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Table of Contents
Year : 2018  |  Volume : 1  |  Issue : 2  |  Page : 124-135

Current concepts in bifurcation stenting

1 Department of Cardiology, Heart Institute, Nanavati Hospital, Mumbai, Maharashtra
2 Department of Cardiology, Bankers Heart Institute, Vadodara, Gujarat, India

Date of Web Publication13-Dec-2018

Correspondence Address:
Dr. Rajiv G Bhagwat
Department of Cardiology, Heart Institute (1st Floor), Nanavati Hospital, S. V. Road, Mumbai, Maharastra 400056

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Source of Support: None, Conflict of Interest: None

DOI: 10.4103/IHJI.IHJI_23_18

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A bifurcation lesion is traditionally defined as a coronary artery narrowing occurring adjacent to and/or involving the origin of a significant side branch. Long before the nomenclature of lesion complexity matured, side-branch involvement was recognized as an unfavorable determinant of angioplasty success. Miere and associates were among the first to define the risk of side-branch occlusion associated with parent vessel angioplasty, emphasizing the importance of plaque extension into the side branch as the predictor of percutaneous coronary intervention (PCI) outcome. PCI of coronary bifurcation lesion poses a challenge to the operator in terms of difficulty in wiring, passage of hardware, recrossing, and immediate/long-term outcomes. Several important factors such as anatomic variation, angulation between branches, downstream territory, and the extent of plaque burden should be taken into consideration when addressing a bifurcation lesion to choose the most appropriate approach and achieve an optimal result. Factors to be considered before strategizing a bifurcation angioplasty include the extent of disease (whether it is limited to ostium or extending beyond), size (>2.5mm reference diameter), and area of distribution of side branch. Implantation of a single stent in the main branch is the most widely used approach and should be considered the default strategy. Two-stent strategy as “intention to treat” should be considered for large side branches or when the disease extends beyond the ostium or a branch supplying a significant territory.

Keywords: Bifurcation stenting, double crush stenting, MADS (main across distal side) classification, medina classification, proximal optimization technique, T-stenting

How to cite this article:
Bhagwat RG, Ruparelia RV. Current concepts in bifurcation stenting. Indian Heart J Interv 2018;1:124-35

How to cite this URL:
Bhagwat RG, Ruparelia RV. Current concepts in bifurcation stenting. Indian Heart J Interv [serial online] 2018 [cited 2021 Apr 19];1:124-35. Available from: https://www.ihji.org/text.asp?2018/1/2/124/247447

  Introduction Top

Coronary bifurcations remain one of the most challenging lesions in interventional cardiology. It carries poor procedural success rate and worst long-term outcome if not performed precisely. In this article, we will discuss the fundamentals of bifurcation anatomy, physiology, classification, and various strategies to treat coronary bifurcation stenosis.

  What is a Bifurcation Lesion? Top

Bifurcation lesion is a stenosis involving the origin (or close proximity to the origin, i.e., up to 3mm from bifurcation point) of a “significant” side branch (SB).[1] It accounts for 15%–20% of all coronary interventions.[2] The stenosis can involve a larger main branch, smaller SB, or both. Depending on the involvement of the components, the bifurcation lesion can be divided into true or false bifurcation lesion [Figure 1].
Figure 1: True and false bifurcation lesions.[53] MB = main branch

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The European Bifurcation Club (EBC) defines bifurcation as: “A coronary artery narrowing occurring adjacent to, and/or involving, the origin of a significant SB. A significant SB is a branch, whose loss is of consequence to a particular patient (symptoms, location of ischemia, viability of the supplied myocardium, collateralizing vessel, left ventricular function).”[3]

  Historical Aspects Top

Treatment of coronary bifurcation stenosis is an integral part of the history of coronary angioplasty,[4],[5],[6] and kissing balloon inflation (KBI) was strongly recommended as early as the 1980s. In those days, two angioplasty balloons were positioned using two separate guiding catheters. Advent of the coronary stent completely changed the approach toward bifurcation lesions. Many stent implantation techniques were described during the 1990s. Drug-eluting stent (DES) revolutionized the treatment of bifurcation lesions, it reduced in-stent restenosis to a great extent. Single-stent technique of stenting of the main branch with a provisional approach for the SB is the most widely accepted one. Six randomized studies[7],[8],[9],[10],[11],[12] as well as various meta-analyses[13],[14],[15],[16],[17] comparing dual-stent techniques with provisional SB stenting have shown that complex strategies may not confer greater benefit.

  Anatomical Considerations Top

Coronary tree follows the principle of fractal geometry. It branches off into asymmetrical sized daughter branches as it bifurcates. Ramification of the coronary tree, as all ramifications in nature, follows the rule of minimum energy cost in providing the underlying myocardium with the amount of blood required. There are three segments in a bifurcation (and not two as previously thought), each one has its own reference diameter [Figure 2]. The relation between the diameter of the proximal segment of the main vessel and the two distal segments is governed by the classic Murray’s law[19] (Dprox3 – Ddist3 + Dside3). The complex formula was recently simplified by Finet[20]: Dprox = (Ddist + Dside) × 0.678.
Figure 2: Newer model of a bifurcation anatomy

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  Physiological Considerations Top

Coronary bifurcation flow has specific characteristics. It follows the Bernoulli’s principle. In the vicinity of the carina (flow divider), as on the outside of the curves, the flow is rapid, linear, and generates intense friction (wall shear stress) on the vessel wall resulting in antiatherogenic molecular, histological, and functional modifications.[21],[22] Opposite the carina, as on the inside of the curves, there is a recirculating, oscillating flow generating low and pro-atherogenic wall shear stress. Carina is generally atheroma free, the atheroma develops in the low shear stress areas in the segments opposite the carina in the vicinity of the bifurcation. Formation of the atheroma alters flow patterns. Distal and circumferential expansion of the plaque may reach as far as the carina.

  Classification of Bifurcation Lesions Top

Many classifications of bifurcation lesion have been proposed [Figure 3]. Few of them are (1) Medina, (2) Duke, (3) Sanborn, (4) Lefevre, (5) Safian, and (6) Movahed. Most of them need to be memorized, except for the widely accepted Medina classification [Figure 4]. It considers the presence of >50% stenosis as significant stenosis in a bifurcation lesion. However, it does not take into account the angle of bifurcation, calcification, lesion length, and size of the SB. Moreover, it considers >50% as a significant lesion, which may not be of physiological/functional significance.
Figure 3: Various classification of bifurcation lesions

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Figure 4: Medina classification.[53]
MB = main branch, SB = side branch

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Overall, none of the classifications is perfect, one has to apply his own experience to decide about the approach and strategy to treat a bifurcation lesion.

  Suggested Approach for Handling a Bifurcation Lesion Top

Treating bifurcation lesion is challenging, but a simple algorithm based on the SB size, stenosis, and angulation can be used [Figure 5].[18]
Figure 5: Strategy to treat a bifurcation lesion based on SB angle, SB size and SB obstruction

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The most important issue in a bifurcation intervention is selecting the most appropriate strategy for an individual bifurcation and optimizing the performance of this technique. Latib and Colombo have suggested that there are three questions [Figure 6], which an operator needs to answer to decide the appropriate strategy, is it a true bifurcation, is the SB disease diffuse, and is the SB suitable for stenting.[16] These questions determine the likelihood of success with a provisional approach and determine whether the operator is willing to accept a suboptimal result in the SB with balloon angioplasty only. If the answers to all these questions are in the affirmative, the bifurcation may still be treated with one stent, but the operator should consider a two-stent approach as intention to treat in view of suboptimal result.[18]
Figure 6: Selection of strategy based on three questions

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When treating bifurcation lesions, close attention must be directed toward choosing a guiding catheter large enough to accommodate two balloons and two stents. A wire should be placed in the SB, especially if there is disease at the ostium or with a problematic takeoff. When the SB is not severely diseased, implantation of a stent in the main vessel (MV) and provisional stenting of the SB is the preferred strategy. However, implantation of two stents is recommended when both branches are large (>2.75mm) and significantly diseased.

  Technical Aspects Top

Many techniques have been described and used successfully in the treatment of bifurcation lesions. Classification of techniques has been complicated and has caused confusion in the past. The EBC has suggested a MADS (main, across, distal, side) classification, taking into account initial stent deployment, which often corresponds to a technical strategy related to the importance of the vessel that is treated first.[23]

As shown in [Figure 7], the first family of technique (M) starts by stent implantation in the proximal main vessel relatively close to the carina. The opening of the stent toward both branches may follow this initial step with subsequent successive or simultaneous stent placement in one or both distal branches. The second family (A) starts with the stenting of the proximal main vessel to the distal main branch across the SB. This may be the first and the last step of the procedure but may also be followed by the opening of the stent struts, delivery of a second stent in the SB, and with or without KBI. The third family (D) involves the distal branches and historically starts with simultaneous stent placement at the ostium of both distal branches (V-stenting). The simultaneous kissing stents (SKS) technique is a variant that creates a new carina. The fourth family (S) involves strategies in which the SB is stented first, either at the ostial level or with a relatively pronounced protrusion into the proximal main vessel. The SB stent may be crushed with a balloon inflated in the main vessel, or a second stent may be deployed in the main vessel across the SB.[23]
Figure 7: MADS classification

Click here to view

The MADS classification, which is for the treatment of bifurcation lesions, does not exhaustively describe the technical aspects of interventional techniques, which include the use of wires, lesion preparation, single balloon inflation, KBI, or using one or two stents. Therefore, Movahed and Stinis[24] have suggested classifying the most common bifurcation techniques with regard to stenting into six categories: one-stent technique, stent with balloon technique, kissing-stent technique, T-stent technique, crush-stent technique, and culotte-stent technique.[25]

The most important issue in bifurcation intervention is selecting the most appropriate strategy for an individual bifurcation and optimizing the performance of this technique.[25]

Main branch stenting only

This strategy is used when the SB has ostial or diffuse disease and is not suitable (too small) for stenting or is clinically irrelevant.[24]

Provisional SB technique

This is the most frequently used technique for bifurcation lesions.

The following approach is followed:

How to perform FKBI?

  • Balloon must be sufficiently short to avoid inflation outside the stent in MV and disease-free area in SB.

  • Diameter of balloon must match with that of the two distal branches.

  • Use of noncompliant balloon allows improved stent expansion in MV while reducing the risk of dissection in SB.

  • Various techniques can be used for FKBI (described below).

  • Problem with FKBI:

  • It increases procedural complexity, ovalization of stent, proximal dissection, and suboptimal deployment of proximal stent segment.

  • Nordic-Baltic Bifurcation Study III[27] and CORPAL Kiss[28] did not reveal any significant difference in FKBI versus no-FKBI group in terms of death, non-procedural-related myocardial infarction (MI), target lesion revascularization, and stent thrombosis. However, angiographic restenosis was significantly reduced with FKBI.

  • Indications for second stent are as follows:

  • SB >2.5mm (with thrombolysis in myocardial infarction flow < Grade III or fractional flow reserve (FFR) <0.80)

  • Flow-limiting dissection

  • Hemodynamically significant SB

  • Residual stenosis of 75%

  • (Note: FFR may be helpful in decision-making when there is a significant residual lesion in SB after provisional stenting.[29])

    Functional significance of SB can be derived by FFR as well as myocardial perfusion imaging (MPI). MPI helps to determine the significance of SB by calculating the percentage of myocardium at risk. Revascularization is helpful when SB is supplying >10% myocardium. Recently modified size, number, highest score has been introduced to determine the clinical significance of SB.

    IX. Various optimization protocols for provisional stenting.

    Multiple provisional stenting optimization protocols have been described.

    1. Classic FKBI: Simultaneous and symmetric inflation pressure (12 and 12 atmospheric pressure [atm]) in MV and SB with noncompliant balloons.

    2. Modified FKBI as described by Mortier et al.[30]: KBI with 12 atm pressure in SB followed by partial deflation to 4 atm, then inflation of MV to 12 atm, and finally, simultaneous deflation.

    3. POT followed by KBI with symmetric inflation pressure with noncompliant balloons.

    4. POT followed by 12 atm SB inflation (without KBI).

    5. POT sequence followed by 12 atm SB inflation and then final POT (without KBI). The full sequence is called re-POT.[31]

    (Tip: Simultaneous deflation reduces the chances of MV deformation.)

    (Tip: Noncompliant balloon should be used at least in SB to prevent the occurrence of dissection, and short balloon should be used to avoid oval distortion in proximal MV segment.)

    Newer concepts

    The detrimental effects of KBI include oblong proximal stent deformation caused by the juxtaposition of the two balloons. Mortier et al.[30] reported an elipticity index of 1.26 with KBI. This elliptical shape of proximal MV stent can have detrimental effects on fluid dynamics.[32] The balloon juxtaposition in the proximal MV is about one-half of the balloon length. If the stented length in the proximal MV is greater than the balloon overlap, the proximal malapposition predicted by fractal bifurcation geometry will not be corrected, and circular proximal malapposition (bottleneck) may be induced.

    The re-POT sequence corrects the elliptical deformation of the proximal MV stent and residual strut malposition induced on the MV side of the flow divider and on the side of the bifurcation facing the SB ostium following SB dilatation after initial POT. That the re-POT sequence can be accomplished through a 5Fr-guiding catheter through the radial route is a major advantage in a single-stent strategy.

    Two-stent strategy as intention to treat

    It requires appropriate patient selection, accurate assessment of the lesion severity, distribution of SB territory, and extent of SB lesion.

    It should be reserved for true bifurcation with SB with the following:

    1. Relatively large in diameter (>2.5mm)

    2. Larger territory of distribution

    3. Severe disease that extends well beyond ostium (>10–20mm)

    4. Unfavorable angle for recrossing after MV-stent implantation

    Various two-stent strategies are as follows:


  • Most frequently used to shift from provisional stenting to stenting of SB [Figure 8]
    Figure 8: T-stenting technique[54]

    Click here to view

  • It is best when angle between MV and SB is close to 90°

  • There are different forms of T-stenting, which are as follows:

  • Classical T-stenting

  • Both branches are wired and dilated

  • Stent is deployed at the ostium of SB carefully to avoid stent protrusion into the MV, at the same time trying to minimize any possible gap

  • Balloon from the SB is removed with wire in place

  • Advance and deploy the stent in the MV

  • Rewiring of the SB

  • SB balloon dilatation

  • Final kissing inflation

  • Modified T-stenting

  • Performed by simultaneously positioning stent at the SB and MV with the SB stent minimally protruding into the MV.[33],[34]

  • SB stent is deployed first and then, after the wire and balloon removal from the SB, the MV stent is deployed. The procedure is completed with an FKBI.

  • Reverse T-stenting

  • Best suitable bailout technique after initial MV stenting

  • Rewiring the SB through the MV stent struts

  • Ballooning and stenting of the SB

  • Final kissing balloon is recommended for optimal result

  • The main limitation of the above three techniques is the possibility of stent gap between MV and SB stent. Additionally, 90° angle between MV and SB is infrequent in non-left main coronary bifurcation. Moreover, it is not easy to recross the wire following T-stenting and protrusion (TAP) in narrow angle. However, the main advantage of T-stenting is that it is easy and not technically demanding.

    T-stenting and protrusion

  • Used to enhance SB ostial coverage.[25]

  • Initial steps are similar to T-stenting except the position of the SB stent, which is intentionally kept protruding in MV.

  • Rest of the steps remains similar to that of classical T-stenting technique.

  • The KBI reorients the protruding SB stent struts, resulting in a small neocarina.[35]

  • (Tip: If SB stent is protruded slightly more into MV, the strategy can be switched to internal crush, and if it is protruded extremely into MV, culotte can be performed as a bailout.)

    V and SKS technique

  • This technique [Figure 9] includes inflating two stents simultaneously.[36],[37]
    Figure 9: V and SKS stenting technique.[54]MB = main branch

    Click here to view

  • In V-stenting, both the stents are pulled back as close as possible to create new carina as close as possible to the original one.

  • Although in SKS technique, two stents protrude into the MV with the creation of double barrel and a very proximal neocarina.

  • Advantages

  • Operator will never lose access to any of the two branches.

  • When final kiss is done, there is no need to recross any stent.

  • Limitations

  • Incomplete proximal alignment of the two stents.

  • Limited ability to effectively treat proximal dissections.

  • Difficult to recross stent with guidewire (if required).

  • Crush technique

    Minicrush is associated with more complete endothelialization and in turn, less stent thrombosis, as well as easier recrossing of the crushed stent [Figure 10].[54]
    Figure 10: Crush stenting[54]

    Click here to view

    Different forms of crush technique are as follows:


    Used when there is a need for two stents, and 6Fr-guiding catheter is the only available option (e.g., radial approach).

  • Both branches are wired and fully dilated.

  • Each stent is advanced and deployed separately.

  • First, a stent is advanced into the SB protruding a few millimeters into the MV.

  • A balloon, rather than a second stent, is advanced into the MV.

  • Stent in the SB is deployed and the stent balloon is removed.

  • Angiography is performed and if the SB result is adequate, the wire is also removed.

  • MV balloon is then inflated to crush the protruding SB stent.

  • MV stent is advanced and deployed.

  • Remaining steps are similar to that of classical crush technique.

  • The result is identical to that obtained with the standard crush technique, except that each stent is advanced and deployed separately.


  • 7Fr- or 8Fr-guiding catheter.

  • Both branches are wired and fully dilated.

  • Both SB and MV stents are advanced.

  • SB stent is positioned so that approximately 1–2mm of the proximal end (minicrush) is within the MV.

  • Rest of the steps are similar to that of standard crush technique.

  • Double kissing crush technique

    Modification of the step-crush procedure in which a balloon kissing inflation is performed twice: First, after a MV balloon crushes the SB stent and then the standard final kissing inflation. The five basic steps of double kissing (DK) crush are as follows:

  • SB stenting

  • Balloon crush

  • First kissing

  • MV stenting and crushing

  • Final kissing

  • DK crush may be superior to the classic crush technique with respect to acute procedural results and clinical outcomes by facilitating successful final kissing inflation in all patients.[38]

    (Tip: Wire can traverse through the inadequately crushed segment in the MV. This has to be identified and rewiring should be performed.)

    The crush may have to be carried out several times to adequately crush the stent and often with more than a nominal pressure. Boost images can help to identify adequately crushed stent.

    Reverse (internal) crush

    An option in the setting of provisional SB stenting using a 6Fr-guiding catheter.

  • After stenting of MV, if the SB result is suboptimal, internal crush could be an option to deploy a second stent in SB.

  • Guidewire is inserted into SB through stent and struts are dilated.

  • Second stent is advanced into the SB and left in position without being deployed.

  • A balloon is advanced into MV at the level of the bifurcation making sure to stay inside the stent, previously deployed in the MV.

  • Stent in SB is retracted approximately 2–3mm into MV and deployed.

  • Stent balloon is removed and an angiogram is obtained to verify that a good result is present at the SB.

  • Wire from SB is removed and balloon in MV is inflated to high pressure.

  • Remaining steps are similar to that of the crush technique.

  • Advantages

  • Immediate patency of both branches is assured.

  • Important when SB is functionally relevant or difficult to be wired.

  • Confirms to vessel geometry, and complete coverage of carina is observed, especially with DK crush technique.

  • DK crush technique has certain advantages over other crush techniques. These include the following:

  • It achieves complete coverage of the carina with minimum metal load.

  • Barring technical difficulties, it gives the least all cause mortality, cardiovascular mortality, re-myocardial infarction and stroke (MACE) rates and target lesion revascularization/target vessel revascularization in most studies.

  • Limitations

  • Need to recross multiple struts with wire and balloon.

  • An angle of 50° or more between the two branches has been suggested to be an independent predictor of MACE after crush stenting.[39]

  • Ormiston et al.[26],[40],[41] have suggested that appropriate SB and MV dilatation is needed to fully expand the stent at SB ostium to widen gaps between stent strut overlying the SB and minimize stent distortion.

    Culotte technique

  • It is referred to as Y stenting or trouser legs [Figure 11].
    Figure 11: Culotte technique[54]

    Click here to view

  • It was associated with high restenosis rate in the past, but has regained popularity in the DES era.[42],[43]

  • It gives maximum coverage at bifurcation at the expense of an excess of metal covering the proximal MV.[42]

  • It can be used in all true bifurcation lesions irrespective of the bifurcation angle and provides more homogenous drug distribution at the side of the bifurcation.

  • The only anatomic limitation is when there is a large mismatch between the proximal MV and SB diameter, which may lead to malapposition of the SB stent within the proximal part of the MV.[44]

  • Culotte can be performed using a 6Fr-guiding catheter.

    Following are the main steps:

  • Both branches are wired and predilated.

  • First, a stent is deployed across the smaller, more angulated branch, usually the SB.

  • Nonstented branch is then rewired through the stent struts and dilatation is performed to facilitate passage of the second stent.

  • Stent is advanced and expanded into the nonstented branch, usually the MV.

  • Finally, KBI is performed with preferably noncompliant balloons, and each limb of the culotte is dilated at a high pressure individually before simultaneously inflating both balloons to a nominal pressure.

  • When rewiring the other branch after stent placement, it is always reasonable to first place the guidewire distal into the stented branch to ensure that the wire has not passed under the stent struts before recrossing into the nonstented branch.


  • It guarantees complete coverage of the SB ostium.

  • Limitations

  • Double-stent layer is observed at the proximal MV and at the level of the carina.

  • This technique is not advisable when there is a large discrepancy between the size of the proximal MV and the SB because of the risk of incomplete wall apposition of the SB stent in the proximal MV segment.

  • Requires rewiring of both branches through the stent strut, it can be technically demanding and time-consuming.

  • With the use of some closed cell stents (e.g., Cypher, Cordis Corporation, USA), the opening of the struts toward the branches may only reach a maximum diameter of 3mm. Because of this, the culotte technique should only be used with stents that have design allowing full opening of the struts toward both branches or when the expected size of the SB <3mm.

  • Predictors of in-stent restenosis post-stenting

    Irrespective of the technique used, following are the key determinants of in-stent restenosis post-stenting:

  • Preprocedural diameter stenosis of the bifurcation core

  • Percentage of SB stenosis preprocedure

  • Higher bifurcation angle (>60°)

  • Diameter ratio of MV and SB

  • One or two stents in DES era?

    Many randomized and nonrandomized trials have compared one- versus two-stent strategies in non-left main bifurcations.[7],[10],[11],[12],[28],[38],[45],[46],[47],[48],[49] Majority of them have shown no advantage of implanting two stents regardless of the lesion type [Table 1]. Meta-analysis[50] of these randomized trials concluded that both strategies result in similar outcomes in terms of the risk of cardiac death, target lesion revascularization, and stent thrombosis. However, the rate of periprocedural MI was significantly higher in the complex strategies.[51] Recently, a 5-year follow-up of DK Crush II and a 1-year follow-up of DK Crush V study observed a significant reduction of MACE rate and target lesion failure in DK Crush Group.
    Table 1: Various trials comparing bifurcation stenting strategies

    Click here to view

    Owing to complexity of other techniques and almost similar outcome with each individual technique, simple provisional SB stenting remains the preferred strategy.

      Current Guidelines Top

    Consensus from the meeting of the EBC on techniques for two-stent strategies was the following[52]:

  • Provisional T-stenting remains the gold standard technique for most bifurcations.

  • Large SB with ostial disease extending >5mm from the carina is likely to require a two-stent strategy.

  • SB whose access is particularly challenging should be secured by stenting once accessed.

  • KBI for carina reconstruction is mandatory in two-stent techniques.

  • Noncompliant balloon is recommended for kissing inflation.

  • Individual noncompliant high-pressure “ostial” post-inflations are mandatory in complex stenting techniques to achieve full-stent expansion.

  • High-pressure proximal stent inflation using a short noncompliant balloon should be considered for the correction of possible proximal stent distortion after KBI.

  • The 2011 American College of Cardiology/American Heart Association/Society of Cardiovascular Angiography & Interventions[23] guidelines for percutaneous coronary interventions have made the following recommendations about bifurcation lesion treatment:

    1. Class I: Provisional SB stenting should be the initial approach in patients with bifurcation lesions when the SB is not large and has only mild or moderate focal disease at the ostium (level of evidence A).

    2. Class IIa: It is reasonable to use elective double stenting in patients with complex bifurcation morphology, involving a large SB where the risk of SB occlusion is high and the likelihood of successful SB reaccess is low (level of evidence B).

      Summary Top

    Though the ideal approach to bifurcation lesions seems to be provisional stenting, it coincides with the minimalist approach to angioplasty. When provisional approach is not feasible, it leads us to two-stent techniques as an intention to treat. Often a lesion can be treated with more than one approach. Each technique has its own advantages and disadvantages. The DK crush techniques by and large appear superior in restoring vessel geometry with complete coverage of the lesion and carina, though the culotte procedure is very close to DK crush in terms of long-term results. For two-stent techniques, the operator should be well versed with the guiding catheter internal diameter/outer diameter, wires, use of noncompliant balloons, and the stent platform, which are very vital in the final result.

    Financial support and sponsorship


    Conflicts of interest

    There are no conflicts of interest.

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      [Figure 1], [Figure 2], [Figure 3], [Figure 4], [Figure 5], [Figure 6], [Figure 7], [Figure 8], [Figure 9], [Figure 10], [Figure 11]

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