Author + information
- Received September 9, 2011
- Revision received November 16, 2011
- Accepted November 24, 2011
- Published online March 1, 2012.
- Antonio Micari, MD, PhD⁎,⁎ (, )
- Angelo Cioppa, MD†,
- Giuseppe Vadalà, MD⁎,
- Fausto Castriota, MD‡,
- Armando Liso, MD§,
- Alfredo Marchese, MD∥,
- Chiara Grattoni, MD‡,
- Paolo Pantaleo, MD¶,
- Alberto Cremonesi, MD‡,
- Paolo Rubino, MD† and
- Giancarlo Biamino, MD, PhD†
- ↵⁎Reprint requests and correspondence:
Dr. Antonio Micari, Maria Eleonora Hospital, Viale Regione Siciliano 1571, 90135 Palermo, Italy
Objectives This study evaluated the use of a paclitaxel-eluting balloon (PEB) for treatment of femoropopliteal arterial disease.
Background Conventional balloon angioplasty and stenting in this setting is associated with high restenosis rates within 12 months. Recent data suggest that PEB use may reduce restenosis. Twelve-month outcomes following PEB use with provisional stenting are described.
Methods This prospective registry enrolled patients (Rutherford class 2 to 4) with reference vessel diameter of 3 to 7 mm and lesion/occlusion length ≤15 cm. Endpoints included primary patency rate, target lesion revascularization, and changes in Rutherford class and ankle-brachial index. Walking capacity, absolute claudication distance, and quality of life were also assessed.
Results The registry enrolled 105 patients. Baseline ankle-brachial index was 0.56 ± 0.15. Baseline Rutherford classification was class 2 or 3 for most patients (91.5%). Most lesions were located in the superficial femoral artery (77.1%). Mean lesion length was 76.3 ± 38.3 mm; 29.8% of lesions were total occlusions. The device was successfully used in all patients and only 12.3% of lesions required stenting. At 12-month follow-up, 92 of 105 patients (87.6%) were evaluable; the primary patency rate was 83.7%; the target lesion revascularization rate was 7.6%; 85.6% of patients were Rutherford class 0 or 1; and mean ankle-brachial index was 0.86 ± 0.15. Quality of life and absolute claudication distance showed significant improvement from baseline to 12-month follow-up.
Conclusions PEB treatment of femoropopliteal arterial disease resulted in consistent clinical improvement across multiple endpoints with a low rate of stenting and target lesion revascularization.
Treatment of femoropopliteal artery disease by percutaneous transluminal angioplasty (PTA) is limited by high rates of restenosis (40% to 60%) 6 to 12 months after conventional balloon angioplasty (1–4). Alternative therapies, such as brachytherapy, atherectomy, and cryoplasty, have not been shown to be superior to PTA in clinical trials (5–7). Randomized controlled trials comparing nitinol stents with PTA to treat moderate to long superficial femoral artery (SFA) lesions demonstrated a significant reduction in restenosis with stenting (4,8); however, no significant difference between nitinol stenting and PTA was demonstrated in short SFA lesions (mean length: 4.5 cm) (9). The successful reduction of restenosis seen with drug-eluting stent treatment of coronary artery disease was not observed in several studies of drug-eluting stent use for obstructive SFA disease (10,11). Although, a recent clinical trial demonstrated a significant improvement in primary patency at 1 and 2 years with a polymer-free paclitaxel-eluting stent versus PTA (12).
The high mechanical stress (bending, compression, torsion) that occurs with normal patient movement in the femoropopliteal arteries is associated with an increased risk for stent fractures and abnormal tortuosities in the adjacent nonstented vessel segments and the deformations of those segments are amplified due to the presence of stents (3,13–17). Stents may also constitute a potential barrier for subsequent surgical or endovascular treatment. Hence, an alternative therapy that may similarly reduce restenosis and improve clinical outcome with minimal need for stent implantation (i.e., mainly reserved for sealing flow-limiting dissections) has been explored.
The potential advantages of an efficacious stent-free approach and promising pre-clinical research led to consideration of drug-eluting balloon technology for prevention of restenosis in this complex peripheral artery disease population (13,18–20).
Paclitaxel is a potent antineoplastic drug that, in small concentrations, delivered locally provides sustained inhibition of vascular smooth muscle cell proliferation and migration (18). Pre-clinical studies of paclitaxel-coated balloons in a porcine model of peripheral vascular disease showed that neointimal proliferation was significantly inhibited without evidence of adverse effects (19,20). Subsequently, randomized trials comparing paclitaxel-eluting balloons (PEB) with conventional uncoated balloon angioplasty in patients with SFA disease were undertaken and demonstrated significant reduction in restenosis rates 6 months after intervention (21–23).
The In.Pact Admiral PEB (Medtronic Inc., Frauenfeld, Switzerland) uses a proprietary hydrophilic coating formulation (Freepac) to facilitate the delivery of paclitaxel from the balloon surface during dilation. The current trial is an observational registry designed to prospectively evaluate the safety and effectiveness of the In.Pact Admiral PEB when used in routine practice with a strict provisional stenting strategy, for treatment of patients with symptoms of claudication and rest pain due to femoropopliteal ischemic vascular disease. Primary patency and reintervention rates at 6 and 12 months, as well as changes in functional status and health-related quality of life (QOL) are reported.
Study design and patient population
The safety and efficacy of PEB technology for treatment of femoropopliteal ischemic vascular disease was prospectively evaluated in this clinical registry. The registry enrolled consecutive patients who met eligibility requirement from 6 participating centers throughout Italy. The registry was approved by local ethics committees, and all enrolled patients were required to sign informed consent forms before treatment. Patients were treated in accordance with the standard practices of the institution providing care and using the In.Pact Admiral PEB currently on the market. Technical details regarding this PEB have been previously described (24).
Adult patients diagnosed with peripheral artery disease for claudication or rest pain as per Rutherford classes 2 through 4 were considered for enrollment. Angiographic inclusion criteria included the SFA and first 2 segments of the proximal popliteal target vessel with reference diameter between 3 and 7 mm and lesion and/or occlusion length ≤15 cm. Long diffuse stenoses and occlusions or multiple adjacent lesions or occlusions were cumulatively considered and treated as a single lesion. Patients were required to have adequate runoff with evidence of at least 1 patent crural vessel to the foot either pre-existing or re-established (patients were eligible if an impaired outflow vessel [>50% stenosis] was successfully treated). Good inflow in the aortic-iliac and common femoral districts (either pre-existing or re-established) was also required for patient inclusion. Long (>15 cm) stenosis (>50%) or occlusions in this area constituted an exclusion criterion, whereas patients presenting with shorter (≤15 cm) stenosis (>50%) and occlusions were eligible if these inflow lesions could be successfully treated before the target SFA lesion. Patients with a previously implanted stent in the target lesion, aneurysm in the target vessel, or acute thrombus in the target limb were excluded. Other exclusions include failure to cross the target lesion with a guidewire, and use of alternative therapies, such as atherectomy, cutting balloon, or laser or radiation therapy as part of the index procedure.
Details of the PTA procedure using the drug-eluting balloon have been previously described (18). In brief, patients not taking aspirin and clopidogrel before study enrollment received loading doses of 300 mg of aspirin and 300 mg of clopidogrel 12 h before the procedure. Post-procedure patients were prescribed 100 mg/day of aspirin to be taken indefinitely and 75 mg clopidogrel daily for 12 weeks and in patients requiring a stent for 6 months. Patients received a bolus of 5,000 IU of heparin after insertion of the sheath in the common femoral artery. Vascular access was accomplished via the contralateral approach in most patients. After crossing the lesion with a guidewire, pre-dilation (2 min) with an undersized, shorter uncoated balloon (0.5 to 1 mm smaller) was followed by insertion of the appropriate size and length PEB. The target lesion was dilated 10 mm beyond both ends of the lesion using a PEB vessel/balloon ratio of 1:1 (based on visual estimation) and an inflation time of 3 min at 6 to 12 atm. Study balloons were inflated only once. An additional long inflation with a shorter (to avoid geographic miss) uncoated balloon was performed if angiography revealed persistent stenosis >50% or a flow-limiting dissection. If suboptimal results persisted (stenosis >50% or flow-limiting dissection), self-expanding nitinol stents were implanted.
The primary endpoint at 12 months after intervention was the primary patency rate defined as freedom from the combined endpoints of target lesion revascularization (TLR), occlusion, and >50% restenosis in the treated lesion. Duplex ultrasonography was performed to assess restenosis and >50% restenosis was defined by a peak systolic velocity ratio (PSVR) >2.4. Rates of TLR, death, and amputation were also analyzed. Secondary endpoints were change in Rutherford class and ankle-brachial index (ABI) from baseline to 12 months. Walking capacity and absolute claudication distance (ACD) were evaluated as functional capacity measures. Walking capacity was measured using a validated 5-point walking impairment questionnaire that assessed walking distance, speed, ability to climb stairs, and symptoms with walking (25). ACD was defined as the distance at which the patient could no longer ambulate based on the 6-min walking test. All endpoints were assessed at baseline and at 3, 6, and 12 months after the procedure. The impact of treatment on health-related QOL was assessed using the Euro QoL-5D Questionnaire at the same time points (26). This tool looks at 5 dimensions of health: mobility, self-care, usual activities, pain/discomfort, and anxiety/depression. Each dimension has 3 levels: no problems, some problems, or extreme problems. During follow-up visits, each patient completed a visual analogue scale (0 to 100) to assess their overall health state. Adverse events, including thrombosis in the target vessel, were collected throughout the study period.
Post-procedural angiography was done to determine percentage of residual stenosis; total treated lesion length; and device, technical, and procedural success rates. Device success was defined as exact deployment of the device according the instructions for use using appropriate imaging modalities. Technical success was defined as successful vascular access, completion of the endovascular procedure, and immediate morphological success with ≤30% residual stenosis of the treated lesion by visual estimate. Procedural success combines technical and device success with absence of procedural complications. Data regarding the number of provisional stents implanted and the reason for stenting (persistent residual stenosis >50%, occlusive complication, or dissection) was also analyzed. Follow-up duplex scan were performed by an independent operator.
Descriptive statistics (frequency and percentage for categorical variables and number of observations, mean, standard deviation, median, minimum, and maximum for continuous variables) were used to present baseline and follow-up variables. Additionally, the Kaplan-Meier estimate was used for presentation of primary patency through 12 months. Inferential statistics were used as follows: Rutherford classification and the categorical variables of QOL were compared using the Kruskal-Wallis test; continuous variables (visual analogue scale, walking impairment questionnaire, ABI, ACD, and PSVR) were compared within group at different time points using the Student t test. There was no correction for multiple comparisons. Primary patency was calculated from the hierarchical composite of TLR, binary restenosis (PSVR >2.4 by duplex ultrasonography), and occlusion (PSVR = 0).
The Euro QoL-5D levels were dichotomized into “no problems” and “problems” for graphical presentation. The data underwent inferential analysis using the Kruskal-Wallis test to determine any statistical difference between the study visits.
An exploratory analysis was undertaken to identify predictors of restenosis. The methodology used was a 2-step approach. First, possible predictors (occlusions, sex, reference vessel diameter, lesion length, residual stenosis, calcification, lesion location, deployment of stents, and diabetes) were selected from the baseline variables and evaluated by analysis of variance for continuous variables and chi-square test versus restenosis for categorical variables. The second step was to enter the variables in a binary logistic linear model (the parameters were estimated via hybrid method (Fisher and Newton-Raphson), chi-square and 95% confidence interval of Wald and maximum likelihood). Variables with a p < 0.05 are considered significant predictors of restenosis.
There were 105 patients representing 114 treated lesions enrolled in the registry. The mean age of patients was 68 ± 9 years and 81% were men. There were high rates of atherosclerotic risk factors among the enrolled patients and 42.9% had a history of coronary artery disease (Table 1). At 12-month follow-up, 92 of 105 (87.6%) enrolled patients were evaluable and duplex ultrasonography was performed on 77 (73.3%) patients (Fig. 1). Patients who did not return for follow-up appointments were contacted by phone; no adverse events were identified that could potentially relate to the use of the PEB.
Lesions were predominantly located in the middle and distal SFA (Table 2). Mean lesion length was 76.3 ± 38.3 mm. Moderate (radiopacities on <50% of the lesion area) to severe (radiopacities on >50% of lesion area usually involving bilateral walls of the artery) calcification was present in 66.7% of lesions and 29.8% of the lesions were totally occluded. There was no significant difference in lesion length, reference vessel diameter, or calcification for the totally occluded lesions compared with the nonoccluded lesions.
Procedural and acute outcomes
All PEBs were successfully deployed in all target vessels (device success = 100%) and the technical success rate was 89.6% (90.7% in totally occluded lesions) with 10.4% of lesions showing immediate residual stenosis >30%. Post-PEB dilation with a shorter conventional uncoated balloon was performed in cases of persistent residual stenosis or dissections in 17.5% of the cases. Ultimately, only 14 lesions (12.3%) were stented: 11 due to persistent flow-limiting dissections and 3 for refractory residual stenosis >50% (Table 3). The need for stenting was similar in occluded and nonoccluded lesions (14.7% vs. 11.2%, p = 0.541).
The primary patency rate at 6 and 12 months was 87.8% and 83.7%, respectively (Fig. 2). There was no significant difference in primary patency between the patients with lesions crossed subintimally and those with true lumen crossings (p = 0.572). One patient death occurred before the 3-month follow-up due to cardiovascular causes with acute pulmonary edema and the second patient death, between 6 and 12 months after procedure, was of noncardiovascular causes (pulmonitis) and unrelated to the device or procedure. The rate of TLR was 4.4% at 6 months and 7.6% at 12 months (Table 4). One patient underwent a second TLR 410 days after the first occurrence. All TLR were clinically driven and confirmed angiographically before treatment; no reintervention was performed on positive duplex findings in the absence of clinical symptoms. TLR events occurred at 4 different sites and were all caused by restenosis; there were no total reocclusions. Overall, the 1-year secondary patency rate was 90.2%. There were 3 (21.4%) restenosis events in the 14 patients who were stented and 12 (14.5%) events in the 83 patients not requiring a stent (p = NS). No predictors of restenosis were identified.
The proportion of patients in Rutherford classes 2, 3, and 4 was significantly reduced by 3 months, and this clinical benefit persisted out to 12 months (p < 0.001) (Fig. 3). Similar observations of significant, sustained improvement were made for change in ABI, PSVR, and ACD from baseline to 12 months (p < 0.0001 for each) (Fig. 4). Changes in Rutherford class, ABI, PSVR, and ACD were examined for the totally occluded versus nonoccluded lesions, and there was no significant difference in any of these outcome measures (p = 0.506, 0.495, 1.000, and 0.434, respectively, at 12 months).
Walking capacity, based on the combined walking impairment questionnaire scores for walking distance, walking speed, ability to climb stairs, and symptoms associated with walking impairment, improved from a median score of 40.3 at baseline to 86.1 at 12 months.
Quality of life
Health-related QOL was also improved at 3, 6, and 12 months after the PEB procedure as reflected in the decreased proportion of patients reporting problems on the Euro QoL-5D questionnaire (Fig. 5). Significantly fewer patients reported problems with mobility, usual activities, pain (p < 0.001 for all 3), and anxiety/depression (p = 0.002) at 3 months, and these benefits persisted throughout the remaining 12-month study period. The overall visual analogue scale health score at baseline was 66.8 ± 12.3. Significant improvement, reported at the 3-month follow-up, was maintained through 12 months (81.3 ± 12.7 at 3 months, 77.6 ± 12.4 at 12 months, p < 0.001 for both).
In the present registry, the safety and efficacy of a new PEB catheter for the prevention of restenosis in atherosclerotic femoropopliteal lesions was evaluated. The results of this registry demonstrate that paclitaxel elution from a balloon is safe for the prevention of restenosis in the superficial femoral and popliteal arteries. Consistent benefit was observed within an array of clinical and functional endpoints, including walking capacity and QOL.
The concept of balloon-mediated elution is based on the observation that sustained drug release is not a prerequisite for long-lasting restenosis inhibition (27–30). Use of PEB avoids or limits the usage of stents with associated risk for stent fractures and combines local drug administration for the prevention of restenosis with the mechanical effect of balloon angioplasty. The efficacy of PEB in preventing restenosis of the superficial femoral and popliteal arteries has been reported in recent studies using the Paccocath technology (MEDRAD Inc., Warrendale, Pennsylvania) (21–23). These trials demonstrated significantly reduced mean late loss and lower rates of TLR for PEB use compared with standard balloon angioplasty (21,22).
After 12 months, the In.Pact Admiral PEB was associated with a high rate of primary (87.3%) and secondary patency (90.2%) with a very low number of stents implanted (12.3%), mainly to seal flow-limiting dissections. No failure in reintervention was observed, showing the repeatability of the intervention after PEB restenosis. Furthermore, there was a similar rate of primary patency and limited stenting in totally occluded lesions, which accounted for almost one-third of treated lesions.
Most important, there was significant clinical benefit to patients, as clearly demonstrated by the improvement in ACD, ABI, and the reduction in Rutherford class. Within 3 months of the intervention, patients were able to walk more than triple the distance they could previously walk, and this functional benefit persisted to 12 months after the PEB procedure. A corresponding shift in Rutherford class occurred, and over 85% of patients remained in Rutherford class 0 or 1 at 12 months. These clinical benefits were similarly observed in patients with totally occluded lesions, providing an important signal regarding the effectiveness of the PEB in both stenotic and occluded SFA lesion.
This registry is the first study of PEB treatment for atherosclerotic disease of the SFA to prospectively measure patients' QOL at baseline and after the intervention. The Euro QoL-5D questionnaire is a standardized measure of health status applicable to a wide range of health conditions and treatments. Across all 5 dimensions of health-related QOL, the proportion of patients claiming a problem declined and significant improvements were notable in the areas of mobility, pain and discomfort, ability to pursue usual activities, and anxiety and depression.
In the present registry, dual antiplatelet therapy was given for 12 weeks (24 weeks if a stent was implanted). At the time of the study design, no literature guided the selected duration of dual antiplatelet therapy, thus it was empirically chosen by the investigators to be longer than recommended by the instructions for use as a precautionary measure at the initial stage of adoption of this new technology. The absence of thrombotic events following thienopyridine discontinuation in the current study suggests the safety of this approach.
No predictors of restenosis were identified, which is not surprising in this relatively small population with a low number of events.
This multicenter registry entails the typical limitation of single-arm studies with the absence of a head-to-head comparator, and events were reported by each study site without further adjudication. Interpretation of functional and QOL results are tempered by the lack of a control group.
PTA of femoropopliteal arterial disease using PEB resulted in a high primary patency rate that was sustained through 12 months with a low rate of stenting. Consistent improvement in clinical endpoints, functional status, and associated QOL were observed. The low rate of TLR over 12 months suggests that the use of PEB offers durable safety and effectiveness in this population. Larger, controlled trials are indicated to further define the role of PEB for management of patients with femoropopliteal arterial disease.
The authors thank Zeno Dal sacco, a Medtronic employee, for statistical analysis, and Colleen Gilbert, PharmD, a Medtronic consultant, for editorial assistance.
Dr. Micari is a Medtronic consultant. Drs. Castriota and Cremonesi have reported relationships with Medtronic, Invatec, and Boston Scientific. Dr. Biamino is a consultant for Spectranetics and Igaki; and is proctor for Proctor EV3 and Hexacath. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- ankle-brachial index
- absolute claudication distance
- paclitaxel-eluting balloon(s)
- peak systolic velocity ratio
- percutaneous transluminal angioplasty
- quality of life
- superficial femoral artery
- target lesion revascularization
- Received September 9, 2011.
- Revision received November 16, 2011.
- Accepted November 24, 2011.
- American College of Cardiology Foundation
- Rocha-Singh K.J.,
- Jaff M.R.,
- Crabtree T.R.,
- Bloch D.A.,
- Ansel G.,
- VIVA Physicians, Inc
- Laird J.R.,
- Katzen B.T.,
- Scheinert D.,
- et al.,
- RESILIENT Investigators
- Minar E.,
- Pokrajac B.,
- Maca T.,
- et al.
- Krankenberg H.,
- Schlüter M.,
- Steinkamp H.J.,
- et al.
- Duda S.H.,
- Pusich B.,
- Richter G.,
- et al.
- Duda S.H.,
- Bosiers M.,
- Lammer J.,
- et al.
- Dake M.,
- Ansel G.,
- Jaff M.,
- et al.
- Scheinert D.
- Jonker F.H.W.,
- Schlosser F.J.V.,
- Moll F.L.,
- Muhs B.E.
- Axel D.I.,
- Kunert W.,
- Goggelmann C.,
- et al.
- Werk M.,
- Langner S.,
- Reinkensmeier B.,
- et al.
- Scheinert D.,
- Zeler T.,
- Duda S.,
- Krankenberg H.,
- Ricke J.,
- Bosier M.
- McDermott M.M.,
- Liu K.,
- Guralnik J.M.,
- Martin G.J.,
- Criqui M.H.,
- Greenland P.
- Herdeg C.,
- Oberhoff M.,
- Baumbach A.,
- et al.
- Scheller B.,
- Speck U.,
- Abramjuk C.,
- Bernhardt U.,
- Böhm M.,
- Nickenig G.
- Unverdorben M.,
- Vallbracht C.,
- Cremers B.,
- et al.