Author + information
- Received April 11, 2019
- Revision received July 29, 2019
- Accepted August 6, 2019
- Published online December 2, 2019.
- William A. Gray, MDa,∗ (, )
- Joseph A. Cardenas, MDb,
- Marianne Brodmann, MDc,
- Martin Werner, MDd,
- Nelson I. Bernardo, MDe,
- Jon C. George, MDf and
- Alexandra Lansky, MDg
- aLankenau Heart Institute, Wynnewood, Pennsylvania
- bYuma Cardiology Associates, Yuma Regional Medical Center, Yuma, Arizona
- cDivision of Angiology, Medical University Graz, Graz, Austria
- dDepartment of Angiology, Hanusch Hospital, Vienna, Austria
- eMedStar Washington Hospital Center, Washington, District of Columbia
- fEinstein Medical Center, Philadelphia, Pennsylvania
- gYale Cardiovascular Research Group, New Haven, Connecticut
- ↵∗Address for correspondence:
Dr. William A. Gray, Lankenau Heart Pavilion, 100 East Lancaster Avenue, Wynnewood, Pennsylvania 19096.
Objectives The aim of this study was to evaluate the Tack Endovascular System (Intact Vascular, Wayne, Pennsylvania) for treating dissections following angioplasty in the superficial femoral artery and/or proximal popliteal artery.
Background Dissection after angioplasty of femoropopliteal arteries with either a plain balloon or a drug-coated balloon (DCB) can negatively affect both short- and long-term outcomes.
Methods TOBA (Tack Optimized Balloon Angioplasty) II is a prospective, single-arm, multicenter study enrolling 213 patients, all with dissection following angioplasty. Eligibility included Rutherford classification 2 to 4 with a de novo or nonstented restenotic lesion in the superficial femoral artery or proximal popliteal artery undergoing plain balloon or DCB angioplasty. Following dilation, lesions with <30% residual stenosis and presence of ≥1 dissection were enrolled. The 12-month efficacy endpoint was primary patency (freedom from duplex-derived binary restenosis and clinically driven target lesion revascularization.
Results Patients’ mean age was 68 ± 9 years, and 43.2% had diabetes. Twenty-three percent of lesions were chronic total occlusions, and ∼60% had moderate to severe calcium. The mean lesion length was 74.3 ± 40.6 mm. Severe dissection (grade ≥C) was present in 69.4%. By operator choice, 57.7% of patients underwent DCB angioplasty. Most (92.1%) dissections resolved completely, and only 1 bailout stent was required. There were no 30-day major adverse events. The 12-month efficacy endpoint was met, with Kaplan-Meier primary patency and freedom from clinically driven target lesion revascularization of 79.3% and 86.5%, respectively. At 12 months, there were no device fractures or clinically significant migrations, and significant improvements were noted in Rutherford category, ankle-brachial index, and quality of life.
Conclusions TOBA II demonstrated the safety and efficacy of the Tack Endovascular System for focal dissection repair following standard and DCB angioplasty.
Peripheral artery disease (PAD) is a chronic occlusive disease characterized by obstructive plaque that can result in claudication and critical limb ischemia (1). Described by Hirsch and Duval (2) as a “pandemic,” lower extremity PAD is estimated to affect 202 million people globally, 20 million people in the United States, and up to 20% of Americans > 75 years of age (3,4). Revascularization, particularly minimally invasive endovascular therapy, remains the treatment of choice for most patients with life-style-limiting or limb-threatening PAD despite optimal medical therapy (5,6). The recurrent nature of the disease following intervention is associated with higher health care–related expenditures (7).
Most endovascular therapeutic approaches to PAD involve percutaneous transluminal angioplasty (PTA) as definitive or adjunctive therapy. Balloon angioplasty functions by both mechanically stretching the atherosclerotic artery and inducing dissection, resulting in acute vascular injury (8). Angiographic evidence of dissections is frequent, reported in up to 84% of femoropopliteal angioplasties (9). Acutely, dissection can reduce or obstruct flow, requiring additional therapeutic intervention, and over the long-term, lesions with dissections have 3.5 times the rate of repeat target lesion revascularization (TLR) than lesions without (10–12). Because dissections can negatively affect procedural and clinical outcomes, most angioplasty trials exclude patients with moderate to severe dissection (13–16) as a potential confounder.
Dissections are mostly treated with stent placement. By scaffolding the vessel wall with high radial outward force, stents treat the dissection but can present additional challenges, especially with longer lesions. Stents have been shown to improve procedural outcomes, but beyond the acute treatment phase, the aggressive radial force combined with an extensive amount of nitinol can cause inflammation and lead to intimal hyperplasia formation, in-stent restenosis, and high rates (20% to 37%) of restenosis 1 year post-treatment (17–20). The dynamic forces exerted in the femoropopliteal segment can lead to additional shear stress, inflammation, and occasional stent fracture (21,22).
Given the inherent limitations of stent placement, limiting the metal footprint for dissection treatment represents an alternative solution. The Tack Endovascular System (Intact Vascular, Wayne, Pennsylvania) is a novel device specifically designed to address the limitations of stents while providing durable repair of post-PTA dissections in the superficial femoral artery (SFA) and infrapopliteal artery. To reduce the metal surface area in contact with the luminal wall, Tack implants are short (6 mm), with an open-cell design resulting in lower chronic outward force compared with similar-sized stents. This allows focal dissection treatment and scaffolding while limiting the amount of biological injury. We report the results of the TOBA (Tack Optimized Balloon Angioplasty) II study evaluating the Tack Endovascular System in treating post-angioplasty dissections in the SFA and/or proximal popliteal artery (PPA).
Design and study population
TOBA II was a prospective, single-arm, multicenter study conducted at clinical centers in the United States and Europe. This was an investigational device exemption study conducted in compliance with the International Conference on Harmonization Good Clinical Practice, ISO 14155, and 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. This study is registered at ClinicalTrials.gov (NCT02522884).
The objectives of the study were to evaluate the safety and efficacy of the Tack Endovascular System for the repair of all dissections types (A to F). The study allowed the use of plain balloon angioplasty (POBA) or Lutonix drug-coated balloons (DCBs) for treatment of patients with PAD of the SFA or PPA. Balloon choice was at the discretion of the operator. Training in dissection identification and the use of the study device was provided to each operator prior to the index procedure.
Eligible participants were ≥18 years of age with Rutherford category (RC) 2 to 4 claudication. Angiographic criteria for enrollment included atherosclerotic lesions (≥70% diameter stenosis) in the SFA, PPA, or both that met the clinical indications for treatment. Specific lesion length inclusion criteria were ≥20 and ≤150 mm for lesions with 70% to 99% stenosis and ≤100 mm for arteries that were occluded, respectively. Reference vessel diameter was required to be between 2.5 and 6.0 mm, inclusive. Key exclusion criteria were previous infrainguinal bypass graft in the target limb; previously implanted stent in the target vessel; planned amputation of the target limb; planned non-PTA treatment (other than a crossing device) of the target lesion; serum creatinine >2.5 mg/dl; acute vessel occlusion or acute or subacute thrombosis in the target lesion; severe calcification (defined as >5 cm of circumferential calcium or calcium that renders the lesion nondilatable); presence of post-dilation residual diameter stenosis ≥30%; and lack of adequate distal runoff, defined as presence of at least 1 patent (<50% diameter stenosis) infrapopliteal vessel that had not been revascularized prior to the index procedure.
The Tack Endovascular System consists of a 6-F (2.0-mm) delivery catheter pre-loaded with 6 independent Nitinol implants that measure 6 mm in length (Central Illustration). The implants are of a single size and self-expanding, treating a full range of vessel diameters from 2.5 to 6.0 mm.
Procedural techniques were performed in accordance with the institutional standard of care for endovascular treatment of the femoropopliteal segment, including appropriate antiplatelet therapy. A baseline angiogram was obtained prior to dilation to confirm baseline angiographic eligibility for inclusion or exclusion, including reference vessel diameter measurement. Pre-enrollment treatment was then performed with POBA or the Lutonix DCB on the basis of operator preference. Post-angioplasty, the target lesion was required to have <30% residual diameter stenosis and presence of at least 1 dissection of any National Heart, Lung, and Blood Institute grade A to F by visual estimate (23). Several angiographic views (at least 2 views 45° apart) were obtained to document the dissections per angiographic protocol.
Following angiographic identification of dissection(s), the delivery catheter was loaded onto a 0.035-inch guidewire. Once the study device was inserted through the introducer sheath, the patient was considered enrolled (Figure 1). The operator evaluated the angiogram and deployed Tack(s) to treat the dissections accordingly, and then post-Tack placement angioplasty was performed to seat the implant(s). Angiography was performed to verify acceptable acute vessel patency.
Angiography and duplex ultrasound
Angiographic data for the determination of study enrollment were obtained by the investigator at the time of the index procedure. Evaluation of the target lesion, dissection grade, and angiographic outcome was conducted by an independent core laboratory (Yale Cardiovascular Research Group Angiographic Core Laboratory). Duplex ultrasound (DUS) was conducted at 1, 6, and 12 months and analyzed by an independent DUS core laboratory (VasCore, Boston, Massachusetts).
The primary endpoints were compared against performance goals derived in cooperation with the U.S. Food and Drug Administration. The primary safety endpoint was freedom from any new-onset major adverse events (MAEs) at 30 days (defined as index limb amputation above the ankle, clinically driven [CD] TLR, or all-cause death), compared to the VIVA Physicians Group performance goal (24). The primary efficacy endpoint compared primary patency at 12 months against a performance goal based on the results of the LEVANT 2 clinical trial (13). Primary patency was defined as freedom from CD TLR and freedom from DUS-derived binary restenosis at 12 months (defined as peak systolic velocity ratio ≥2.5). The data constituting the primary endpoints were collected at the investigative centers and independently adjudicated by an independent clinical events committee (amputation, CD TLR, death) or by the DUS core laboratory (primary patency).
Study outcomes and follow-up
Periprocedural outcomes assessed included device success and procedure success. Device success was defined as successful deployment of the Tack(s) at the intended target site(s), successful withdrawal of the delivery catheter from the introducer sheath, and Tack implant(s) remaining in position through completion of the index procedure. Procedure success was defined as vessel patency (<30% residual stenosis by visual estimate) without the use of a bailout stent or the occurrence of MAEs upon completion of the index procedure.
After procedure completion, follow-up was conducted at 1, 6, and 12 months after the procedure. Evaluations conducted through follow-up included DUS, RC, ankle-brachial index, peripheral artery questionnaire (25), quality of life assessed using the EQ-5D-3L (26), and walking impairment questionnaire (27). Radiographic evaluation of Tack integrity was conducted at 12 months and evaluated by the angiographic core laboratory. The study was complete with respect to the evaluation of the primary endpoints at 12 months of follow-up.
The intention-to-treat population was used for the efficacy analysis. The intention-to-treat population consisted of all patients who underwent PTA, had post-PTA dissections identified by the investigator, and had the Tack Endovascular System advanced through the introducer sheath. The performance goal for this study was derived from the lower limit of the 95% confidence interval for the DCB and PTA groups in the LEVANT 2 trial (28). It was hypothesized that the Tack Endovascular System would resolve dissections without negatively affecting primary patency at 12 months. On the basis of the LEVANT 2 results, the primary patency rate was dependent on the type of balloon used, and therefore the performance goal was calculated using the proportion of patients enrolled who were treated with DCB or PTA. The sample size was calculated using PASS 2012, a 1-sample exact test, power of 90%, 1-sided type I error controlled at 2.5%, and setting the maximum proportion of patients treated with DCBs enrolled at 60%. In this case, the performance goal for primary patency at 12 months was 53%. Conservatively, the primary patency for DCB plus Tack and control PTA plus Tack was assumed to be 65% for the purposes of the sample size calculation. Using those assumptions, it was estimated that 178 patients were required to have data evaluable at 1 year for the primary efficacy endpoint. On the basis of estimated attrition of 15%, enrollment of 210 patients was planned.
The primary safety endpoint of the study was freedom from the occurrence of any new-onset MAEs (above-the-ankle index limb amputation, CD TLR, or all-cause death at 30 days). The percentage of patients with no MAEs within 30 days was calculated, along with an exact 1-sided 95% confidence interval. The objective of this endpoint was met if this confidence interval exceeded the pre-defined VIVA performance goal of 88% (24).
Standard summary statistics were calculated for all patients and study outcome variables. Continuous variables were summarized using means and SDs. Categorical data were summarized using frequencies and percentages. Freedom-from-event analyses were conducted using the Kaplan-Meier methodology. Changes from baseline in RC, ankle-brachial index, and the questionnaires was evaluated using the Wilcoxon signed rank test or McNemar test. A p value <0.05 was considered to indicate statistical significance.
Enrollment and follow-up
A total of 213 patients at 33 clinical sites in the United States and Europe were entered into the study. Among the enrolled patients, 195 (91.5%) completed the 12-month follow-up, and 183 (85.9%) were evaluable for the primary efficacy endpoint with either a readable 12-month DUS study or angiogram or CD TLR prior to the end of the 12-month follow-up window.
Demographics and clinical characteristics
Baseline demographic and clinical characteristics are summarized in Table 1. The mean age was 68.2 ± 9.1 years, and 151 of 213 (70.9%) were men. Most patients (95.7%) had claudication (RC 2 or 3), while the remaining 4.2% were classified in RC 4 with ischemic rest pain. The most common comorbidities were hypertension (89.7%) and hyperlipidemia (87.2%), and 60.7% had coronary artery disease. Treated lesions were primarily de novo (94.8%), and the most common lesion location was the SFA (87.2%). The mean lesion length was 74.3 ± 40.6 mm, and occlusions accounted for 23.2% of lesions. Moderate or severe calcification was present in 59.3% of the lesions. The mean pre-procedure stenosis was 73.5%.
Table 2 summarizes procedural data and outcomes. The study distribution of balloon types was 42.3% standard balloons and 57.7% DCBs, on the basis of operator choice during the index procedure. A total of 417 dissections were site reported, while 369 dissections (99.5%) were adjudicated by the core laboratory, with a mean of 1.8 ± 0.9 dissections per patient. The average dissection length was 20.7 mm.
Dissection grades were reported both for all dissections and for the most severe dissection for each patient. In general, the investigator and core laboratory analyses were similar for dissection grade. A majority of the dissections were severe, with the core laboratory identifying 69.4% of patients having dissections grade C or higher. Table 3 contains data on the number and grade of dissections.
All patients received at least 1 Tack implant during the procedure, with an average of 4.1 Tacks deployed per patient (range 1 to 15 Tacks). Two hundred thirty-nine Tack catheters were introduced for use into the 213 patients, with a total of 871 Tacks implanted. All but 9 devices successfully delivered Tacks to the desired location and, the device success per patient was 204 of 213 (95.8%). Procedure success was achieved in 212 of 213 patients (99.5%), with only 1 patient requiring a bailout stent. After Tack treatment, 92.1% of all dissections were completely resolved as adjudicated by the core laboratory.
There were no MAEs associated with the primary safety endpoint reported through the 30 days of follow-up, thus meeting the pre-defined performance goal of 88% being MAE free (p < 0.0001).
Primary efficacy endpoint
DUS follow-up or documented occurrence of a TLR was available for 183 patients (85.9%) at 12 months. The Tack implant met the primary endpoint by exceeding the target performance goal of 52.7% (p = 0.0006). The binary estimate for primary patency in the intention-to-treat population was 65.6%, with a 95% lower confidence bound of 58.2%. The Kaplan-Meier patency estimate at 12 months is 79.3% (Figure 2). The median length of follow-up was 364 days (interquartile range: 337 to 378 days). Through 12 months of follow-up, the rate of MAEs remained acceptably low: no major amputations were reported, and 4 deaths occurred, none of which were attributed to the device or the procedure. Thirty-one CD TLRs occurred. The Kaplan-Meier freedom from CD TLR at 12-month window is 86.5% (Figure 3).
Additional follow-up evaluations
There was a significant (p < 0.0001) improvement in RC over time (Figure 4). By protocol, all patients were in RC 2 to 4 at enrollment. At 12-month follow-up, 137 of 191 (71.7%) of patients reported either no symptoms or mild claudication (RC 0 or 1), and 81.2% of all patients improved by 1 or more RC from baseline to 12 months. Likewise, there was significant (p < 0.0001) improvement in the ankle-brachial index in the target limb from baseline through all follow-up visits (Figure 5).
The data from the peripheral artery questionnaire, EQ-5D-3L, and walking impairment questionnaire are consistent with improved outcomes in this patient cohort. There was significant improvement (p < 0.001) from baseline to all follow-up visits in the 5 peripheral artery questionnaire functional categories (physical function, stability, symptoms, quality of life, and social limitation) and overall. In the EQ-5D-3L, patients reported significant (p < 0.05) improvement in mobility, usual activity, pain or discomfort, and visual analog scale score for state of health. There was no significant (p > 0.05) change from baseline self-care or anxiety or depression.
Similarly, the walking impairment questionnaire showed significant (p < 0.0001) improvement over time in the overall assessment as well as each of the 3 individual components (distance, speed, and stair).
Tack endovascular system stability and durability
Radiographic images at 12 months were available for 730 implanted Tacks in 186 patients. Independent adjudication of these images showed that there were no Tack fractures. Furthermore, there was no evidence of Tack embolization. Only 1 minor migration was reported, which consisted of 2.6 mm of movement in a single Tack implant. No adverse events were reported in this patient, and the artery remained patent at 12 months.
Evaluation of DCB and POBA subgroups
Although the study was not powered to assess for differences in outcomes by type of balloon type used, we conducted an exploratory analysis of balloon type subgroups (summarized in Table 4). As balloon type was chosen according to physician preference, lesions treated with DCBs tended to be more complex, with significantly longer lesions (85.1 ± 40.6 mm vs. 59.8 ± 35.8 mm; p < 0.0001) and significantly more occlusions (33.9% vs. 8.9%; p < 0.0001). There were, however, no differences (p > 0.05) in the number of patients with moderate to severe calcification or with dissection severity grade ≥C. The primary patency at 12 months for the POBA subgroup was 89.6%, with a lower confidence bound of 81.0%. The primary patency for the DCB subgroup in the same time frame was 71.9%, with a lower confidence bound of 62.8% (Central Illustration).
The prospective multicenter TOBA II study demonstrated that in a population composed exclusively of patients with post-angioplasty dissection after POBA or DCB, the use of Tacks was successfully and safely able to repair dissections in the SFA or PPA, with an improvement in 1-year patency outcomes compared with an objective performance goal and no device failures. Tacking was associated with sustained improvement in measures of patient outcome in the clinical, hemodynamic, functional, and satisfaction domains.
This study confirms and expands upon the results obtained from earlier studies of the Tack Endovascular System. 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% (8). Similarly, in the TOBA study, which was conducted in 130 patients with 74% with grade ≥C dissections following POBA angioplasty, the 12-month patency was 76.4%, and freedom from TLR was 89.5% (29). A pilot study conducted in 32 patients with below-the-knee lesions (TOBA-BTK) also exhibited a high 12-month patency rate of 78.4% by vessel and 77.4% by patient, and freedom from CD TLR was 93.5% (30).
The outcomes of this study compare favorably with published results of the randomized trials that compared POBA with DCB. Of note, in our cohort, patients treated with standard balloons had better primary patency at 12 months than did the DCB group. This is likely related to fact that the DCB patients were more complex, with longer lesions and more total occlusions that pre-disposed them to worse outcomes. These TOBA II results differ from those published in randomized control trials comparing DCB with POBA. In the LEVANT 2 trial, the 12-month Kaplan-Meier primary patency rate was significantly greater for the DCB group (73.5% vs. 56.8%; p < 0.001) (13). IN comparison, the more complex DCB TOBA II lesions had similar primary patency, and the POBA group of similar complexity fared substantially better. The positive outcomes of the TOBA II study are all the more remarkable in that all enrolled patients had post-treatment dissections, and many of them were severe (∼70% grade >C). Because patients with significant dissections were programmatically excluded from the DCB trials, LEVANT 2 reported a 7.5% rate of dissection grade ≥C (13).
Overall, these data provide evidence that Tacks can improve post-treatment outcomes in dissected vessels. Unlike stents, Tacks are composed of a minimal metal scaffold of very short length. Although Tacks, like stents, also facilitate the apposition of dissection flaps to the luminal surface, they use lower radial outward force to minimize the biological effect and resultant hyperplastic response (31–33). This minimalist approach has other potential benefits. If future treatment is required, the reduced metal burden, compared with stents, allows multiple potential options to be considered.
TOBA II was conducted as a single-arm study without an active control group. However, the performance goal for the efficacy endpoint was derived from a recent study with similar inclusion criteria. The performance goal for the safety endpoint has been widely used in assessing safety of studies with similar patients. Also, this study was not powered to detect differences in balloon type used. The observed differences could be due to a variety of factors, including operator bias for balloon selection according to patient and lesion characteristics or some other factor, and require further evaluation.
The TOBA II study results support the use of the Tack Endovascular System as a therapeutic option that is both safe and effective for focal dissection repair following standard and DCB angioplasty of the SFA and PPA.
WHAT IS KNOWN? Dissection is the mechanism by which angioplasty and is often underestimated in frequency and severity. Balloon angioplasty creates luminal gain, but dissection can negatively affect acute and long-term clinical outcomes.
WHAT IS NEW? Focal dissection repair, after standard or DCB angioplasty, using a minimal metal implant, improves vessel patency without the drawbacks of conventional stenting.
WHAT IS NEXT? Peripheral dissections are classified using the National Heart, Lung, and Blood Institute system intended for the coronary arteries. A dissection index classification (number and severity of dissections within a single vessel) specific to the peripheral vasculature could identify post-PTA dissections at higher risk for restenosis.
This study was funded by Intact Vascular. The authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- drug-coated balloon
- duplex ultrasound
- major adverse event
- peripheral artery disease
- plain balloon angioplasty
- proximal popliteal artery
- percutaneous transluminal angioplasty
- Rutherford category
- superficial femoral artery
- target lesion revascularization
- Received April 11, 2019.
- Revision received July 29, 2019.
- Accepted August 6, 2019.
- 2019 The Authors
- Hardman R.,
- Jazaeri O.,
- Yi J.,
- Smith M.,
- Gupta R.
- Fitzgerald P.J.,
- Ports T.A.,
- Yock P.G.
- Scully R.,
- Smith A.,
- Arnaoutakis D.,
- Semel M.,
- Nguyen L.
- Schneider P.A.,
- Giasolli R.,
- Ebner A.,
- Virmani R.,
- Granada J.F.
- Fujihara M.,
- Takahara M.,
- Sasaki S.,
- et al.
- Kokkinidis D.G.,
- Armstrong E.J.
- Tepe G.,
- Laird J.,
- Schneider P.,
- et al.
- Schroeder H.,
- Werner M.,
- Meyer D.-R.,
- et al.
- Krishnan P.,
- Faries P.,
- Niazi K.,
- et al.
- Krankenberg H.,
- Schlüter M.,
- Steinkamp H.J.,
- et al.
- Laird J.R.,
- Katzen B.T.,
- Scheinert D.,
- et al.
- Scheinert D.,
- Scheinert S.,
- Sax J.,
- et al.
- ↵(1985) Coronary artery angiographic changes after PTCA: In: Manual of Operations NHBLI PTCA Registry (National Heart, Lung, and Blood Institute, Bethesda, Maryland), pp 6–9.
- Rocha-Singh K.J.,
- Jaff M.R.,
- Crabtree T.R.,
- Bloch D.A.,
- Ansel G.,
- VIVA Physicians, Inc
- Regensteiner J.,
- Steiner J.,
- Panzer R.,
- Hiatt W.
- Rosenfield K.,
- Jaff M.R.,
- White C.J.
- Bosiers M.,
- Scheinert D.,
- Hendriks J.M.H.,
- et al.
- Brodmann M.,
- Wissgott C.,
- Holden A.,
- et al.