardizereporting and guide PCI technique selection
(Fig. 1). The most recent and widely used classification is the Medina classification (Fig. 2) (13).
1,1,1 1,1,0 1,0,1 0,1,1 1,0,0 0,1,0
0,1
MV
(Distal)
,,
MV
(Proximal)
Figure 2 Medina classification. The Medina classification divides the bifurcation lesion into three segments, the
proximal MV, the distal MV, and the SB, and assign each segment a binary value (1, 0) according to the presence
or absence of obstruction (DS > 50%).
SB
Source
: Adapted from Ref. 13.
0,1
0,0,1
0,1
CORONARY ARTERY BIFURCATION INTERVENTIONS
Although the Medina classification is intuitive and much easier to remember, it has not added
any descriptive elements beyond the other classifications (i.e., it continue to ignore the importance of the size of the SB, the severity and the length of the SB lesion, the SB angle, and the
relationship between the SB ostial stenosisand theMV stenosis). A telling example of the limited
ability of the Medina classification to provide an accurate anatomic description of bifurcations
is found in Figure 3(A) and 3(B). It is clear from these figures that bifurcation lesions with similar Medina classification can significantly differ with regard to ostial SB lesion severity, ostial
SB lesion length, SB angle, and most importantly SB size and its corresponding myocardial
territory. These anatomic elements are critical to technique selection, procedural success, and
the risk of SB occlusion, yet it is not reflected in any of the above classification. A recent classification was proposed by Movahed (14) to account for these elements, but this classification is
difficult to remember and to use in everyday practice. The implications of this issue is that the
current bifurcation classifications schemes are not reliable indicators of the complexity of bifurcations included in the RCTs, and therefore it can be fairly stated that the degree of bifurcation
complexity in these trials remains a “black box”!
How Do We Apply the Results of the RCTs in the Context of Patient-Centered Decision Making?
The most effective approach toprovide guidance regarding the use of the results of the RCTs for
decision making in individual patients is to simulate the process of technical decision making
in patients with coronary bifurcation lesions. Patients in Figure 4(A) and 4(B) have ischemia
producing coronary bifurcation lesions that require PCI. How would an interventionalist make
a decision as towhich technique to use in each ofthese patients? Currently, physicians prescribe
to one of the two following distinct approaches:
5
1. One approach would advocate the literal application of the results of the RCTs choosing the
methodology that was used in these trials (i.e., choose one technique to treat all patients).
Hence, they would adapt universal PS for all patients with bifurcation lesions irrespective
of the specifics of the anatomy of each bifurcation. The assumption being made is that all
patients with bifurcation lesions were well represented in these trials, and therefore they
would have similar outcome to the patients enrolled in these trials!
2. The secondapproach wouldadvocate patient-centereddecision makingand thereforewould
not choose one technique to treat all patients with bifurcation lesions but rather match the
technique to the individual bifurcation anatomy guided by the available data as well as by
personal experience. The assumption being made is that the results of the RCTs cannot be
generalized to all patients encountered in clinical practice, because patients with “complex”
bifurcations were not well represented in these trials.
These twodivergent approaches illustratethe gap betweenthe methodology and findings
of clinicalresearch as wellas the dynamics of patient-centered decision making.Who is right? Is
there anyone wrong? An approach that would satisfy both perspectives is to determine which
patients are well represented in the RCTs and which patients are not. Surely, no one can argue
for the application of the results of the RCTs in patients who were not well represented in these
trials!
For the purpose of this discussion, we will address the largest RCTs published in peerreviewed journals (NORDIC, BBK, and CACTUS) (10–12). The BBC trial will not be discussed
because the angiographic and morphologic information are not yet available. As shown in
Table 3, patients included in these RCTs had
focal lesions of moderate severity in the SB ostium.
This means that patients withlong and/or severe stenosesin the ostial SB were largely excluded,
although these anatomic variables were not prespecifiedas exclusion criteria.
natural bias to exclude patients with “high-risk” bifurcation anatomy from randomization.
a
This may indicate
Furthermore, nodata were provided in thesetrials regarding other important anatomic features
such as
the myocardial territory supplied by the SB, the angle of the SB, and the presence or
absence of distal SB disease. Therefore, when one contemplates how to apply the evidencebased knowledge derived from these RCTs to an individual patient, one should first ask the
question whether the patient was well represented in these trials or not! For example, let us
use this process for decision making for patients in Figure 4(A) and 4(B). It is clear that the
patient in Figure 4(A) is representative of patients included in the above RCTs and therefore PS
6
MOUSSA AND COLOMBO
(a)
0,1,1
(b)
0,1,1
(A)
(a) (b)
1,0,1
1,0,1
(B)
Figure 3 Case examples illustrating the limitations of the Medina classification. (A) Coronary angiography in
two different patients with Medina class 0,1,1 bifurcation lesions: (a) LCX/OM1 bifurcation lesion and (b) LAD/2nd
diagonal bifurcation lesion. Note the difference in SB lesion length between the two patients. (B) Coronary
angiography in two different patients with Medina class 1,0,1 bifurcation lesions: (a) LAD/2nd diagonal bifurcation
lesion and (b) LCX/OM1 bifurcation lesion. Note the difference in SB size. It is clear from these examples that the
Medina classification is not a sufficient descriptor of bifurcation anatomy.
CORONARY ARTERY BIFURCATION INTERVENTIONS
would be a safe and effective approach. On the other hand, patients in Figure 4(B) are not well
represented in the RCTs, and PS may not be a safe and effective approach.
WHAT IS THE COST OF INAPPROPRIATE GENERALIZABILITY OF THE RCTs
TO ALL PATIENTS WITH BIFURCATION LESIONS?
The primary reason why PCI of bifurcation lesions has been a challenge is the risk of SB
occlusion (SBO)or compromiseafter treatingthe MV. Almost 25 years ago, Meierand colleagues
(15) demonstrated that coronary angioplasty in coronary stenoses that involve a diseased SB
results in SBO in 14% of patients. They also noted that CK-MB elevation (non–Q-wave MI in
today’s terminology) occurred in 30% of these patients. These results were obtained in patients
with small SBs because patients with large SBs were disqualified from undergoing PCI. These
results were corroborated by Arora et al. (16) who evaluated 167 patients (181 bifurcations
lesions) with SB occlusions during PCI of the MV. In this study, 14% of patients developed
postprocedure myocardialinfarction (MI) despite successfulSB reopening in 16% ofpatients. Of
course, one would be quick to note that antithrombotic therapy, PCI technology, and techniques
have progressed so much that results are now much better. However, despite the significant
aforementioned progress, SBO and/or compromise remains a problem particularly in patients
with “at risk” bifurcations. In a study by Chaudhry et al. (17), 158 patients with bifurcation
lesions with SBs ≥2 mm were treated with single stenting approach (MV stent). In this study,
16% of patients had SB compromise (TIMI flow <3 and/or ≥70% stenosis); SB compromise
(b)
7
(a)
(A)
Figure 4 Case examples demonstrating a wide range of bifurcation lesions to illustrate which lesions were,
and which lesions were not, well represented in the RCTs of PS versus EDS. (A) Coronary angiography in
the RAO cranial (a) and LAO cranial (b) projections, demonstrating two bifurcation lesions (proximal LAD/1st
diagonal branch and mid-LAD/2nd diagonal branch), which are representative of bifurcation lesions included
in the RCTs. Note that both bifurcation lesions have only
Case examples of bifurcation lesions that were not well represented in the RCTs: (a) LCX/large OM1 bifurcation
lesion with subocclusive stenosis in both branches, (b) proximal LAD/large diagonal branch bifurcation lesion with
aneurysmal dilatation at the SB ostium, (c) proximal LAD/large diagonal branch bifurcation lesion with focal but
severe
stenosis at the SB ostium, (d) Proximal LAD/very large diagonal branch bifurcation lesion with focal but
severely stenosed and angulated SB, and (e) proximal LAD/diagonal branch bifurcation lesion with focal ostial SB
lesion but with a 90-degree takeoff angle. (
moderate
and
focal
stenosis in the SB ostium. (B)
Continued on page 8
)
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