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Paclitaxel eluting balloon plus spot bare metal stenting for diffuse and very long coronary disease. (PEB-long pilot study)
Clinical Trials and Regulatory Science in Cardiology 27 (2017) 1–7
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Paclitaxel eluting balloon plus spot bare metal stenting for diffuse and very long coronary disease. (PEB-long pilot study) Ahmed Rezqa,c,d,f,⁎, Giuseppe Biondi Zoccaib, Azeem Latibc,d, Enrico Romagnolie, Alessandro Aprilef, Andrea Amatof, Maria Grazia Modenaf, Antonio Colomboc,d, Giuseppe Sangiorgig a
Department of Cardiology, Ain Shams University, Cairo, Egypt Department of Cardio-Thoracic Surgery, University of Roma La Sapienza, Rome, Italy c Interventional Cardiology Unit, San Raffaele Scientific Institute, Milan, Italy d Interventional Cardiology Unit, EMO-GVM Centro Cuore Columbus, Milan, Italy e Department of Cardiology, Policlinico Casilino, Rome, Italy f Interventional Cardiology Unit, University of Modena and Reggio Emilia, Modena, Italy g Department of Internal Medicine, Cardiac Cath Lab, University of Tor Vergata, Rome, Italy b
A R T I C L E I N F O
A B S T R A C T
Keywords: PEB Spot BMS PEB plus BMS Long lesions
Background: Albeit DES might be considered as a breakthrough against neointimal hyperplasia, concerns on stent thrombosis and increase incidence of in-stent restenosis after multiple DES implantations in complex, long lesions still exist. Hereby, we tried to test efficacy and safety of using PEB in long lesions followed by focal BMS implantation in a pilot multicenter study. Methods: This study enrolled 16 patients with long lesions (> 30 mm) that were treated with PEB angioplasty followed by focal stenting with BMS. IVUS was performed before, after PEB and post stenting. Clinical and angiographic follow-up was done at 6 months. The primary end-point was angiographic late lumen loss. Results: Patient age was 64.6 ± 8.1 years, 15 (93.7%) were males, and 7 (43.7%) diabetics. Target vessels were most commonly the left anterior descending (6 [31.6%]) and the right coronary artery (6 [31.6%]). PEB diameter was 2.8 ± 0.4 mm with a 31.3 ± 8.9 mm length. Stents per patient were 2.1 ± 0.8. No overlapping stents were deployed. Angiographic success was achieved in 100% of patients. Peri-procedural myocardial infarction occurred in 4 patients (25%). At 6 months follow-up angiography, MLD was 1.55 ± 0.53 mm with a late loss of 0.48 ± 0.52 mm, a binary re-stenosis rate of 2 (12.5%). Conclusion: Using PEB with focal stenting by BMS proved to be a feasible, safe, and promising strategy in long coronary lesions. However larger study are needed to confirm these data.
1. Introduction Plain balloon angioplasty revolutionized coronary revascularization but early elastic recoil and long-term neointimal formation caused by smooth muscle cellular proliferation remained the major drawback of this technique in the early period of mechanical revascularization [1]. Nowadays, the use of drug-eluting stents (DES) significantly attenuates the cellularity and the need for repeat revascularization. However, late stent thrombosis, dependency on prolonged dual antiplatelet therapy (DAT), and restenosis (all of which had declined with advanced technologies, and new generation stents) led to a quest for new treatment modalities [2]. One of the problems with the use of DES is the failure to convey the drug to the entire vessel wall, allowing areas
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for potential cellular growth in the gaps between the struts [3]. Recently, with the introduction of drug eluting balloons (DEB), local delivery of the anti-proliferative drugs directly to the vessel wall was achieved, eliminating the potential problems of stenting especially in small sized vessels [4]. In addition, the absence of polymer might reduce the chronic inflammation and theoretically decreases the triggers for late stent thrombosis [5]. However, DEB are still unable to overcome the problem of acute elastic recoil after balloon angioplasty. The combination of a DEB with bare metal stents (BMS) might help to overcome this limitation without long term dependence on DAT [1]. In this study we evaluated the efficacy of the combination of DEB plus spot stenting using BMS in long coronary lesions.
Corresponding author at: Department of cardiology, Ain Shams University, Cairo, Egypt. E-mail address: [email protected] (A. Rezq).
http://dx.doi.org/10.1016/j.ctrsc.2017.04.001 Received 13 September 2016; Received in revised form 6 April 2017; Accepted 11 April 2017 Available online 25 April 2017 2405-5875/ © 2017 Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).
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2. Study hypothesis and objectives
3.3. Quantitative coronary angiography (QCA)
Our hypothesis was that paclitaxel-eluting balloon (PEB) plus spot BMS implantation might help in reducing restenosis rates in long coronary artery lesions. Combination with spot stenting using BMS could be a reasonable option particularly if long term DAT is not recommended. Thus, the aim of the study was to assess the efficacy of this combination technique in terms of rates of restenosis, late loss, binary stenosis, as well as the occurrence of major adverse cardiac events (MACE).
Angiograms were analyzed by an independent, angiographic core laboratory (I3SD, Rome, Italy) using a computer based system (Medis v 7.2, Leidin, the Netherlands). QCA was performed before and after using PEB as well as after stenting for the whole length of the plaque to evaluate the reference vessel diameter (RVD), minimal lumen diameter (MLD), percentage of diameter stenosis (%DS) and percentage of area stenosis (%AS). At 6 months follow up, QCA was performed for the follow up angiograms to determine the binary stenosis and late lumen loss.
2.1. Device description 3.4. In-hospital assessment and clinical follow-up IN.PACT Falcon (Invatec, Roncadelle, Italy) is a drug-eluting coronary angioplasty balloon catheter designed specifically to treat atherosclerotic lesions in coronary arteries. The drug utilized is paclitaxel at a concentration of 3 μg per mm2 and the coating is the proprietary Freepac, utilized to frees and separates paclitaxel molecules and facilitates their absorption into the wall of the artery. Free Pac reduces the total drug (Paclitaxel) elution time to 30 to 60 s; balloon inflation beyond 60 s can be maintained without additional drug release. 3. Methods
All patients underwent pre-procedural, 6 and 12 h blood draws to measure CK, CK-MB mass. In hospital follow up was performed to detect other possible complications including acute and subacute stent thrombosis, hemorrhagic complications and cerebrovascular stroke. All patients were given DAPT during their hospital stay and for one month after discharge. Following discharge, telephone-based interviews and office-based direct visits were performed at 1and 6 months, for endpoint adjudication. Coronary angiography was performed at 6 months for all enrolled patients. QCA was done at the time of angiographic control to evaluate the late loss and binary stenosis.
3.1. Study design and patient population
3.5. Endpoints
This study was designed as a multicenter, non randomized study that was conducted on a consecutive series of patients presented in our cath lab. All patients had long atherosclerotic coronary artery lesions ≥ 30 mm at the coronary angiogram by visual estimation and subsequent IVUS confirmation. All patients provided written informed consent to the procedure. Major exclusion criteria were: ST-segment elevation myocardial infarction (STEMI), serum creatinine > 2.5 mg/dL, stenosis of the unprotected left main coronary artery, visible thrombus within the target lesion, previous PTCA in the same vessel, contraindication or suspected intolerance to double anti-platelet drug therapy.
The primary end-point was the late luminal loss as well as the rate of binary restenosis of the deployed BMS at 6 months angiographic followup. Secondary endpoints were major adverse cardiovascular events (MACE), defined as the composite of cardiovascular death, non-fatal myocardial infarction, or clinically driven target vessel revascularization (TVR). 3.6. Definitions Late lumen loss, the primary study end-point, was defined as the difference between the minimal lumen diameter at the completion of the stent procedure and at 6 months follows up. Binary stenosis is defined as > 50% diameter stenosis in the target lesion. Myocardial infarction was distinguished as new pathologic Q-waves in > 2 contiguous leads or non-Q-wave MI (peak CK-MB mass > 3 times the upper limit of normal together with abnormal CK). Angiographic success is defined as a < 50% residual stenosis in the target vessel, with TIMI 3 flow at the end of the procedure. Procedural success is defined as angiographic success without the occurrence of death, non-Q-wave or Q-wave MI, and repeat revascularization of the target lesion during hospital stay. Target lesion revascularization (TLR) was defined as a revascularization procedure (repeat angioplasty or coronary bypass surgery) performed because of angiographic restenosis at the site of the lesion treated associated with clinical (patient symptoms) or objective evidence (stress test, myocardial scintigraphy) of myocardial ischemia for lesions between 50 and 70%. Re-interventions was considered appropriate for lesions over 70% even in absence of ischemia. Any revascularization procedure (PTCA, Stenting or CABG) performed on the stented vessel and/or on its proximal segment was defined as Target vessel revascularization (TVR). Stent thrombosis was classified utilizing the Academic Research Consortium (ARC) definition as definite, probable, or possible and as early (0 to 30 days), late (31 to 360 days), or very late (> 360 days) [7]. The definition of definite stent thrombosis required the presence of an acute coronary syndrome with angiographic or autopsy evidence of thrombus or occlusion. Probable stent thrombosis included unexplained deaths within 30 days after the procedure or acute myocardial infarc-
3.2. Procedure Coronary angioplasty and intracoronary stent implantation were performed using standard percutaneous techniques [6]. All patients enrolled received 325 mg of aspirin and a 300 mg loading-dose of clopidogrel 12 h before the procedure, respectively if not on chronic utilization. Intravenous heparin was administered to maintain an activated clotting time ≥ 250 s during the procedure. Administration of glycoprotein IIb/IIIa inhibitors was left to the operator's discretion. Eagle's eye intravascular ultrasound (IVUS) catheter (Volcano corp.) was introduced along a 0.014″ guide wire, to assess plaque burden and minimal lumen diameter. Then, standard semi-compliant (uncoated) PTCA balloons were introduced to pre-dilate the lesions from distal to proximal with balloon to artery ratio of 0.75:1. Paclitaxel eluting balloon (PEB); IN·PACT Falcon (Medtronic, US) was then introduced across the lesion and was inflated once for single drug delivery from distal to proximal with balloon to artery ratio of 1:1. Inflation time was ≥ 50 s, and inflation pressure did not exceed the burst pressure of the balloon. If the balloon did not covered the entire lesion length a second one was utilized. IVUS was then performed again to evaluate the plaque, and guide the decision of focal stenting at the spots of heavy thrombus burden, tight stenosis or possible dissection. Focal stenting with BMS was performed either at the sites of flow limiting dissection, or at the sites of residual stenosis ≥30% as assessed angiographically and by IVUS. At the end of the procedure, IVUS was performed again to evaluate the residual plaque burden, the stent symmetricity index, and stent eccentricity index. 2
3
2.34 ± 0.53 mma
2.86 ± 0.43 mma
3.33 ± 0.48 mma
4.16 ± 0.6 mma
2.54 ± 0.28 mma
61.69 ± 5.8%b
2.82 ± 0.55 mma
58.15 ± 9.6%b
2.042 ± 0.32 mma
3.88 ± 0.44 mma
57.48 ± 11.8%b
2.32 ± 0.29 mma
1.94 ± 0.32 mma
3.48 ± 0.33 mma
3.13 ± 0.3 mma
2.52 ± 0.3 mma
2.21 ± 0.25 mma
3.22 ± 0.23 mma
2.92 ± 0.24 mma
3.12 ± 0.61 mma
2.72 ± 0.53 mma
4.16 ± 0.64 mma
3.8 ± 0.55 mm
12.63 ± 3.68 mm2a 6.92 ± 2.7 mm2
4.32 ± 0.47 mma
3.43 ± 0.42 mma
7.485 ± 1.73 mm2a 4.47 ± 1.067 mm2a
3.75 ± 0.66 mma
8.66 ± 1.6 mm2a 3.65 ± 0.95 mm2a
3.96 ± 0.43 mma
10.83 ± 2.48 mm2a 4.03 ± 0.97 mm2a
0.588 ± 0.078a 1.62 ± 2.38a
3.3 ± 0.92 mma
3.1 ± 0.53 mma
4.49 ± 0.62 mma
4.14 ± 0.58 mma
14.32 ± 4.72 mm2a 8.48 ± 2.98 mm2a
1.54 ± 3.2a 1.6 ± 2.4a
3.25 ± 0.57 mma
2.8 ± 0.59 mma
4.12 ± 0.67 mma
3.8 ± 0.7 mma
12.32 ± 4.64 mm2a 7.26 ± 2.8 mm2a
Mid lesion
12.86 ± 4.19 mm2a 5.51 ± 2.43 mm2a
Prox. lesion
13.49 ± 2.82 mm2a 7.74 ± 2.2 mm2a
Min. = minimal, Max. = maximal, Prox. = proximal, Ref. = reference. SEI = stent eccentricity index, SSI = stent symmetricity index. a Data are presented as the mean value ± SD. b Data are expressed as mean percentages.
Vessel area Lumen area Min. vessel diameter Max. vessel diameter Min. lumen diameter Max. lumen diameter Plaque burden Post stenting (final result) SEI SSI
Distal Ref. vessel
Prox. Ref. vessel
Distal lesion
Prox. lesion
Prox. Ref. vessel
Mid lesion
IVUS measurements post PEB and final results post stenting
Baseline IVUS measurements
Table 1 IVUS measurements.
1.38 ± 2.7a 1.35 ± 1.52a
2.65 ± 0.26 mma
2.27 ± 0.29 mma
3.64 ± 0.38 mma
3.35 ± 0.36 mma
9.48 ± 1.67 mm2a 5 ± 1.46 mm2a
Distal lesion
2.6 ± 0.3 mma
2.26 ± 0.28 mma
3.25 ± 0.3 mma
2.98 ± 0.3 mma
7.6 ± 1.4 mm2a 4.7 ± 1.02 mm2a
Distal Ref. vessel
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tion involving the target-vessel territory without angiographic confirmation. Possible stent thrombosis included all unexplained deaths occurring at least 30 days after the procedure. 3.7. Statistical analysis All statistical analyses were performed with SPSS for Windows (version 18.0, Chicago, USA). Continuous variables were described as mean ± SD, and categorical variables were reported as percentages or proportions. 4. Results 4.1. Patient characteristics The clinical characteristics of the patients are described in Table 1. A total of 16 patients (19 target vessels) were enrolled, with a mean age of 64.6 ± 8.1 years, 15 (93.7%) males, 7 (43.7%) diabetics, 8 (50%) hypertensives, 7 (43.7%) smokers, 8 (50%) hypercholesterolemics, 2 (12.5%) with chronic renal impairment, and 1 (6.3%) with chronic obstructive pulmonary disease (COPD). Nine (56.3%) patients had history of previous acute coronary syndrome, and 1 (6.3%) had undergone coronary artery bypass grafting (CABG). 4.2. Angiographic and procedural data A total of 19 target vessels were treated; 6 (31.6%) LADs, 6 (31.6%) RCAs, 2 (10.5%) LCX, 4 (21.1%) Obtuse Marginal branch and 1 (5.3%) Diagonal branch. As for the lesion type, all were type C. Mean lesion length was 73.81 ± 18.5 mm. Mean diameter of the PTCA balloons was 2.3 ± 0.3 mm, inflated at a mean pressure of 8.6 ± 2.1 atm. The mean diameter of the PEB used was 2.8 ± 0.4 mm, and the mean length was 31.3 ± 8.9 mm. They were inflated at a mean of 6.2 ± 1.4 atm. Focal stenting using BMS was performed in 16 (84.2%) vessels, while in 3 (15.8%) diffusely diseased vessels, satisfactory results were obtained after using PEB, and no stenting was performed in these cases. Stenting was performed as a bailout technique in cases of dissection (2 vessels, 10.5%) or unsatisfactory result of balloon dilatation based on IVUS evaluation in 14 (73.7%). No other intraprocedural complications were encountered (including vessel perforation, major side branch compromise, balloon rupture, false lumen stenting, IVUS induced complications as dissection or perforation, slow flow after balloon dilatation or stenting, or cardiac tamponade). The mean stent diameter was 2.86 ± 0.34 mm, mean length was 16 ± 3.4 mm, and they were inflated at a mean atmospheric pressure of 11.4 ± 0.93 atm. Number of stents per patient were 2.1 ± 0.8, and number of stents per vessel were 1.7 ± 0.8 stents. No overlapping stents were deployed. IVUS showed a baseline mean minimal lumen diameters (MLD) of “2.34 ± 0.53 mm, 2.04 ± 0.32 mm, 1.94 ± 0.32 mm” and a lumen area of “5.5 ± 2.43 mm2, 4.03 ± 0.97 mm2, 3.65 ± 0.95 mm2 “at proximal, mid and distal lesions respectively. Plaque burden was “58.15 ± 9.6%, 61.69 ± 5.8%, 57.48 ± 11.8%” for proximal, mid and distal segments respectively. Post PEB, MLDs were “3.1 ± 0.53 mm, 2.8 ± 0.59 mm, 2.27 ± 0.29 mm”, and lumen areas were “8.48 ± 2.98 mm2, 7.26 ± 2.8 mm2, 5 ± 1.46 mm2” for the proximal, mid segment and distal lesions respectively. (Tables 1) (Fig. 1A, B, C). Quantitative coronary angiography (QCA) showed a baseline mean MLD of 0.7 ± 0.35 mm. MLD post PEB was 1.56 ± 0.41 mm, post stenting was 2.015 ± 0.24 mm with an acute gain of 1.27 ± 0.45. At 6 months follow up angiography, MLD was 1.55 ± 0.53 mm with a late loss of 0.48 ± 0.52. Binary re-stenosis (diameter stenosis > 50%) was detected in 2 patients (16.7%) out of 12 (both in RCA lesions).The rest of QCA details are described in Table 2.
Fig. 1. Intravascular ultrasound (IVUS) still frame showing: A. Fibrocalcific plaque in a right coronary artery. Plaque burden is 72.7%, MLA is 2.2 mm2, MLD is 1.6 mm. B. The same plaque after using PEB. Plaque burden is 49.8%, MLA is 3.9 mm2, MLD is 1.8 mm. C. MLD post stenting 2.9 mm, MLA 6.9 mm2.
4.3. In hospital and 6 months follow up Periprocedural ischemia was detected in 4 patients (25%) with the mean value of the post procedural CPK-MB fraction among the study population 6.9 ± 5.4 IU/L (Normal value = 0–3.5 IU/L). Otherwise, no other complications were recorded during the in-hospital stay among the study group. At 6 months follow up, TLR was needed in 2
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Table 2 Quantitative coronary angiography measurements of the target vessels.
Baseline QCA QCA post PEB QCA post stenting Follow up QCA Acute gain Late loss
Lesion length (mm)
RVD (mm)
MLD (mm)
% diameter stenosis
% area stenosis
73.81 ± 18.5 72.6 ± 17.9 74.46 ± 23.4 73.82 ± 21 1.27 ± 0.45 0.48 ± 0.52
2.36 ± 0.56 2.51 ± 0.58 2.9 ± 0.3 2.43 ± 0.78
0.7 ± 0.35 1.56 ± 0.41 2.015 ± 0.24 1.55 ± 0.53
69.93 ± 13.4 37.8 ± 8.7 30.42 ± 5.63 40.46 ± 17.5
89.27 61 ± 51 ± 60.92
± 8.09 11.4 8.6 ± 13.4
Data are presented as the mean value ± SD.
specifying the MLD or dissections that necessitate stenting and thereby, reduces the geographic miss. This study opens a new horizon for interventional cardiologists in terms of optimizing the treatment for diffusely diseased coronaries. Treating long atherosclerotic lesions has always been a debate among operators. Many strategies have been adopted for such long and complex lesions as long drug eluting stents deployment, overlapping stents or full metal jacket. However, problems were always the occurrence of restenosis and neointimal formation post stenting [8–10]. Our group has previously demonstrated that stent length is an independent predictor of restenosis and a significant difference in the rate of restenosis as well as the occurrence of MACE within 6 months follow up was evident between groups treated with short focal stents and those treated with long ones [11–12]. Moreover, we have also demonstrated that in this patient subset the utilization of overlapping stents significantly increases the incidence of Non-Q wave MI (16.6%) and acute in-stent thrombosis during hospital stay and at 6 months follow up [13]. Many other studies also demonstrated that full metal jacket carried a higher incidence of MACE including higher mortality and TLR, and obviously making the native vessels inoperable if bypass is needed thereafter [14]. Posa et al. [15] have shown that short exposure of the coronary artery to paclitaxel with a coated balloon resulted in a significant accumulation of the drug in the arterial tissue. Forty-eight hours postdilatation the investigators could still detect about 25% of the paclitaxel, thereby suggesting high concentrations of paclitaxel are maintained in the tissue for long periods of time even after a single administration. This makes paclitaxel a promising candidate for local drug therapy independent of stent, intended to address the proliferative and migratory processes involved in restenosis [16,17]. This might be also attributed to the fact that Paclitaxel is highly lipophilic and binds quickly and tightly to the tissue, resulting in rapid cellular uptake and retention at the site of delivery. When compared with hydrophilic drugs, the efficacy of local drug delivery is 10 to 20 times higher for lipophilic drugs [18]. The potential advantages of non-stent-based local drug delivery are numerous: (1) it could allow a homogenous drug transfer to the vessel wall and not only to the areas directly covered by the stent strut. This uniformity of deliverance could enhance the efficacy of the drug to the artery; (2) the drug concentrations at the vessel wall would be the highest at the time of injury when the neointimal process is the most vigorous. Afterward, the absence of drug in the arterial wall could help to better re-endothelialize the stent (if used) and limit the risk for late stent thrombosis; (3) the absence of polymer could decrease the stimulus of chronic inflammation and the trigger for late thrombosis; (4) the absence of a stent allows preserving the original anatomy of the arteries, notably in cases of bifurcation or small vessels, leaving no stent scaffold and hence, diminishing abnormal flow patterns observed in these cases with stent implantation; (5) overdependence on antiplatelet therapy could be limited, especially in patients requiring urgent surgical interventions or when long term DAT is not recommended. (6) Local drug delivery could also be applied in situations where stents are not used or undesirable, such as in very small vessels, in-stent restenosis, or for the treatment of the side branch in bifurcation lesions;
Fig. 2. Angiographic picture showing: A. Final angiographic result after using PEB + spot stenting with 2 BMS, Distally 2.25 × 13 and proximally 3 × 18. B. Follow up angiographic result after 6 months.
patients (12.5%) (Fig. 2 A,B). The first had a chronic total occlusion at the distal edge of the stent deployed in the mid RCA, while the other had significant type II instent restenosis (ISR) in the distal RCA. However, no other MACE were reported in the study group. 5. Discussion This pilot study demonstrated that; 1) PEB could be considered as an interesting treating modality in long atherosclerotic lesions with satisfactory short term results (6 months late loss of 0.48 ± 0.52) avoiding the need of overlapping DES placement for long segment of the vessel. 2) This treatment modality could reduce the peri-procedural CPK-MB increase as seen in previous study from our group with full metal jacket stenting. 3) PEB + BMS might be well thought-out as a favorable therapy particularly in cases where long term DAT is contraindicated. 4) IVUS might help optimizing the use of PEB + BMS by 5
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and (7) finally, if a stent was used, there would be no limitation to a particular type of stent. It is worthy to point out that DEB for de novo lesions is less studied. The only registry available is PEPCAD I, which targeted small vessels [19]. Of the 114 patients treated with DEB, 32 required stenting postprocedural. The late loss and binary restenosis in the DEB-alone group was only 0.18 ± 0.38 mm and 5.5% respectively, while the DEB with BMS had higher late loss and restenosis of 0.73 ± 0.74 mm and 44.8%, respectively. In addition, the rate of stent thrombosis in the DEB and BMS group was 6.3%. The authors attributed the poor results of the DEB with BMS to geographic miss and concluded that the paclitaxel-eluting balloon catheter, SeQuent Please (B.·Braun Melsungen AG, Melsungen, Germany) was safe, was associated with a high procedural success rate in small de novo lesions, and exhibited low late lumen loss after 6 months in small vessel disease. The question of DEB in conjunction with BMS remains a concern because of high restenosis rates. Angiographic results of drug eluting stents (DES) were superior to both BMS and DEB in the setting of acute myocardial infarction as was demonstrated in the DEB-AMI study. Moreover, DEB before implantation induced more uncovered and malapposed stent struts than BMS, but less than after DES [20]. In addition, combination therapy with DEB was recently reported. Scoring balloon (SCB) devices prevent balloon slippage and enhance local plaque disruption during angioplasty but have failed to demonstrate an advantage when used as stand-alone therapy. As an adjunct to DEB, scoring balloon pre-dilatation might enhance tissue uptake and improve clinical outcomes. ISAR-DESIRE 4 trial enrolled 252 patients with limus-eluting stent restenosis and signs of ischemia. Patients were randomized 1:1 to a scoring balloon plus paclitaxel-coated balloon (N = 125) or standard balloon plus paclitaxel-coated balloon (N = 127) during angioplasty. The primary endpoint was the percent diameter stenosis at follow-up angiography. The results were 40.4% ± 21.4 for the SCB plus PCB group vs. 35% ± 16.8 for the PCB-alone group (p = 0.047). The secondary endpoint of binary restenosis was also lower in SCB plus PCB compared to PCB alone (18.5% vs. 32%, P = 0.03). The rates of target lesion revascularization (16.8% vs. 22.6%, P = 0.25) and death/myocardial infarction (3.4% vs. 3.3%, P > 0.99) were similar for both groups. The results of our study seem to be very promising, as the acute angiographic success was achieved in 100% of patients. Cumulative MACE as well as TLR were detected in 2 (12.5%) patients, with no other MACE detected. Acute gain and late loss of 1.27 ± 0.45 mm and 0.48 ± 0.52 mm respectively might hold up the appliance of this novel technique till large randomized studies are designed to attest this concept. On the other hand, operators should pay heed to the geographic miss that resulted in the disappointing results of DEB + BMS group of the PEPCAD I study. Utilizing IVUS might help the operators to identify precisely the tightest spots, or dissections that require spot stenting with a BMS following PEB. It seems that using PEB and spot BMS should be delicately performed with great meticulousness, in order to obtain the finest results. BMS should be deployed as a bailout in cases of dissections and enduring tight stenoses after PEB and should be as short as possible to curtail the occurrence of ISR.
7. Conclusions The use of drug-coated balloons appears to hold promise as a viable alternative to stand-alone balloon angioplasty and stent implantation for the treatment of de novo coronary lesions. This study demonstrated that the use of PEB combined with focal stenting using BMS might improve the outcome of patients affected by diffuse coronary disease. This technique could be considered as a bailout strategy whenever long term DAT is not recommended. However, data from large clinical trials and registries are needed in order to verify the safety and efficacy of this strategy. References [1] Ron Waksman, RajbabuPakala, Drug-eluting balloon: the comeback kid? Circ. Cardiovasc. Interv. 2 (2009) 352–358. [2] E. Camenzind, P.G. Steg, W. Wijns, Stent thrombosis late after implantation of firstgeneration drug-eluting stents: a cause for concern, Circulation 115 (2007) 1440–1455. [3] J.W. Moses, M.B. Leon, J.J. Popma, P.J. Fitzgerald, D.R. Holmes, C. O'Shaughnessy, R.P. Caputo, D.J. Kereiakes, D.O. Williams, P.S. Teirstein, J.L. Jaeger, R.E. Kuntz, S.I.R.I.U.S. Investigators, Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery, N. Engl. J. Med. 349 (2003) 1315–1323. [4] A. Latib, A. Colombo, F. Castriota, A. Micari, A. Cremonesi, F. De Felice, A. Marchese, M. Tespili, P. Presbitero, G.A. Sgueglia, F. Buffoli, C. Tamburino, F. Varbella, A. Menozzi, A randomized multicenter study comparing a paclitaxel drug-eluting balloon with a paclitaxel-eluting stent in small coronary vessels: the BELLO (Balloon Elution and Late Loss Optimization) study, J. Am. Coll. Cardiol. 60 (24) (2012) 2473–2480. [5] A. De Labriolle, R. Pakala, L. Bonello, G. Lemesle, M. Scheinowitz, R. Waksman, Paclitaxel-eluting balloon: from bench to bed, Catheter. Cardiovasc. Interv. 73 (2009) 643–652. [6] D.R. Holmes Jr., Technical aspects, in: R.E. Vliestra, D.R. HolmesJr. (Eds.), Percutaneous Transluminal Coronary Angioplasty, F.A. 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Popma, J. Koglin, M.E. Russell, TAXUS V Investigators, Comparison of a polymer-based paclitaxel-eluting stent with a bare metal stent in patients with complex coronary artery disease: a randomized controlled trial, JAMA 294 (2005) 1215–1223. [11] Jong-Young Lee, Duk-Woo Park, Young-Hak Kim, Sung-Cheol Yun, Won-Jang Kim, Soo-Jin Kang, Seung-Whan Lee, Cheol-Whan Lee, Seong-Wook Park, SeungJung Park, Incidence, predictors, treatment, and long-term prognosis of patients with restenosis after drug-eluting stent implantation for unprotected left main coronary artery disease, J. Am. Coll. Cardiol 57 (2011) 1349–1358. [12] Ioannis Iakovou, Thomas Schmidt, Erminio Bonizzoni, Lei Ge, Giuseppe M. Sangiorgi, Goran Stankovic, Flavio Airoldi, Alaide Chieffo, Matteo Montorfano, Mauro Carlino, Iassen Michev, Nicola Corvaja, Carlo Briguori, Ulrich Gerckens, Eberhard Grube, Antonio Colombo, Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents, JAMA 293 (2005) 2126–2130. [13] Eleftheria Tsagalou, Alaide Chieffo, Ioannis Iakovou, Lei Ge, Giuseppe M. Sangiorgi, Nicola Corvaja, Flavio Airoldi, Matteo Montorfano, Iassen Michev, Antonio Colombo, Multiple overlapping drug-eluting stents to treat diffuse disease of the left anterior descending coronary artery, J. Am. Coll. Cardiol. 45 (2005) 1570–1573. [14] E.J. Topol, P.W. Serruys, Frontiers in interventional cardiology, Circulation 98 (1998) 1802–1820. [15] A. Posa, R. Hemetsberger, O. Petnehazy, Z. Petrasi, M. Testor, D. Glogar, M. Gyöngyösi, Attainment of local drug delivery withpaclitaxel-eluting balloon in porcine coronary arteries, Coron. Artery Dis. 19 (2008) 243–247. [16] S.J. Sollot, L. Cheng, R.R. Pauly, G.M. Jenkins, R.E. Monticone, M. Kuzuya, J.P. Froehlich, M.T. Crow, E.G. Lakatta, E.K. Rowinsky, J.L. Kinsella, Taxol inhibits neointimal smooth muscle cell accumulation after angioplasty in the rat, J. Clin. Invest. 95 (1995) 1869–1876. [17] M.D. Sauro, D.A. Camporesi, R.L. Sudakow, The anti-tumor agent, taxol, attenuates contractile activity in rat aortic smooth muscle, Life Sci. 56 (1996) PL157–PL161. [18] C. Herdeg, M. Oberhoff, A. Baumbach, A. Blattner, D.I. Axel, S. Schröder, H. Heinle, K.R. Karsch, Local paclitaxel delivery for the prevention of restenosis: biological
6. Study limitations This is a pilot study with a very limited number of patients, therefore obtained data can't be considered sufficient to establish the safety and efficacy of this strategy. Using BMS in a diffusely diseased vessel especially in diabetic patients carried the risk of having a high incidence of ISR, however, our hypothesis was to prove that using DEB plus spot BMS may reduce the incidence of peri-procedural and longterm events in pts affected by diffuse coronary artery disease.
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ChunLai Shao, Eric Van Belle, Thierry Wildbergh, Luigi Politi, Pieter A. Doevendans, Giuseppe M. Sangiorgi, Pieter R. Stella, First results of the DEB-AMI (drug eluting balloon in acute ST-segment elevation myocardial infarction) trial a multicenter randomized comparison of drug-eluting balloon plus bare-metal stent versus bare-metal stent versus drug-eluting stent in primary percutaneous coronary intervention with 6-month angiographic, intravascular, functional, and clinical outcomes, J. Am. Coll. Cardiol. 25 (2012) 2327–2337.
effects and efficacy in vivo, J. Am. Coll. Cardiol. 35 (2000) 1969–1976. [19] L.S. Maier, C. Maack, O. Ritter, M. Böhm, Hotline update of clinical trialsand registries presented at the German Cardiac Society meeting 2008. (PEPCAD, LokalTax, INH, German ablation registry, German device registry, DESDE registry, DHR, Reality, SWEETHEART registry, ADMA, GERSHWIN), Clin. Res. Cardiol. 97 (2008) 356–363. [20] Anouar Belkacemi, Pierfrancesco Agostoni, Hendrik M. Nathoe, Michiel Voskuil,
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Contents lists available at ScienceDirect
Clinical Trials and Regulatory Science in Cardiology journal homepage: www.elsevier.com/locate/ctrsc
Paclitaxel eluting balloon plus spot bare metal stenting for diffuse and very long coronary disease. (PEB-long pilot study) Ahmed Rezqa,c,d,f,⁎, Giuseppe Biondi Zoccaib, Azeem Latibc,d, Enrico Romagnolie, Alessandro Aprilef, Andrea Amatof, Maria Grazia Modenaf, Antonio Colomboc,d, Giuseppe Sangiorgig a
Department of Cardiology, Ain Shams University, Cairo, Egypt Department of Cardio-Thoracic Surgery, University of Roma La Sapienza, Rome, Italy c Interventional Cardiology Unit, San Raffaele Scientific Institute, Milan, Italy d Interventional Cardiology Unit, EMO-GVM Centro Cuore Columbus, Milan, Italy e Department of Cardiology, Policlinico Casilino, Rome, Italy f Interventional Cardiology Unit, University of Modena and Reggio Emilia, Modena, Italy g Department of Internal Medicine, Cardiac Cath Lab, University of Tor Vergata, Rome, Italy b
A R T I C L E I N F O
A B S T R A C T
Keywords: PEB Spot BMS PEB plus BMS Long lesions
Background: Albeit DES might be considered as a breakthrough against neointimal hyperplasia, concerns on stent thrombosis and increase incidence of in-stent restenosis after multiple DES implantations in complex, long lesions still exist. Hereby, we tried to test efficacy and safety of using PEB in long lesions followed by focal BMS implantation in a pilot multicenter study. Methods: This study enrolled 16 patients with long lesions (> 30 mm) that were treated with PEB angioplasty followed by focal stenting with BMS. IVUS was performed before, after PEB and post stenting. Clinical and angiographic follow-up was done at 6 months. The primary end-point was angiographic late lumen loss. Results: Patient age was 64.6 ± 8.1 years, 15 (93.7%) were males, and 7 (43.7%) diabetics. Target vessels were most commonly the left anterior descending (6 [31.6%]) and the right coronary artery (6 [31.6%]). PEB diameter was 2.8 ± 0.4 mm with a 31.3 ± 8.9 mm length. Stents per patient were 2.1 ± 0.8. No overlapping stents were deployed. Angiographic success was achieved in 100% of patients. Peri-procedural myocardial infarction occurred in 4 patients (25%). At 6 months follow-up angiography, MLD was 1.55 ± 0.53 mm with a late loss of 0.48 ± 0.52 mm, a binary re-stenosis rate of 2 (12.5%). Conclusion: Using PEB with focal stenting by BMS proved to be a feasible, safe, and promising strategy in long coronary lesions. However larger study are needed to confirm these data.
1. Introduction Plain balloon angioplasty revolutionized coronary revascularization but early elastic recoil and long-term neointimal formation caused by smooth muscle cellular proliferation remained the major drawback of this technique in the early period of mechanical revascularization [1]. Nowadays, the use of drug-eluting stents (DES) significantly attenuates the cellularity and the need for repeat revascularization. However, late stent thrombosis, dependency on prolonged dual antiplatelet therapy (DAT), and restenosis (all of which had declined with advanced technologies, and new generation stents) led to a quest for new treatment modalities [2]. One of the problems with the use of DES is the failure to convey the drug to the entire vessel wall, allowing areas
⁎
for potential cellular growth in the gaps between the struts [3]. Recently, with the introduction of drug eluting balloons (DEB), local delivery of the anti-proliferative drugs directly to the vessel wall was achieved, eliminating the potential problems of stenting especially in small sized vessels [4]. In addition, the absence of polymer might reduce the chronic inflammation and theoretically decreases the triggers for late stent thrombosis [5]. However, DEB are still unable to overcome the problem of acute elastic recoil after balloon angioplasty. The combination of a DEB with bare metal stents (BMS) might help to overcome this limitation without long term dependence on DAT [1]. In this study we evaluated the efficacy of the combination of DEB plus spot stenting using BMS in long coronary lesions.
Corresponding author at: Department of cardiology, Ain Shams University, Cairo, Egypt. E-mail address: [email protected] (A. Rezq).
http://dx.doi.org/10.1016/j.ctrsc.2017.04.001 Received 13 September 2016; Received in revised form 6 April 2017; Accepted 11 April 2017 Available online 25 April 2017 2405-5875/ © 2017 Published by Elsevier B.V. This is an open access article under the CC BY-NC-ND license (http://creativecommons.org/licenses/BY-NC-ND/4.0/).
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2. Study hypothesis and objectives
3.3. Quantitative coronary angiography (QCA)
Our hypothesis was that paclitaxel-eluting balloon (PEB) plus spot BMS implantation might help in reducing restenosis rates in long coronary artery lesions. Combination with spot stenting using BMS could be a reasonable option particularly if long term DAT is not recommended. Thus, the aim of the study was to assess the efficacy of this combination technique in terms of rates of restenosis, late loss, binary stenosis, as well as the occurrence of major adverse cardiac events (MACE).
Angiograms were analyzed by an independent, angiographic core laboratory (I3SD, Rome, Italy) using a computer based system (Medis v 7.2, Leidin, the Netherlands). QCA was performed before and after using PEB as well as after stenting for the whole length of the plaque to evaluate the reference vessel diameter (RVD), minimal lumen diameter (MLD), percentage of diameter stenosis (%DS) and percentage of area stenosis (%AS). At 6 months follow up, QCA was performed for the follow up angiograms to determine the binary stenosis and late lumen loss.
2.1. Device description 3.4. In-hospital assessment and clinical follow-up IN.PACT Falcon (Invatec, Roncadelle, Italy) is a drug-eluting coronary angioplasty balloon catheter designed specifically to treat atherosclerotic lesions in coronary arteries. The drug utilized is paclitaxel at a concentration of 3 μg per mm2 and the coating is the proprietary Freepac, utilized to frees and separates paclitaxel molecules and facilitates their absorption into the wall of the artery. Free Pac reduces the total drug (Paclitaxel) elution time to 30 to 60 s; balloon inflation beyond 60 s can be maintained without additional drug release. 3. Methods
All patients underwent pre-procedural, 6 and 12 h blood draws to measure CK, CK-MB mass. In hospital follow up was performed to detect other possible complications including acute and subacute stent thrombosis, hemorrhagic complications and cerebrovascular stroke. All patients were given DAPT during their hospital stay and for one month after discharge. Following discharge, telephone-based interviews and office-based direct visits were performed at 1and 6 months, for endpoint adjudication. Coronary angiography was performed at 6 months for all enrolled patients. QCA was done at the time of angiographic control to evaluate the late loss and binary stenosis.
3.1. Study design and patient population
3.5. Endpoints
This study was designed as a multicenter, non randomized study that was conducted on a consecutive series of patients presented in our cath lab. All patients had long atherosclerotic coronary artery lesions ≥ 30 mm at the coronary angiogram by visual estimation and subsequent IVUS confirmation. All patients provided written informed consent to the procedure. Major exclusion criteria were: ST-segment elevation myocardial infarction (STEMI), serum creatinine > 2.5 mg/dL, stenosis of the unprotected left main coronary artery, visible thrombus within the target lesion, previous PTCA in the same vessel, contraindication or suspected intolerance to double anti-platelet drug therapy.
The primary end-point was the late luminal loss as well as the rate of binary restenosis of the deployed BMS at 6 months angiographic followup. Secondary endpoints were major adverse cardiovascular events (MACE), defined as the composite of cardiovascular death, non-fatal myocardial infarction, or clinically driven target vessel revascularization (TVR). 3.6. Definitions Late lumen loss, the primary study end-point, was defined as the difference between the minimal lumen diameter at the completion of the stent procedure and at 6 months follows up. Binary stenosis is defined as > 50% diameter stenosis in the target lesion. Myocardial infarction was distinguished as new pathologic Q-waves in > 2 contiguous leads or non-Q-wave MI (peak CK-MB mass > 3 times the upper limit of normal together with abnormal CK). Angiographic success is defined as a < 50% residual stenosis in the target vessel, with TIMI 3 flow at the end of the procedure. Procedural success is defined as angiographic success without the occurrence of death, non-Q-wave or Q-wave MI, and repeat revascularization of the target lesion during hospital stay. Target lesion revascularization (TLR) was defined as a revascularization procedure (repeat angioplasty or coronary bypass surgery) performed because of angiographic restenosis at the site of the lesion treated associated with clinical (patient symptoms) or objective evidence (stress test, myocardial scintigraphy) of myocardial ischemia for lesions between 50 and 70%. Re-interventions was considered appropriate for lesions over 70% even in absence of ischemia. Any revascularization procedure (PTCA, Stenting or CABG) performed on the stented vessel and/or on its proximal segment was defined as Target vessel revascularization (TVR). Stent thrombosis was classified utilizing the Academic Research Consortium (ARC) definition as definite, probable, or possible and as early (0 to 30 days), late (31 to 360 days), or very late (> 360 days) [7]. The definition of definite stent thrombosis required the presence of an acute coronary syndrome with angiographic or autopsy evidence of thrombus or occlusion. Probable stent thrombosis included unexplained deaths within 30 days after the procedure or acute myocardial infarc-
3.2. Procedure Coronary angioplasty and intracoronary stent implantation were performed using standard percutaneous techniques [6]. All patients enrolled received 325 mg of aspirin and a 300 mg loading-dose of clopidogrel 12 h before the procedure, respectively if not on chronic utilization. Intravenous heparin was administered to maintain an activated clotting time ≥ 250 s during the procedure. Administration of glycoprotein IIb/IIIa inhibitors was left to the operator's discretion. Eagle's eye intravascular ultrasound (IVUS) catheter (Volcano corp.) was introduced along a 0.014″ guide wire, to assess plaque burden and minimal lumen diameter. Then, standard semi-compliant (uncoated) PTCA balloons were introduced to pre-dilate the lesions from distal to proximal with balloon to artery ratio of 0.75:1. Paclitaxel eluting balloon (PEB); IN·PACT Falcon (Medtronic, US) was then introduced across the lesion and was inflated once for single drug delivery from distal to proximal with balloon to artery ratio of 1:1. Inflation time was ≥ 50 s, and inflation pressure did not exceed the burst pressure of the balloon. If the balloon did not covered the entire lesion length a second one was utilized. IVUS was then performed again to evaluate the plaque, and guide the decision of focal stenting at the spots of heavy thrombus burden, tight stenosis or possible dissection. Focal stenting with BMS was performed either at the sites of flow limiting dissection, or at the sites of residual stenosis ≥30% as assessed angiographically and by IVUS. At the end of the procedure, IVUS was performed again to evaluate the residual plaque burden, the stent symmetricity index, and stent eccentricity index. 2
3
2.34 ± 0.53 mma
2.86 ± 0.43 mma
3.33 ± 0.48 mma
4.16 ± 0.6 mma
2.54 ± 0.28 mma
61.69 ± 5.8%b
2.82 ± 0.55 mma
58.15 ± 9.6%b
2.042 ± 0.32 mma
3.88 ± 0.44 mma
57.48 ± 11.8%b
2.32 ± 0.29 mma
1.94 ± 0.32 mma
3.48 ± 0.33 mma
3.13 ± 0.3 mma
2.52 ± 0.3 mma
2.21 ± 0.25 mma
3.22 ± 0.23 mma
2.92 ± 0.24 mma
3.12 ± 0.61 mma
2.72 ± 0.53 mma
4.16 ± 0.64 mma
3.8 ± 0.55 mm
12.63 ± 3.68 mm2a 6.92 ± 2.7 mm2
4.32 ± 0.47 mma
3.43 ± 0.42 mma
7.485 ± 1.73 mm2a 4.47 ± 1.067 mm2a
3.75 ± 0.66 mma
8.66 ± 1.6 mm2a 3.65 ± 0.95 mm2a
3.96 ± 0.43 mma
10.83 ± 2.48 mm2a 4.03 ± 0.97 mm2a
0.588 ± 0.078a 1.62 ± 2.38a
3.3 ± 0.92 mma
3.1 ± 0.53 mma
4.49 ± 0.62 mma
4.14 ± 0.58 mma
14.32 ± 4.72 mm2a 8.48 ± 2.98 mm2a
1.54 ± 3.2a 1.6 ± 2.4a
3.25 ± 0.57 mma
2.8 ± 0.59 mma
4.12 ± 0.67 mma
3.8 ± 0.7 mma
12.32 ± 4.64 mm2a 7.26 ± 2.8 mm2a
Mid lesion
12.86 ± 4.19 mm2a 5.51 ± 2.43 mm2a
Prox. lesion
13.49 ± 2.82 mm2a 7.74 ± 2.2 mm2a
Min. = minimal, Max. = maximal, Prox. = proximal, Ref. = reference. SEI = stent eccentricity index, SSI = stent symmetricity index. a Data are presented as the mean value ± SD. b Data are expressed as mean percentages.
Vessel area Lumen area Min. vessel diameter Max. vessel diameter Min. lumen diameter Max. lumen diameter Plaque burden Post stenting (final result) SEI SSI
Distal Ref. vessel
Prox. Ref. vessel
Distal lesion
Prox. lesion
Prox. Ref. vessel
Mid lesion
IVUS measurements post PEB and final results post stenting
Baseline IVUS measurements
Table 1 IVUS measurements.
1.38 ± 2.7a 1.35 ± 1.52a
2.65 ± 0.26 mma
2.27 ± 0.29 mma
3.64 ± 0.38 mma
3.35 ± 0.36 mma
9.48 ± 1.67 mm2a 5 ± 1.46 mm2a
Distal lesion
2.6 ± 0.3 mma
2.26 ± 0.28 mma
3.25 ± 0.3 mma
2.98 ± 0.3 mma
7.6 ± 1.4 mm2a 4.7 ± 1.02 mm2a
Distal Ref. vessel
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tion involving the target-vessel territory without angiographic confirmation. Possible stent thrombosis included all unexplained deaths occurring at least 30 days after the procedure. 3.7. Statistical analysis All statistical analyses were performed with SPSS for Windows (version 18.0, Chicago, USA). Continuous variables were described as mean ± SD, and categorical variables were reported as percentages or proportions. 4. Results 4.1. Patient characteristics The clinical characteristics of the patients are described in Table 1. A total of 16 patients (19 target vessels) were enrolled, with a mean age of 64.6 ± 8.1 years, 15 (93.7%) males, 7 (43.7%) diabetics, 8 (50%) hypertensives, 7 (43.7%) smokers, 8 (50%) hypercholesterolemics, 2 (12.5%) with chronic renal impairment, and 1 (6.3%) with chronic obstructive pulmonary disease (COPD). Nine (56.3%) patients had history of previous acute coronary syndrome, and 1 (6.3%) had undergone coronary artery bypass grafting (CABG). 4.2. Angiographic and procedural data A total of 19 target vessels were treated; 6 (31.6%) LADs, 6 (31.6%) RCAs, 2 (10.5%) LCX, 4 (21.1%) Obtuse Marginal branch and 1 (5.3%) Diagonal branch. As for the lesion type, all were type C. Mean lesion length was 73.81 ± 18.5 mm. Mean diameter of the PTCA balloons was 2.3 ± 0.3 mm, inflated at a mean pressure of 8.6 ± 2.1 atm. The mean diameter of the PEB used was 2.8 ± 0.4 mm, and the mean length was 31.3 ± 8.9 mm. They were inflated at a mean of 6.2 ± 1.4 atm. Focal stenting using BMS was performed in 16 (84.2%) vessels, while in 3 (15.8%) diffusely diseased vessels, satisfactory results were obtained after using PEB, and no stenting was performed in these cases. Stenting was performed as a bailout technique in cases of dissection (2 vessels, 10.5%) or unsatisfactory result of balloon dilatation based on IVUS evaluation in 14 (73.7%). No other intraprocedural complications were encountered (including vessel perforation, major side branch compromise, balloon rupture, false lumen stenting, IVUS induced complications as dissection or perforation, slow flow after balloon dilatation or stenting, or cardiac tamponade). The mean stent diameter was 2.86 ± 0.34 mm, mean length was 16 ± 3.4 mm, and they were inflated at a mean atmospheric pressure of 11.4 ± 0.93 atm. Number of stents per patient were 2.1 ± 0.8, and number of stents per vessel were 1.7 ± 0.8 stents. No overlapping stents were deployed. IVUS showed a baseline mean minimal lumen diameters (MLD) of “2.34 ± 0.53 mm, 2.04 ± 0.32 mm, 1.94 ± 0.32 mm” and a lumen area of “5.5 ± 2.43 mm2, 4.03 ± 0.97 mm2, 3.65 ± 0.95 mm2 “at proximal, mid and distal lesions respectively. Plaque burden was “58.15 ± 9.6%, 61.69 ± 5.8%, 57.48 ± 11.8%” for proximal, mid and distal segments respectively. Post PEB, MLDs were “3.1 ± 0.53 mm, 2.8 ± 0.59 mm, 2.27 ± 0.29 mm”, and lumen areas were “8.48 ± 2.98 mm2, 7.26 ± 2.8 mm2, 5 ± 1.46 mm2” for the proximal, mid segment and distal lesions respectively. (Tables 1) (Fig. 1A, B, C). Quantitative coronary angiography (QCA) showed a baseline mean MLD of 0.7 ± 0.35 mm. MLD post PEB was 1.56 ± 0.41 mm, post stenting was 2.015 ± 0.24 mm with an acute gain of 1.27 ± 0.45. At 6 months follow up angiography, MLD was 1.55 ± 0.53 mm with a late loss of 0.48 ± 0.52. Binary re-stenosis (diameter stenosis > 50%) was detected in 2 patients (16.7%) out of 12 (both in RCA lesions).The rest of QCA details are described in Table 2.
Fig. 1. Intravascular ultrasound (IVUS) still frame showing: A. Fibrocalcific plaque in a right coronary artery. Plaque burden is 72.7%, MLA is 2.2 mm2, MLD is 1.6 mm. B. The same plaque after using PEB. Plaque burden is 49.8%, MLA is 3.9 mm2, MLD is 1.8 mm. C. MLD post stenting 2.9 mm, MLA 6.9 mm2.
4.3. In hospital and 6 months follow up Periprocedural ischemia was detected in 4 patients (25%) with the mean value of the post procedural CPK-MB fraction among the study population 6.9 ± 5.4 IU/L (Normal value = 0–3.5 IU/L). Otherwise, no other complications were recorded during the in-hospital stay among the study group. At 6 months follow up, TLR was needed in 2
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Table 2 Quantitative coronary angiography measurements of the target vessels.
Baseline QCA QCA post PEB QCA post stenting Follow up QCA Acute gain Late loss
Lesion length (mm)
RVD (mm)
MLD (mm)
% diameter stenosis
% area stenosis
73.81 ± 18.5 72.6 ± 17.9 74.46 ± 23.4 73.82 ± 21 1.27 ± 0.45 0.48 ± 0.52
2.36 ± 0.56 2.51 ± 0.58 2.9 ± 0.3 2.43 ± 0.78
0.7 ± 0.35 1.56 ± 0.41 2.015 ± 0.24 1.55 ± 0.53
69.93 ± 13.4 37.8 ± 8.7 30.42 ± 5.63 40.46 ± 17.5
89.27 61 ± 51 ± 60.92
± 8.09 11.4 8.6 ± 13.4
Data are presented as the mean value ± SD.
specifying the MLD or dissections that necessitate stenting and thereby, reduces the geographic miss. This study opens a new horizon for interventional cardiologists in terms of optimizing the treatment for diffusely diseased coronaries. Treating long atherosclerotic lesions has always been a debate among operators. Many strategies have been adopted for such long and complex lesions as long drug eluting stents deployment, overlapping stents or full metal jacket. However, problems were always the occurrence of restenosis and neointimal formation post stenting [8–10]. Our group has previously demonstrated that stent length is an independent predictor of restenosis and a significant difference in the rate of restenosis as well as the occurrence of MACE within 6 months follow up was evident between groups treated with short focal stents and those treated with long ones [11–12]. Moreover, we have also demonstrated that in this patient subset the utilization of overlapping stents significantly increases the incidence of Non-Q wave MI (16.6%) and acute in-stent thrombosis during hospital stay and at 6 months follow up [13]. Many other studies also demonstrated that full metal jacket carried a higher incidence of MACE including higher mortality and TLR, and obviously making the native vessels inoperable if bypass is needed thereafter [14]. Posa et al. [15] have shown that short exposure of the coronary artery to paclitaxel with a coated balloon resulted in a significant accumulation of the drug in the arterial tissue. Forty-eight hours postdilatation the investigators could still detect about 25% of the paclitaxel, thereby suggesting high concentrations of paclitaxel are maintained in the tissue for long periods of time even after a single administration. This makes paclitaxel a promising candidate for local drug therapy independent of stent, intended to address the proliferative and migratory processes involved in restenosis [16,17]. This might be also attributed to the fact that Paclitaxel is highly lipophilic and binds quickly and tightly to the tissue, resulting in rapid cellular uptake and retention at the site of delivery. When compared with hydrophilic drugs, the efficacy of local drug delivery is 10 to 20 times higher for lipophilic drugs [18]. The potential advantages of non-stent-based local drug delivery are numerous: (1) it could allow a homogenous drug transfer to the vessel wall and not only to the areas directly covered by the stent strut. This uniformity of deliverance could enhance the efficacy of the drug to the artery; (2) the drug concentrations at the vessel wall would be the highest at the time of injury when the neointimal process is the most vigorous. Afterward, the absence of drug in the arterial wall could help to better re-endothelialize the stent (if used) and limit the risk for late stent thrombosis; (3) the absence of polymer could decrease the stimulus of chronic inflammation and the trigger for late thrombosis; (4) the absence of a stent allows preserving the original anatomy of the arteries, notably in cases of bifurcation or small vessels, leaving no stent scaffold and hence, diminishing abnormal flow patterns observed in these cases with stent implantation; (5) overdependence on antiplatelet therapy could be limited, especially in patients requiring urgent surgical interventions or when long term DAT is not recommended. (6) Local drug delivery could also be applied in situations where stents are not used or undesirable, such as in very small vessels, in-stent restenosis, or for the treatment of the side branch in bifurcation lesions;
Fig. 2. Angiographic picture showing: A. Final angiographic result after using PEB + spot stenting with 2 BMS, Distally 2.25 × 13 and proximally 3 × 18. B. Follow up angiographic result after 6 months.
patients (12.5%) (Fig. 2 A,B). The first had a chronic total occlusion at the distal edge of the stent deployed in the mid RCA, while the other had significant type II instent restenosis (ISR) in the distal RCA. However, no other MACE were reported in the study group. 5. Discussion This pilot study demonstrated that; 1) PEB could be considered as an interesting treating modality in long atherosclerotic lesions with satisfactory short term results (6 months late loss of 0.48 ± 0.52) avoiding the need of overlapping DES placement for long segment of the vessel. 2) This treatment modality could reduce the peri-procedural CPK-MB increase as seen in previous study from our group with full metal jacket stenting. 3) PEB + BMS might be well thought-out as a favorable therapy particularly in cases where long term DAT is contraindicated. 4) IVUS might help optimizing the use of PEB + BMS by 5
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and (7) finally, if a stent was used, there would be no limitation to a particular type of stent. It is worthy to point out that DEB for de novo lesions is less studied. The only registry available is PEPCAD I, which targeted small vessels [19]. Of the 114 patients treated with DEB, 32 required stenting postprocedural. The late loss and binary restenosis in the DEB-alone group was only 0.18 ± 0.38 mm and 5.5% respectively, while the DEB with BMS had higher late loss and restenosis of 0.73 ± 0.74 mm and 44.8%, respectively. In addition, the rate of stent thrombosis in the DEB and BMS group was 6.3%. The authors attributed the poor results of the DEB with BMS to geographic miss and concluded that the paclitaxel-eluting balloon catheter, SeQuent Please (B.·Braun Melsungen AG, Melsungen, Germany) was safe, was associated with a high procedural success rate in small de novo lesions, and exhibited low late lumen loss after 6 months in small vessel disease. The question of DEB in conjunction with BMS remains a concern because of high restenosis rates. Angiographic results of drug eluting stents (DES) were superior to both BMS and DEB in the setting of acute myocardial infarction as was demonstrated in the DEB-AMI study. Moreover, DEB before implantation induced more uncovered and malapposed stent struts than BMS, but less than after DES [20]. In addition, combination therapy with DEB was recently reported. Scoring balloon (SCB) devices prevent balloon slippage and enhance local plaque disruption during angioplasty but have failed to demonstrate an advantage when used as stand-alone therapy. As an adjunct to DEB, scoring balloon pre-dilatation might enhance tissue uptake and improve clinical outcomes. ISAR-DESIRE 4 trial enrolled 252 patients with limus-eluting stent restenosis and signs of ischemia. Patients were randomized 1:1 to a scoring balloon plus paclitaxel-coated balloon (N = 125) or standard balloon plus paclitaxel-coated balloon (N = 127) during angioplasty. The primary endpoint was the percent diameter stenosis at follow-up angiography. The results were 40.4% ± 21.4 for the SCB plus PCB group vs. 35% ± 16.8 for the PCB-alone group (p = 0.047). The secondary endpoint of binary restenosis was also lower in SCB plus PCB compared to PCB alone (18.5% vs. 32%, P = 0.03). The rates of target lesion revascularization (16.8% vs. 22.6%, P = 0.25) and death/myocardial infarction (3.4% vs. 3.3%, P > 0.99) were similar for both groups. The results of our study seem to be very promising, as the acute angiographic success was achieved in 100% of patients. Cumulative MACE as well as TLR were detected in 2 (12.5%) patients, with no other MACE detected. Acute gain and late loss of 1.27 ± 0.45 mm and 0.48 ± 0.52 mm respectively might hold up the appliance of this novel technique till large randomized studies are designed to attest this concept. On the other hand, operators should pay heed to the geographic miss that resulted in the disappointing results of DEB + BMS group of the PEPCAD I study. Utilizing IVUS might help the operators to identify precisely the tightest spots, or dissections that require spot stenting with a BMS following PEB. It seems that using PEB and spot BMS should be delicately performed with great meticulousness, in order to obtain the finest results. BMS should be deployed as a bailout in cases of dissections and enduring tight stenoses after PEB and should be as short as possible to curtail the occurrence of ISR.
7. Conclusions The use of drug-coated balloons appears to hold promise as a viable alternative to stand-alone balloon angioplasty and stent implantation for the treatment of de novo coronary lesions. This study demonstrated that the use of PEB combined with focal stenting using BMS might improve the outcome of patients affected by diffuse coronary disease. This technique could be considered as a bailout strategy whenever long term DAT is not recommended. However, data from large clinical trials and registries are needed in order to verify the safety and efficacy of this strategy. References [1] Ron Waksman, RajbabuPakala, Drug-eluting balloon: the comeback kid? Circ. Cardiovasc. Interv. 2 (2009) 352–358. [2] E. Camenzind, P.G. Steg, W. Wijns, Stent thrombosis late after implantation of firstgeneration drug-eluting stents: a cause for concern, Circulation 115 (2007) 1440–1455. [3] J.W. Moses, M.B. Leon, J.J. Popma, P.J. Fitzgerald, D.R. Holmes, C. O'Shaughnessy, R.P. Caputo, D.J. Kereiakes, D.O. Williams, P.S. Teirstein, J.L. Jaeger, R.E. Kuntz, S.I.R.I.U.S. Investigators, Sirolimus-eluting stents versus standard stents in patients with stenosis in a native coronary artery, N. Engl. J. Med. 349 (2003) 1315–1323. [4] A. Latib, A. Colombo, F. Castriota, A. Micari, A. Cremonesi, F. De Felice, A. Marchese, M. Tespili, P. Presbitero, G.A. Sgueglia, F. Buffoli, C. Tamburino, F. Varbella, A. Menozzi, A randomized multicenter study comparing a paclitaxel drug-eluting balloon with a paclitaxel-eluting stent in small coronary vessels: the BELLO (Balloon Elution and Late Loss Optimization) study, J. Am. Coll. Cardiol. 60 (24) (2012) 2473–2480. [5] A. De Labriolle, R. Pakala, L. Bonello, G. Lemesle, M. Scheinowitz, R. Waksman, Paclitaxel-eluting balloon: from bench to bed, Catheter. Cardiovasc. Interv. 73 (2009) 643–652. [6] D.R. Holmes Jr., Technical aspects, in: R.E. Vliestra, D.R. HolmesJr. (Eds.), Percutaneous Transluminal Coronary Angioplasty, F.A. 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Sangiorgi, Goran Stankovic, Flavio Airoldi, Alaide Chieffo, Matteo Montorfano, Mauro Carlino, Iassen Michev, Nicola Corvaja, Carlo Briguori, Ulrich Gerckens, Eberhard Grube, Antonio Colombo, Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents, JAMA 293 (2005) 2126–2130. [13] Eleftheria Tsagalou, Alaide Chieffo, Ioannis Iakovou, Lei Ge, Giuseppe M. Sangiorgi, Nicola Corvaja, Flavio Airoldi, Matteo Montorfano, Iassen Michev, Antonio Colombo, Multiple overlapping drug-eluting stents to treat diffuse disease of the left anterior descending coronary artery, J. Am. Coll. Cardiol. 45 (2005) 1570–1573. [14] E.J. Topol, P.W. Serruys, Frontiers in interventional cardiology, Circulation 98 (1998) 1802–1820. [15] A. Posa, R. Hemetsberger, O. Petnehazy, Z. Petrasi, M. Testor, D. Glogar, M. Gyöngyösi, Attainment of local drug delivery withpaclitaxel-eluting balloon in porcine coronary arteries, Coron. Artery Dis. 19 (2008) 243–247. [16] S.J. 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6. Study limitations This is a pilot study with a very limited number of patients, therefore obtained data can't be considered sufficient to establish the safety and efficacy of this strategy. Using BMS in a diffusely diseased vessel especially in diabetic patients carried the risk of having a high incidence of ISR, however, our hypothesis was to prove that using DEB plus spot BMS may reduce the incidence of peri-procedural and longterm events in pts affected by diffuse coronary artery disease.
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ChunLai Shao, Eric Van Belle, Thierry Wildbergh, Luigi Politi, Pieter A. Doevendans, Giuseppe M. Sangiorgi, Pieter R. Stella, First results of the DEB-AMI (drug eluting balloon in acute ST-segment elevation myocardial infarction) trial a multicenter randomized comparison of drug-eluting balloon plus bare-metal stent versus bare-metal stent versus drug-eluting stent in primary percutaneous coronary intervention with 6-month angiographic, intravascular, functional, and clinical outcomes, J. Am. Coll. Cardiol. 25 (2012) 2327–2337.
effects and efficacy in vivo, J. Am. Coll. Cardiol. 35 (2000) 1969–1976. [19] L.S. Maier, C. Maack, O. Ritter, M. Böhm, Hotline update of clinical trialsand registries presented at the German Cardiac Society meeting 2008. (PEPCAD, LokalTax, INH, German ablation registry, German device registry, DESDE registry, DHR, Reality, SWEETHEART registry, ADMA, GERSHWIN), Clin. Res. Cardiol. 97 (2008) 356–363. [20] Anouar Belkacemi, Pierfrancesco Agostoni, Hendrik M. Nathoe, Michiel Voskuil,
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