Author + information
- Received October 16, 2012
- Revision received January 7, 2013
- Accepted January 8, 2013
- Published online March 1, 2013.
- 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 Cardiology Unit, GVM Care and Research, Maria Eleonora Hospital, Viale Regione Siciliana 1571, 90135 Palermo, Italy
Objectives This study aimed to appraise 2-year outcomes after percutaneous treatment of femoropopliteal artery disease with paclitaxel-eluting balloons.
Background Percutaneous transluminal angioplasty with paclitaxel-eluting balloons for femoropopliteal artery disease has provided favorable 1-year results.
Methods Consecutive patients with Rutherford class 2 to 4 disease due to femoropopliteal lesions ≤15 mm long and with 3- to 7-mm reference vessel diameter were prospectively enrolled in a multicenter registry. Endpoints of interest included primary patency, major adverse events (the composite of death, amputation, or target lesion revascularization), changes in Rutherford class, ankle-brachial index, absolute claudication distance, and quality of life after ≥24 months.
Results A total of 105 patients (114 lesions) treated with paclitaxel-eluting balloons and provisional stenting were enrolled, and final procedural success was obtained in all. Follow-up after 27 ± 3 months was obtained in 98 (93.3%) patients, showing that primary patency was maintained in 71 (72.4%), and major adverse events had occurred in 17 (17.5%), with persistently significant benefits in Rutherford class, ankle-brachial index, absolute claudication distance, and quality of life (all p < 0.001). Secondary patency rate was achieved in 89 cases (84.7%).
Conclusions PEBs are associated with favorable functional and clinical outcomes at 2 years in patients with femoropopliteal artery disease requiring percutaneous revascularization.
Ongoing developments in devices and techniques for percutaneous transluminal angioplasty (PTA) have made this minimally invasive treatment strategy a mainstay in the management of patients with femoropopliteal artery disease requiring revascularization, especially when atherosclerotic burden or surgical risk do not favor bypass surgery (1–3). Among the multiple technological developments, the introduction of paclitaxel-eluting balloons (PEB) holds the promise of a safe and effective therapy for atherosclerotic disease in this vascular district, limiting stenting—with its potential negative consequences, such as stent fracture—to bail-out indications (4–7). However, all PEB published trials so far have been based on a 6-month angiographic primary endpoint, and none have looked at Primary Patency at 1 and 2 years or extended the analysis to functional endpoints. This holds true for PEB as well as for new devices in general, because objective lesion specific endpoints such as primary patency and more meaningful functional outcomes such as walking capacity and quality of life are not always reported, thus limiting sound clinical decision-making.
We have previously reported the findings of a prospective multicenter study, including 105 patients undergoing femoropopliteal PTA with PEB and showing favorable clinical results up to 12 months (7). With the objective of providing similarly detailed results on this treatment strategy at long-term follow-up, we hereby report on the 24-month outcomes of this patient cohort.
This was an independent, nonindustry-supported prospective multicenter study aimed to appraise in detail fatal and nonfatal outcomes after femoropopliteal PTA with the In.Pact Admiral PEB (Medtronic, Frauenfeld, Switzerland) (7). The registry was approved by local ethics committees, and all patients signed an informed consent form.
Adult patients diagnosed with peripheral artery disease for claudication or rest pain as per Rutherford class 2 to 4 were screened. Angiographic inclusion criteria included atherosclerotic disease of the superficial femoral artery, including the first 2 segments of the popliteal artery, with reference diameter between 3 and 7 mm, having stenotic lesions or occlusions for a total length ≤150 mm by visual estimate. Long lesions or multiple adjacent lesions 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% diameter stenosis] was treated during the index procedure). Unhindered inflow in the aortic-iliac and common femoral districts (either pre-existing or re-established) was also required for patient inclusion. Long (>150 mm) inflow lesions constituted an exclusion criterion, whereas patients presenting with shorter lesions were deemed eligible if these inflow lesions could be successfully treated before the target femoropopliteal lesion. In-stent restenosis, aneurysm in the target vessel, or acute thrombus in the target limb constituted exclusion criteria. Other exclusion criteria included failure to cross the target lesion with a guidewire, and concomitant (intentional or accidental) use of alternative therapies in the target vessel, including atherectomy, excimer laser, or cutting balloon during the index procedure.
Procedures and devices
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. After PTA, all subjects received 100 mg/day of aspirin indefinitely and 75 mg/day clopidogrel for 12 weeks (6 months in case of stenting). 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 or ipsilateral approach. After crossing the lesion with a guidewire, pre-dilation (2 min) with an undersized uncoated balloon (0.5 to 1 mm smaller) was followed by insertion of PEB of appropriate size and length. The target lesion was dilated 10 mm beyond both ends of the lesion with a PEB with vessel/balloon ratio of 1:1 (on the basis of visual estimate) and an inflation time of 3 min at 6 to 12 atm. Study balloons were inflated only once. An additional long (at least 3 min) inflation with an adequate (same size or 0.5-mm larger than PEB) uncoated balloon was performed in the tract where angiography revealed persistent stenosis >50% or dissection. If suboptimal results persisted after such repeated dilation, self-expanding nitinol stents were implanted as bail-out, in all cases covering the whole lesion length.
Definitions and endpoints
Device success was defined as successful vascular access and exact deployment of the device according the instructions for use, whereas technical success was defined as device success plus completion of the endovascular procedure, obtaining <30% residual stenosis of the treated lesion by visual estimate.
Endpoints of interest were primary patency rate, defined as freedom from the combined endpoints of target lesion revascularization (TLR), occlusion, and >50% restenosis in the treated lesion as appraised by duplex ultrasound performed by an independent reader (peak systolic velocity ratio >2.4); secondary patency, defined as freedom from >50% restenosis (as previously specified) even if after a re-intervention to restore patency; major adverse events (the composite of death, amputation, or TLR); change in Rutherford class; change in ankle-brachial index; change in walking capacity; change in absolute claudication distance (ACD); and change in quality of life parameters (7). Notably, walking capacity was measured with a validated 5-point walking impairment questionnaire that assessed walking distance, speed, ability to climb stairs, and symptoms with walking (8). Absolute claudication distance was defined as the distance at which the patient could no longer ambulate on the basis of the 6-min walking test. Quality of life was assessed with the Euro QoL-5D Questionnaire (9). 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. Finally, during each follow-up visit, patients completed a visual analogue scale (0 to 100) to assess their overall health state. All such endpoints were collected at baseline and 3, 6, 12, and—for the purpose of the present study—24 months after the index procedure.
Descriptive statistics (frequency and percentage for categorical variables and mean ± SD for continuous variables) were used to present baseline and follow-up variables. Additionally, the Kaplan-Meier estimate was used for primary patency. Inferential statistics were used as follows: Rutherford classification and the categorical variables of quality of life were compared with the Kruskal-Wallis test; continuous variables (visual analogue scale, walking impairment questionnaire, ankle-brachial index, ACD, and peak systolic velocity ratio) were compared with the Student t test. The EuroQoL-5D levels were dichotomized into “no problems” and “problems” for graphical presentation. The data underwent inferential analysis with the Kruskal-Wallis test to determine any statistical difference between the study visits. Statistical significance was set at the 2-tailed 0.05 level, and p values unadjusted for multiplicity are reported throughout. The independent sample tests instead of pair tests, with all available data, have been used in the analysis because not all patients showed up at all follow-up visits.
A total of 105 patients were enrolled, being treated with 135 PEBs in 114 femoropopliteal lesions, which were 76 ± 38 mm long and had a 5.2 ± 0.6 mm reference vessel diameter and a 92.5 ± 8.2% diameter stenosis, as evaluated by visual estimation by an independent operator (Tables 1, 2, and 3).⇓⇓ Procedural success was obtained in all cases, with bail-out stenting in 14 (12.3%) lesions.
Further to the primary patency of 83.7% reported at 1 year, clinical follow-up at 27 ± 3 months was obtained in 98 (93.3%) patients, showing that primary patency had been maintained in 71 (72.4%) patients at 2 years (Fig. 1), with secondary patency rate in 89 cases (84.7%). All TLR at any time-point were performed with standard PTA and without adjunctive stenting. The 12- to 27-month primary patency among the patients who had not binary restenosis or TLR at 1 year was 85.1%, and TLR rate was 7.1%, showing no late catch-up phenomenon. Involvement of popliteal artery disease determined a decreased albeit nonstatistically significant primary patency rate (Fig. 2). No statistically significant difference in patency rates was noted in stented patients compared with nonstented (69.2% vs. 75.4%, p = 0.426) (Fig. 3), in patients presenting with occlusive versus nonocclusive stenosis (Fig. 4) and in patients with severe calcified lesions versus non-severely calcified lesions (Fig. 5). Also the number of patent crural vessels seems to influence patency (Fig. 6). As expected, patency rate was significantly affected by lesion length: the univariate Cox analysis for lesion length gave a significant hazard ratio of 1.016 (95% confidence interval: 1.004 to 1.027, p = 0.006).
At 27 ± 3-month follow-up, major adverse events had occurred in 17 (17.5%), with death in 2 (2.2%), amputation in 1 (1.0%), and TLR in 14 (14.3%) (Fig. 7). In all cases TLR was successful. Appraisal of changes in ankle-brachial index showed persistent improvements up to 27 ± 3 months (0.88 at such time point versus 0.86 at 12 months, and 0.56 at baseline; p < 0.001) (Fig. 8), with similarly favorable results for ACD (418 m vs. 316 m and 111 m, respectively; p < 0.001) (Fig. 9), Rutherford class (p < 0.001) (Fig. 10), and key quality of life functional measurements (p < 0.001 for mobility, usual activities, pain/discomfort) (Fig. 11).
The present report, providing detailed long-term follow-up on a prospective multicenter registry of PEB for femoropopliteal PTA, has the following implications: 1) primary patency was favorably maintained in most patients despite a low stenting rate during the index procedure; 2) accordingly, a successful repeat revascularization was required in only a minority of patients (14.3%); and 3) these benefits were accompanied by similarly favorable results on ankle-brachial index, ACD, Rutherford class, and quality of life. Nevertheless, it should be recognized that such endpoints were assessed at fixed time points of 1 and 2 years; hence overall patient benefit, besides due to the drug-eluting balloon effect, might likely have been impacted also by the reported re-interventions.
Despite ongoing improvements in the endovascular armamentarium, there is still uncertainty on the most appropriate minimally invasive treatment strategy for femoropopliteal artery disease. Despite its established limitations, standard PTA (balloon-only) is still used by many centers, especially for simple and short lesions. Self-expandable bare-metal stents have recently been shown to be beneficial in comparison with standard PTA, especially when new-generation devices are used (10,11). Specifically, primary bare-metal stenting was associated with an 87.3% 12-month freedom from TLR in comparison with standard balloons in the RESILIENT trial (Edwards Lifesciences Self-Expanding Stent Peripheral Vascular Disease Study), which was largely maintained at 36 months (75.5% vs. 41.8%, respectively) (11). Similar findings were provided by Schillinger et al. (12) after a total of 98 patients for 24 months after randomization to default bare-metal stent implantation or standard balloon angioplasty, with TLR in 37.0% and 53.8%, respectively. However, the inherent theoretical drawback of such permanent prostheses have not convinced all operators to use them in routine fashion.
Contrary to the initial findings with everolimus-eluting devices (13,14), latest results with paclitaxel-eluting stents seem promising (15,16). In particular, primary paclitaxel-eluting stenting was associated with an 83.1% primary patency at 12 months in comparison with standard balloon angioplasty in the Zilver PTX randomized trial (15). Indeed, results of the drug-eluting stent arm of the Zilver PTX trial seem similar to those hereby achieved.
In contrast to an elective stent strategy, such as drug-eluting stents, PEBs might best fit a long-term therapy strategy as needed for claudicant patients. With the unavoidable disease progress within and outside the treated lesion, PEBs represent a viable option that is less likely to impact future interventions when compared with any first-line stent strategy.
PEBs have been proposed in the last few years as a novel technology for femoropopliteal PTA, given their favorable risk-benefit balance in the available randomized trials and the theoretical advantage of a treatment that does not require any implantation of permanent prostheses (4,5). Long-term results on the PaccoCath PEBs have also been reported (4,5); however, these studies were primarily designed upon a 6-month angiographic primary endpoint and did not provide functional assessment.
To expand the assessment of PEBs beyond the boundaries typical of proof-of-concept randomized trials, we have designed a multicenter prospective registry of PEBs for femoropopliteal revascularization and built upon a primary patency primary endpoint and various functional secondary endpoints. Clinical results up to 12 months have been reported in detail elsewhere (7), but given the lack of carefully collected long-term data on such a clinical topic, clinical follow-up was prolonged to 24 months, including adjudication of adverse events as well as appraisal of key quantitative and objective estimates pertinent to patients with claudication and rest-pain, such as primary patency, ankle-brachial index, ACD, and quality of life measurements. We continued to focus on primary patency as primary endpoint, because this can best appraise the results after revascularization, as indeed other endpoints (such as TLR rate) might suggest more optimistic results for a given revascularization technique.
We found that PEBs were associated with favorable results at more than 2 years after the index procedure. Although some attrition between 1 and 2 years in primary patency, TLR rates, Rutherford class, and quality of life was evident, this should come as no surprise in light of the natural course of the disease, which typically progresses beyond the target lesion. Conversely, the favorable trends in ankle-brachial index and ACD, which showed an overall increase during such time (from 0.86 to 0.88 and from 361 to 418, respectively), support the favorable risk-benefit balance of PEBs in this clinical setting. Finally, no evidence of late catch-up phenomenon was found, despite a dual antiplatelet therapy limited by protocol to 12 weeks (unless bail-out stenting occurred). Results on subgroups (stented vs. not stented, calcified vs. not calcified, popliteal involvement vs. no involvement, occlusion vs. stenoses) are interesting but, due the small number, should not be considered conclusive.
Limitations of this work include the nonrandomized design, the focus on a single treatment strategy, and the focus on patients without severe critical limb ischemia with femoropopliteal lesions up to 15 cm. However, these features might offer clear and unconfounded insights on the long-term clinical outlook of patients with femoropopliteal artery disease and Rutherford class 2 to 4 presentation treated with PEBs. Further insights on the risk-benefit balance of these devices will necessarily require careful analysis of recent or ongoing randomized clinical trials, comparing them with standard balloon-only PTA and routine stenting.
PEBs are associated with favorable long-term clinical outcomes in patients with femoropopliteal artery disease requiring percutaneous revascularization. These findings signal that a stent-less therapy approach with IN.PACT Admiral PEB and optimal PTA provides favorable outcomes and is likely to leave more interventional options open for the future.
The authors thank Zeno Dal Sacco, a Medtronic employee, for statistical analysis, and Giuseppe Biondi-Zoccai, Sapienza University of Rome, for editorial assistance.
Dr. Micari has been a consultant to Medtronic. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
- Abbreviations and Acronyms
- absolute claudication distance
- paclitaxel-eluting balloons (s)
- percutaneous transluminal angioplasty
- target lesion revascularization
- Received October 16, 2012.
- Revision received January 7, 2013.
- Accepted January 8, 2013.
- American College of Cardiology Foundation
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