Comparative assessment of the antirestenotic efficacy of two paclitaxel drug-eluting balloons with different coatings in the treatment of in-stent restenosis

Background/objectives Preclinical investigations have suggested that coating technology is crucial for the efficacy of drug-eluting balloons (DEB). Aim of this study is to compare the antirestenotic efficacy of two paclitaxel DEB with different coatings in the treatment of in-stent restenosis (ISR) by means of a morphological and functional assessment. Methods In a single center, prospective, non-randomized study, the shellac-paclitaxel coated DIOR, and the urea-paclitaxel coated IN.PACT Falcon were compared in the setting of ISR. Quantitative angiography, fractional flow reserve (FFR), and optical coherence tomography (OCT) were performed at baseline, postprocedure and 6-month follow-up. Main endpoints were QCA, FFR and OCT-based parameters of restenosis. Results Forty-five patients were included, 20 (44 %) received treatment with the DIOR and 25 (56 %) with the IN.PACT Falcon. Angiographic and device success were 100 and 90 % for the DIOR, and 100 and 92 % for the IN.PACT Falcon, respectively. After 6-months, in-segment late lumen loss (−0.03 ± 0.43 vs. 0.36 ± 0.48 mm, p = 0.014) and diameter stenosis (30.7 ± 16.2 vs. 41.3 ± 22.6 %, p = 0.083) were lower for the IN.PACT Falcon. FFR distal of the stent was significantly higher in the IN.PACT Falcon group (0.92 ± 0.07 vs. 0.84 ± 0.13, p = 0.029) and in-stent FFR gradient was lower (0.05 ± 0.05 vs. 0.13 ± 0.12, p = 0.002). Between postprocedure and follow-up, a 16 % decrease in neointimal volume was observed for the IN.PACT Falcon, while a 30 % increase was observed for the DIOR (p = 0.006). Conclusions The IN.PACT Falcon DEB showed higher antirestenotic efficacy than the DIOR in the treatment of ISR, demonstrating that DEB with an excipient-based coating is not equally effective. Electronic supplementary material The online version of this article (doi:10.1007/s00392-015-0934-0) contains supplementary material, which is available to authorized users.


Devices
The paclitaxel DEB used in this study are the DIOR II (EuroCor GmbH, Bonn, Germany) and IN.PACT Falcon (Medtronic Vascular Inc., Santa Rosa, CA, USA), both devices have been described in detail elsewhere [1,2].
Both DEB consist of a semi-compliant angioplasty balloon which is loaded with paclitaxel in a concentration of 3 µg/mm 2 balloon surface. The DIOR balloon coating contains shellac (a natural resin composed of shellolic and alleuritic acid) as excipient in a 1:1 mixture with paclitaxel and is applied to the balloon surface through a micropipetting procedure. The IN.PACT Falcon is coated with the FreePac TM hydrophilic coating formulation, which contains the naturally occurring urea as excipient, by a dispersion method. Recommended inflation time is 30 to 60 seconds for both DEB to allow sufficient drug transfer to the vessel wall.

Quantitative coronary angiography, optical coherence tomography and fractional flow reserve
All study investigations were performed before the procedure, immediately after the procedure and at 6-months follow-up. Quantitative Coronary Angiography (QCA) and Optical Coherence Tomography (OCT) images were analyzed by an independent operator. Dedicated software (CAAS 5.9.1 Research Edition, Pie Medical Imaging, Maastricht, The Netherlands) was used to perform QCA in a standardized fashion [3]. In the preprocedure, postprocedure and follow-up images, the stent(s) and additional 5 mm proximal and distal to the stent(s) edges were analyzed. Lesion length and minimal lumen diameter were directly determined by the QCA software, whereas reference vessel diameter was estimated by an interpolation method. Percent diameter stenosis was subsequently computed. Binary restenosis was defined as diameter stenosis ≥50% at angiographic follow-up. Late lumen loss was defined as the difference in postprocedure and follow-up minimal lumen diameter in the same segment (proximal to the stent, in-stent, distal to the stent or in-segment).  [4]. Automated pullback speed and frame rate were 2 mm/s and 20 fps for the M3 and 20 mm/s and 100 fps for the C7XR system, respectively. All cross-sectional images (frames) were screened for quality and excluded if reliable analysis was impeded by residual blood, side-branches, imaging artifacts or reverberation, or if any portion of the stent was out of the screen.
Dedicated software (Curad BV, Amsterdam, The Netherlands) including automated contour detection algorithms was used for image analysis. Two contours were automatically delineated: the lumen contour (for each frame) and the stent contour (every 2 frames for the C7XR and every 5 frames for the M3 system, corresponding with every 0.4 and 0.5 mm, respectively). In-between frames an automated contour interpolation was performed. Manual corrections were applied where needed. Lumen, stent and neointima dimensions were calculated by the software.
Stent struts were semi-automatically detected and classified as: covered embedded, covered protruding, uncovered apposed, and malapposed. Definitions and strut classification were outlined in a previous publication [1].

Follow-up and endpoints
Angiographic follow-up was scheduled per protocol at 6 months, unless indicated earlier on clinical grounds.
Clinical follow-up was obtained simultaneously with angiography or by telephone interviews at 6 months. All clinical events were documented after careful examination of relevant hospital files.
Antirestenotic efficacy, the outcome of interest, refers to the potency of the DEB to inhibit neointimal growth, not to the prevention of clinical restenosis per se. Main endpoints of this study were angiographic insegment late luminal loss (LLL) and diameter stenosis, percentage changes in FFR and OCT parameters, and clinical outcomes according to the Academic Research Consortium criteria. Target lesion revascularization (TLR) was defined as any repeat intervention (percutaneous or surgical) to address recurrent restenosis of the treated segment (including the stent and the proximal and distal 5 mm segments). Revascularization of a target lesion was clinically indicated in case of restenosis >50% associated with angina pectoris and/or objective signs of ischemia (stress test or FFR), or in case of restenosis >70% in the absence of the above mentioned signs or symptoms.
Angiographic success was defined as attainment of final residual stenosis <30% (by visual estimation) and TIMI 3 flow, using any percutaneous technique. Device success was defined as achievement of angiographic success by using the DEB device (no additional stenting allowed). Procedural success was defined as angiographic success in the absence of any in-hospital major adverse cardiac events.