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Results from the Tack Optimized Balloon Angioplasty (TOBA) study demonstrate the benefits of minimal metal implants for dissection repair after angioplasty
Results from the Tack Optimized Balloon Angioplasty (TOBA) study demonstrate the benefits of minimal metal implants for dissection repair after angioplasty Marc Bosiers, MD,a Dierk Scheinert, MD,b Jeroen M. H. Hendriks, MD, PhD,c Christian Wissgott, MD, PhD,d Patrick Peeters, MD,e Thomas Zeller, MD,f Marianne Brodmann, MD,g and Robert Staffa, MD,h for the TOBA investigators, Dendermonde, Edegem (Antwerp), and Bonheiden, Belgium; Leipzig, Heide, and Bad Krozingen, Germany; Graz, Austria; and Brno, Czech Republic Objective: The mechanism of angioplasty is disruption of atherosclerotic plaque, which often results in dissections. Dissection after percutaneous transluminal angioplasty (PTA) remains a significant clinical problem and untreated may cause acute occlusion or later restenosis. Stents are used to manage dissections, which is often followed by in-stent restenosis and occasionally stent fracture. Tack (Intact Vascular, Wayne, Pa) implants have minimal metal and low radial force and are specifically designed for dissection repair. This study evaluated Tack implants for treatment of dissections resulting from standard balloon PTA for femoral-popliteal arterial disease. Twelve-month outcomes after Tack treatment of post-PTA dissections are described. Methods: This prospective, single-arm study evaluated patients with ischemia (Rutherford clinical category 2-4) caused by lesions of the superficial femoral and popliteal arteries. Patients were treated with standard balloon angioplasty, and postPTA dissections were treated with Tacks. The primary end points were core laboratory-adjudicated device technical success, defined as the ability of the Tack implants to resolve post-PTA dissection, and device safety, defined as the absence of new-onset major adverse events. Patients were followed up to 12 months after implantation. Results: Tacks were used in 130 patients with post-PTA dissections (74.0% $ grade C). Technical success was achieved in 128 (98.5%) patients with no major adverse events at 30 days. The 12-month patency was 76.4%, and freedom from target lesion revascularization was 89.5%. Significant improvement from baseline was observed in Rutherford clinical category (82.8% with grade #1) and ankle-brachial index (0.68 6 0.18 to 0.94 6 0.15; P < .0001). Conclusions: Tack implant treatment of post-PTA dissection was safe, produced reasonable patency, and resulted in low rates of target lesion revascularization. Tack treatment represents a new, minimal metal paradigm for dissection repair that can safely improve the clinical results associated with PTA. (J Vasc Surg 2016;-:1-8.)
Percutaneous transluminal angioplasty (PTA) is commonly used for femoral-popliteal revascularization in patients with lower extremity ischemia and has been a workhorse tool for interventionists for 50 years.1 Because the angioplasty mechanism functions primarily by producing dissection, PTA as a stand-alone therapy is associated with poor outcomes, with acute dissection visible in 47% to 88% of cases2,3 and 1-year restenosis rates of 40% to 60%.1,4-6 Untreated post-PTA dissection has been associated with poor
results, both acute and in the long term.3 The target lesion revascularization (TLR) rate, compared with lesions without identifiable acute dissections, is 3.5-fold higher (10.5% vs 37%) at 6 months after PTA.3,5 Whereas there is an association between severity of dissection and TLR rate, lesions with less severe dissections (National Heart, Lung, and Blood Institute grades A and B) had only a slightly lower incidence of TLR than more severe (grades C-E) dissections (33% vs 44%, respectively).3
From the AZ St. Blasius Hospital, Dendermondea; the University-Hospital Leipzig, Leipzigb; the Antwerp University Hospital, Edegem (Antwerp)c; the Academic Teaching Hospital of the Universities of Kiel, Luebeck, and Hamburg, Heided; the Imeldaziekenhuis, Bonheidene; the UniversitätsHerzzentrum Freiburg-Bad Krozingen, Bad Krozingenf; the Medical University Hospital Graz, Grazg; and the St. Anne’s University Hospital and Faculty of Medicine, Masaryk University, Brno.h This work was funded by Intact Vascular. Intact Vascular had no involvement in the study design; collection, analysis, and interpretation of data; manuscript writing; or the decision to submit the manuscript for publication. Clinical Trial registration: NCT01663818. Author conflict of interest: T.Z. received honoraria from Abbott Vascular, Bard Peripheral Vascular, Veryan, Biotronik, Boston Scientific, Cook Medical, Cordis, Covidien, W. L. Gore & Associates, Medtronic, Spectranetics, Straub Medical, TriReme, and VIVA Physicians; he is a consultant for Abbott Vascular, Bard Peripheral Vascular, Boston Scientific, Cook Medical, W. L. Gore & Associates, Medtronic, Spectranetics, and ReCor;
and he has received research, clinical trial, or drug study funds from 480 Biomedical, Bard Peripheral Vascular, Veryan, Biotronik, Cook Medical, Cordis, Covidien, W. L. Gore & Associates, Abbott Vascular-IDEV Technologies Inc, Medtronic, Spectranetics, Terumo, TriReme, and Volcano. D.S. acts as a member/consultant of the advisory board of Abbott, Angioslide, Atheromed, Biotronik, Boston Scientific, Cook Medical, Cordis, Covidien, CR Bard, Gardia Medical, Hemoteq, Intact Vascular Inc, Medtronic, Ostial Inc, and TriReme. Correspondence: Marc Bosiers, MD, AZ St. Blasius Hospital, Kroonveldiaan 50, 9200 Dendermonde, Belgium (e-mail: [email protected]). The editors and reviewers of this article have no relevant financial relationships to disclose per the JVS policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest. 0741-5214 Copyright Ó 2016 by the Society for Vascular Surgery. Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jvs.2016.02.043
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The usual approach to treatment of post-PTA dissection during the past 20 years has been stent placement. Although stenting has improved acute PTA outcomes, stents have also been shown to induce chronic injury and inflammation, leading to 1-year restenosis rates ranging from 20% to 37%.7-10 One possible solution is a minimal metal, relatively inert implant to mechanically appose dissection flaps to the vessel wall while limiting the outward force and metal burden. This would permit focal treatment, allowing the operator to control the procedure and the location and amount of scaffolding. Herein we report the first large-scale, prospective, multicenter study evaluating the safety and efficacy of the Tack Endovascular System (Intact Vascular, Wayne, Pa) for treatment of post-PTA dissections.
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Fig 1. Tack implant compared with conventional stent.
METHODS The Tack Optimized Balloon Angioplasty (TOBA) study was an early-phase, prospective, single-arm, multicenter, open-label, nonrandomized study. The study was conducted in accordance with the Declaration of Helsinki. The local ethics committees at the participating sites approved the study protocol, and all patients provided written informed consent before undergoing any study procedures. Patients who provided informed consent and met the study entrance criteria were considered enrolled. The objective of this study was to evaluate the performance of the Tack Endovascular System for the treatment of dissections resulting from PTA of the superficial femoral artery (SFA) or popliteal artery. Patient population. Patient enrollment criteria were assessed by the physician investigator during preprocedure assessments and procedural angiography. Patients were required to have angiographic documentation of an SFA or popliteal lesion located between the origin of the SFA and 2.0 cm below the tibial plateau. Major inclusion criteria included Rutherford clinical category (RCC) score 2 to 4,11 ankle-brachial index (ABI) #0.90, reference vessel diameter between 2.5 and 5.5 mm, target lesion stenosis $70% or occlusion, target lesion length #10 cm, and presence of at least one tibial runoff vessel. Major exclusion criteria included previous ipsilateral SFA or popliteal artery stent or bypass, severe calcification of the target lesion (defined as circumferential calcification or dense calcium plaque that extends for $5 cm), and stenosis or occlusion of the inflow tract not treated before or during the index procedure. The patients underwent standard balloon angioplasty. The angioplasty balloon was selected to match (1:1) or slightly exceed the reference vessel diameter. When possible, a single balloon was used to dilate the entire lesion length, typically with a minimum of 5 mm of balloon length extending beyond the end of the lesion. The balloon was inflated to nominal pressure or higher if required to expand any residual waist on the balloon. Balloon inflation was typically maintained for a minimum of 30 seconds. Post-PTA angiograms were taken. If there
was significant residual stenosis (ie, >30%), the lesion was treated with repeated PTA at longer inflation times or increased pressure per the clinician’s judgment. Patients with >30% residual stenosis after repeated PTA were screen failures. If no dissection was observed on the initial postPTA angiogram, oblique views were obtained to further evaluate the treatment site. Patients with <30% residual stenosis and evidence of dissection were treated with Tacks. When there was no dissection and optimal angioplasty was achieved, the patient did not receive Tack implants but was observed for 30 days. Tack Endovascular System. The Tack Endovascular System contains a self-expanding nitinol implant that measures 6 mm in length and treats reference vessel diameters ranging from 2.5 to 5.5 mm. Unlike stents, the Tack implant is designed to exert essentially the same radial force on the artery across this entire range of diameters, which permits one-size Tack to adapt to the full range of diameters referenced. The short longitudinal length in combination with an open-cell design acts to minimize the amount of metal that is in contact with the artery compared with stents (Fig 1). The Tack implants are designed to treat acute dissections by exerting minimal focal pressure that facilitates the apposition of damaged tissue to the inner luminal surface of the artery. To enable accurate placement and anchoring of the dissection flap to the vessel wall, each Tack implant contains six radiopaque gold markers in the center, along with six pairs of anchors that elevate slightly on deployment of the Tack and serve to mitigate movement of the Tack once it is deployed. Four independent Tack implants were provided preloaded onto a single 6F delivery catheter. Tacks were deployed as previously described.12 Briefly, after angiographic identification of a dissection, the delivery catheter was loaded onto the same guidewire used during the PTA procedure and advanced to the treatment site using fluoroscopic guidance. Based on the investigator’s evaluation of the angiogram, the Tack implants were deployed separately with gaps of $6 mm between the individual Tacks. The number of Tacks used was based on the
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Fig 2. Patient disposition.
requirements to completely treat the dissection. After deployment across the dissected segment, post-Tack placement angioplasty was performed to secure the implants. Angiography was performed to verify acceptable acute vessel patency. Antiplatelet medication. Premedication was per the investigator’s clinical judgment or institutional practice and included a loading dose of aspirin (80-500 mg) and clopidogrel (75-600 mg). Most patients continued to take aspirin (median dose, 100 mg) throughout the 12-month follow-up period. Clopidogrel (median dose, 75 mg) was continued for 30 days after the procedure in 81% of the patients. Angiography and duplex ultrasound. The investigator performed evaluation of angiographic data for the determination of study enrollment at the time of the procedure. Angiographic images were sent to an independent core laboratory (Yale University School of Medicine Angiographic Core Laboratory, New Haven, Conn) for blinded evaluation of the target lesions and outcomes. For comparison purposes, both the site-reported and core laboratory analyses of dissection severity are included in this report. Dissections were graded on the basis of angiographic evaluation of intimal disruption using the National Heart, Lung, and Blood Institute classification system.13 Duplex ultrasound (DUS) was conducted at 6 and 12 months and analyzed by an independent DUS core laboratory (VasCore, Boston, Mass) to evaluate arterial patency at the target lesion location. Arteries were considered to be patent if they had <50% residual stenosis as determined by a peak systolic velocity ratio <2.5. All study-defined angiography and DUS end points were assessed on the basis of data provided by the respective core laboratories. Study end points. The primary efficacy end point was device technical success, defined as the ability of the Tack implants to resolve post-PTA dissection, which was achieved when the dissection was no longer visible by angiography and acute arterial patency was maintained at the implant location. The primary safety end point was a
composite of all new-onset major adverse events (MAEs), which were defined as device and arterial embolization, need for emergency surgical revascularization, amputation above the ankle, or clinically driven TLR through 30 days after the procedure. Clinically driven TLR was defined as any repeated percutaneous (endovascular) or surgical intervention to treat objectively documented signs or symptoms of recurrent ischemia attributable to the index lesion. Objective evidence of recurrent ischemia caused by the index lesion was required, including evidence of recurrent stenosis $70% and decrease in ABI of 0.1 or more from post-index procedure result. Patients were followed up through 12 months after the procedure for continued assessment of MAEs, changes in RCC and ABI from baseline, DUS of arterial patency, and radiographic evaluation of device migration and fracture evaluated by the angiographic core laboratory. In addition, an analysis of “metal burden” was conducted. For each case, the investigator prospectively recorded the stent type and length that would have been required to treat the lesion if the operator had selected that mode of therapy. The total metal to artery surface contact area of the implanted Tacks and the alternative stent approach was calculated by lesion length category (#40 mm, 6080 mm, and $100 mm) using a computer-modeled algorithm.14 Statistical analysis. The necessary sample size for testing the end point of device technical success was constructed using Wilson’s method to provide a sufficient number of patients to result in one-sided 95% confidence bounds that were no wider than 10%. Based on this construct, a minimum sample size of 94 Tack-treated patients was required for this study. The intention-to-treat population was used for the efficacy analysis. The intention-to-treat population consisted of all patients who underwent a PTA, had post-PTA dissections identified, and had treatment of the dissections with the Tack Endovascular System. Data analysis was descriptive. Standard summary statistics were calculated for all
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Table I. Baseline patient demographic and clinical characteristics (N ¼ 130) Age, years Men Hypertension Diabetes mellitus Hyperlipidemia Current smoker Target limb Right Left RCC 2 3 4 ABI in target leg (n ¼ 123) Target limb pain symptoms No pain Pain on exercise Rest pain Not done Lesion location Ostial SFA Proximal SFA Mid SFA Distal SFA Proximal popliteal Mid popliteal Lesion type De novo Restenotic
Table II. Baseline angiographic characteristics
68.1 6 9.7 87 (66.9) 101 (77.7) 37 (28.5) 87 (66.9) 56 (43.1) 65 (50) 65 (50) 27 (20.8) 96 (73.8) 7 (5.4) 0.68 6 0.18 7 115 5 3
(5.4) (88.5) (3.8) (2.3)
1 19 58 41 10 1
(0.8) (14.6) (44.6) (31.5) (7.7) (0.8)
127 (97.7) 3 (2.3)
ABI, Ankle-brachial index; RCC, Rutherford clinical category; SFA, superficial femoral artery. Values are mean 6 standard deviation or number (%).
patients and study outcome variables. Continuous variables were summarized using estimated means, standard deviations, minimums, maximums, medians, and interquartile ranges. Categorical data were summarized using frequencies, percentages, and 95% confidence intervals. RESULTS A total of 138 patients at 13 clinical sites were entered into the trial. Of the 138 patients, 130 met the intentionto-treat criteria as determined by the investigator and were included in the analysis of effectiveness (Fig 2). Among the remaining eight patients, six had optimal PTA procedures and did not require the Tack implant to treat dissections, and two patients did not meet the post-PTA enrollment criteria (one had a vessel diameter >5.5 mm, and the other had a residual stenosis >30% and was treated with a stent). Blinded angiographic core laboratory analysis indicated that additional patients met these criteria. Specifically, 37 patients had residual stenosis >30%, and 61 patients had a reference vessel diameter >5.5 mm. Baseline clinical and lesion characteristics are detailed in Table I. The baseline ABI was 0.68 6 0.18. The most common comorbidities were hypertension (77.7%) and hyperlipidemia (66.9%). The target lesion was located in the SFA in 91.5% of patients, with most lesions being located in the mid (44.6%) and distal (31.5%) SFA. The majority of the lesions were de novo (97.7%).
Characteristic
No.
Lesion length, mm Calcification None/mild Moderate Severe Proximal RVD, mm Distal RVD, mm Total occlusion Pre-PTA diameter stenosis, % Post-PTA diameter stenosis, % Baseline dissection gradea A B C D E 0
128 129
128 128 130 129 130 127
51.4 6 29.5 44 (34.1) 78 (60.5) 7 (5.4) 5.5 6 0.7 5.5 6 0.7 45 (34.4) 81.8 6 15.6 20.9 6 7.6 6 24 79 15 0 3
(4.7) (18.9) (62.2) (11.8) (0) (2.4)
PTA, Percutaneous transluminal angioplasty; RVD, reference vessel diameter. Values are mean 6 standard deviation or number (%). a Reports most severe baseline dissection grade.
Table II summarizes the angiographic characteristics of the patients as reported by the core laboratory. The severity of lesion calcification was graded as none/mild in 34.1% of the patients, moderate in 60.5%, and severe in 5.4%. The mean diameter stenosis was 81.8% 6 15.6%, and the mean post-PTA diameter stenosis was 20.9% 6 7.6%. Within a treated lesion, if there were multiple post-PTA dissections, the most severe dissection was reported. There was discordance between investigator-reported and core laboratory-adjudicated dissection grades (Fig 3). Investigators graded dissection as $C in 25.8%, whereas the core laboratory determined that dissection $C was present in 74.0%. Procedure characteristics are outlined in Table III. There was a mean of 1.7 6 1.0 dissections per patient. The mean number of Tacks used per patient was 3.7 6 2.1 (range, 1-12). In two patients (1.5%), bailout stenting was performed. Device technical success was achieved in 128 of 130 patients (98.5%). MAE outcomes are summarized in Table IV. Of the 128 patients who met the criteria for technical success, 126 had 30 days of follow-up. No patients experienced MAEs in the 30-day postprocedure period. At 12 months of follow-up, 14 patients (12.0%) had experienced a MAE, 13 of which consisted of TLR and 1 emergent revascularization in the nontarget limb. The angiographic core laboratory evaluated plain radiographs of the Tack implants for migration (6 and 12 months) and fracture (12 months). Twelve-month radiographic review of implanted Tacks by the core laboratory showed that device migration was negligible, and there was no evidence of device fracture. Kaplan-Meier primary patency was 76.4% at 12 months (lower 95% confidence interval, 69.6%; Fig 4), and freedom from TLR was 89.5%. Changes in RCC and ABI over time are displayed in Figs 5 and 6, respectively. At baseline and
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Site Reported
Bosiers et al 5
Core Lab Reported
Table III. Procedure summary and outcomes
Percent of Total PaƟents
70
Patients (N ¼ 130)
Characteristic
60
49.2 6 23.9 11.2 6 5.6 117.0 6 45.6
Procedure time, minutes Fluoroscopy time, minutes Contrast media volume, mL Approach Contralateral Ipsilateral Dissections Tacks used Technical success
50 40 30 20 10 0
54 (41.5) 76 (58.5) 1.7 6 1.0 3.7 6 2.1 128 (98.5)
Values are mean 6 standard deviation or number (%).
A
B
C D DissecƟon Grade
E
Fig 3. Dissection severity grade: site reported vs core laboratory reported.
according to the study enrollment criteria, 100% of patients had an RCC score of 2 to 4. At 12 months after the procedure, 82.8% of the patients were RCC class 0 or 1. An RCC score >3 was reported for 3.2% of the patients at 12 months. There was also a significant (P < .0001) and sustained improvement in the mean ABI from baseline (0.68 6 0.18) to 0.99 6 0.16 and 0.94 6 0.15 at 30 days and 12 months, respectively. The evaluation of metal burden is presented in Fig 7. There were 95 evaluable cases, and results were based on the length of stent that would have been required by the investigator to treat the lesion. Tack implant use resulted in a reduction in metal surface contact with the artery lumen surface of up to 81%. DISCUSSION The prospective multicenter TOBA study demonstrated the safety and feasibility of the use of the Tack Endovascular System for treatment of post-PTA dissections. In this early-phase assessment of the technology, the study specifically evaluated how this new therapy would perform in lesions up to 10 cm in length and across all dissection grades. In this prespecified population of patients, the primary end point of device technical success was achieved in 98.5% of patients. The primary safety end point of the absence of new MAEs at 30 days was achieved in 100% of patients. Twelve-month freedom from TLR was 89.5%, and patency was 76.4%. In addition, there were significant sustained clinical improvements in ABI and RCC. Device migration was negligible, and there was no radiographic evidence of device fracture. The Tack implant has previously been evaluated in preclinical and first-in-human studies. Preclinical studies demonstrated that the Tack was substantially more resistant to acute and chronic inflammation than a comparative, commercially available stent. In a swine model, treated arteries were evaluated at 3 months after implantation, and the Tack-implanted vessels exhibited reduced stenosis (16.8% 6 2.6% vs 46.4% 6 9.8%), reduced inflammation,
Table IV. Major adverse events (MAEs) at 1 month and 12 months 1 Month (n ¼ 126 patients)
MAEs Tack embolization Emergent revascularization Target lesion Revascularization Amputation
No. with event
12 Months (n ¼ 120 patients)
95% CI
No. with event
95% CI
0 0
(0.0%-3.0%) (0.0%-3.0%)
14 0
(7.1%-18.6%) (0.0%-3.1%)
0 0 0
(0.0%-3.0%) (0.0%-3.0%) (0.0%-3.0%)
1 13 0
(0.1%-4.6%) (6.4%-17.7%) (0.0%-3.1%)
CI, Confidence interval.
reduced neointimal tissue formation, and reduced injury scores compared with the stented arteries.12 In the first human experience in 15 limbs in 11 patients (25 lesions) with the Tack device, technical success was achieved in all cases, and 1-year angiographic patency was 83.3%.12 Balloon angioplasty is a mainstay among therapeutic strategies for lower extremity revascularization. Balloon angioplasty mechanically increases the vessel lumen by disrupting the plaque and stretching the vessel, a byproduct of which is dissection. The severity of dissection can range from mild disruptions of the vessel wall to severe flowlimiting dissections.15 In current practice, when dissections must be managed, stenting is the only available treatment option. Unfortunately, just about every feature of stent construction has been associated with failure, usually due to restenosis, including stent material, outward force, cell design, strut thickness, and other features.16-22 Stent overlap, whereby the metal layer is doubled and arterial flexibility is further reduced, is often associated with failure. The so-called full-metal jacket, with longer stent lengths and increased scaffolding of the flexible femoral-popliteal arteries, has a high failure rate and is avoided by most clinicians whenever possible. Up to 50% of all femoral-popliteal stent failures present with occlusion, and repair of this condition has an unfavorable success rate, in the range of 20% at 1 year.23 In comparison, the Tack system not only avoids
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80 70 Percent of PaƟents
60 RCC 0 1 2 3 4 5
50 40 30 20 10 0
Baseline
1 Month
6 Months
12 Months
Fig 5. Rutherford clinical category (RCC) scores. The number at baseline, 1 month, 6 months, and 12 months was 130, 128, 119, and 122, respectively.
1.25 *
Fig 4. Primary patency: 12-month freedom from target lesion revascularization (TLR), occlusion, and >50% restenosis. The vertical bars represent 95% confidence intervals. Ankle-Brachial Index
the full-metal jacket effect but reduces metal burden by its shorter longitudinal length and open cell design. To evaluate how much the Tacks reduced metal burden, physician investigators provided assessments of the stent length they would have used to treat dissections had Tacks not been used. This mathematical model showed a mean 81% reduction of metal in contact with arterial surface by using Tacks rather than stents to treat dissections. In addition, the shorter longitudinal length of Tacks should make them less susceptible to fracture and easier to cross should reintervention be required. Stent fracture has been associated with the type, length, and location of the stent.10,24-26 The presence of fractured stents is a predictor (P < .00001) of lower primary patency.24 In this study, there was no evidence of Tack fractures. Additional data suggest that untreated post-PTA dissection, not just flow-limiting dissection, is associated with reduced patency. In one study, the 6-month TLR rate was 10.5% for patients without dissections and 33% and 44% for patients with grade A-B and C-E dissections, respectively.3 Although post-PTA dissection is a wellknown and widely reported feature of vascular intervention, accurate assessment of the severity and the clinical sequelae of dissections at the time of procedure has proved difficult. This clinical trial endeavored to treat all dissections in an effort to reduce the negative consequences associated with untreated dissections. Comparison of evaluations by the treating physician and an independent angiographic core laboratory shows that the treating physicians rated the majority of the dissections as less severe grades A and B (73.5%), whereas the core laboratory graded 74.0% of dissections as more severe grades C and above.
1.00
*
*
0.99 0.94
0.94
6 Months
12 Months
0.75 0.68
0.50
0.25
Baseline
1 Month
Fig 6. Change in ankle-brachial index (ABI) from baseline. *P < .0001 from baseline.
These data support the concept that treatment of dissections has a beneficial effect on clinical outcomes. The 12-month primary patency rate in patients treated with Tacks was 76.4%. This result was better than would be predicted on the basis of the recently published results of randomized trials that reported the 12-month primary patency rates of 33% to 52% after standard balloon angioplasty.10,26,27 Tack implants are specifically designed to provide the structural support necessary to repair dissections while limiting the adverse outcomes associated with stent use. Like a stent, Tack implants serve to facilitate apposition of dissection flaps to the luminal surface. However, unlike a stent, Tack implants employ a minimalist approach in that each implant length is limited to 6 mm and consists of an open lattice design to reduce the metal surface area in contact with the arterial luminal surface. This novel design also reduces radial force exerted on the vessel wall and allows the Tack to adapt to a wide range of vessel diameters.
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TLR. Treatment of dissections with Tack implants may represent a versatile and viable alternative to stenting that markedly reduces the metal burden in the treated vessel. The authors also wish to thank and acknowledge Carol Burns and Robert Giasolli for their help in planning and designing the study. AUTHOR CONTRIBUTIONS
Fig 7. Computer-modeled total metal surface area of Tacks vs stents. TOBA, Tack Optimized Balloon Angioplasty study.
Reducing metal surface and the negative constraints placed on the vessel wall would be predictive for lower rates of restenosis and TLR. Because this was an early-phase evaluation of the technology, we chose to limit the study to patients with lesions up to 10 cm above the knee. The broad applicability of these results will require further study. Using the data obtained in the TOBA study, additional follow-on studies, TOBA-Below the Knee (TOBA-BTK) and TOBA II, were designed to evaluate below-the-knee lesions and longer, more complex femoral-popliteal lesions. In addition, new technologies, such as drug-coated balloons (DCBs), may represent a significant new advance in the treatment of SFA and popliteal arterial disease. Whereas the sustained effect of the paclitaxel seems to improve longer term patency, the acute mechanical effects of the balloon angioplasty produce the same damage and dissections as standard PTA does. Future studies evaluating Tacks in the context of DCB angioplasty would provide insight as to the potential benefits of combined use of these technologies. Limitations. This study was conducted as a single-arm study, and there was no contemporary comparator group to either stenting or DCB. All patients were treated with balloons, without antiproliferative drug coating, so it is not known if additional benefit could be obtained by combining DCB with Tack devices. Predilation was performed on the basis of the investigator’s medical judgment rather than according to a prescribed procedure. As such, the variations in predilation could have affected outcomes. Further, the study enrolled only patients with lesions #10 cm, and most lesions were above the knee. It is unknown if the results from this study can be repeated in longer lesions or lesions below the knee. As noted, further studies of the Tack system are ongoing to evaluate these lesion types. CONCLUSIONS Treatment of post-PTA dissections with Tack implants resulted in long-term clinical improvement and low rates of
Conception and design: MEB, DS Analysis and interpretation: MEB, DS, CW, TZ, MB Data collection: MEB, DS, JH, CW, PP, TZ, MB, RS Writing the article: MEB, DS, JH, CW, PP, TZ, MB, RS Critical revision of the article: MEB, DS, JH, CW, PP, TZ, MB, RS Final approval of the article: MEB, DS, JH, CW, PP, TZ, MB, RS Statistical analysis: Not applicable Obtained funding: Not applicable Overall responsibility: MEB REFERENCES 1. Norgren L, Hiatt WR, Dormandy J, Nehler MR, Harris KA, Fowkes FG; TASC II Working Group. Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II). J Vasc Surg 2007;45(Suppl S):S5-67. 2. Werk M, Albrecht T, Meyer DR, Ahmed MN, Behne A, Dietz U, et al. Paclitaxel-coated balloons reduce restenosis after femoro-popliteal angioplasty: evidence from the randomized PACIFIER trial. Circ Cardiovasc Interv 2012;5:831-40. 3. Tepe G, Zeller T, Schnorr B, Claussen CD. High-grade, non-flowlimiting dissections do not negatively impact long-term outcome after paclitaxel-coated balloon angioplasty: an additional analysis from the THUNDER study. J Endovasc Ther 2013;20:792-800. 4. Rocha-Singh KJ, Jaff MR, Crabtree TR, Bloch DA, Ansel G. Performance goals and endpoint assessments for clinical trials of femoropopliteal bare nitinol stents in patients with symptomatic peripheral arterial disease. Catheter Cardiovasc Interv 2007;69:910-9. 5. Tepe G, Zeller T, Albrecht T, Heller S, Schwarzwälder U, Beregi J-P, et al. Local delivery of paclitaxel to inhibit restenosis during angioplasty of the leg. N Engl J Med 2008;358:689-99. 6. Werk M, Langner S, Reinkensmeier B, Boettcher HF, Tepe G, Dietz U, et al. Inhibition of restenosis in femoropopliteal arteries: paclitaxel-coated versus uncoated balloon: femoral paclitaxel randomized pilot trial. Circulation 2008;118:1358-65. 7. Schillinger M, Sabeti S, Loewe C, Dick P, Amighi J, Mlekusch W, et al. Balloon angioplasty versus implantation of nitinol stents in the superficial femoral artery. N Engl J Med 2006;354:1879-88. 8. Krankenberg H, Schlüter M, Steinkamp HJ, Bürgelin K, Scheinert D, Schulte KL, et al. Nitinol stent implantation versus percutaneous transluminal angioplasty in superficial femoral artery lesions up to 10 cm in length: the Femoral Artery Stenting Trial (FAST). Circulation 2007;116:285-92. 9. Bosiers M, Torsello G, Gissler H-M, Ruef J, Müller-Hülsbeck S, Jahnke T, et al. Nitinol stent implantation in long superficial femoral artery lesions: 12-month results of the DURABILITY I study. J Endovasc Ther 2009;16:261-9. 10. Laird JR, Katzen BT, Scheinert D, Lammer J, Carpenter J, Buchbinder M, et al. Nitinol stent implantation versus balloon angioplasty for lesions in the superficial femoral artery and proximal popliteal artery: twelve-month results from the RESILIENT randomized trial. Circ Cardiovasc Interv 2010;3:267-76. 11. Rutherford RB, Baker JD, Ernst C, Johnston KW, Porter JM, Ahn S, et al. Recommended standards for reports dealing with lower extremity ischemia: revised version. J Vasc Surg 1997;26:517-38.
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12. Schneider PA, Giasolli R, Ebner A, Virmani R, Granada JF. Early experimental and clinical experience with a focal implant for lower extremity post-angioplasty dissection. JACC Cardiovasc Interv 2015;8: 347-54. 13. National Heart, Blood and Lung Institute. Coronary artery angiographic changes after PTCA. In: Manual of operations: NHLBI PTCA registry. Bethesda, MD: National Heart, Lung, and Blood Institute; 1985. p. 6-9. 14. Arkowski J, Wawrzynska M, Bialy D, Sobieszczanska B, Mazurek W. The reduction of restenosis in cardiovascular stents. In: Tofail SAM, editor. Biological interactions with surface charge in biomaterials. Cambridge: The Royal Society of Chemistry; 2012. p. 222-9. RSC Nanoscience and Nanotechnology No. 21. 15. Fitzgerald PJ, Ports TA, Yock PG. Contribution of localized calcium deposits to dissection after angioplasty. An observational study using intravascular ultrasound. Circulation 1992;86:64-70. 16. Nelken N, Schneider PA. Advances in stent technology and drugeluting stents. Surg Clin North Am 2004;84:1203-36. v. 17. Cha S-H, Han MH, Choi YH, Yoon CJ, Baik SK, Kim SJ, et al. Vascular responses in normal canine carotid arteries: comparison between various self-expanding stents of the same unconstrained size. Invest Radiol 2003;38:95-101. 18. Finn AV, Joner M, Nakazawa G, Kolodgie F, Newell J, John MC, et al. Pathological correlates of late drug-eluting stent thrombosis: strut coverage as a marker of endothelialization. Circulation 2007;115:2435-41. 19. van Beusekom HM, Whelan DM, Hofma SH, Krabbendam SC, van Hinsbergh VW, Verdouw PD, et al. Long-term endothelial dysfunction is more pronounced after stenting than after balloon angioplasty in porcine coronary arteries. J Am Coll Cardiol 1998;32:1109-17.
APPENDIX. TOBA Investigators Koen Deloose, AZ St. Blasius Hospital, Dendermonde, Belgium; Jean-Paul P. M. de Vries, Department of Vascular Surgery, St. Antonius Hospital, Nieuwegein, The Netherlands; Daniël A. F. van den Heuvel, Department of Interventional Radiology, St. Antonius Hospital, Nieuwegein, The Netherlands; Hans Krankenberg, Center for Cardiology and Vascular Intervention, Hamburg, Germany; Lubos Kubicek, St. Anne’s University Hospital and Faculty of Medicine, Masaryk University, Brno, Czech Republic; Andreas Dorr, Medical University Hospital Graz, Austria; Hans M. Gissler, Hochrhein-Eggberg Clinic, Bad Säckingen, Germany; Andrej Schmidt, Sven Braunlich, Matthias Ulrich, Johannes Schuster, Susanne Scheinert,
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20. Lau K-W, Mak K-H, Hung J-S, Sigwart U. Clinical impact of stent construction and design in percutaneous coronary intervention. Am Heart J 2004;147:764-73. 21. Hara H, Nakamura M, Palmaz JC, Schwartz RS. Role of stent design and coatings on restenosis and thrombosis. Adv Drug Deliv Rev 2006;58:377-86. 22. Morton AC, Crossman D, Gunn J. The influence of physical stent parameters upon restenosis. Pathol Biol (Paris) 2004;52:196-205. 23. Tosaka A, Soga Y, Iida O, Ishihara T, Hirano K, Suzuki K, et al. Classification and clinical impact of restenosis after femoropopliteal stenting. J Am Coll Cardiol 2012;59:16-23. 24. Scheinert D, Scheinert S, Sax J, Piorkowski C, Bräunlich S, Ulrich M, et al. Prevalence and clinical impact of stent fractures after femoropopliteal stenting. J Am Coll Cardiol 2005;45:312-5. 25. Duda SH, Bosiers M, Lammer J, Scheinert D, Zeller T, Oliva V, et al. Drug-eluting and bare nitinol stents for the treatment of atherosclerotic lesions in the superficial femoral artery: long-term results from the SIROCCO trial. J Endovasc Ther 2006;13:701-10. 26. Dake MD, Ansel GM, Jaff MR, Ohki T, Saxon RR, Smouse HB, et al. Paclitaxel-eluting stents show superiority to balloon angioplasty and bare metal stents in femoropopliteal disease: twelve-month Zilver PTX randomized study results. Circ Cardiovasc Interv 2011;4:495-504. 27. Tepe G, Laird J, Schneider P, Brodmann M, Krishnan P, Micari A, et al. Drug-coated balloon versus standard percutaneous transluminal angioplasty for the treatment of superficial femoral and popliteal peripheral artery disease: 12-month results from the IN.PACT SFA randomized trial. Circulation 2014;131:495-502. Submitted Dec 11, 2015; accepted Feb 9, 2016.
Yvonne Bausback, Michael Piorkowski, and Martin Werner, University-Hospital Leipzig, Leipzig, Germany; Jürgen Verbist, Imeldaziekenhuis, Bonheiden, Belgium; Lieven Maene and Roel Beelen, Onze-Lieve-Vrouwziekenhuis, Aalst, Belgium; Uwe Schwarzwälder, Aljoscha Rastan, and Ulrich Beschorner, Universitäts-Herzzentrum Freiburg-Bad Krozingen, Bad Krozingen, Germany; Sebastian Sixt, Center for Cardiology and Vascular Intervention, Hamburg, Germany; Ernst Pilger and Philipp Eller, Medical University Hospital Graz, Graz, Austria; Jens Ricke and Maciej Pech, Universitätsklinikum Magdeburg AoR, Magdeburg, Germany; Christopher Ludtke, Academic Teaching Hospital of the Universities of Kiel, Luebeck, and Hamburg, Germany; Bob Vojtisek and Robert Vlachovsky, St. Anne’s University Hospital and Faculty of Medicine, Masaryk University, Brno, Czech Republic.
Percutaneous transluminal angioplasty (PTA) is commonly used for femoral-popliteal revascularization in patients with lower extremity ischemia and has been a workhorse tool for interventionists for 50 years.1 Because the angioplasty mechanism functions primarily by producing dissection, PTA as a stand-alone therapy is associated with poor outcomes, with acute dissection visible in 47% to 88% of cases2,3 and 1-year restenosis rates of 40% to 60%.1,4-6 Untreated post-PTA dissection has been associated with poor
results, both acute and in the long term.3 The target lesion revascularization (TLR) rate, compared with lesions without identifiable acute dissections, is 3.5-fold higher (10.5% vs 37%) at 6 months after PTA.3,5 Whereas there is an association between severity of dissection and TLR rate, lesions with less severe dissections (National Heart, Lung, and Blood Institute grades A and B) had only a slightly lower incidence of TLR than more severe (grades C-E) dissections (33% vs 44%, respectively).3
From the AZ St. Blasius Hospital, Dendermondea; the University-Hospital Leipzig, Leipzigb; the Antwerp University Hospital, Edegem (Antwerp)c; the Academic Teaching Hospital of the Universities of Kiel, Luebeck, and Hamburg, Heided; the Imeldaziekenhuis, Bonheidene; the UniversitätsHerzzentrum Freiburg-Bad Krozingen, Bad Krozingenf; the Medical University Hospital Graz, Grazg; and the St. Anne’s University Hospital and Faculty of Medicine, Masaryk University, Brno.h This work was funded by Intact Vascular. Intact Vascular had no involvement in the study design; collection, analysis, and interpretation of data; manuscript writing; or the decision to submit the manuscript for publication. Clinical Trial registration: NCT01663818. Author conflict of interest: T.Z. received honoraria from Abbott Vascular, Bard Peripheral Vascular, Veryan, Biotronik, Boston Scientific, Cook Medical, Cordis, Covidien, W. L. Gore & Associates, Medtronic, Spectranetics, Straub Medical, TriReme, and VIVA Physicians; he is a consultant for Abbott Vascular, Bard Peripheral Vascular, Boston Scientific, Cook Medical, W. L. Gore & Associates, Medtronic, Spectranetics, and ReCor;
and he has received research, clinical trial, or drug study funds from 480 Biomedical, Bard Peripheral Vascular, Veryan, Biotronik, Cook Medical, Cordis, Covidien, W. L. Gore & Associates, Abbott Vascular-IDEV Technologies Inc, Medtronic, Spectranetics, Terumo, TriReme, and Volcano. D.S. acts as a member/consultant of the advisory board of Abbott, Angioslide, Atheromed, Biotronik, Boston Scientific, Cook Medical, Cordis, Covidien, CR Bard, Gardia Medical, Hemoteq, Intact Vascular Inc, Medtronic, Ostial Inc, and TriReme. Correspondence: Marc Bosiers, MD, AZ St. Blasius Hospital, Kroonveldiaan 50, 9200 Dendermonde, Belgium (e-mail: [email protected]). The editors and reviewers of this article have no relevant financial relationships to disclose per the JVS policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest. 0741-5214 Copyright Ó 2016 by the Society for Vascular Surgery. Published by Elsevier Inc. http://dx.doi.org/10.1016/j.jvs.2016.02.043
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The usual approach to treatment of post-PTA dissection during the past 20 years has been stent placement. Although stenting has improved acute PTA outcomes, stents have also been shown to induce chronic injury and inflammation, leading to 1-year restenosis rates ranging from 20% to 37%.7-10 One possible solution is a minimal metal, relatively inert implant to mechanically appose dissection flaps to the vessel wall while limiting the outward force and metal burden. This would permit focal treatment, allowing the operator to control the procedure and the location and amount of scaffolding. Herein we report the first large-scale, prospective, multicenter study evaluating the safety and efficacy of the Tack Endovascular System (Intact Vascular, Wayne, Pa) for treatment of post-PTA dissections.
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Fig 1. Tack implant compared with conventional stent.
METHODS The Tack Optimized Balloon Angioplasty (TOBA) study was an early-phase, prospective, single-arm, multicenter, open-label, nonrandomized study. The study was conducted in accordance with the Declaration of Helsinki. The local ethics committees at the participating sites approved the study protocol, and all patients provided written informed consent before undergoing any study procedures. Patients who provided informed consent and met the study entrance criteria were considered enrolled. The objective of this study was to evaluate the performance of the Tack Endovascular System for the treatment of dissections resulting from PTA of the superficial femoral artery (SFA) or popliteal artery. Patient population. Patient enrollment criteria were assessed by the physician investigator during preprocedure assessments and procedural angiography. Patients were required to have angiographic documentation of an SFA or popliteal lesion located between the origin of the SFA and 2.0 cm below the tibial plateau. Major inclusion criteria included Rutherford clinical category (RCC) score 2 to 4,11 ankle-brachial index (ABI) #0.90, reference vessel diameter between 2.5 and 5.5 mm, target lesion stenosis $70% or occlusion, target lesion length #10 cm, and presence of at least one tibial runoff vessel. Major exclusion criteria included previous ipsilateral SFA or popliteal artery stent or bypass, severe calcification of the target lesion (defined as circumferential calcification or dense calcium plaque that extends for $5 cm), and stenosis or occlusion of the inflow tract not treated before or during the index procedure. The patients underwent standard balloon angioplasty. The angioplasty balloon was selected to match (1:1) or slightly exceed the reference vessel diameter. When possible, a single balloon was used to dilate the entire lesion length, typically with a minimum of 5 mm of balloon length extending beyond the end of the lesion. The balloon was inflated to nominal pressure or higher if required to expand any residual waist on the balloon. Balloon inflation was typically maintained for a minimum of 30 seconds. Post-PTA angiograms were taken. If there
was significant residual stenosis (ie, >30%), the lesion was treated with repeated PTA at longer inflation times or increased pressure per the clinician’s judgment. Patients with >30% residual stenosis after repeated PTA were screen failures. If no dissection was observed on the initial postPTA angiogram, oblique views were obtained to further evaluate the treatment site. Patients with <30% residual stenosis and evidence of dissection were treated with Tacks. When there was no dissection and optimal angioplasty was achieved, the patient did not receive Tack implants but was observed for 30 days. Tack Endovascular System. The Tack Endovascular System contains a self-expanding nitinol implant that measures 6 mm in length and treats reference vessel diameters ranging from 2.5 to 5.5 mm. Unlike stents, the Tack implant is designed to exert essentially the same radial force on the artery across this entire range of diameters, which permits one-size Tack to adapt to the full range of diameters referenced. The short longitudinal length in combination with an open-cell design acts to minimize the amount of metal that is in contact with the artery compared with stents (Fig 1). The Tack implants are designed to treat acute dissections by exerting minimal focal pressure that facilitates the apposition of damaged tissue to the inner luminal surface of the artery. To enable accurate placement and anchoring of the dissection flap to the vessel wall, each Tack implant contains six radiopaque gold markers in the center, along with six pairs of anchors that elevate slightly on deployment of the Tack and serve to mitigate movement of the Tack once it is deployed. Four independent Tack implants were provided preloaded onto a single 6F delivery catheter. Tacks were deployed as previously described.12 Briefly, after angiographic identification of a dissection, the delivery catheter was loaded onto the same guidewire used during the PTA procedure and advanced to the treatment site using fluoroscopic guidance. Based on the investigator’s evaluation of the angiogram, the Tack implants were deployed separately with gaps of $6 mm between the individual Tacks. The number of Tacks used was based on the
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Bosiers et al 3
Fig 2. Patient disposition.
requirements to completely treat the dissection. After deployment across the dissected segment, post-Tack placement angioplasty was performed to secure the implants. Angiography was performed to verify acceptable acute vessel patency. Antiplatelet medication. Premedication was per the investigator’s clinical judgment or institutional practice and included a loading dose of aspirin (80-500 mg) and clopidogrel (75-600 mg). Most patients continued to take aspirin (median dose, 100 mg) throughout the 12-month follow-up period. Clopidogrel (median dose, 75 mg) was continued for 30 days after the procedure in 81% of the patients. Angiography and duplex ultrasound. The investigator performed evaluation of angiographic data for the determination of study enrollment at the time of the procedure. Angiographic images were sent to an independent core laboratory (Yale University School of Medicine Angiographic Core Laboratory, New Haven, Conn) for blinded evaluation of the target lesions and outcomes. For comparison purposes, both the site-reported and core laboratory analyses of dissection severity are included in this report. Dissections were graded on the basis of angiographic evaluation of intimal disruption using the National Heart, Lung, and Blood Institute classification system.13 Duplex ultrasound (DUS) was conducted at 6 and 12 months and analyzed by an independent DUS core laboratory (VasCore, Boston, Mass) to evaluate arterial patency at the target lesion location. Arteries were considered to be patent if they had <50% residual stenosis as determined by a peak systolic velocity ratio <2.5. All study-defined angiography and DUS end points were assessed on the basis of data provided by the respective core laboratories. Study end points. The primary efficacy end point was device technical success, defined as the ability of the Tack implants to resolve post-PTA dissection, which was achieved when the dissection was no longer visible by angiography and acute arterial patency was maintained at the implant location. The primary safety end point was a
composite of all new-onset major adverse events (MAEs), which were defined as device and arterial embolization, need for emergency surgical revascularization, amputation above the ankle, or clinically driven TLR through 30 days after the procedure. Clinically driven TLR was defined as any repeated percutaneous (endovascular) or surgical intervention to treat objectively documented signs or symptoms of recurrent ischemia attributable to the index lesion. Objective evidence of recurrent ischemia caused by the index lesion was required, including evidence of recurrent stenosis $70% and decrease in ABI of 0.1 or more from post-index procedure result. Patients were followed up through 12 months after the procedure for continued assessment of MAEs, changes in RCC and ABI from baseline, DUS of arterial patency, and radiographic evaluation of device migration and fracture evaluated by the angiographic core laboratory. In addition, an analysis of “metal burden” was conducted. For each case, the investigator prospectively recorded the stent type and length that would have been required to treat the lesion if the operator had selected that mode of therapy. The total metal to artery surface contact area of the implanted Tacks and the alternative stent approach was calculated by lesion length category (#40 mm, 6080 mm, and $100 mm) using a computer-modeled algorithm.14 Statistical analysis. The necessary sample size for testing the end point of device technical success was constructed using Wilson’s method to provide a sufficient number of patients to result in one-sided 95% confidence bounds that were no wider than 10%. Based on this construct, a minimum sample size of 94 Tack-treated patients was required for this study. The intention-to-treat population was used for the efficacy analysis. The intention-to-treat population consisted of all patients who underwent a PTA, had post-PTA dissections identified, and had treatment of the dissections with the Tack Endovascular System. Data analysis was descriptive. Standard summary statistics were calculated for all
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Table I. Baseline patient demographic and clinical characteristics (N ¼ 130) Age, years Men Hypertension Diabetes mellitus Hyperlipidemia Current smoker Target limb Right Left RCC 2 3 4 ABI in target leg (n ¼ 123) Target limb pain symptoms No pain Pain on exercise Rest pain Not done Lesion location Ostial SFA Proximal SFA Mid SFA Distal SFA Proximal popliteal Mid popliteal Lesion type De novo Restenotic
Table II. Baseline angiographic characteristics
68.1 6 9.7 87 (66.9) 101 (77.7) 37 (28.5) 87 (66.9) 56 (43.1) 65 (50) 65 (50) 27 (20.8) 96 (73.8) 7 (5.4) 0.68 6 0.18 7 115 5 3
(5.4) (88.5) (3.8) (2.3)
1 19 58 41 10 1
(0.8) (14.6) (44.6) (31.5) (7.7) (0.8)
127 (97.7) 3 (2.3)
ABI, Ankle-brachial index; RCC, Rutherford clinical category; SFA, superficial femoral artery. Values are mean 6 standard deviation or number (%).
patients and study outcome variables. Continuous variables were summarized using estimated means, standard deviations, minimums, maximums, medians, and interquartile ranges. Categorical data were summarized using frequencies, percentages, and 95% confidence intervals. RESULTS A total of 138 patients at 13 clinical sites were entered into the trial. Of the 138 patients, 130 met the intentionto-treat criteria as determined by the investigator and were included in the analysis of effectiveness (Fig 2). Among the remaining eight patients, six had optimal PTA procedures and did not require the Tack implant to treat dissections, and two patients did not meet the post-PTA enrollment criteria (one had a vessel diameter >5.5 mm, and the other had a residual stenosis >30% and was treated with a stent). Blinded angiographic core laboratory analysis indicated that additional patients met these criteria. Specifically, 37 patients had residual stenosis >30%, and 61 patients had a reference vessel diameter >5.5 mm. Baseline clinical and lesion characteristics are detailed in Table I. The baseline ABI was 0.68 6 0.18. The most common comorbidities were hypertension (77.7%) and hyperlipidemia (66.9%). The target lesion was located in the SFA in 91.5% of patients, with most lesions being located in the mid (44.6%) and distal (31.5%) SFA. The majority of the lesions were de novo (97.7%).
Characteristic
No.
Lesion length, mm Calcification None/mild Moderate Severe Proximal RVD, mm Distal RVD, mm Total occlusion Pre-PTA diameter stenosis, % Post-PTA diameter stenosis, % Baseline dissection gradea A B C D E 0
128 129
128 128 130 129 130 127
51.4 6 29.5 44 (34.1) 78 (60.5) 7 (5.4) 5.5 6 0.7 5.5 6 0.7 45 (34.4) 81.8 6 15.6 20.9 6 7.6 6 24 79 15 0 3
(4.7) (18.9) (62.2) (11.8) (0) (2.4)
PTA, Percutaneous transluminal angioplasty; RVD, reference vessel diameter. Values are mean 6 standard deviation or number (%). a Reports most severe baseline dissection grade.
Table II summarizes the angiographic characteristics of the patients as reported by the core laboratory. The severity of lesion calcification was graded as none/mild in 34.1% of the patients, moderate in 60.5%, and severe in 5.4%. The mean diameter stenosis was 81.8% 6 15.6%, and the mean post-PTA diameter stenosis was 20.9% 6 7.6%. Within a treated lesion, if there were multiple post-PTA dissections, the most severe dissection was reported. There was discordance between investigator-reported and core laboratory-adjudicated dissection grades (Fig 3). Investigators graded dissection as $C in 25.8%, whereas the core laboratory determined that dissection $C was present in 74.0%. Procedure characteristics are outlined in Table III. There was a mean of 1.7 6 1.0 dissections per patient. The mean number of Tacks used per patient was 3.7 6 2.1 (range, 1-12). In two patients (1.5%), bailout stenting was performed. Device technical success was achieved in 128 of 130 patients (98.5%). MAE outcomes are summarized in Table IV. Of the 128 patients who met the criteria for technical success, 126 had 30 days of follow-up. No patients experienced MAEs in the 30-day postprocedure period. At 12 months of follow-up, 14 patients (12.0%) had experienced a MAE, 13 of which consisted of TLR and 1 emergent revascularization in the nontarget limb. The angiographic core laboratory evaluated plain radiographs of the Tack implants for migration (6 and 12 months) and fracture (12 months). Twelve-month radiographic review of implanted Tacks by the core laboratory showed that device migration was negligible, and there was no evidence of device fracture. Kaplan-Meier primary patency was 76.4% at 12 months (lower 95% confidence interval, 69.6%; Fig 4), and freedom from TLR was 89.5%. Changes in RCC and ABI over time are displayed in Figs 5 and 6, respectively. At baseline and
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Site Reported
Bosiers et al 5
Core Lab Reported
Table III. Procedure summary and outcomes
Percent of Total PaƟents
70
Patients (N ¼ 130)
Characteristic
60
49.2 6 23.9 11.2 6 5.6 117.0 6 45.6
Procedure time, minutes Fluoroscopy time, minutes Contrast media volume, mL Approach Contralateral Ipsilateral Dissections Tacks used Technical success
50 40 30 20 10 0
54 (41.5) 76 (58.5) 1.7 6 1.0 3.7 6 2.1 128 (98.5)
Values are mean 6 standard deviation or number (%).
A
B
C D DissecƟon Grade
E
Fig 3. Dissection severity grade: site reported vs core laboratory reported.
according to the study enrollment criteria, 100% of patients had an RCC score of 2 to 4. At 12 months after the procedure, 82.8% of the patients were RCC class 0 or 1. An RCC score >3 was reported for 3.2% of the patients at 12 months. There was also a significant (P < .0001) and sustained improvement in the mean ABI from baseline (0.68 6 0.18) to 0.99 6 0.16 and 0.94 6 0.15 at 30 days and 12 months, respectively. The evaluation of metal burden is presented in Fig 7. There were 95 evaluable cases, and results were based on the length of stent that would have been required by the investigator to treat the lesion. Tack implant use resulted in a reduction in metal surface contact with the artery lumen surface of up to 81%. DISCUSSION The prospective multicenter TOBA study demonstrated the safety and feasibility of the use of the Tack Endovascular System for treatment of post-PTA dissections. In this early-phase assessment of the technology, the study specifically evaluated how this new therapy would perform in lesions up to 10 cm in length and across all dissection grades. In this prespecified population of patients, the primary end point of device technical success was achieved in 98.5% of patients. The primary safety end point of the absence of new MAEs at 30 days was achieved in 100% of patients. Twelve-month freedom from TLR was 89.5%, and patency was 76.4%. In addition, there were significant sustained clinical improvements in ABI and RCC. Device migration was negligible, and there was no radiographic evidence of device fracture. The Tack implant has previously been evaluated in preclinical and first-in-human studies. Preclinical studies demonstrated that the Tack was substantially more resistant to acute and chronic inflammation than a comparative, commercially available stent. In a swine model, treated arteries were evaluated at 3 months after implantation, and the Tack-implanted vessels exhibited reduced stenosis (16.8% 6 2.6% vs 46.4% 6 9.8%), reduced inflammation,
Table IV. Major adverse events (MAEs) at 1 month and 12 months 1 Month (n ¼ 126 patients)
MAEs Tack embolization Emergent revascularization Target lesion Revascularization Amputation
No. with event
12 Months (n ¼ 120 patients)
95% CI
No. with event
95% CI
0 0
(0.0%-3.0%) (0.0%-3.0%)
14 0
(7.1%-18.6%) (0.0%-3.1%)
0 0 0
(0.0%-3.0%) (0.0%-3.0%) (0.0%-3.0%)
1 13 0
(0.1%-4.6%) (6.4%-17.7%) (0.0%-3.1%)
CI, Confidence interval.
reduced neointimal tissue formation, and reduced injury scores compared with the stented arteries.12 In the first human experience in 15 limbs in 11 patients (25 lesions) with the Tack device, technical success was achieved in all cases, and 1-year angiographic patency was 83.3%.12 Balloon angioplasty is a mainstay among therapeutic strategies for lower extremity revascularization. Balloon angioplasty mechanically increases the vessel lumen by disrupting the plaque and stretching the vessel, a byproduct of which is dissection. The severity of dissection can range from mild disruptions of the vessel wall to severe flowlimiting dissections.15 In current practice, when dissections must be managed, stenting is the only available treatment option. Unfortunately, just about every feature of stent construction has been associated with failure, usually due to restenosis, including stent material, outward force, cell design, strut thickness, and other features.16-22 Stent overlap, whereby the metal layer is doubled and arterial flexibility is further reduced, is often associated with failure. The so-called full-metal jacket, with longer stent lengths and increased scaffolding of the flexible femoral-popliteal arteries, has a high failure rate and is avoided by most clinicians whenever possible. Up to 50% of all femoral-popliteal stent failures present with occlusion, and repair of this condition has an unfavorable success rate, in the range of 20% at 1 year.23 In comparison, the Tack system not only avoids
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6 Bosiers et al
80 70 Percent of PaƟents
60 RCC 0 1 2 3 4 5
50 40 30 20 10 0
Baseline
1 Month
6 Months
12 Months
Fig 5. Rutherford clinical category (RCC) scores. The number at baseline, 1 month, 6 months, and 12 months was 130, 128, 119, and 122, respectively.
1.25 *
Fig 4. Primary patency: 12-month freedom from target lesion revascularization (TLR), occlusion, and >50% restenosis. The vertical bars represent 95% confidence intervals. Ankle-Brachial Index
the full-metal jacket effect but reduces metal burden by its shorter longitudinal length and open cell design. To evaluate how much the Tacks reduced metal burden, physician investigators provided assessments of the stent length they would have used to treat dissections had Tacks not been used. This mathematical model showed a mean 81% reduction of metal in contact with arterial surface by using Tacks rather than stents to treat dissections. In addition, the shorter longitudinal length of Tacks should make them less susceptible to fracture and easier to cross should reintervention be required. Stent fracture has been associated with the type, length, and location of the stent.10,24-26 The presence of fractured stents is a predictor (P < .00001) of lower primary patency.24 In this study, there was no evidence of Tack fractures. Additional data suggest that untreated post-PTA dissection, not just flow-limiting dissection, is associated with reduced patency. In one study, the 6-month TLR rate was 10.5% for patients without dissections and 33% and 44% for patients with grade A-B and C-E dissections, respectively.3 Although post-PTA dissection is a wellknown and widely reported feature of vascular intervention, accurate assessment of the severity and the clinical sequelae of dissections at the time of procedure has proved difficult. This clinical trial endeavored to treat all dissections in an effort to reduce the negative consequences associated with untreated dissections. Comparison of evaluations by the treating physician and an independent angiographic core laboratory shows that the treating physicians rated the majority of the dissections as less severe grades A and B (73.5%), whereas the core laboratory graded 74.0% of dissections as more severe grades C and above.
1.00
*
*
0.99 0.94
0.94
6 Months
12 Months
0.75 0.68
0.50
0.25
Baseline
1 Month
Fig 6. Change in ankle-brachial index (ABI) from baseline. *P < .0001 from baseline.
These data support the concept that treatment of dissections has a beneficial effect on clinical outcomes. The 12-month primary patency rate in patients treated with Tacks was 76.4%. This result was better than would be predicted on the basis of the recently published results of randomized trials that reported the 12-month primary patency rates of 33% to 52% after standard balloon angioplasty.10,26,27 Tack implants are specifically designed to provide the structural support necessary to repair dissections while limiting the adverse outcomes associated with stent use. Like a stent, Tack implants serve to facilitate apposition of dissection flaps to the luminal surface. However, unlike a stent, Tack implants employ a minimalist approach in that each implant length is limited to 6 mm and consists of an open lattice design to reduce the metal surface area in contact with the arterial luminal surface. This novel design also reduces radial force exerted on the vessel wall and allows the Tack to adapt to a wide range of vessel diameters.
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TLR. Treatment of dissections with Tack implants may represent a versatile and viable alternative to stenting that markedly reduces the metal burden in the treated vessel. The authors also wish to thank and acknowledge Carol Burns and Robert Giasolli for their help in planning and designing the study. AUTHOR CONTRIBUTIONS
Fig 7. Computer-modeled total metal surface area of Tacks vs stents. TOBA, Tack Optimized Balloon Angioplasty study.
Reducing metal surface and the negative constraints placed on the vessel wall would be predictive for lower rates of restenosis and TLR. Because this was an early-phase evaluation of the technology, we chose to limit the study to patients with lesions up to 10 cm above the knee. The broad applicability of these results will require further study. Using the data obtained in the TOBA study, additional follow-on studies, TOBA-Below the Knee (TOBA-BTK) and TOBA II, were designed to evaluate below-the-knee lesions and longer, more complex femoral-popliteal lesions. In addition, new technologies, such as drug-coated balloons (DCBs), may represent a significant new advance in the treatment of SFA and popliteal arterial disease. Whereas the sustained effect of the paclitaxel seems to improve longer term patency, the acute mechanical effects of the balloon angioplasty produce the same damage and dissections as standard PTA does. Future studies evaluating Tacks in the context of DCB angioplasty would provide insight as to the potential benefits of combined use of these technologies. Limitations. This study was conducted as a single-arm study, and there was no contemporary comparator group to either stenting or DCB. All patients were treated with balloons, without antiproliferative drug coating, so it is not known if additional benefit could be obtained by combining DCB with Tack devices. Predilation was performed on the basis of the investigator’s medical judgment rather than according to a prescribed procedure. As such, the variations in predilation could have affected outcomes. Further, the study enrolled only patients with lesions #10 cm, and most lesions were above the knee. It is unknown if the results from this study can be repeated in longer lesions or lesions below the knee. As noted, further studies of the Tack system are ongoing to evaluate these lesion types. CONCLUSIONS Treatment of post-PTA dissections with Tack implants resulted in long-term clinical improvement and low rates of
Conception and design: MEB, DS Analysis and interpretation: MEB, DS, CW, TZ, MB Data collection: MEB, DS, JH, CW, PP, TZ, MB, RS Writing the article: MEB, DS, JH, CW, PP, TZ, MB, RS Critical revision of the article: MEB, DS, JH, CW, PP, TZ, MB, RS Final approval of the article: MEB, DS, JH, CW, PP, TZ, MB, RS Statistical analysis: Not applicable Obtained funding: Not applicable Overall responsibility: MEB REFERENCES 1. Norgren L, Hiatt WR, Dormandy J, Nehler MR, Harris KA, Fowkes FG; TASC II Working Group. Inter-Society Consensus for the Management of Peripheral Arterial Disease (TASC II). J Vasc Surg 2007;45(Suppl S):S5-67. 2. Werk M, Albrecht T, Meyer DR, Ahmed MN, Behne A, Dietz U, et al. Paclitaxel-coated balloons reduce restenosis after femoro-popliteal angioplasty: evidence from the randomized PACIFIER trial. Circ Cardiovasc Interv 2012;5:831-40. 3. Tepe G, Zeller T, Schnorr B, Claussen CD. High-grade, non-flowlimiting dissections do not negatively impact long-term outcome after paclitaxel-coated balloon angioplasty: an additional analysis from the THUNDER study. J Endovasc Ther 2013;20:792-800. 4. Rocha-Singh KJ, Jaff MR, Crabtree TR, Bloch DA, Ansel G. Performance goals and endpoint assessments for clinical trials of femoropopliteal bare nitinol stents in patients with symptomatic peripheral arterial disease. Catheter Cardiovasc Interv 2007;69:910-9. 5. Tepe G, Zeller T, Albrecht T, Heller S, Schwarzwälder U, Beregi J-P, et al. Local delivery of paclitaxel to inhibit restenosis during angioplasty of the leg. N Engl J Med 2008;358:689-99. 6. Werk M, Langner S, Reinkensmeier B, Boettcher HF, Tepe G, Dietz U, et al. Inhibition of restenosis in femoropopliteal arteries: paclitaxel-coated versus uncoated balloon: femoral paclitaxel randomized pilot trial. Circulation 2008;118:1358-65. 7. Schillinger M, Sabeti S, Loewe C, Dick P, Amighi J, Mlekusch W, et al. Balloon angioplasty versus implantation of nitinol stents in the superficial femoral artery. N Engl J Med 2006;354:1879-88. 8. Krankenberg H, Schlüter M, Steinkamp HJ, Bürgelin K, Scheinert D, Schulte KL, et al. Nitinol stent implantation versus percutaneous transluminal angioplasty in superficial femoral artery lesions up to 10 cm in length: the Femoral Artery Stenting Trial (FAST). Circulation 2007;116:285-92. 9. Bosiers M, Torsello G, Gissler H-M, Ruef J, Müller-Hülsbeck S, Jahnke T, et al. Nitinol stent implantation in long superficial femoral artery lesions: 12-month results of the DURABILITY I study. J Endovasc Ther 2009;16:261-9. 10. Laird JR, Katzen BT, Scheinert D, Lammer J, Carpenter J, Buchbinder M, et al. Nitinol stent implantation versus balloon angioplasty for lesions in the superficial femoral artery and proximal popliteal artery: twelve-month results from the RESILIENT randomized trial. Circ Cardiovasc Interv 2010;3:267-76. 11. Rutherford RB, Baker JD, Ernst C, Johnston KW, Porter JM, Ahn S, et al. Recommended standards for reports dealing with lower extremity ischemia: revised version. J Vasc Surg 1997;26:517-38.
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APPENDIX. TOBA Investigators Koen Deloose, AZ St. Blasius Hospital, Dendermonde, Belgium; Jean-Paul P. M. de Vries, Department of Vascular Surgery, St. Antonius Hospital, Nieuwegein, The Netherlands; Daniël A. F. van den Heuvel, Department of Interventional Radiology, St. Antonius Hospital, Nieuwegein, The Netherlands; Hans Krankenberg, Center for Cardiology and Vascular Intervention, Hamburg, Germany; Lubos Kubicek, St. Anne’s University Hospital and Faculty of Medicine, Masaryk University, Brno, Czech Republic; Andreas Dorr, Medical University Hospital Graz, Austria; Hans M. Gissler, Hochrhein-Eggberg Clinic, Bad Säckingen, Germany; Andrej Schmidt, Sven Braunlich, Matthias Ulrich, Johannes Schuster, Susanne Scheinert,
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20. Lau K-W, Mak K-H, Hung J-S, Sigwart U. Clinical impact of stent construction and design in percutaneous coronary intervention. Am Heart J 2004;147:764-73. 21. Hara H, Nakamura M, Palmaz JC, Schwartz RS. Role of stent design and coatings on restenosis and thrombosis. Adv Drug Deliv Rev 2006;58:377-86. 22. Morton AC, Crossman D, Gunn J. The influence of physical stent parameters upon restenosis. Pathol Biol (Paris) 2004;52:196-205. 23. Tosaka A, Soga Y, Iida O, Ishihara T, Hirano K, Suzuki K, et al. Classification and clinical impact of restenosis after femoropopliteal stenting. J Am Coll Cardiol 2012;59:16-23. 24. Scheinert D, Scheinert S, Sax J, Piorkowski C, Bräunlich S, Ulrich M, et al. Prevalence and clinical impact of stent fractures after femoropopliteal stenting. J Am Coll Cardiol 2005;45:312-5. 25. Duda SH, Bosiers M, Lammer J, Scheinert D, Zeller T, Oliva V, et al. Drug-eluting and bare nitinol stents for the treatment of atherosclerotic lesions in the superficial femoral artery: long-term results from the SIROCCO trial. J Endovasc Ther 2006;13:701-10. 26. Dake MD, Ansel GM, Jaff MR, Ohki T, Saxon RR, Smouse HB, et al. Paclitaxel-eluting stents show superiority to balloon angioplasty and bare metal stents in femoropopliteal disease: twelve-month Zilver PTX randomized study results. Circ Cardiovasc Interv 2011;4:495-504. 27. Tepe G, Laird J, Schneider P, Brodmann M, Krishnan P, Micari A, et al. Drug-coated balloon versus standard percutaneous transluminal angioplasty for the treatment of superficial femoral and popliteal peripheral artery disease: 12-month results from the IN.PACT SFA randomized trial. Circulation 2014;131:495-502. Submitted Dec 11, 2015; accepted Feb 9, 2016.
Yvonne Bausback, Michael Piorkowski, and Martin Werner, University-Hospital Leipzig, Leipzig, Germany; Jürgen Verbist, Imeldaziekenhuis, Bonheiden, Belgium; Lieven Maene and Roel Beelen, Onze-Lieve-Vrouwziekenhuis, Aalst, Belgium; Uwe Schwarzwälder, Aljoscha Rastan, and Ulrich Beschorner, Universitäts-Herzzentrum Freiburg-Bad Krozingen, Bad Krozingen, Germany; Sebastian Sixt, Center for Cardiology and Vascular Intervention, Hamburg, Germany; Ernst Pilger and Philipp Eller, Medical University Hospital Graz, Graz, Austria; Jens Ricke and Maciej Pech, Universitätsklinikum Magdeburg AoR, Magdeburg, Germany; Christopher Ludtke, Academic Teaching Hospital of the Universities of Kiel, Luebeck, and Hamburg, Germany; Bob Vojtisek and Robert Vlachovsky, St. Anne’s University Hospital and Faculty of Medicine, Masaryk University, Brno, Czech Republic.