Author + information
- Received February 29, 2016
- Revision received May 6, 2016
- Accepted June 1, 2016
- Published online August 22, 2016.
- Ramon L. Varcoe, MBBS, MS, PhDa,b,c,∗ (, )
- Olaf Schouten, MD, PhDa,d,
- Shannon D. Thomas, BSc Med Hons, MBBSa,b,c and
- Andrew F. Lennox, MBBS, MSca,c
- aDepartment of Vascular Surgery, Prince of Wales Hospital, Sydney, Australia
- bFaculty of Medicine, University of New South Wales, Sydney, Australia
- cThe Vascular Institute, Prince of Wales, Sydney, Australia
- dDepartment of Surgery, Reinier de Graaf Hospital, Delft, the Netherlands
- ↵∗Reprint requests and correspondence:
Dr. Ramon L. Varcoe, Suite 8, Level 7, Prince of Wales Private Hospital, Randwick, NSW 2031, Australia.
Objectives The aim of this study was to investigate the midterm performance of an everolimus-eluting, bioresorbable vascular scaffold (Absorb, Abbott Vascular, Santa Clara, California) for the treatment of focal tibial and distal popliteal lesions.
Background Drug-eluting stents are used below the knee to improve technical success and durability, but the ongoing presence of a permanent metal scaffold may have deleterious effects on the local vessel.
Methods Tibial and distal popliteal angioplasty with scaffold placement was performed using an everolimus-eluting, bioresorbable scaffold (Absorb). Clinical and ultrasound follow-up was performed at 1, 3, 6, 12, and 24 months to detect binary restenosis and evaluate safety, restenosis, and clinical improvement.
Results Thirty-eight limbs in 33 patients were treated for critical limb ischemia (68.4%) or severe claudication (31.6%). Fifty scaffolds were used to treat a total of 43 lesions, with a mean length of 19.2 ± 11.6 mm. During a mean follow-up period of 12.0 ± 3.9 months, 5 patients died, and all others were available for follow-up. Among the 38 treated limbs, clinical improvement was present in 30 (79%). Binary restenosis was detected in 3 of 50 scaffolds (6%). Using the Kaplan-Meier method, rates of primary patency were 96% and 84.6% at 12 and 24 months, respectively, and rates of freedom from clinically driven target lesion revascularization were 96% and 96% at 12 and 24 months, respectively. Complete wound healing occurred in 64% of those treated for tissue loss, with no major amputation and a limb-salvage rate of 100%.
Conclusions Twelve-month follow-up demonstrated excellent safety, patency, and freedom from target lesion revascularization using the Absorb bioresorbable vascular scaffold below the knee.
- absorbable implants
- arterial occlusive diseases
- lower extremity
- peripheral arterial disease
Drug-eluting stents (DES) are effective for the treatment of Inter-Society Consensus for the Management of Peripheral Arterial Disease types A and B atherosclerotic arterial disease below the knee, reducing both abrupt closure and restenosis rates in the midterm (1–4). However, the metallic implant has several detrimental effects on the vessel wall, which include the permanent prevention of vasomotion, autoregulation, and adaptive remodeling. Moreover, there is a recognized risk for late target vessel failure that may result from incomplete endothelialization, stent fracture, or malapposition (5,6). Even with preserved patency, metallic stents may cause artifacts on noninvasive imaging and act as impediments to future revascularization attempts if required, issues that may be avoided through the use of a fully bioresorbable scaffold.
The Absorb bioresorbable vascular scaffold (BVS) (Abbott Vascular, Santa Clara, California) has similar mechanical scaffolding and antiproliferative properties to current-generation DES. However, following revascularization and vessel wall stabilization, it is resorbed by the body through the inert process of hydrolysis. The resorbable nature of the device gives it significant potential for positive blood vessel wall remodeling, stabilization of the atheromatous plaque, and return of contractile function, a new paradigm of vascular restorative therapy.
Following encouraging results from coronary studies (7,8) and our previous published work in the periphery (9), the aim of this study was to examine the midterm performance efficacy of the Absorb BVS in de novo atherosclerotic lesions of arteries below the knee.
This single-center study was designed to prospectively evaluate the treatment of patients with chronic lower limb ischemia. It was undertaken to obtain performance data for the treatment of distal popliteal and tibial stenotic lesions treated with an everolimus-eluting BVS system (Absorb). Special access was obtained for the use of the unapproved device through the Australian Therapeutic Goods Administration for 3 attending vascular specialists at our institution. The human research and ethics committee executive assessed and approved the proposed study. All patients provided written informed consent for the procedure, and procedural and demographic data were collected prospectively in an electronic database (Excel 2007, Microsoft Corporation, Redmond, Washington).
Inclusion and exclusion criteria
Patients were considered suitable for treatment with a BVS if they had chronic lower limb ischemia (Rutherford-Becker classes 3 to 6) from de novo stenotic lesions >60% of the tibial or distal popliteal arteries with length ≤5 cm and vessel diameters of 2.5 to 4.0 mm in which significant inflow stenoses had been successfully treated, and if they had at least 1 single-vessel outflow to the foot, including that distal to the target lesion.
Patients were excluded if they or their next of kin were unable to give informed consent, they had life expectancy <12 months, they had significant contrast allergy or renal impairment that precluded angiography, or they were known to be intolerant to dual-antiplatelet therapy. Calcified lesions were not excluded.
Study device: The BVS
The BVS consists of a poly(l-lactic acid) (PLLA) structure coated with a 7-μm poly(d,l-lactide) polymer that controls the release of the antiproliferative drug everolimus at a concentration of 100 μg/mm2. Both structure and polymer are fully biodegradable. The drug dose density and elution profile are identical to that of the XIENCE Prime DES (Abbott Vascular). As reported previously, the long chains of poly(d,l-lactide) and PLLA are progressively shortened as ester bonds between lactide repeat units are hydrolyzed, and toward the end of the resorption process, small particles <2 μm in diameter are phagocytosed by macrophages (10). Ultimately, both PLLA and poly(d,l-lactide) degrade to lactic acid and are metabolized through the Krebs cycle to form carbon dioxide and water. The design of the current-generation BVS used in this study is shown in Figure 1 and consists of circumferential hoops connected to one another by straight bridges. The Absorb BVS struts are 157 μm thick, and the scaffold lengths are 4-fold: 8, 18, 23, and 28 mm. Diameters range in 0.5-mm increments between 2.5 and 3.5 mm and can be safely post-dilated 0.5 mm beyond their nominal diameter.
All procedures were performed by 1 of 3 endovascular specialists experienced in peripheral intervention. Patients were pre-loaded for at least 1 week with both aspirin (100 mg/day) and clopidogrel (75 mg/day) or alternatively given a loading dose of 300 mg aspirin and 300 mg clopidogrel at the time of the procedure if they were medication naive. After diagnostic angiography, intravenous heparin administration (70 IU/kg), and the treatment of any inflow stenoses, a long sheath was positioned to the level of the knee joint. Each target lesion underwent mandatory pre-dilation with a noncompliant angioplasty balloon (NC Trek, Abbott Vascular), which was chosen to match the size of the disease-free vessel proximal and distal to the lesion. Up to 2 (abutting) balloon-mounted bioresorbable scaffolds were then implanted to treat each suitable lesion according to the manufacturer’s instructions for use (Figure 2). This involved a slow inflation of 2 atm every 5 s to the desired pressure and related diameter. Maximum inflation was held for at least 30 s to facilitate complete expansion of the scaffold and optimize wall apposition. Post-dilation occurred at the discretion of the individual surgeon but was favored as our experience grew. Scaffold sizing was matched 1:1 with the reference vessel diameter.
Systematic, predetermined follow-up was conducted before hospital discharge and then at intervals of 1, 3, and 6 months and then every 12 months following the procedure. The follow-up visit took place with the attending endovascular specialist; it included a history and physical examination, assessment of Rutherford-Becker class, and color-flow Doppler ultrasound investigation. Unplanned or interim imaging information was also recorded.
The primary endpoint was freedom from binary restenosis. Color-flow Doppler was used to assess the scaffold, which was readily identified at the earlier time points. The location of each scaffold was mapped to facilitate evaluation of the correct arterial segment as it underwent bioresorption. Peak systolic velocities were ascertained by an independent ultrasound technician proximal to, within, and distal to the scaffolded segment to determine a peak systolic velocity ratio. A sensitive peak systolic velocity ratio >2.0 was used to define a binary restenosis.
Secondary endpoints were clinically driven target lesion revascularization, amputation, bypass surgery, cardiovascular and all-cause mortality, as well as any related morbidity within 30 days of the index procedure. Primary patency, defined as freedom from clinically driven target lesion revascularization and binary restenosis, was also determined.
Technical success was defined as the ability to successfully cross the target lesion and deploy the bioresorbable scaffold without a sign of immediate thrombosis or >30% residual stenosis. To assist with accurate localization, images were provided to the ultrasound technician demonstrating the position of the final scaffold deployment.
Continuous data are presented as mean ± SD or as median (range). Although no inferential, comparative statistical analysis was performed, primary patency and target lesion revascularization rates were analyzed using Kaplan-Meier curves to determine time-to-event rates. Statistical analysis was performed using SPSS version 22 (IBM, Armonk, New York).
Baseline characteristics and lesions
Between September 2013 and November 2015, 33 patients (18 men; mean age 81.8 ± 7.9 years) meeting the inclusion criteria were studied. In these patients, 38 limbs were treated for critical limb ischemia (68.4%) or severe claudication (31.6%). Patient characteristics are given in Table 1.
Fifty separate scaffolds were used to treat 43 distinct lesions; details are shown in Table 2. The mean lesion length was 19.2 ± 11.6 mm, and the mean number of scaffolds used was 1.2 (range: 1 to 2). Thirteen of 38 of the limbs (34%) had inflow stenoses or occlusions treated prior to scaffold placement during the same procedure. Of those, 4 interventions (30.8%) were performed on the superficial femoral artery and 4 (30.8%) on the popliteal femoral artery, with the remaining 5 interventions (38.5%) extending across both arterial segments.
Technical success was achieved in all patients. No patient experienced any amputation, death, or target limb bypass surgery within 30 days of the index procedure. One patient underwent clinically driven target lesion revascularization on the second day following the procedure. This was due to ischemic symptoms, and angiography confirmed occlusion of 2 of the 3 BVS. These occlusions were relined with a covered and an uncovered metal stent. That event was thought to have occurred because the patient had been taken off warfarin prior to the index procedure and no antiplatelet therapy had been commenced. The other adverse events were 3 femoral pseudoaneurysms (7.9%). The first developed immediately following the procedure and required return to the operating theater for covered stent placement. The second and third developed on the 4th and 75th post-procedural days, respectively. One of these required open surgical repair at another institution, and the second was managed percutaneously with a covered stent at ours (Table 3).
Clinical and color-flow doppler follow-up
The mean duration of follow-up was 12.0 ± 3.9 months. Twenty-eight of 33 patients (84.8%) were alive, and all others were available for their pre-determined clinical and ultrasound follow-up. No limb had undergone bypass surgery or any amputation over that period. One patient had presented with an acutely ischemic limb 5 months after the placement of single BVS in the ipsilateral posterior tibial artery. Angiography confirmed the occlusion of a pre-existing popliteal stent graft, which had been used for the treatment of a popliteal aneurysm, but the distal BVS remained patent, with no evidence of restenosis, and the limb was salvaged using catheter-directed thrombolysis. At ultrasound follow-up, 3 of 50 scaffolds (6%) patent on hospital discharge had developed binary restenoses. Freedom from clinically driven target lesion revascularization was estimated at 96.0% at 6, 12, and 24 months by the Kaplan-Meier method (Figure 3). The primary patency rate was 96.0% at 6 months, 96.0% at 12 months, and 84.6% at 24 months (Figure 3). All binary restenoses were in the 50% to 75% range, and only 1 resulted in clinical deterioration that required revascularization, 26 months after scaffold implantation. On the basis of wound status and patient symptoms, 30 of 38 limbs (79%) had improved clinically, 7 (18%) were unchanged, and 1 (2.6%) was worse (Figure 4). Of those limbs in Rutherford-Becker categories 4 to 6, 73% had improved, and of those with ischemic tissue loss (Rutherford-Becker category 5 or 6), 64% had completely healed during the follow-up period.
This experience with the Absorb BVS is the first in the published research and provides a useful insight into the longer term performance of the scaffold below the knee. Although our previous study found encouraging safety and technical feasibility parameters at a mean follow-up of 6.1 months, this more mature experience provides further insight into this novel technology with larger numbers and longer follow-up (9). This study has demonstrated rates of freedom from binary restenosis and target lesion revascularization of 96.0% at 12 months of follow-up, promising early results in the interventional practice of below-the-knee arteries, which began 25 years ago.
The endovascular treatment of crural blood vessels began with simple percutaneous transluminal angioplasty (PTA), documented in the first case reports from the early 1990s (11). Those initial experiences were collected in a 2008 meta-analysis that analyzed 30 studies using infrapopliteal angioplasty published between 1990 and 2006. That analysis found patency rates that were disappointing by today’s standards: cumulative primary patency of just 65.0%, 58.1%, and 48.6% at 6, 12, and 36 months, respectively (12). Although this was a historical snapshot, those PTA results remain consistent with results observed in more recent randomized studies (58% to 66%, 12-month primary patency), in which angioplasty has been included as a treatment arm for Inter-Society Consensus for the Management of Peripheral Arterial Disease types A and B disease (3,10). Bare-metal stents have been used as both primary therapy and for bailout after PTA, and although they are effective for the treatment of elastic recoil and flow-limiting dissection, several studies have demonstrated that they offer no patency advantage over simple PTA (10,13–15). In contrast, a number of randomized controlled trials and meta-analyses have demonstrated the superiority of metal DES over both PTA and bare-metal stenting (1–3,16,17). These antiproliferative drug-coated devices have achieved excellent primary patency rates of 78% to 85% at 12 months in lesions range from 17 to 31 mm in length (1–3). Such consistently encouraging results from high-quality trials have made DES the gold standard for the treatment of short, atherosclerotic disease against which all other therapies must be judged. The 12-month primary patency of 96% in the present study compares favorably with those DES results, using a device which has advantages over these permanent metallic implants.
BVS devices are a concept with inherent advantages over metal DES. In theory, they provide the same mechanical properties during the blood vessel remodeling phase that follows angioplasty, while delivering antiproliferative drug directly to the site of vascular injury to minimize neointimal hyperplasia. However, once those functions are complete, the device begins a gentle resorption process that sees it disappear entirely, leaving the native artery free of the metal assembly that would restrict its ability to pulsate, vasoregulate, and adapt. Prior to Absorb, a number of other bioresorbable scaffolds have been used in human clinical trials. The first was the Igaki-Tamai stent (Kyoto Medical Planning, Kyoto, Japan), which has a helical zig-zag design also made of PLLA, but with no antiproliferative drug coating. The results from the first-in-human experience in coronary arteries were published in 2000 and found comparable with the contemporary DES of the time (18). A larger version of that device was also recently evaluated in the superficial femoral artery (19). The investigators reported a high degree of technical success (96.7%) but found that the device was limited by an unacceptable rate of restenosis (67.9% at 12 months), inferior to standard angioplasty or bare-metal stent results in that region. Bioresorbable, magnesium-alloy stents have been used in both coronary and peripheral applications (20–23). Following promising early clinical results in animals and humans (21,22) a randomized study to investigate the use of the AMS bioresorbable stent (Biotronik, Berlin, Germany) in 117 patients with short (<15 mm) tibial lesions was conducted. Those results were also disappointing, with the magnesium stent inferior to standard PTA therapy. A 6-month angiographic patency rate of 31.8% was observed, compared with 58% for PTA alone (p = 0.013) (20).
The Absorb PLLA, everolimus-eluting scaffold has been in clinical use within human coronary arteries for some time. The first-generation scaffold (version 1.0) was used in the ABSORB Cohort A trial, which found a slightly higher rate of elastic recoil than standard metal DES at 6 months (24). After a modification in polymer formulation and strut design, the current-generation BVS (version 1.1) was evaluated in 101 patients as part of the ABSORB Cohort B trial (NCT00856856), in which less recoil and late luminal loss were observed compared with the earlier study (8,25). Further encouraging results from that trial found a reduction in plaque burden, return of vasomotor function, and positive remodeling on serial optical coherence tomographic evaluation, together confirming that this new scaffold design had both stentlike mechanical properties and the potential to return the blood vessel to a normal physiological state. Most recently, the large-scale, multicenter ABSORB III trial (NCT01751906) randomized 2,008 patients to Absorb BVS or the XIENCE stent (7). They found statistically indistinguishable rates of target lesion failure (7.8% vs. 6.1%, p = 0.16), cardiac death (0.6% vs 0.1%, p = 0.29), target vessel myocardial infarction (6.0% vs. 4.6%, p = 0.18), and ischemia-driven target lesion revascularization (3.0% vs. 2.5%, p = 0.50) at 1 year, concluding that the BVS was noninferior in this group of simple coronary lesions.
Coronary artery patency failure after treatment with current-generation DES is uncommon, but they perform less reliably in the tibial arteries, in which restenosis is seen in approximately 20% of stents at 12 months. This illustrates the difference between the vascular territories, in which despite similarities in blood vessel diameter we observe disparate vessel wall histological findings and atheromatous plaque morphology. With a higher failure rate also comes significant potential for improvement in interventional durability. Our results suggest that the bioresorbable scaffold may at least offer patency equivalence while maintaining advantages related to its dissolution. This may allay some fears that DES, which provide an effective mechanical scaffold and drug delivery vehicle, might also act as a barrier to future reintervention in an area that has been plagued by poor durability and the need for frequent reintervention.
First, our numbers were small, and we included only patients with single short lesions which means that these results cannot be generalized to a broader cohort with a variety of long and complex lesions. We have not randomized the use of the BVS to standard angioplasty or stent treatment in tibial arteries, so no direct comparison can be made with those therapies. Furthermore, the study follow-up period was insufficient to provide meaningful long-term patency information, but our intention is to follow this preliminary cohort with ongoing ultrasound and clinical follow-up out to 5 years.
This current experience with the Absorb BVS in tibial arteries has once again demonstrated that it may be implanted safely and with high rates of technical success. Encouraging patency and freedom from target lesion revascularization results at 12 months of follow-up, together with advantages related to its complete dissolution, suggest that it has significant potential to become the favored class of therapy in this group of patients.
WHAT IS KNOWN? DES are superior to both angioplasty and bare-metal stents in the interventional treatment of short tibial artery lesions, but the permanent metallic implant has several disadvantages.
WHAT IS NEW? Our early results using a drug-eluting, bioresorbable scaffold for these lesions suggest that they have patency rates at least equivalent to metal DES, with inherent advantages related to their resorption.
WHAT IS NEXT? Further trials are required with larger numbers, the involvement of multiple centers, and control groups to compare bioresorbable scaffolds with conventional therapy.
The authors thank Abbott Vascular for providing photographs of the Absorb bioresorbable scaffold and the permission for their use.
Dr. Varcoe is a consultant and advisory board member for Abbott Vascular; and a consultant for Medtronic, Boston Scientific, and W.L. Gore. Drs. Thomas and Lennox are consultants for Abbott Vascular. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- bioresorbable vascular scaffold
- critical limb ischemia
- drug-eluting stent(s)
- poly-l-lactic acid
- percutaneous transluminal angioplasty
- target lesion revascularization
- Received February 29, 2016.
- Revision received May 6, 2016.
- Accepted June 1, 2016.
- American College of Cardiology Foundation
- Rastan A.,
- Tepe G.,
- Krankenberg H.,
- et al.
- Scheinert D.,
- Katsanos K.,
- Zeller T.,
- et al.
- Jaff M.R.,
- White C.J.,
- Hiatt W.R.,
- et al.
- Joner M.,
- Finn A.V.,
- Farb A.,
- et al.
- Otsuka F.,
- Vorpahl M.,
- Nakano M.,
- et al.
- Serruys P.W.,
- Onuma Y.,
- Dudek D.,
- et al.
- Varcoe R.L.,
- Schouten O.,
- Thomas S.D.,
- Lennox A.F.
- Iyer S.S.,
- Dorros G.,
- Zaitoun R.,
- Lewin R.F.
- Biondi-Zoccai G.G.,
- Sangiorgi G.,
- Lotrionte M.,
- et al.
- Rocha-Singh K.J.,
- Jaff M.,
- Joye J.,
- et al.
- Antoniou G.A.,
- Chalmers N.,
- Kanesalingham K.,
- et al.
- Fusaro M.,
- Cassese S.,
- Ndrepepa G.,
- et al.
- Tamai H.,
- Igaki K.,
- Kyo E.,
- et al.
- Werner M.,
- Micari A.,
- Cioppa A.,
- et al.
- Peeters P.,
- Bosiers M.,
- Verbist J.,
- Deloose K.,
- Heublein B.