Author + information
- Received June 7, 2013
- Revision received July 30, 2013
- Accepted August 14, 2013
- Published online December 1, 2013.
- Massimiliano Fusaro, MD∗,
- Salvatore Cassese, MD∗∗ (, )
- Gjin Ndrepepa, MD∗,
- Gunnar Tepe, MD†,
- Lamin King, MD∗,
- Ilka Ott, MD∗,
- Mateja Nerad, MD‡,
- Heribert Schunkert, MD∗,§ and
- Adnan Kastrati, MD∗,§
- ∗Deutsches Herzzentrum, Technische Universität, Munich, Germany
- †Radiologische Klinik, Diagnostische und Interventionelle Radiologie, Karls-Universität, Tübingen, Germany
- ‡Klinische Abteilung für Kardiologie, Universität Graz, Graz, Austria
- §DZHK–German Centre for Cardiovascular Research, partner site Munich Heart Alliance, Munich, Germany
- ↵∗Reprint requests and correspondence:
Dr. Salvatore Cassese, Deutsches Herzzentrum, Technische Universität, Lazarettstrasse 36, Munich 80636, Germany.
Objectives This study sought to undertake an updated meta-analysis of randomized trials investigating the outcomes of percutaneous revascularization with primary drug-eluting stenting in patients with atherosclerotic disease of infrapopliteal arteries.
Background In atherosclerotic disease of infrapopliteal arteries, drug-eluting stents (DESs) improve patency rates compared with plain balloon angioplasty or bare-metal stents (BMSs). However, the clinical impact of DES placement in this vascular territory still remains uncertain.
Methods We searched MEDLINE, Embase, CENTRAL (Cochrane Central Register of Controlled Trials), scientific session abstracts, and relevant Websites. The keywords used were “below the knee,” “infrapopliteal artery,” “angioplasty,” “drug-eluting stent(s),” “bare metal stent(s),” “trial,” and “randomized trial.” Inclusion criteria were randomized design, intention-to-treat analysis, and a minimum of 6-month follow-up. Exclusion criteria were vessels treated other than infrapopliteal arteries; devices used other than DESs, plain balloons, or BMSs; and duplicated data. The primary endpoint was target lesion revascularization; secondary endpoints were restenosis, amputation, death, and improvement in Rutherford class.
Results A total of 611 patients from 5 trials were randomly assigned to DESs (n = 294) versus control therapy (plain balloon angioplasty/BMS implantation, n = 307). Overall, the median lesion length was 26.8 mm (interquartile range [IQR]: 18.2 to 30.0 mm) with a reference vessel diameter of 2.86 mm (IQR: 2.68 to 3.00 mm). At a median follow-up of 12 months (IQR: 12 to 36 months), DESs reduced the risk of target lesion revascularization (odds ratio [OR]: 0.31; 95% confidence interval [CI]: 0.18 to 0.54; p < 0.001), restenosis (OR: 0.25; 95% CI: 0.15 to 0.43; p < 0.001), and amputation (OR: 0.50; 95% CI: 0.26 to 0.97); p = 0.04) without a significant difference in terms of death (OR: 0.81; 95% CI: 0.45 to 1.49; p = 0.50) and Rutherford class improvement (OR: 1.36; 95% CI: 0.91 to 2.04; p = 0.13) versus control therapy.
Conclusions In focal disease of infrapopliteal arteries, DES therapy reduces the risk of reintervention and amputation compared with plain balloon angioplasty or BMS implantation without any impact on mortality and Rutherford class at 1-year follow-up.
Endovascular therapy represents the preferred option for patients with occlusive atherosclerotic disease of infrapopliteal arteries requiring revascularization (1). In this setting, plain balloon angioplasty is still a first-line recommendation due to the high percentage of acute success and relatively low cost (2,3). In contrast, stent implantation is recommended as an acute “bail-out” or “salvage” procedure in the event of a suboptimal result or failure of balloon dilation (2,3). However, the lack of a proven durable antirestenotic effect after plain balloon angioplasty has led to the investigation of alternative strategies (4).
The similar vessel diameter of coronary and infrapopliteal arteries had fueled the use of coronary stent platforms in this peripheral vascular bed. Several small studies investigated the angiographic outcomes of drug-eluting stents (DESs) compared with either plain balloons or bare-metal stents (BMSs) for revascularization of infrapopliteal arteries (5). According to available data, primary drug-eluting stenting demonstrates superior antirestenotic potency compared with either plain balloons or BMSs with higher patency rates at mid-term follow-up (6–8). However, the impact of DESs on clinical outcomes such as repeat revascularization, amputation, and mortality still remains a matter of uncertainty. On the one hand, the existing randomized, controlled trials individually lack the statistical power to discriminate differences in rare clinical outcomes, and results have been inconsistent (4). On the other hand, recent meta-analyses considered only a limited number of the available randomized, controlled trials (9,10).
Therefore, the purpose of the present study was to undertake an updated meta-analysis of randomized trials investigating outcomes associated with a strategy of percutaneous revascularization with primary drug-eluting stenting in patients with atherosclerotic disease of infrapopliteal arteries.
Search strategy and selection criteria
We searched MEDLINE, Embase, CENTRAL (Cochrane Central Register of Controlled Trials), scientific sessions abstracts, and relevant Websites (www.cardiosource.com, www.clinicaltrialresults.org, www.escardio.org, www.tctmd.com, www.theheart.org) without restricting language or publication status. The reference lists from all eligible studies and previously published meta-analyses dealing with a similar topic (5,9–11) were checked to identify further citations. The final search was performed on March 23, 2013. Search terms included the keywords and the corresponding Medical Subject Headings for “below the knee,” “infrapopliteal artery,” “angioplasty,” “drug-eluting stent(s),” “bare metal stent(s),” “trial,” and “randomized trial.” Inclusion criteria were randomized design, intention-to-treat analysis, and a minimum of 6 months of follow-up. Exclusion criteria were vessels treated other than infrapopliteal arteries, devices used other than DESs, plain balloons, or BMSs, and duplicated data.
Data collection and assessment of risk of bias
Two investigators (S.C. and G.N.) independently assessed publications for eligibility at the title and/or abstract level, with differences resolved by a third investigator (M.F.). Studies that met inclusion criteria were selected for further analysis. Freedom of bias was evaluated for each study by the same investigators, in accordance with the Cochrane Collaboration method (12) on the basis of the following methodological items: adequacy of random sequence generation and allocation concealment, blinding (at participant or outcome assessor level), completeness of reporting outcome data, selective presentation of outcomes, completeness and adequacy of description of sample size calculation, and appropriate disclosure of funding sources. We avoided formal quality score adjudications as they have previously been found potentially misleading (13).
The degree of restenosis quantifies the response of the vessel wall to interventions (14) and may not be synonymous of revascularization (15). The primary outcome of the present study was target lesion revascularization (TLR) driven from clinical symptoms as well as from invasive surveillance. Secondary outcomes were restenosis, amputation, Rutherford class (RC) improvement, and death. All endpoints were evaluated at the longest available follow-up according to per-protocol definitions: the most updated or most inclusive data for a given study were analyzed. Where further details were required, we attempted to obtain them from the study investigators directly. However, we did not request patient-level data from the investigators of original studies.
Statistical analysis was performed using the RevMan (Review Manager [RevMan] Version 5.1, The Cochrane Collaboration, Copenhagen, Denmark), and Stata version 11.2 (StataCorp, College Station, Texas) software packages.
The к statistic was used to assess agreement between reviewers for study selection. Odds ratio (OR) and 95% confidence interval (CI) were used as summary statistics and were derived for comparison of DESs and pooled plain balloons/BMSs (the control therapy). To test whether the pooling of plain balloons and BMSs as control therapy affected the analysis of the main outcomes, the risk estimates associated with DES therapy were also calculated after stratification for plain balloons or BMSs as the control arm. The Mantel-Haenszel random-effects model (DerSimonian and Laird) was used to calculate pooled OR for categorical variables (16). In the case of statistical significance, absolute risk reduction (ARR) and the number needed to treat (NNT) with 95% CI were provided. The Breslow-Day chi-square test and the I2 statistic were used to test heterogeneity across the studies. As a guide, I2 values <25% indicated low, 25% to 50% moderate, and >50% high heterogeneity (12). To estimate the additive (between-study) component of variance, the restricted maximum likelihood method (Tau2) took into account the occurrence of residual heterogeneity. Visual estimation of funnel plots as well as statistical tests assessed possible publication bias for primary outcome (17–19). Similarly, an influence analysis, in which meta-analysis estimates are computed omitting 1 study at a time, was performed for primary outcome. A random-effects sensitivity analysis evaluated the extent to which several covariates—trial size, length of clinical follow-up, protocol-mandated angiography, lesion length, vessel diameter, and length of dual antiplatelet therapy (DAPT)—might have influenced the risk estimates for the primary outcome. A random-effects meta-regression analysis assessed the relationship between the baseline disease severity (expressed as the proportion of patients with critical limb ischemia [CLI] or with infrapopliteal artery occlusions and the mean length of the lesions) and the risk estimates for TLR. Two adjusted indirect comparisons according to the method of Bucher et al. (20) and Song et al. (21) investigated whether the various DES platforms included in the experimental arm (everolimus- vs. sirolimus-eluting stents; polymer-free vs. durable-polymer DESs) provided differences in the main outcomes.
This study was performed in compliance with the PRISMA (Preferred Reporting Items for Systematic reviews and Meta-Analyses) statement (22).
The process of trial selection is summarized in Figure 1. We excluded the trial of Rand et al. (23) because it investigated the outcomes of patients randomly assigned to carbon film–coated BMS implantation versus plain balloon angioplasty. Finally, 5 trials (6–8,24,25), all with full-length reports, were selected. In the DES and BMS arms of original studies, pre-dilation was allowed before stent implantation, whereas patients in the plain balloon arm received no therapy other than plain balloon angioplasty. Thus, for the current analysis, the control therapy comprised patients treated with BMS implantation (with or without pre-dilation) and patients receiving plain balloon angioplasty alone. One trial had a 4-arm design and randomly assigned patients to DES implantation or plain balloon angioplasty or BMS implantation after a pre-treatment with a glycoprotein IIb/IIIa inhibitor (abciximab) versus plain balloon angioplasty alone (25). For the purpose of this meta-analysis, the outcome data from the plain balloon and BMS arms of this trial were grouped to derive pooled estimates. One trial (26) recently reported long-term outcomes, which were included in the present analysis. Thus, a total of 611 patients (294 randomized to DES therapy and 307 to control therapy) were studied. Interobserver agreement for study selection was very good, with a к value of 0.95.
The main characteristics of the studies included are described in detail in Table 1. Three (6–8) of 5 trials had a multicenter design. Patients with evidence of >50% to ≥70% stenosis or occlusion of the infrapopliteal arteries and with symptoms from disabling intermittent claudication to CLI were randomized to percutaneous revascularization with DESs versus control therapy. Patients presenting with an RC of 3 to 5 (6–8,24) or 6 (25) were enrolled in trials. One trial included 10 patients (6.2%) with an RC of 2 at admission (6). Patients with acute limb ischemia, untreated in-/outflow lesions or aneurysms, and previous stenting of the target lesion were excluded. Among trials comparing DES therapy and plain balloon angioplasty, few cases treated by balloon required crossover to provisional stenting due to a suboptimal initial result after angioplasty (7,25). Protocol-mandated angiography was performed in 4 (7,8,24,25) of 5 trials. Patients enrolled in the DES arms received limus-eluting stents approved for coronary interventions (sirolimus-eluting stent [6,7,24,25] [Cypher or Cypher Select, Cordis, Johnson & Johnson, Bridgewater, New Jersey; Yukon DES, Translumina, Hechingen, Germany]; everolimus-eluting stent  [Xience V, Abbott Laboratories, Abbott Park, Illinois]). Patients enrolled in the BMS arms received conventional 316L stainless steel stents (Bx-Velocity  or Sonic , Cordis, Johnson & Johnson) or microstructured 316L stainless steel, microporous stents (6) (Yukon, Translumina) or 605L cobalt-chromium, thin-strut stents (8) (Multilink Vision, Abbott Laboratories, Abbott Park, Illinois).
The median number of patients included in the trials was 140 (interquartile range [IQR]: 60 to 161) and their clinical characteristics matched typical patients with infrapopliteal artery disease (Table 2). Overall, the median lesion length was 26.8 mm (IQR: 18.2 to 30.0 mm) with a reference vessel diameter of 2.86 mm (IQR: 2.68 to 3.00 mm). More specifically, patients undergoing DES implantation had a median lesion length of 26.9 mm (IQR: 17.4 to 27.0 mm) and a reference vessel diameter of 2.90 mm (IQR: 2.69 to 3.00 mm). Patients receiving control therapy had a median lesion length of 26.8 mm (IQR: 18.9 to 30.0 mm) and a reference vessel diameter of 2.83 mm (IQR: 2.68 to 2.91 mm).
An overview of endpoint definitions among trials included is reported in Online Table 1. In all cases but 1 (25), the primary endpoint was binary restenosis at 6- or 12-month follow-up. The remaining trial primarily evaluated the rate of target-vessel reocclusion at 2-month follow-up. All patients received active or control treatment in addition to standard medical therapy. Details of post-procedural antiplatelet management and prescription were available in all trials. Median duration of DAPT was 12 months (IQR: 12 to 36 months).
The risk of bias among studies is reported in Online Table 2. Of those randomized, 589 patients (96.3%) were available for assessment of outcomes of interest. The median follow-up was 12 months (IQR: 12 to 36 months).
TLR occurred in 97 patients (17.5%; data available for 554 [94%] patients, all trials). DES versus control therapy significantly decreased the risk of TLR (OR: 0.31; 95% CI: 0.18 to 0.54; p < 0.001; I2 = 15%, p for heterogeneity [phet] = 0.32; ARR: 15.5%; 95% CI: 9.3 to 21.6; NNT: 7; 95% CI: 5 to 11) (Fig. 2A).
Restenosis occurred in 183 patients (36.4%; data available for 502 patients [85%], all trials). DES versus control therapy significantly decreased the risk of restenosis (OR: 0.25; 95% CI: 0.15 to 0.43; p < 0.001; I2 = 38%, phet = 0.17; ARR: 29.6%; 95% CI: 21.7 to 37.6; NNT: 4; 95% CI: 3 to 5) (Fig. 2B).
Amputation occurred in 52 patients (10.3%; data available for 504 patients [85.6%], 4 trials [6–8,25]). DES versus control therapy significantly decreased the risk of amputation (OR: 0.50; 95% CI: 0.26 to 0.97; p = 0.04; I2 = 0%, phet = 0.61; ARR: 7.5%; 95% CI: 2.2 to 12.7; NNT: 13; 95% CI: 8 to 45) (Fig. 2C).
Death occurred in 96 patients (16.2%) (data available for all patients). No significant difference in terms of risk of death was found with DES therapy compared with control therapy (OR: 0.81; 95% CI: 0.45 to 1.49; p 0.50; I2 = 32%; phet = 0.22) (Fig. 2D).
An improvement in RC occurred in 246 patients (55%; data available for 448 patients [76%], 3 trials [6–8]). No significant difference in terms of RC improvement was found with DES therapy compared with control therapy (OR: 1.36; 95% CI: 0.91 to 2.04; p = 0.13; I2 = 6%, phet = 0.34) (Fig. 2E).
DES therapy compared with either plain balloon angioplasty or BMS implantation significantly decreased the risk of TLR, restenosis, and amputation without affecting mortality or improving RC (Online Table 3).
Small study effects, influence, and sensitivity analyses
Funnel plot distribution of primary outcomes was derived from the SE of the natural logarithm OR plotted against the OR of TLR (Online Fig. 1A). Of note, the absence of bias due to small study effects was confirmed both visually and mathematically. Additionally, the influence analysis demonstrated that no single study significantly altered the summary OR for TLR (Online Fig. 1B).
There was no modification of risk estimates for TLR according to trial size, length of clinical follow-up, protocol-mandated angiography, lesion length, vessel diameter, and length of DAPT (Fig. 3). Similarly, the degree of baseline disease severity did not affect the risk estimates for TLR (Online Figs. 2A to 2C). On adjusted indirect comparison (Online Table 4), the everolimus- versus sirolimus-eluting stents, as well as the polymer-free versus durable-polymer DESs did not affect the risk estimates for the main outcomes.
We undertook this updated meta-analysis to investigate the outcomes associated with primary drug-eluting stenting for percutaneous revascularization of patients with atherosclerotic disease of infrapopliteal arteries. The main findings are that at 1-year follow-up, DES therapy demonstrated reduced restenosis and greater clinical efficacy compared with plain balloon angioplasty or BMS therapy with a reduced risk of reintervention and amputation, although a lack of RC improvement and DESs have a safety profile comparable to that of alternative therapy, with no impact on mortality.
Patients with atherosclerotic disease of infrapopliteal arteries represent an important challenge due to compromised functional status, coexisting morbidities, and poor outcomes (1). In this context, endovascular revascularization has become a first-line treatment option in light of superior feasibility and similar efficacy compared with surgical repair (2,3,11). Although in the past decades, percutaneous revascularization has become synonymous with stenting, in infrapopliteal artery disease, plain balloon angioplasty remains the treatment of choice due to the diffuse nature of infrapopliteal atherosclerosis and the lack of data definitively supporting a stent-based strategy in this vascular bed (2,3).
In recent studies, BMSs have shown almost similar survival, limb salvage, and patency rates compared with plain balloon angioplasty at 1-year follow-up (5,23). In a meta-analysis of observational studies evaluating bail-out stenting after failed angioplasty (5), stents significantly improved patency rates at mid-term follow-up without affecting the risk of TLR and amputation. Although different stent scaffolds (balloon expandable, self-expandable, bioabsorbable) and types of stents (bare metal, carbon coated, drug eluting) contributed to the outcome data, the highest antirestenotic efficacy was attributable to DESs (5).
Initial data from observational registries (27,28) as well as subsequent randomized trials (6–8) consistently showed less neointimal proliferation at mid-term follow-up after DES implantation versus plain balloon angioplasty or BMS implantation in patients with infrapopliteal artery disease treated percutaneously. However, the superior antirestenotic properties of DESs did not always translate into a meaningful clinical advantage. In a meta-analysis of 3 randomized trials, Katsanos et al. (9) confirmed the antiproliferative efficacy of DESs for atherosclerotic disease of the infrapopliteal arteries. However, RC improvement, nor amputation, nor mortality benefits were found, suggesting a possible discrepancy between mechanistic and clinical measures of efficacy in this setting. Antoniou et al. (10) conducted a meta-analysis of both randomized and observational studies investigating only DES versus BMS therapy for disease of infrapopliteal arteries. The authors concluded that DES therapy reduces the risk of reintervention and improves RC without affecting amputation and survival. As a consequence, given the lack of incontrovertible evidence, current guideline-writing authorities still assign the highest grade of recommendation to plain angioplasty in patients with infrapopliteal atherosclerotic disease, leaving stents with a “bail-out” or “salvage” indication after failed angioplasty (2,3).
Against this background, we conducted the present meta-analysis to investigate the impact of primary drug-eluting stenting in the largest population of patients with occlusive infrapopliteal atherosclerotic disease undergoing percutaneous revascularization in the context of randomized trials: at 1-year follow-up, DES therapy compared with plain balloon angioplasty and BMS therapy reduced the risk of reintervention and amputation with no impact on mortality and RC. These results merit careful consideration.
First, the present study reports a lower risk of restenosis and reintervention at 1-year follow-up with DES therapy versus plain balloon angioplasty or BMS therapy. The most important drawback of plain balloon angioplasty or BMS therapy in the infrapopliteal vascular territory is the poor durability of acute results due to vessel re-narrowing after intervention (29). In this respect, the finding of reduced rates of TLR with DES therapy at 1-year follow-up, in keeping with published meta-analyses (9,10), is an important one. Of interest, 4 of the 5 trials included in the present meta-analysis (6,7,24,25) found no difference in terms of TLR between DESs and comparators. This is most likely attributable to design of original studies, which contained only sufficient power for angiographic rather than rarer clinical outcomes, and reinforces the necessity of a meta-analysis.
In this study, the observed benefit of DES therapy versus plain balloon angioplasty or BMS therapy in terms of TLR is independent from trial size, length of clinical follow-up, protocol-mandated angiography, lesion length, vessel diameter, and length of DAPT. These results notwithstanding, some safety considerations exist regarding the risk of DES thrombosis due to suboptimal duration of DAPT (30), and dedicated trials are awaited to ascertain the contribution of duration of DAPT to the safety and efficacy of DES for infrapopliteal arteries.
Second, in contrast to the meta-analysis of Katsanos et al. (9), we demonstrated that DESs are associated with a significant reduction in the risk of amputation at 1-year follow-up. As many as 50% of patients with infrapopliteal artery occlusive disease may require amputation at various levels within the first year after the diagnosis, especially in those patients presenting with CLI (1,31). As known, less perfusion is needed to maintain tissue integrity than to avoid amputation: for this reason, restenosis does not always result in recurrent symptoms unless there has been repeated injury of the affected limb (32). Assessing prevention of amputation rather than angiographic patency should become the main goal of trials investigating revascularization of the infrapopliteal arteries (32). In line with these arguments, the lower risk of amputation and the higher antirestenotic efficacy associated with DESs in the current analysis are remarkable, especially when a last remaining infrapopliteal vessel must be preserved to warrant straightforward distal perfusion.
In the current study, the use of DES therapy versus plain balloon angioplasty or BMS therapy has no impact on mortality. On the one hand, this analysis confirms that the superior clinical efficacy of DES therapy versus plain balloon angioplasty or BMS therapy has no trade-off in safety. On the other hand, even reducing reinterventions and amputations, a strategy of primary percutaneous revascularization with DESs is still not sufficient to lower the intrinsic mortality risk associated with patients with atherosclerotic disease of infrapopliteal arteries (2). The possible inadequacy of the sample size and the selective nature per se of patients enrolled in randomized trials could be responsible for the lack of effect. In addition, pre-existing comorbidities, as well as poor functional status, 2 common features of patients with infrapopliteal artery disease (32), may have further contributed to mask significance. Similarly, these features may account for the failure of DES therapy compared with control therapy to significantly improve RC, although lowering the risk of revascularization and amputation as observed in the present study. Taken together, all these considerations reinforce the necessity of more deserved investigations in this setting to address the portfolio of therapeutic options, other than the revascularization strategies, should be reserved for patients with infrapopliteal artery disease (33).
The present study included a total of 611 patients by pooling the results of 5 randomized trials enrolling patients with infrapopliteal artery disease. Although the number of trials and patients is relatively small, it represents the largest population analyzed in such studies. However, it presents some limitations. First, this meta-analysis is based on study-level data and shares the possible flaws of the original trials. Moreover, the lack of patient-level data precluded in-depth investigation of the planned/unplanned nature of amputations. Second, different devices are grouped in the experimental and control arms, even though efficacy profiles may vary between platforms and devices. Furthermore, none of the included trials considered newer-generation balloons coated with antiproliferative drugs. Third, the median follow-up is limited to 1 year. Longer-term follow-up would certainly be valuable in assessing the late clinical performance of revascularization strategies. Fourth, the protocol-mandated angiography may have magnified differences in absolute proportion of revascularizations across groups, although the relative differences are likely to remain unaffected. Notwithstanding the possible influence of protocol-mandated angiography on revascularizations, available data showed that most of repeat procedures were driven by clinical symptoms. Finally, the population included in this analysis, reporting disabling claudication as well as CLI, with an overall median lesion length of 26.8 mm and a reference vessel diameter of 2.86 mm, could be perceived as not representative of that encountered in daily practice, often presenting with very diffuse disease (>10 cm) and very extensive wounds. For these reasons, the present findings should apply only to patients with characteristics similar to those enrolled in this study and presenting with focal lesions.
This meta-analysis suggests that in patients with focal disease of infrapopliteal arteries, DES therapy reduces the risk of reintervention and amputation compared with plain balloon angioplasty or BMS therapy without any impact on mortality and RC at 1-year follow-up. Further randomized trials with a focus on clinical endpoints and longer follow-up are still awaited to provide the best scientific evidence regarding the preferred endovascular treatment for patients with occlusive disease of infrapopliteal arteries.
For supplemental material, tables, and figures, please see the online version of this article.
Dr. Kastrati has received lecture fees or honoraria from Abbott, AstraZeneca, Biosensors, Biotronik, Bristol-Myers Squibb, Merck, The Medicines Company, and St. Jude Medical. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose. Dr. Fusaro and Dr. Casseese contributed equally to the manuscript and are joint first authors.
- Abbreviations and Acronyms
- absolute risk reduction
- bare-metal stent(s)
- confidence interval
- critical limb ischemia
- dual antiplatelet therapy
- drug-eluting stent(s)
- interquartile range
- number needed to treat
- odds ratio
- Rutherford class
- target lesion revascularization
- Received June 7, 2013.
- Revision received July 30, 2013.
- Accepted August 14, 2013.
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