First Optical Coherence Tomography Follow-up of Coronary Bifurcation Lesions Treated by Drug-Eluting Balloons

Abstract: Background. A strategy of percutaneous bifurcation intervention with provisional bare-metal stent (BMS) implantation followed by drug-eluting balloon (DEB) treatment represents a valuable opportunity in patients not compliant with long-duration dual-antiplatelet therapy. We used optical coherence tomography (OCT) to assess coronary bifurcation lesions treated by BMS and DEB, and secondarily, to better explore the association between stent geometry and tissue coverage. Methods. Twelve patients underwent frequency-domain OCT 6 months after undergoing percutaneous bifurcation intervention with BMS implantation followed by kissing DEB. The same type of BMS was correspondingly implanted in silicone bifurcation models and scanned by microcomputed tomography. Results. Overall, a total 2914 struts were analyzed, revealing 0.6% malapposed struts and 3.1% uncovered struts, with neointimal thickness of covered struts measured at 0.19 ± 0.13 mm. Findings were homogeneous among patients with the exception of one outlier who presented a significant distortion of the stent geometry, suggesting proximal cell rewiring prior to kissing DEB, as supported by the microcomputed tomography model. This pattern was not present in the other cases, which showed struts optimally apposed and nicely scaffolding the side-branch ostium. Conclusion. This is the first study describing the effects of DEB in percutaneous bifurcation interventions according to OCT parameters. The results show that a strategy of kissing DEB following BMS is associated with low neointimal thickness and high rate of covered stent struts. Moreover, these results appear to be dependent on the quality of bifurcation intervention, with distal cell rewiring more favorable than proximal cell rewiring.

J INVASIVE CARDIOL 2015;27(4):191-198

Key words: drug-eluting balloon, bifurcation lesions, optical coherence tomography

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Interventional cardiologists have always faced challenges when approaching coronary bifurcation lesions.¹ Indeed, until the advent of dedicated techniques and drug-eluting stent (DES) implantation, bifurcation treatment has been associated with unsatisfactory outcomes.^2,3 However, because of delayed healing, DES implantation requires prolonged dual-antiplatelet therapy (DAPT) to avoid stent thrombosis, as recommended by current guidelines on percutaneous coronary revascularization.^4,5 Long-duration DAPT is especially important after percutaneous bifurcation interventions, thus limiting their use to patients who are compliant with at least 12 months of treatment with aspirin and a P2Y₁₂ receptor blocking agent such as clopidogrel, prasugrel, or ticagrelor.^6-9 Unfortunately, a significant proportion of patients with coronary artery disease requiring percutaneous coronary intervention to treat complex lesions do not qualify for prolonged DAPT because of scheduled surgery, cognitive impairment, or associated disease, which represents a growing concern in an aging population.

The drug-eluting balloon (DEB) is a new technology that has demonstrated success in the treatment of in-stent restenosis^10,11 and small-vessel disease.¹² Yet, DEB utilization has also been proposed as a new opportunity in percutaneous bifurcation interventions by allowing local antiproliferative drug delivery without the use of long-lasting polymers, such as those present in DES types, which have been associated with stent thrombosis and late restenosis.¹³

Notably, a strategy consisting of simple provisional bare-metal stent (BMS) implantation followed by kissing DEB has shown encouraging preliminary clinical results.¹⁴ We have therefore designed an optical coherence tomography (OCT) study to uniquely assess the tissue coverage and apposition of BMS implantation in coronary bifurcation lesions according to the simple provisional technique followed by simultaneous inflation of two DEB devices. Moreover, we have developed microcomputed tomography models to provide further insight into the association between observed tissue coverage and implanted stent geometry as revealed by OCT.

Methods

Patients. From May 2010 to June 2011, a total of 15 patients undergoing coronary angiography because of stable or unstable coronary artery disease or silent myocardial ischemia who showed one major coronary bifurcation de novo lesion with a visual reference vessel diameter ranging from 2.25-4.0 mm for both branches were treated by BMS implantation followed by kissing DEB in the following circumstances anticipating low compliance or contraindication to prolonged DAPT: (1) associated disease with significant bleeding risk; (2) anticoagulant therapy; (3) scheduled major surgery; (4) cognitive impairment; and (5) limited access to drug treatment.¹⁴ The first 12 patients underwent 6-month follow-up angiography and were enrolled in the present study after giving informed consent. 

Percutaneous bifurcation intervention. During the index procedure, unfractionated heparin was administrated to maintain an activated clotting time ≥250 seconds. All procedures were performed through transradial access with a 6 Fr guiding catheter and conducted according to the kissing DEB approach that has been previously described.^13,14 Briefly, the main vessel (MV) and side branch (SB) were wired first, and predilation of the MV lesion was performed according to operator’s judgment, while SB predilation was avoided to prevent possible vessel dissection and the risk of rewiring through a dissection plane.^15,16 An Integrity BMS (Medtronic) was implanted in the MV, jailing the SB guidewire. Guidewires were then switched, paying attention to recross the SB through the cell closest to the carina.^15,16 Finally, simultaneous kissing inflation of two DEB devices completed the procedure to ensure uniform paclitaxel transfer to the entire bifurcation lesion, with the DEB used in the MV exceeding the distal and proximal margins of the stented segment by 1-2 mm. Figure 1 outlines the key steps of the kissing DEB approach. Indications for SB stenting were: (1) residual diameter stenosis >75%; (2) Thrombolysis in Myocardial Infarction (TIMI) flow <3; or (3) fractional flow reserve <0.75. If SB stenting was required, the T-stenting and small protrusion (TAP) technique had to be implemented with no further kissing inflation of the two DEB devices to avoid excessive paclitaxel transfer to the vessel wall and possible toxicity.^17,18 

Different second-generation, paclitaxel-based DEB brands, implementing a molecular carrier that efficiently binds the anti-proliferative drug to the balloon surface (thus avoiding its dispersion in the bloodstream) have been used in this study, and include the SeQuent Please (B. Braun; n = 6), In.Pact Falcon (Medtronic Invatec; n = 6), DIOR II (Eurocor; n = 6), and Pantera Lux (Biotronik; n = 6). Two of the same DEB brand were always used during the kissing inflation. The two kissing DEB diameters corresponded to the reference vessel diameter of the distal MV and SB.¹⁹ A three-way stopcock connected to a single inflation device was used to allow simultaneous inflation (and deflation) of both DEB devices at nominal pressure according to the compliance chart provided by the manufacturer. Inflation was set to last 60 seconds. At the time of percutaneous coronary intervention, all patients were on DAPT with aspirin (100 mg daily) and clopidogrel (300 mg loading dose on the day before the percutaneous coronary intervention or 75 mg daily for more than 3 days before the procedure). Post procedure, DAPT with aspirin 100 mg and clopidogrel 75 mg was prescribed for 3 months unless otherwise clinically indicated. 

Quantitative coronary angiography. Quantitative coronary angiography (QCA) was performed offline according to standard procedures by two independent operators who were blinded to the OCT result using the dedicated QCA module of the Estensa package (Esaote). Three segments were analyzed in each bifurcation: (1) proximal MV; (2) distal MV; and (3) SB (within 5 mm of the carina). Late lumen loss (LLL) was defined as the difference between minimal lumen diameter (MLD) post procedure and MLD at follow-up, whereas binary restenosis was defined as diameter stenosis >50% at angiographic follow-up. 

Optical coherence tomography. All OCT imaging studies were performed after 200 µg intracoronary nitroglycerin injection. The rapid exchange DragonFly probe (LightLab Imaging) was connected to the frequency-domain OCT system C7-XR FD (LightLab Imaging) and advanced over a 0.014˝ coronary guidewire distally to the previously treated bifurcation. Images were acquired at an automated pullback speed of 20 mm/s and a frame rate of 100 Hz during contrast flushing and were digitally stored to be analyzed offline.²⁰ Both MV and SB were imaged and the stented bifurcation segment was divided into four segments (proximal, bifurcation, distal, and side branch).

Cross-sections within the stent were examined every three frames. After initial quality assessment, cross-sections with any portion of the stent out of the screen or with residual blood, artifact, or reverberation were excluded from analysis. Lumen and stent areas were calculated in each analyzed cross-section; neointimal hyperplasia area and in-stent percent neointimal volume obstruction were also calculated.

Quantitative strut level analysis was performed on each analyzed cross-section. Struts were classified as covered or uncovered and apposed or malapposed. Tissue coverage thickness was measured from the marker of each visible strut following a straight perpendicular line to the lumen contour. Strut malapposition was diagnosed if the distance between the endoluminal surface of a strut and the vessel wall was greater than the thickness of the strut that is 91 µm according to the stent manufacturer specifications, plus a 15 µm margin of error consistent with the axial resolution of OCT. Struts located at the SB ostium, with no vessel wall behind, were excluded from the analysis of apposition.

Microcomputed tomography. Main-vessel stent geometry after kissing balloon following distal or proximal cell rewiring was assessed in silicone bifurcation models (reference distal diameter, 3.5 mm) implementing Integrity stent implantation at nominal pressure. After rewiring the SB through the distal or proximal cell, respectively, kissing balloon was performed with a 2.75 x 15 mm balloon in the SB and a 3.5 x 18 mm balloon in the MV simultaneously inflated at 10 atm for 20 seconds. The models were scanned after stent implantation and kissing balloon inflation using microcomputed tomography (HMX ST microcomputed tomography scanner, X-Tek Systems) at a resolution up to 15 x 15 x 15 µm. 

Statistical analysis. Continuous variables with a normal distribution, according to Kolmogorov-Smirnov test, were compared by Student’s t-test or analysis of variance, while skewed ones were compared by Mann-Whitney U-test. Categorical variables were compared by Pearson’s chi-square test or Fisher’s exact test as appropriate. Correlation analyses were performed with Pearson’s correlation. If an observation was identified as a potential outlier, root cause analysis was performed to determine whether an assignable cause could be found for the spurious result and thus appropriately handle (remove or retain) the data point. Due to the hierarchical nature of data (stent struts, cross-sections, segments, and patients), a multilevel model was implemented for OCT data analysis. Data are reported as mean ± standard deviation, unless otherwise indicated. Two-sided P<.05 was required for statistical significance. 

Results

Patients and procedural characteristics. Main features of the study population are summarized in Table 1. The enrolled patients have real-world characteristics with a high prevalence of diabetes mellitus and unstable presentation. Reasons for a reduced DAPT length and treatment according to kissing DEB strategy were: associated disease with significant bleeding risk (n = 4), scheduled major surgery (n = 5), cognitive impairment (n = 2), and limited access to drug treatment (n = 1). 

Treated bifurcation involved mainly the left circumflex coronary artery. A true bifurcation (ie, with critical stenosis of both MV and SB) was present in 7 patients (58%). No patient had any indication for SB stenting. Procedural success was obtained in all cases. 

Quantitative coronary angiography. Table 2 shows main QCA results. Average lesion length was 15.7 ± 0.9 mm in the MV and 7.8 ± 2.2 mm in the SB. At the end of the percutaneous bifurcation intervention, MLD increased and diameter stenosis decreased significantly in all three segments (P<.001 for both parameters). At 6-month follow-up, LLL was 0.28 ± 0.39 mm in the proximal MV, 0.36 ± 0.41 mm in the distal MV, and 0.18 ± 0.44 mm in the SB. In 1 patient, a binary restenosis was observed in the SB segment.

Stent coverage. A total of 353 cross-sections were examined (Table 3) and 2914 struts were analyzed (Table 4). Mean stent area and mean lumen area were 6.9 ± 2.2 mm² and 5.3 ± 2.2 mm², respectively, and in-stent percent neointimal volume obstruction was 25.5 ± 11.9%. Strut-level analysis revealed 0.6% malapposed struts and 3.1% uncovered struts and a mean neointimal thickness of covered struts of 0.19 ± 0.13 mm. Notably, tissue coverage showed an inverse gradient from distal MV and SB segments toward bifurcation and proximal MV segments (Figure 2). 

Patient-level analysis showed a significant correlation between malapposed and uncovered struts (r = 0.89; P<.001) and revealed a uniform distribution among patients of malapposed and uncovered struts with the notable exception of 1 outlier (Figure 3). For this patient, OCT images showed a significant distortion of the stent geometry, including floating struts facing the SB ostium, suggesting proximal cell rewiring at the time of the kissing DEB (Figure 4B). This pattern was not present in the other cases, which showed struts optimally apposed and nicely scaffolding SB ostium (Figure 4C).

Geometry analysis. According to the MV stent cell recrossed during the wire switch (proximal or distal), final kissing balloon yielded markedly different stent geometries (Figure 5). Moreover, results of the microcomputed tomography model implementing final kissing balloon following distal cell recrossing perfectly fitted, by visual comparison, with the dominant OCT pattern of optimally apposed struts, with fine scaffolding of the SB ostium. On the other hand, the OCT pattern of malapposed stent struts, including floating struts facing the SB, was superimposed on the microcomputed tomography model showing the marked geometrical distortion occurring after final kissing balloon has been performed following proximal cell rewiring. 

Discussion

This is the first study to assess DEB treatment of coronary bifurcation lesions according to OCT parameters. Due to its unparalleled accuracy and precision in assessing stent apposition and neointimal coverage, OCT provided two main findings in this study: (1) the mean neointimal thickness of BMS implanted in bifurcation lesions that have been successively optimized by kissing DEB inflation is similar to that reported for paclitaxel-eluting stents, lower than in some other drug-eluting stents, and far better than that of BMS alone (Figure 6);²¹ and (2) there is a possible association between the cell of the MV stent that has been recrossed toward the SB (ie, proximal or distal) and neointimal coverage of the implanted stent.

Overall, our results indicate that the combination of DEB and BMS in bifurcation lesions could bring together the advantages of both technologies (namely, limited neointimal hyperplasia due to local drug delivery by DEB and diffuse strut coverage of the implanted BMS), but not their main limitations including lack of a scaffolding platform and excessive restenosis, respectively. Actually, the DEB allows very quick one-shot transfer of paclitaxel to the vessel wall with the goal of counteracting the response to injury occurring soon after the barotrauma produced by angioplasty or stent implantation. The drug is retained at an effective concentration in the vessel wall for just a few days. It is therefore extremely unlikely to have an antiproliferative effect persisting more than 2 weeks after DEB treatment. On the other hand, mechanisms leading to endothelial coverage of BMS are known to be completed within a few months, with little or nothing occurring beyond 6 months.

Moreover, OCT results serendipitously reveal, for the first time in the setting of the simple provisional technique, the possibility that the quality of the kissing-balloon inflation, beyond its mere implementation, has a marked impact on the biological response to the implanted stent. 

Evidence coming from randomized controlled trials has crowned simple provisional stenting as the preferred technique in percutaneous bifurcation intervention.^22-27 As extensively reviewed,¹⁷ struts opening toward the SB by kissing-balloon inflation is advised to preserve MV stent geometry following stent implantation in the MV.^15,17,28 

Moreover, for simple bifurcation treatment, bench tests have shown that recrossing through the cell closest to the carina yields optimal stent deformation with nice scaffolding of the SB ostium.^16,17 Conversely, recrossing a proximal cell determines marked distortions of the MV stent geometry. Whether such an issue could have a direct clinical impact is unexplored. Our findings suggest it does, since it has been previously shown that incomplete stent apposition is associated with both neointimal coverage issues and stent thrombosis at follow-up.^9,29 This could perhaps explain why the Nordic-Baltic Bifurcation Study III and other published trials assessing final kissing balloon after provisional stenting have not shown any advantage or penalty of this strategy at 6-12 months of follow-up, when patients are still under DAPT.^30-32 Of note, a recent bench test study suggested sequential inflation as a simpler, and possibly equally effective, alternative to final kissing-balloon inflation.³³ Moreover, as pointed out in a previous pilot study, OCT guidance of distal cell recrossing reduced malapposition toward the SB by more than 80%, suggesting the use of OCT to improve percutaneous bifurcation interventions.³⁴ Yet, during the kissing inflation, the SB balloon produces a localized barotrauma followed by neointimal response, even if the SB ostium is free of disease. Hence, localized antiproliferative drug delivery in the SB is appealing even in non-true bifurcations.

Previous studies investigating DEB potential in the treatment of bifurcation lesions have implemented another approach consisting of sequential treatment of both the bifurcation branches prior to BMS implantation. The DEBIUT (Drug-Eluting Balloon in Bifurcations Trial) study assessed DEB in association with BMS in the treatment of bifurcation lesions in comparison to either a DES-based or BMS-based approach.³⁵ At 6-month follow-up, no significant differences in LLL were found between the DEB and BMS groups. The use of a first-generation DEB (ie, a balloon with a microporous surface on which paclitaxel was dissolved) with poor drug release properties³⁶ probably accounts for the lack of advantage associated with DEB use in this study, and doesn’t contribute significantly to the knowledge base on DEB treatment of bifurcation lesions. The PEPCAD (Paclitaxel-Eluting PTCA Balloon in Coronary Artery Disease) V trial showed a 9-month binary restenosis rate of 3.8% in the MV site and 7.7% in the SB.³⁷ In this study, patients were treated with a second-generation DEB that implemented a carrier molecule on the balloon surface to enhance paclitaxel binding and release during device tracking and inflation. Notably, the rate of SB binary restenosis was about half of that found when the SB is treated by either a second stent implantation or balloon inflation, as observed in major trials comparing simple to complex bifurcation treatment strategies.³⁸ However, among the 28 patients enrolled in this study, 2 experienced late stent thrombosis, which has been reported to depend on incomplete stent expansion. Remarkably, this untoward complication has been sometimes cited as a reason of concern for the treatment of complex lesions with DEB. However, no other stent thrombosis after DEB treatment of bifurcation lesions has been reported.¹³ Similar safety issues were raised regarding the association of a DEB with a BMS, on the basis of the clinical results of an unpublished study on an investigational device consisting of a BMS crimped onto a DEB.³⁹ However, safety endpoints in all published studies reporting on the systematic use of a DEB and BMS association do not support this concern.^40-42 

When approaching bifurcation lesions, the scaffolding properties of a stent are certainly of the highest importance due to the higher atherosclerotic burden of such complex lesions.⁴³ This cannot be accomplished by a BMS alone due to an unacceptably high rate of restenosis.^2,3 The results of our study actually support the use of DEB in association with a BMS as a valuable opportunity in the treatment of coronary bifurcation of patients who are not compliant with the prolonged DAPT required by DES when implanted in complex lesions. 

Study limitations. Some limitations apply to our study and underline its hypothesis-generating nature. First, the patient population of this study was limited to a small sample size given its exploratory character and the cost of the technology employed. However, our study is numerically comparable to the only other OCT study assessing DEB treatment prior to or following BMS implantation in simple coronary lesions (n = 10 and n = 12, respectively).⁴⁴ Also, no control group was planned because the study included patients with anticipated low compliance or contraindication to prolonged DAPT in whom DES implantation would have been unwise given its 12 months DAPT requirement. Also, different types of second-generation DEB were used in different patients, always coupling two of the same DEB type in each kissing-inflation procedure. This is a minor limitation since consistent findings were found independently of the DEB type. Indeed, the aim of the study was to assess the kissing DEB approach as an overall strategy rather than to test the performance of a specific DEB brand. This goal was planned on the coherent results provided by all different DEB types tested in the most studied setting of in-stent restenosis.^10,11,45-50 Although differences between DEB types were found comparing first-generation (without any molecular binder or excipient improving paclitaxel delivery to the vessel wall) and second-generation devices (implementing a molecular binder or excipient technology),^36,51,52 there is actually no evidence of different performances among second-generation DEB devices, thus suggesting that the efficacy of DEB technology is mainly linked to an effective transfer of the antiproliferative drug to the vessel wall. Also, the use of two DEB devices introduced in the coronary vasculature one after the other does not represent an issue for drug loss because of rubbing or drug dispersion in the bloodstream. Indeed, very effective inhibition of neointimal proliferation and similar values of neointimal thickness in both distal branches of the bifurcation (SB and distal MV), as well as its inverse gradient from the two branches to the proximal MV, suggest the lack of any significant drug loss. Finally, it should be acknowledged that geometry analysis relies on a limited observation.

Conclusion

In our study, OCT follow-up of coronary bifurcations treated according to a strategy of provisional BMS implantation followed by kissing DEB inflation has shown a mean neointimal thickness as low as published for some DES types and a rate of covered stent struts akin to BMS implantation. Moreover, due to its unique precision in assessing neointimal coverage, OCT suggests that these results could be possibly dependent on the quality of the kissing-balloon inflation, namely due to distal rather than proximal cell rewiring. These favorable findings deserve further clinical assessment and suggest a possibly important role of new stents designed for optimized SB access in association with DEB use in the treatment of bifurcation lesions in patients who are poor candidates for prolonged DAPT. Moreover, if our results were confirmed in an appropriately sized trial, the indication for the kissing DEB approach could also be extended to patients with anticipated good compliance with long-duration DAPT.

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From the ¹Division of Cardiology, Sant’Eugenio Hospital, Rome, Italy; ²National Heart Centre Singapore; ³Interventional Cardiology, S.M. Goretti Hospital, Latina, Italy; and ⁴Biomedical Research Unit, Royal Brompton & Harefield NHS Trust, London, United Kingdom.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts regarding the content herein. 

Manuscript submitted April 14, 2014, provisional acceptance given May 5, 2014, final version accepted July 31, 2014.

Address for correspondence: Dr Gregory A. Sgueglia, UOC Cardiologia, Piazzale dell’Umanesimo, 10, 00144 Rome, Italy. Email: g.a.sgueglia@gmail.com