Treatment of coronary bifurcations: might less be more?
1 University of Texas Southwestern Medical School, Dallas, TX, USA
2 Geisinger Center for Clinical Studies, 100 North Academy Avenue, MC 44-00, Danville, PA 17822, USA
* Corresponding author. Email address: pbberger{at}geisinger.edu
This editorial refers to ‘Physiological evaluation of the provisional side branch intervention strategy for bifurcation lesions using fractional flow reserve’
by B.-K. Koo et al., on page 726
Footnotes
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
Percutaneous coronary interventions (PCIs) on coronary arteries in which the lesion involves a clinically significant side branch, termed a bifurcation lesion, are among the most challenging lesions for intervention.1 Coronary occlusions are often cited as the most challenging type of lesion, but an unsuccessful PCI on a coronary occlusion is rarely associated with a clinically important event, and initial success is only rarely complicated by late adverse events. In contrast, PCI of bifurcation lesions is associated with an unusually high risk, perhaps the highest risk, for both early and late complications. For every bifurcation lesion on which a PCI is attempted, two major procedural questions must be answered: (i) should the side branch be treated in addition to the main branch; and, if the answer is yes, (ii) how should it be treated?
Prior to beginning the percutaneous treatment of a bifurcation lesion, the decision about whether to treat a side branch lesion is usually based on whether there is a flow-limiting lesion in it before the procedure is initiated. When evaluating the functional significance of ostial side branch stenoses, it must be remembered that coronary angiography often leads to an overestimation (and less often an underestimation) of the functional significance of ostial branch lesions; more so than do lesions in other parts of the coronary circulation. This is in part due to difficulties in visualizing ostial lesions in multiple orthogonal views, and in part due to the fact that such lesions are often very short, reducing the likelihood that they limit blood flow. Measurement of the fractional flow reserve (FFR) can overcome the limitations of coronary angiography and should probably be considered the gold standard for assessing whether any lesions, let alone difficult to visualize lesions, are functionally significant.2 Guidewires that can measure the FFR, however, are often less flexible and steerable than standard guidewires, and wiring certain side branches with them can occasionally be a problem, especially after the main branch has been stented. This can almost always be accomplished with additional time and exchange catheters, but can be cumbersome, time-consuming, and expensive.
In the Nordic bifurcation study, the largest and most elegant randomized study of the treatment of bifurcation lesions, the criterion for whether the side branch should be intervened upon after the main branch had been stented was a reduction in resting flow into the side branch; only side branches with reduced flow (less than TIMI grade 3 flow) were dilated, and stents were placed only if there was no flow (TIMI grade 0 flow) after balloon angioplasty.3 Only about a third of side branches required balloon dilation when these guidelines for intervention were used, and 4.3% required stent placement. Also, patient outcome in the Nordic study was generally excellent: 97% of patients treated in this manner remained free of death, myocaridal infarction, target vessel revascularization, or stent thrombosis, and only 9% had Canadian Cardiovascular Society angina class 2 or more at any time during follow-up.
It is against this backdrop that the study by Koo et al. was performed.4 The study tested a strategy of drug-eluting stent placement in the main branch with provisional treatment of the diseased side branch only if the FFR was <0.75. When the FFR was <0.75, the study protocol required that ‘kissing balloon angioplasty’, i.e. simultaneous inflation of balloons in both the main branch and the side branch, using an undersized balloon in the side branch, be performed. Surprisingly, not one patient in the FFR group required a stent in the side branch after balloon angioplasty (although in two patients the FFR remained <0.75 after balloon angioplasty). The comparator arm were patients whose bifurcation lesions were managed in what the authors term was a more ‘conventional’ way, with balloon angioplasty and stent placement performed in 45 and 9%, respectively, of side branches in this group. During a median follow-up of 6 months, patients whose treatment had been guided by FFR had excellent outcomes, similar to the outcomes of the group of patients whose side branches were treated far more frequently guided by angiography; nearly half of those patients had had interventions performed on their side branches, similar to the frequency reported in previously published trials, in which angiographic decisions guided the treatment of side branches.5 Only approximately a third of the side branches with ostial disease had had an initial FFR <0.75, although most were described as having had an angiographically severe stenosis. These same investigators have previously demonstrated that many ‘severe’ ostial branch lesions are not functionally significant (again defined as an FFR < 0.75).6 The FFR could be measured in nearly all (92 of 96) side branch lesions, which could in part be related to the experience, skill, and commitment of the operators in this study.
What are the strengths and limitations of the study by Koo et al.4? Data from the DEFER study suggest that deferring intervention in lesions with an FFR 
0.75 is associated with an excellent long-term outcome, no worse (and no better) than the outcome in patients whose borderline lesions are treated.7 The study by Koo et al.4 is similar to the DEFER study in that regard, demonstrating excellent outcomes when side branches with an FFR 0.75 are managed medically.
Perhaps the most controversial aspect of the study design of Koo et al. involves the use of undersized balloons (with a balloon to vessel ratio of 0.85) in functionally significant side branch lesions. Although the FFR increased to 0.75 in 24 of 26 lesions treated in that manner, and there was no significant reduction in FFR after a median of 6 months on follow-up measurement, undersized balloons have not been associated with as excellent a short-term outcome or as high a freedom from restenosis as appropriately sized balloons in the balloon angioplasty era. Thus, one wonders if the result might have been better (although it is true that they might also have been worse) if ‘appropriately sized balloons’ with the more typical balloon:artery ratio of at least 1:1 had been used. The use of drug-eluting stents in the main branch might, to some extent, inhibit neontima hyperplasia in the ostium of the side branch and may have contributed to the excellent outcome in the patients in both groups, although there are also concerns that placement of a drug-eluting stent across a side branch might delay re-endothelization and predispose to stent thrombosis, a relatively rare event which did not show up in this small study but might nonetheless be an issue.8 It is also possible that avoidance of stents following balloon inflation contributed to the excellent outcomes in the study group, since the use of stents in both limbs of a bifurcation lesion has been associated with an increased frequency of periprocedural myocardial infarction3 as well as stent thrombosis,9 which most often occurs within the stent in the side branch.10 No study has yet suggested that routinely placing a stent in ostial side branch lesions is advantageous compared with balloon angioplasty and stent placement only when a satisfactory result cannot be achieved (termed provisional side branch stenting).3,5,11 Admittedly, wide differences exist in what is felt to represent an angiographically acceptable result, particularly among younger interventional cardiologists who trained in the stent era, who are generally less familiar with the 30–50% residual stenoses often present at the treatment site when ostial lesions are dilated
Other limitations of the study of Koo et al.4 should also be considered when deciding whether or to what degree these results ought to influence current practice patterns. First, a side branch may not be able to be wired after stenting of the main branch, particularly with a wire capable of measuring FFR, although this is uncommon in the hands of experienced operators. However, to reduce the likelihood of being unable to wire a side branch after treatment of the main branch, some interventionalists place a guidewire in both the main branch and the side branch, and then place a stent in the main branch, trapping the guidewire in the side branch between the stent and vessel wall; this wire can now only serve as a marker of the side branch if it is occluded, facilitating rewiring of it with another guidewire through the cells of the stent. Only rarely has difficulty removing the guidewire and fracture of the guidewire been reported. Secondly, FFR measurement requires skill and time, and may actually increase the amount of fluoroscopy and contrast required over medical management; whether it increases or decreases time, fluoroscopy, and contrast compared with simply treating the side branch lesion is not clear. The administration of adenosine, which is required to assess FFR, is very safe, and only rarely causes heart block or bronchospasm, both of which can usually be easily treated. Thirdly, most of the lesions included in the study were left anterior descending—diagonal lesions; whether the results would apply to other bifurcation lesions, such as left main bifurcation lesions, or posterior descending—posterolateral lesions, is unclear. Fourthly, and perhaps most importantly, this study was not a randomized comparison, and the non-randomized nature allows for confounders, recognized and unrecognized, which limit the degree of certainty readers should have in accepting the conclusions suggested by the data.
Despite these limitations, the randomized Nordic trial and now the non-randomized study of Koo et al. add a large amount to the other data suggesting that interventionalists ought to resist the urge to treat all relatively severe stenoses in the ostium of side branches arising from diseased main branches, but rather treat only those side branches with reduced flow at rest or with a reduced FFR. In the future, bifurcation stents that are currently unavailable in the USA, but are being evaluated in many different studies, will provide an alternative and perhaps a superior approach.
Conflict of interest: none declared.
Footnotes
The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.
doi:10.1093/eurheartj/ehn045 
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